Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[S:11][CH:12]=1)=O)C>C(O)C>[CH:13]1([C:10]2[S:11][CH:12]=[C:8]([CH2:6][OH:5])[N:9]=2)[CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1csc(C2CCC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1csc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 30 h
Yield: 101.1 %

Procedure:
Sodium borohydride (2.3 g) was added in portions over a 10 min period to an ice cold solution of 6.3 g of 2-cyclobutyl-4-thiazolecarboxylic acid ethyl ester in 100 ml of ethyl alcohol. The ice bath was removed and the reaction mixture stirred at room temperature for 30 hr during which an additional 0.46 g of sodium borohydride was added. The reaction mixture was then diluted with 200 ml of ice water and extracted with ethyl ether. The combined extracts were washed with water, dried (MgSO4) and condensed in vacuo to yield 5.1 g of 2-cyclobutyl-4-thiazole methanol as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.CC[C:16](CC)=[C:17]([C:20]([O-])([O-])[O-:21])CC.CC(C)(C)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1[CH2:16][CH2:17][C:20](=[O:21])[O:13][C:8]=1[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: CCC(CC)=C(CC)C([O-])([O-])[O-]
Agent: CC(C)(C)C(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c3c(ccc2c1)OC(=O)CC3
Yield: 86.4 %

Procedure:
Starting with a solution of 6.29 g (36.1 mmol) of 6-methoxy-2-naphthalenol, 12.58 g (72.2 mmol) of triethyl orthoacrylate and 1.84 g (18.1 mmol) of trimethylacetic acid in 70 mL of toluene, the title compound (7.12 g; 86.4%) was obtained as a white solid, mp 122°-123° C., using the procedure of example 220.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])([CH3:15])[CH3:13])[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: CC(C)(O)COCCc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)COCCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 1-[2-(6-bromopyridin-2-yl)ethoxy]-2-methylpropan-2-ol (53 mg, 0.19 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.19 mmol) as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=S)c1cc(N)c(C)s1
Product: COC(=S)c1cc(Nc2ccc(Cl)cc2)c(C)s1
Yield: 12.4 %

Procedure:
Using a procedure similar to Example 208, step (a), 66.6 mg (0.32 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 100 mg (2 equiv, 0.64 mmol) of 4-chlorophenyl boronic acid to give 11.8 mg (11.7%) of methyl 4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxylate and 21 mg (31.5%) of unreacted starting material. 1H NMR (CDCl3, 400 MHz) δ2.41 (s, 3H), 3.89 (s, 3H), 6.09 (bs, 1H), 6.94 (d, 2H, J=8.6 Hz), 7.25 (d, 2H, J=8.6 Hz), 7.70 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]C)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:5][C:4]=2[N:3]=1.CO>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.8 %

Procedure:
A stirring solution of 1-[4-amino-2-(methoxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (460 mg, 1.04 mmol) in chloroform (120 mL) was sealed with a septum and purged with nitrogen gas. The solution was cooled in an ice water bath and a solution of 1.0 M boron tribromide in dichloromethane (6.6 mL) was added via syringe. The reaction was stirred for 18 hours while warming to ambient temperature. In order to complete the reaction three additional portions (3 mL, 10 mL, and 10 mL) of 1.0 M boron tribromide in dichloromethane were added at approximately 18 hour intervals. Methanol (75 mL) was added. The reaction was concentrated to a dark purple liquid and then stirred in 10% aqueous hydrochloric acid (100 mL) for three days. Solid sodium carbonate was slowly added until the pH equaled 10. The solution was concentrated to a white solid. The solid was washed with methanol (2×100 mL) and filtered. The filtrate was absorbed onto silica (2 tbsp) and then purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-20% CMA over 1400 mL, followed by 20-30% CMA over 1600 mL) to provide 48 mg of 1-[4-amino-2-(hydroxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white crystalline solid, mp 223-225° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([CH3:34])[CH2:14][CH2:15][CH2:16][C:17]1(O)[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[S:21][C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[CH2:18]1>CC1C=CC=CC=1C>[CH3:12][N:13]([CH2:14][C:15]#[C:16][C:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[S:21][C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[CH:18]=1)[CH3:34]
Reactant: CN(C)CCCC1(O)Cc2ccccc2Sc2ccc(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CN(C)CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21

Procedure:
63 G. of p-toluenesulfonic acid and 1,800 ml. of o-xylene are heated to boiling and the water present is distilled. The solution is reacted with 90 g. of 10-[3-(dimethylamino)-1-propyl]-8-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol. The reaction mixture is maintained at the boiling temperature for 45 minutes, whereby the remaining water is distilled. The mixture is cooled and poured into 90 ml. of 2N aqueous sodium hydroxide. The aqueous phase is extracted with ether. The resulting organic phase is washed three times with water and subsequently extracted three times with aqueous methanesulfonic acid. The aqueous phase is washed with water and made alkaline with concentrated sodium hydroxide. The reaction mixture is then extracted with ether, and the ether extract washed with water, dried and evaporated, whereby there is obtained N,N-dimethyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine, which after recrystallization from hexane, has a melting point of 118°-120°. The maleate is precipitated from ethanol and melts at 178°-180°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[C:5]([F:13])[C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:16]1=[O:27].[Cl:28][C:29]1[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([N:24]2[CH2:23][CH2:22][CH:21]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][C:4]4[C:3]([F:2])=[CH:8][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]=4[F:13])[C:16]3=[O:27])[CH2:26][CH2:25]2)=[N:33][CH:34]=1
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)c(F)c1
Reactant: Clc1cnc(Cl)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A flask was charged with (S)-3-(2,6-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (0.250 g, 0.590 mmol), 2,5-dichloropyrazine (0.105 g, 0.708 mmol), Hunig's base (0.309 mL, 1.77 mmol), and DMF (5 mL). The reaction mixture was stirred at 100° C. overnight. The organic solvents were removed under reduced pressure. The residue was purified using silica gel column chromatography eluting with ethyl acetate to provide (S)-1′-(5-chloropyrazin-2-yl)-3-(2,6-difluoro-4-(methylsulfonyl)phenylamino)-[1,4′-bipiperidin]-2-one (0.102 g, 0.204 mmol, 34.6% yield) as light yellow solid. Mass spectrum (apci) m/z=500.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([OH:29])([CH3:28])[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.C[Mg]Br.BrC1C=C2C(C(=O)C(=O)N2)=CC=1>>[OH:29][C:22]1([CH3:28])[C:21]2[C:25](=[CH:26][C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[N:12][CH:11]=[CH:10][N:9]4[N:13]=3)=[CH:19][CH:20]=2)[NH:24][C:23]1=[O:27]
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Reactant: CC1(O)C(=O)Nc2cc(Br)ccc21
Agent: C[Mg]Br
Agent: O=C1Nc2cc(Br)ccc2C1=O
Product: Cn1cc(-c2nccn3nc(Nc4ccc5c(c4)NC(=O)C5(C)O)nc23)cn1

Procedure:
8-(1-Methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine is reacted with 6-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one, available via addition of methymagnesiumbromide to 6-bromo-Isatin, to give the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 59.4 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (76 mg, 0.15 mmol), 3-tributylstannanyl-pyridine (0.074 mL, 0.23 mmol) and PdCl2(PPh3)2 (22 mg, 0.031 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH) to give 44 mg of the title compound. MS: (+) m/z 494.39 (M+1).
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[C:11]1[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=1.C[O:20][C:21](=[O:43])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]3[O:35][CH:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH2:33][C:32]=3[CH:42]=2)=[CH:24][CH:23]=1>O1CCCC1>[CH2:17]([C:14]1[CH:13]=[N:12][C:11]([N:39]2[CH2:40][CH2:41][CH:36]([CH:34]3[CH2:33][C:32]4[CH:42]=[C:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([OH:43])=[O:20])=[CH:27][CH:26]=5)[CH:29]=[CH:30][C:31]=4[O:35]3)[CH2:37][CH2:38]2)=[N:16][CH:15]=1)[CH3:18]
Reactant: CCc1cnc(Cl)nc1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(C(=O)O)cc5)ccc4O3)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyldiisopropylamine (1.38 mL) and 2-chloro-5-ethylpyrimidine (380 μL) are added to a solution of 4-(2-piperidin-4-yl-2,3-dihydro-benzofuran-5-yl)-benzoic acid methyl ester (0.90 g) in tetrahydrofuran (20 mL) and the reaction mixture is heated to reflux for 48 h. The solvent is evaporated after cooling to room temperature. Dichloromethane and water are added; the aqueous phase is separated and extracted with dichloromethane. The combined organic phases are dried over MgSO4 and the solvent is evaporated. The residue is mixed with methanol (20 mL) and 1 M aqueous sodium hydroxide solution (6.67 mL). The reaction mixture is stirred at 55° C. for 12 h. The solvent is evaporated after cooling to room temperature. Dichloromethane and water are added; the organic phase is separated and extracted with water. The combined aqueous phases were adjusted to pH 2 with 1 M hydrochloric acid. The title compound is collected by filtration and dried at 50° C. in vacuo. LC (method 8): tR=1.56 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:8]=1.Cl.CN(C)CCCN=C=NCC.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[S:38]([NH2:41])(=[O:40])=[O:39]>CN(C)C1C=CN=CC=1.C(O)(C)(C)C.ClCCl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[S:38]([NH:41][C:12]([C:10]1[N:11]=[C:6]2[CH:5]=[N:4][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:8][N:7]2[CH:9]=1)=[O:14])(=[O:40])=[O:39]
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)ncc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)ncc3n2)c1
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
To the product of Step B (120 mg, 0.52 mmol) was added a solution of 4-(dimethylamino)pyridine (183 mg, 1.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (248 mg, 1.3 mmol) in t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 minutes, 2-chloro-5-methoxybenzenesulfonamide (92 mg, 0.41 mmol) was added, and stirring was continued at room temperature overnight. Dichloromethane (100 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×100 mL), and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether and dried to afford. 89 mg of the title compound, a compound of this invention, as a white solid, m.p. 236-237° C. 1H NMR (CDCl3) δ 9.99 (br s, 1H), 9.23 (s, 1H), 8.56 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.37 (d, 1H), 7.10 (dd, 1H) 3.91 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:12][C:13]([C:15]1[C:16](=[O:29])[N:17]([CH3:28])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][CH:19]=2)=O)C.C(O)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([C:15]1[C:16](=[O:29])[N:17]([CH3:28])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][CH:19]=2)=[O:12])[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CCOC(=O)c1c(O)c2c(OC)cccc2n(C)c1=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=O)c1c(O)c2c(OC)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
N-Ethylaniline (3.0 g, 25 mmol) was dissolved in 80 ml of toluene and about 30 ml of the solvent was distilled off in order to obtain a dry solution. To this boiling solution was added 1,2-dihydro-4hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (2.7 g, 10 mmol). The ethanol formed during the reaction was distilled off together with some toluene for about 4 hours. The reaction mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (2.8 g), yield 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[N:7]1[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42](O)=[O:43])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[N:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1)=[O:43]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@H](N)C1
Yield: 17 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 127 as a white solid (20 mg, 17%) over two steps. 1H NMR (400 MHz, DMSO) δ 7.67 (d, J=19.5, 1H), 7.62-7.45 (m, 3H), 7.28 (t, J=8.7, 2H), 3.63 (s, 3H), 3.53 (s, 1H), 3.20 (dt, J=8.9, 4.4, 2H), 2.84 (d, J=10.2, 2H), 2.05-1.84 (m, 2H), 1.75 (s, 2H). ESIMS m/z=420.1 (M+1)
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[O:17][CH3:18])[CH2:9][CH2:8]1)C.[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OC)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:16][C:12]1[C:11]([O:17][CH3:18])=[C:10]([C:7]2([CH2:6][C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH:4]=[O:20])[CH2:8][CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(=O)CC1(c2cccc(Cl)c2OC)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1c(Cl)cccc1C1(CC(O)(C=O)C(F)(F)F)CC1
Reaction time: 8 h
Yield: 35.6 %

Procedure:
6.18 g (20.83 mmol) of ethyl-3-[1-(3-chloro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate is dissolved in 33 ml of tetrahydrofuran and mixed with 3.55 g (24.99 mmol) of (trifluoromethyl)-trimethylsilane. After 51 mg of tetrabutylammonium fluoride is added, the batch is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, washed once with water and then with brine. After the usual working-up, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). The isolated 5.65 g (66.4%) of the product is mixed in 76 ml of tetrahydrofuran with 4.34 g (13.75 mmol) of tetrabutylammonium fluoride and stirred for one hour at room temperature. After the reaction mixture is mixed with water, it is extracted with methyl tert-butyl ether. After the usual working-up, the residue is chromatographed on a Flashmaster. 2.39 g (47.4%) of the desired compound: ethyl-2-[1-(3-chloro-2-methoxyphenyl)-cyclopropylmethyl]-3,3,3-trifluoro-2-hydroxypropionate is isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](OC(C)C)=[CH:35][CH:34]=3)=[CH:29][C:28]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.C(OC1C=CC(B(O)O)=CC=1)(C)C>>[C:33]1([C:30]2[CH:31]=[CH:32][C:27]([C@@H:22]([O:21][C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]4[CH2:9][CH2:10][C:11]5([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]5)[CH2:19][CH2:20]4)[CH:5]=3)[C:23]([F:26])([F:24])[F:25])=[C:28]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:29]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1
Agent: CC(C)Oc1ccc(B(O)O)cc1
Product: Nc1nc(O[C@H](c2ccc(-c3ccccc3)cc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substituting phenyl boronic acid for 4-isopropoxyphenyl boronic acid in Step 2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@:14]2([NH2:24])[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[O:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[O:25]=[C:26]1[C:35](=[O:36])[NH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:37](Cl)=[O:38])[CH:32]=2)[NH:27]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([C@:14]2([NH:24][C:37]([C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26](=[O:25])[C:35](=[O:36])[NH:34]4)=[O:38])[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[O:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:11])[F:12]
Reactant: O=C(Cl)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Reactant: N[C@]1(c2ccc(OC(F)(F)F)c(F)c2)CCOc2cccnc21
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@]1(c2ccc(OC(F)(F)F)c(F)c2)CCOc2cccnc21)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (0.300 g, 1.455 mmol) in DCM (3 mL) was added oxalyl chloride (0.387 mL, 4.37 mmol) and a drop of DMF (anhydrous). The resulting mixture was then stirred at room temperature for 2 h, then the mixture was concentrated in vacuo to give 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonyl chloride. A solution of (S)-4-(3-fluoro-4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (50 mg, 0.137 mmol) in DCM (1 mL) at 0° C. was added 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonyl chloride (326 mg, 1.453 mmol), and DIEA (0.072 mL, 0.411 mmol). The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for overnight. The reaction was diluted with H2O (5 mL) and EtOAc (7 mL). The mixture was then stirred at room temperature for 30 min. The mixture was then filtered and the organic layer was dried over MgSO4, and concentrated in vacuo. The residue was dissolved in DMSO (2 mL) and solution was purified by preparative HPLC (0-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 517.0 (MH+). 1H NMR (400 MHz, d4-MeOH) δ: 8.27 (dd, J=4.8, 1.3 Hz, 1H), 7.60-7.69 (m, 3H), 7.51-7.58 (m, 1H), 7.42-7.48 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 4.45-4.59 (m, 1H), 4.16-4.35 (m, 1H), 3.07-3.27 (m, 1H), 2.84-3.05 (m, 1H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:17][CH2:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CO.O>[C:1]([S:4][CH2:5][CH:6]([CH2:17][CH2:18][CH:19]([OH:23])[CH:20]([CH3:21])[CH3:22])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CCC(=O)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)SCC(CCC(O)C(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-[2-(acetylthiomethyl)-5-oxo-6-methylheptanoyl]-L-proline (1.5 g.) is dissolved in cold methanol (10 ml.) and sodium borohydride (0.12 g.) is added. After two hours the reaction mixture is diluted with water (100 ml.) acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to give 1-[2-(acetylthiomethyl)-5-hydroxy-6-methylheptanoyl]-L-proline.