Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10](O)[CH:11]=1)=[O:5])[CH3:2].P(Br)(Br)([Br:19])=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Br:19])[CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1cc(O)nc2[nH]nc(C)c12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(Br)nc2[nH]nc(C)c12
Temperature: 110 °C
Reaction time: 5 h
Yield: 26.1 %

Procedure:
A mixture of 6-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (13.7 g) and phosphorous oxybromide (19.5 g) in toluene (300 mL) was stirred at 110° C. for 5 h, cooled to r.t., and added dropwise into an ice cold solution of potassium acetate (18.2 g) in water (300 mL). The mixture was extracted twice with ethyl acetate, the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo. 6-Bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (4.6 g, 26%) were obtained. This material was dissolved in THF (60 mL), and 3,4-dihydro-2H-pyran (1.6 mL) and p-toluenesulfonic acid monohydrate (0.91 g) were added. The solution was stirred at r.t. for 48 h, then 3,4-dihydro-2H-pyran (1.6 mL) were added and the solution stirred again for 48 h. The mixture was poured into water and extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient). 2.2 g (38%) of the title compound were obtained.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[S:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>O1CCCC1.CO>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)sc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 24 h
Yield: 86.5 %

Procedure:
To 2-{4-[2-(2-biphenyl-3-yl-5-methyl-thiazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester (470 mg, 0.94 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL) was added 2 mL of a 5N NaOH solution. After 24 h, the solution was concentrated in vacuo. The residue was partioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to afford 385 mg (87% yield) of 2-{4-[2-(2-biphenyl-3-yl-5-methyl-thiazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.78 (d, 1H), 7.61-7.55 (m, 3H), 7.45-7.40 (m, 3H), 7.35-7.31 (m, 1H), 6.86-6.82 (m, 2H), 6.79-6.76 (m, 2H), 4.24 (t, 2H), 3.16 (t, 2H), 2.43 (s, 3H), 1.46 (s, 6H). MS EI+ (m/e) 474.1.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:45]2[C:50]([NH2:51])=[CH:49][N:48]=[C:47]3[N:52]([S:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)(=[O:57])=[O:56])[CH:53]=[CH:54][C:46]=23)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH2:40][CH:41]([NH:44][C:45]2[C:50]([NH:51][C:7](=[O:9])[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:49][N:48]=[C:47]3[N:52]([S:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)(=[O:56])=[O:57])[CH:53]=[CH:54][C:46]=23)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)CC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 45.1 %

Procedure:
Cyclopentylacetic acid (0.532 ml, 4.24 mmol), diisopropylethylamine (1.5 ml, 8.50 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.89 g, 4.70 mmol) were added sequentially to a solution of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 4.00 mmol) in CH2Cl2 (60 ml) at 25° C. The reaction mixture was stirred for 9 h at 25° C., then was partitioned between 1.0 M HCl (125 ml) and CH2Cl2 (125 ml). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 4-[1-benzenesulfonyl-5-(2-cyclopentyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 40%) as an off-white solid. LCMS (Method G, ESI): RT=1.15 min, m+H=582.5. This material was used in the next step below without additional characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([CH2:25][C:26](Cl)=O)([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:26]([CH2:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
Following the procedure of Example 5, 2.0 g of 7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine is reacted with 1.01 ml of tert-butyl acetylchloride to yield 1.17 g of title product with melting point 229.5°-232° C. and 0.30 g of title product with melting point 205°-219° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].CCN(CC)CC>CCOCC>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[CH:8]=[C:9]([I:12])[CH:10]=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1cc(I)ccc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2cc(I)ccc2F)noc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 2-fluoro-5-iodobenzoyl chloride oxime (2.24 g, 7.48 mmol) and ethyl-2-butynoate (1.74 ml, 14.96 mmol, 2 eq.) in Et2O (28 ml) under N2 stirring at 0-5° C., was added dropwise a solution of Et3N (1.35 ml, 9.72 mmol, 1.3 eq) in Et2O (3.6 ml) over 1 h. Reaction was allowed to warm to room temperature and stirred overnight. It was then partitioned between Et2O and H2O, washed with brine, dried (MgSO4), filtered, and concentrated. The crude residue was chromatographed on silica gel using (1-10%) ethyl acetate in hexanes to give the title compound (2.06 g, 73%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[OH:32][CH2:33][C@H:34]1[NH:39][CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+].Cl>ClCCl.C(O)(=O)C.O1CCOCC1.CO>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:39]3[CH2:38][CH2:37][NH:36][CH2:35][C@H:34]3[CH2:33][OH:32])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCNC[C@H]3CO)c2c1
Reaction time: 12 h

Procedure:
The product of Example 75 step i) (0.4 g), (S)-3-hydroxymethyl-piperazine-1-carboxylic acid, tert-butyl ester (0.83 g) and sodium triacetoxyborohydride (0.81 g) were stirred in dichloromethane (20 mL) at room temperature for 12 hours. A few drops of acetic acid were added and stirring continued for 12 hours. Methanol (10 ml) and sodium cyanoborohydride (0.70 g) were added and stirring continued for a further 12 hours. Methanol (10 ml) and 4M HCl in 1,4-dioxane (10 ml) were added and stirred for 12 hours. The volatiles were removed under vacuum, dilute aqueous ammonia was added and the mixture extracted into dichloromethane. The organics were combined and evaporated under reduced pressure. The residue was purified by HPLC to give the title compound (0.035 g) as a solid.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=4[CH3:27])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH2:31][C:32]#[N:33])=[CH:10][CH:9]=1.C(I)C>O1CCCC1.[Cl-].[NH4+]>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=4[CH3:27])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:31]([CH2:1][CH3:2])[C:32]#[N:33])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(CC#N)c23)c(C)n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.3 %

Procedure:
Potassium t-butoxide (908 mg, 8.09 mmol) was added to a stirred solution of [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (1.41 g, 3.68 mmol) and ethyl iodide (1.43 g, 9.20 mmol) in tetrahydrofuran (18 mL) at 0° C., and the mixture was stirred at 0° C. for 50 min. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.20 g, 2.92 mmol, 79%).
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH3:20][S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)N1CCC(C(=O)O)CC1
Yield: 73 %

Procedure:
1-Methanesulfonyl-piperidine-4-carboxylic acid benzyl ester (0.8 g, 26.7 mmol) from step 4, was dissolved in ethyl acetate (100 ml) and methanol (10 ml), Pd/C 10% (80 mg) was added and the resulting mixture was hydrogenated at 1 bar. The catalyst was filtered over celite, the solvent was removed under reduced pressure to give a white solid. Yield 73%, 0.4 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)O)[N:10]([CH3:12])[N:11]=1.ClCCl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][CH:16]=2)[N:10]([CH3:12])[N:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(NCc3cccc(Cl)c3)nn2C)c2cc(Cl)cnc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCc2cccc(Cl)c2)cc1Cc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
[5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (649, 0.033 g, 0.059 mmol) was combined with dichloromethane (5 mL, 0.08 mol) and triethylsilane (200 μL, 1.0 mmol) was added, followed by trifluoroacetic acid (100 μL, 1.0 mmol). The reaction was stirred at room temperature overnight and then concentrated. Ethyl acetate was added and the organic portion was washed with 1 M potassium carbonate, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography eluting with a gradient of methanol (2-20%) and dichloromethane followed by washes with a mixture of ethyl acetate:hexane gave the desired compound (P-0410, 0.0039 g, 17%). (ESI) [M+H+]+=387.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6]>CN(C)C1C=CN=CC=1.CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)c1ccnc(Cl)c1
Reaction time: 17 h

Procedure:
A 1-L jacketed 3-neck round bottom flask equipped with overhead stirrer, N2-inlet vented to the atmosphere and thermocouple was charged with 2-chloroisonicotinic acid (78.0 g, 495 mmol), di-tert-t-butyl dicarbonate (230.1 g, 1054 mmol), and 1-methyl-2-pyrrolidinone (179.3 g). A solution of 4-dimethylamino pyridine (11.61 g, 95 mmol) dissolved in 1-methyl-2-pyrrolidinone (60.0 g) was charged to the mixture and the temperature was adjusted to 25±10° C. The reaction was quenched after stirring for about 17 hours by the addition of an ice-cold solution of sodium chloride (30.0 g) and monobasic potassium phosphate (30.2 g) in water (320.7 g). Methyl tert-butyl ether (278 g) was added, and the mixture was stirred and allowed to settle. The layers were separated. The organic phase was washed three times with water (˜230-240 g each) then diluted with toluene (239 g) and distilled under vacuum to a red oil (150.8 g, KF 29.9 ppm H2O). 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 9H) 7.69-7.72 (m, 1H) 7.79-7.81 (m, 1H) 8.49 (dd, J=5.08, 0.69 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:34][C@H:35]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)[CH2:36][C@@H:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[C:48]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:47]=[CH:46][C:45]([CH2:44][C@@H:35]([NH:34][C:8]([C:5]2[S:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=2)=[O:10])[CH2:36][C@@H:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:50][CH:49]=1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: COc1ncc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(OC)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methoxythiazole-5-carboxylic acid (101 mg, 0.64 mmol) in DMF (6 mL) is added HOAt (107 mg, 0.58 mmol), EDCl (133 mg, 0.69 mmol), and TEA (0.48 mL, 3.47 mmol). The crude is stirred at room temperature for 15 mins. To this crude is added (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt. The crude is stirred at room temperature for overnight. The crude is quenched with 1 N HCl and water, diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified via flash column chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxythiazole-5-carboxamido)-2-methylpentanoate (170 mg). HPLC retention time 1.94 minutes (condition A); MS 453.3 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.71 (ddd, J=14.0, 9.9, 3.9 Hz, 1H), 1.88-2.04 (m, 1H), 2.56-2.73 (m, 1H), 2.78-2.96 (m, 1H), 2.96-3.09 (m, 1H), 4.09 (s, 3H), 4.09-4.18 (m, 2H), 4.30-4.47 (m, 1H), 6.15 (d, J=8.1 Hz, 1H), 7.27 (d, J=6.8 Hz, 2H), 7.29-7.36 (m, 1H), 7.42 (t, J=7.6 Hz, 2H), 7.49 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.57 (d, J=7.3 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10])[OH:8].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(C(C)=O)C(C)C>[OH:8][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[O:10][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCBr
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCCCCOc1ccccc1O
Yield: 56.5 %

Procedure:
95.1 g (0.69 mol) of potassium carbonate and 321.2 g of methyl isobutyl ketone were added to 137.64 g (1.25 mol) of pyrocatechol and 188.63 g (1.25 mol) of 1-bromopentane, and the mixture was then refluxed for 23 hours. The mixture was cooled, after which the potassium carbonate was filtered off and the methyl isobutyl ketone was distilled off under reduced pressure. The oily residue was then subjected to fractional distillation over a short column under reduced pressure from an oil pump. 127.3 g of 1-hydroxy-2-pentoxybenzene were obtained at 5 bar and a boiling point of 88°-92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1)=O.[F:23][C:24]([F:32])([F:31])[C:25](=[O:30])[CH2:26][C:27](=O)[CH3:28].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:22][C:17]1[CH:16]=[C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:27]([CH3:28])[C:26]=2[C:25](=[O:30])[C:24]([F:32])([F:31])[F:23])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(F)c(F)c1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccc(F)c(F)c2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 36 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(3,4-difluoro-phenyl)-methanone [example A12] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 36%; MS: m/z=435 (M).
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:21])[CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.N1C=CC=CC=1SC(=O)CC[C:32]1[CH2:37][CH2:36][CH2:35][CH2:34]C=1>>[CH:34]1([C:8](=[O:21])[CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH2:35][CH2:36][CH2:37][CH2:32]1
Reactant: O=C(CCC1=CCCCC1)Sc1ccccn1
Reactant: COc1ccc2c(c1)CCC2CC(=O)Sc1ccccn1
Product: COc1ccc2c(c1)CCC2CC(=O)C1CCCC1

Procedure:
The title compound was prepared as described in Step 4 of Example A(13), where (5-Methoxy-indan-1-yl)-thioacetic acid S-pyridin-2-yl ester (from Step 3) was substituted in place of 3-Cyclohex-1-enyl-thiopropionic acid S-pyridin-2-yl ester.
Reaction SMILES: [NH2:1][C:2](=[O:32])[C@H:3]([NH:8][C:9]1[CH:18]=[C:17]([C:19]#[N:20])[C:12]([C:13]([O:15]C)=O)=[C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=2)[N:10]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]>CO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH3:6][CH:5]([CH3:7])[CH2:4][C@@H:3]([NH:8][C:9]1[N:10]=[C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:23]=2)[C:12]2[C:13](=[O:15])[NH:20][CH2:19][C:17]=2[CH:18]=1)[C:2]([NH2:1])=[O:32]
Reactant: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](Nc1cc2c(c(Nc3cccc(S(C)(=O)=O)c3)n1)C(=O)NC2)C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.4 %

Procedure:
A mixture of (R)-methyl 6-(1-amino-4-methyl-1-oxopentan-2-ylamino)-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (73.2 mg, 0.159 mmol) and palladium hydroxide on carbon (23.2 mg, 0.165 mmol) in MeOH (6 mL) and HOAc (3 mL) was stirred at RT for 12 h under a hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (20 mL) and MeOH (20 mL). The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (30 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from EtOH to give the title compound as a white solid (18.8 mg, 27%). 1H-NMR (DMSO-d6) δ ppm 0.87-0.94 (m, 6H), 1.54-1.63 (m, 2H), 1.76 (br s, 1H), 3.32 (s, 3H), 4.24 (s, 2H), 4.50 (br s, 1H), 6.17 (s, 1H), 7.00-7.04 (m, 2H), 7.22 (br s, 1H), 7.47-7.57 (m, 2H), 8.01 (br s, 1H), 8.06 (s, 1H), 8.45 (br s, 1H), 9.23 (s, 1H). [M+H] calc'd for C20H26N5O4S, 432. found, 432.5.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][O:13][CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[CH2:11][CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:29].OO.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:28][C:25]([F:26])([F:27])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[CH2:14][O:13][CH2:12][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:10][CH:9]([OH:29])[CH2:8]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CC=CC2)cc(C(F)(F)F)c1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(((1-phenylcyclopent-3-enyl)methoxy)methyl)-3,5-bis(trifluoromethyl)benzene (200 mg) in THF (0.55 mL) at 0° C. was added borane-tetrahydrofuran complex (1.0 M solution, 0.55 mL) dropwise, and the resulting solution was warmed to room temperature and stirred at room temperature for 12 h. The reaction mixture was cooled to 0° C., and water (1.0 mL) was added slowly followed by 30% hydrogen peroxide (0.19 mL) and 1 N sodium hydroxide (0.55 mL). The resulting solution was stirred at room temperature for 5 min, and ethyl acetate (2.0 mL) was added. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC eluting with 40% ethyl acetate/60% hexanes to give the title compound as an oily material. 1H NMR (400 MHz, CDCl3) δ 2.06 (m), 1.9-2.6 (m), 3.42 (s), 3.57 (q, J=8.8 Hz), 4.45 (s), 4.3-4.6 (m), 7.1-7.5 (m), 7.47 (s), 7.64 (s), 7.74 (s), and 7.76 (s).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>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].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[O:16]=[C:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Br
Reactant: O=C1CCCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=Cc1cccnc1N1CCCCC1=O
Temperature: 120 °C
Yield: 50 %

Procedure:
2-Bromopyridine-3-carbaldehyde a4-0 (0.5 g, 2.7 mmol, 1 eq) is dissolved in dry and degassed 1,4-dioxane (15 ml). Piperidin-2-one (0.4 g, 4.03 mmol, 1.5 eq), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.31 g, 0.538 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (0.123 g, 0.134 mmol, 0.05 eq) and cesium carbonate (1.752 g, 5.376 mmol, 2 eq) are added. The mixture is heated in a sealed tube in a microwave oven at 120° C. for 45 min. The resulting suspension is filtered over celite and the celite washed with 1,4-dioxane. The filtrate is evaporated under reduced pressure. The residue is then dispersed in ethyl acetate, sonicated, filtered and the filtrate is evaporated under reduced pressure to afford 1.1 g of crude 2-(2-oxopiperidin-1-yl)pyridine-3-carbaldehyde a4-1 which is used in the next step without any further purification.