Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[S:18][CH:19]=2)=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[CH2:31]([O:30][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[S:18][CH:19]=2)=[CH:9][C:8]=1[CH3:29])[C:4]([OH:33])=[O:3])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)C)cc3)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2csc(-c3ccc(C(C)C)cc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:29]=[C:28]([NH2:30])[C:27]4[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[C:9]([N+:35]([O-:37])=[O:36])[CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:30][C:28]1[C:27]2[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2)[N:21]=[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:38])=[O:5])=[CH:8][C:9]=3[N+:35]([O-:37])=[O:36])[CH2:15][CH2:16]2)[N:29]=1
Reactant: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4[N+](=O)[O-])CC3)nc(N)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)O)cc4[N+](=O)[O-])CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (6) (0.03 g, 0.057 mmol) in TFA (5 mL) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was evaporated to a pale yellow solid residue (0.026 g, 78 %); 1H NMR (DMSO) δ 11.75 (br s, 1H), 8.81 (s, 1H), 8.69 (s, 1H), 8.61 (d, 1H, J=1.9), 8.24 (d, 1H, J=7.7), 7.99 (d, 1H, J=7.3), 7.67 (s, 1H), 7.34 (d, 1H, J=9.3), 7.20 (s, 1H), 4.49 (d, 2H, J=13.2), 4.11 (m, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.37 (t, 2H, J=11.8), 2.12 (d, 2H, J=10.3), 1.76 (m, 2H); 13C NMR (DMSO) δ 165.8, 161.4, 157.8, 155.4, 151.2, 146.8, 146.2, 136.1, 130.6, 128.6, 117.5, 115.0, 104.8, 101.6, 98.8, 56.1, 56.0, 48.8, 43.3, 30.4; HRMS (FAB) m/z 469.1816 (M+H)+ (C22H24N6O6 requires 469.1830); Anal. (C22H24N6O6 ·11/2CF3COOH·11/4H2O·1/4CH3OH) C, H, N.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:25][N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccsc1
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: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Under an argon atmosphere, a suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (232 mg), 3-thienylboronic acid (138 mg), tetrakis(triphenylphosphine)palladium (31.3 mg) and sodium carbonate (175 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 189 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OCC6C=CC=CC=6)[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1.C1CC=CCC=1>C(O)C.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@@H:25]([NH2:29])[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](NC(=O)OCc6ccccc6)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](N)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Temperature: 100 °C
Yield: 71.8 %

Procedure:
In a 5-mL high-pressure vial was placed benzyl (4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate (110.0 mg, 0.18 mmol), 1,4-cyclohexadiene (102 μL, 1.09 mmol) in ethanol (8.3). 10% Pd on C (11.0 mg) was added, and the reaction mixture was vacuum purged with N2 3×. The vial was sealed and the reaction mixture was stirred at 100° C. After 2 h additional 10% Pd on C (11.0 mg) and 1,4-cyclohexadiene (102 μL) were added. The vial was resealed and the reaction mixture was stirred at 100° C. for 14 h. The cooled reaction was filtered reaction through a pad of Celite®, and the pad was rinsed with EtOAc (3×5 mL), MeOH (3×5 mL), DCM (3×5 mL), and a final rinse of EtOAc (3×5 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 0-80% MeOH in EtOAc+1% Et3N) to give (4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-amine as a solid (61.1 mg, 71.3%). LC/MS: m/z 473.3 [M+1].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:24]1[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N1CCN(C(=O)C(C)(C)NC(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A suspension of 2-benzyloxycarbonylamino-2-methyl-propionic acid (2.37 g), 1-isopropylpiperazine (1.54 g), 1-hydroxybenzotriazole (1.49 g), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (2.88 g) and triethylamine (2.79 mL) in N,N-dimethylformamide (20 mL) was stirred at 50° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous ammonium chloride solution, water, 0.5 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was washed with a mixed solvent of n-hexane and ethyl acetate (2/1), and dried under reduced pressure to give 1-(2-benzyloxycarbonylamino-2-methylpropionyl)-4-isopropyl-piperazine (1.83 g). This material was dissolved in methanol (20 mL). To the solution was added 10% palladium-carbon powder (0.60 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was crystallized from a mixed solvent of n-hexane and ethyl acetate, and the crystals were collected by filtration. The crystals were washed with n-hexane, and dried under reduced pressure to give the title compound (0.76 g).
Reaction SMILES: [CH:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:5](=[O:10])/[CH:6]=[C:7](\[NH2:9])/[CH3:8])([CH3:3])[CH3:2].N.[H][H]>[Ni].CO>[NH2:9][CH:7]([CH3:8])[CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: [H][H]
Reactant: C/C(N)=C/C(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(N)CC(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 79.4 %

Procedure:
(Z)-3-Aminobut-2-enoic acid N-isopropyl-N-[4-(phenylamino)phenyl]amide (13.9 g, 0.0449 mol) and Raney nickel (K0840 Ni B113W) (2.0 g) in methanol (140 g) were introduced into an autoclave. Ammonia (5.5 g, 0.3230 mol) was introduced in the course of 5 minutes. The temperature of the reaction mixture was 25° C. The pressure rose to 5 bar. After the introduction of ammonia, the reaction mixture was warmed to 80° C. (no further pressure rise). Hydrogen was injected at 80° C. until the pressure was 100 bar. The reaction mixture was heated to 110° C. and stirred at this temperature for 4.5 h. In the course of this, a pressure of 100 bar was maintained by continuous injection of hydrogen. The reaction mixture was cooled to 25° C. and the pressure was carefully let down. The reaction mixture was filtered off and the filtrate was concentrated to one half. The concentrate was treated with 1 g of active carbon, stirred for 1 h, filtered and concentrated to dryness. 12.8 g of crude product were obtained, which was melted at 175° C. The melt could be crystallized on an aluminium foil. 11.1 g of 3-amino-N-isopropyl-N-[4-(phenylamino)phenyl]butyramide (79.3%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 90.7 %

Procedure:
A mixture of 4.4 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 2.12 g of 2-(dimethylamino)ethyl chloride hydrochloride, 4.06 g of potassium carbonate and 200 ml of acetone is refluxed for 20 hours. After the reaction is completed, insoluble materials are removed by filtration and then washed with ethanol. The filtrate and the washing are combined and then evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and then evaporated to remove solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 4.85 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [F:1][C@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C:16](=[CH:17][CH2:18]3)[CH2:15][C@@H:14]([OH:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C:5](=[O:22])[CH2:4][CH2:3]2.[H][H]>C(O)C.[Pd]>[F:1][C@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C@@H:16]([CH2:17][CH2:18]3)[CH2:15][C@@H:14]([OH:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C:5](=[O:22])[CH2:4][CH2:3]2
Reactant: [H][H]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12F
Agent: [Pd]
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12F
Yield: 39.2 %

Procedure:
14α-Fluoro-3β-hydroxyandrost-5(6)-en-17-one (400 mg) in ethanol (70 ml) was hydrogenated over palladium-charcoal (5%; 250 mg) until uptake of hydrogen ceased (72 hr). The solvent was evaporated in vacuo and the crude product was recrystallised from acetone: hexane to give prisms of 14α-fluoro-3β-hydroxy-5α-androstan-17-one (158 mg) m.p. 201°-202°; [α]D23 +83° (c 0.84, CHCl3); vmax 3500 and 1730 cm-1 ; the PMR spectrum included signals at δ0.83 (3H, s, 19-Me), 1.00 (3H, s, 18-Me) and 3.6 (1H, m, 3-CHOH); FMR φ*+164 ppm (broad multiplet ca 80 Hz wide).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)[CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][N:10]1[CH2:11][CH2:12][CH:13]([NH:16][C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:14][CH2:15]1
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(CN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.223 ml) was added to a stirred suspension of the product from step (ii) (0.2 g) in dimethylformamide. After 5 min 3,4-dichlorobenzaldehyde (0.175 g) then sodium triacetoxyborohydride (0.212 g) was added and the mixture stirred at room temperature for 3 h. The mixture was partitioned between 2M hyrochloric acid and ether, the aqueous layer was basified with aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate/ether and the solid collected. Yield 0.045 g.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8](=[O:18])[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[Cl:17])[C:4]([O:6][CH3:7])=[O:5].[CH:19]1(N)[CH2:21][CH2:20]1>C(#N)C>[CH:19]1([NH:1][CH:2]=[C:3]([C:8](=[O:18])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=2[Cl:17])[C:4]([O:6][CH3:7])=[O:5])[CH2:21][CH2:20]1
Reactant: COC(=O)C(=CN)C(=O)c1cc(F)c(F)cc1Cl
Reactant: NC1CC1
Solvent: CC#N
Product: COC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)cc1Cl

Procedure:
2 g of the product from Example 5 and 0.62 g of cyclopropylamine were stirred in 30 ml of dry acetonitrile at room temperature for 30 minutes. The volatile constituents were then stripped off on a rotary evaporator and the evaporation residue was recrystallized from ether.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C.Cl>CN(C)C=O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[O:20][C:21](=[O:23])[CH3:22])#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A mixture of 5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (900 mg, 3.37 mmol), acetic anhydride (1.7 mL, 18 mmol), triethylamine (1.4 mL, 10 mL) in N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. The mixture was acidified with 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (1:1 hexane/ethyl acetate) to give 5-(4-cyano-3-acetoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (818 mg, 79%).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]>[Pd].CO>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: C=Cc1ccc(-c2cc(C(N)=O)c(NC(N)=O)[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(-c2cc(C(N)=O)c(NC(N)=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 62.2 %

Procedure:
10% Palladium on activated carbon (6 mg) was added to a solution of 2-aminocarbonylamino-5-(4-vinylphenyl)pyrrole-3-carboxamide (Compound No. 9-1, 16 mg, 0.059 mmol) in methanol (2 mL) and the mixture was stirred at room temperature for 4.5 hours under hydrogen gas atmosphere. After the reaction solution was filtered, the filterate was concentrated in vacuo. The obtained solid was washed with diethyl ether (2 mL) and dried under reduced pressure to give the target compound (10 mg) as a colorless solid (Yield 62%).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Reactant: BrCc1ccccc1
Product: O=C(O)CCc1ccc(OCc2cccc(N(Cc3ccccc3)c3ccccc3)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 302 from methyl 3-[4-[(3-anilinobenzyl)oxy]phenyl]propanoate and benzylbromide. colorless crystals (yield 74%). MS (APCI−): 436 (M−H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH2:7]([OH:11])[CH:8]([CH3:10])[CH3:9].CCOCC>>[CH2:7]([O:11][C:1](=[O:5])[C:2]([Cl:4])=[O:3])[CH:8]([CH3:10])[CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CO
Solvent: CCOCC
Product: CC(C)COC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chloro-oxo-acetic acid isobutyl ester was prepared by adding oxalyl chloride (21 μL, 252 μmol) to a solution of isobutanol (21 μL, 226 μmol) in ether (206 μL, 2.0 mmol). The mixture was stirred at room temperature for 15 min and then evaporated.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]([CH3:31])([CH3:30])[CH2:11][CH2:12][N:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[O:15][C:14]1=[O:29].[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([C:51](=[O:57])[CH:52](OCC)O)[C:43]2[O:48][CH2:47][C:46](=[O:49])[NH:45][C:44]=2[CH:50]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[BH4-].[Li+]>C1COCC1.ClCCl.O>[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([CH:51]([OH:57])[CH2:52][NH:9][C:10]([CH3:30])([CH3:31])[CH2:11][CH2:12][N:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[O:15][C:14]2=[O:29])[C:43]2[O:48][CH2:47][C:46](=[O:49])[NH:45][C:44]=2[CH:50]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CCCC1(CCC)OC(=O)N(CCC(C)(C)N)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
86 μL (0.619 mmol) of triethylamine is added to a solution of 200 mg (0.564 mmol) of 1-(3-amino-3methylbutyl)-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one hydrochloride in absolute THF (5 mL) at RT under a nitrogen atmosphere and the mixture is stirred for 30 minutes, 200 mg (0.560 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one is added and the mixture is stirred for another 2 h at RT. The mixture is cooled to 10° C., combined with 51 mg (2.34 mmol) of lithium borohydride, heated to RT, and stirred for 1 hour at RT. It is again cooled to 10° C. and slowly combined with 15 mL water and 20 mL dichloromethane. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried with sodium sulfate and evaporated down in vacuo. The residue is dissolved in EtOAc (8 mL) and acidified to pH 2 by the addition of HCl solution (saturated in EtOAc). The precipitate formed is filtered off, washed with EtOAc and dried in vacuo. Yield: 270 mg (74%; hydrochloride), HPLC-MS: Rt=18.7 min. (method A).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]2[CH3:26])=[CH:5][C:6](=[O:18])[N:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)[CH:8]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH:34]2[CH2:36][CH2:35]2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:2][C:3]1[C:4]([O:19][C@H:20]2[CH2:25][CH2:24][N:23]([C:28]3[N:33]=[CH:32][C:31]([CH:34]4[CH2:36][CH2:35]4)=[CH:30][N:29]=3)[CH2:22][C@H:21]2[CH3:26])=[CH:5][C:6](=[O:18])[N:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)[CH:8]=1
Reactant: CC1CNCCC1Oc1cc(=O)n(-c2ccc(C#N)c(F)c2)cc1Cl
Reactant: Clc1ncc(C2CC2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2ncc(C3CC3)cn2)CC[C@@H]1Oc1cc(=O)n(-c2ccc(C#N)c(F)c2)cc1Cl
Temperature: 100 °C
Yield: 5.3 %

Procedure:
A mixture of 4-(5-chloro-4-(3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile hydrochloride (159 mg, 0.399 mmol), 2-chloro-5-cyclopropylpyrimidine (67.9 mg, 0.439 mmol) and potassium carbonate (221 mg, 1.597 mmol) in DMSO (1.5 mL) was heated at 90-110° C. for 40 hrs and then additional potassium carbonate (110 mg, 0.788 mmol) was added. The resulting mixture was continuously heated at 100° C. overnight and then partitioned between EtOAc and water. The aqueous layer was extracted further with EtOAc (3×). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane) to yield cis-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (10.2 mg, 5%, top spot on TLC plate) as a light yellow solid and to yield trans-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (34.4 mg, 15%, bottom spot on TLC plate) as a light yellow solid. Cis-isomers: 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 2H), 7.76 (t, J=7.42 Hz, 1H), 7.36-7.41 (m, 2H), 7.33 (d, J=8.25 Hz, 1H), 6.04 (s, 1H), 4.48-4.62 (m, 2H), 4.16 (td, J=8.80, 3.85 Hz, 1H), 3.19-3.29 (m, 1H), 2.98 (dd, J=13.75, 9.90 Hz, 1H), 2.18-2.30 (m, 1H), 2.01-2.12 (m, 1H), 1.63-1.77 (m, 2H), 1.08 (d, J=6.60 Hz, 3H), 0.89-0.95 (m, 2H), 0.57-0.62 (m, 2H). MS (ESI) 480 (M+H). Trans-isomers: 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 2H), 7.76 (t, J=7.42 Hz, 1H), 7.36-7.43 (m, 2H), 7.33 (d, J=8.25 Hz, 1H), 6.03 (s, 1H), 4.58 (app br s, 1H), 4.29-4.42 (m, 2H), 3.28-3.40 (m, 2H), 2.01-2.17 (m, 2H), 1.77-1.89 (m, 1H), 1.68-1.77 (m, 1H), 0.99-1.12 (m, 3H), 0.85-0.97 (m, 2H), 0.51-0.63 (m, 2H). MS (ESI) 480 (M+H).