Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:26]([CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:25]=[CH:24][C:7]=3[C:8](=[O:23])[N:9](CC3C=CC(OC)=CC=3OC)[C:10]=2[CH:11]=1.[CH3:33][O:34][C:35]1[N:40]=[C:39]([CH3:41])[C:38](B(O)O)=[C:37]([CH3:45])[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.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>[CH3:33][O:34][C:35]1[N:40]=[C:39]([CH3:41])[C:38]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:26]([CH:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[N:25]=[CH:24][C:7]=4[C:8](=[O:23])[NH:9][C:10]=3[CH:11]=2)=[C:37]([CH3:45])[CH:36]=1
Reactant: COc1cc(C)c(B(O)O)c(C)n1
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(Br)cc32)c(OC)c1
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn(C4CCOCC4)c23)c(C)n1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
7-bromo-5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one obtained in Preparation Example 1(4) (41 mg) was dissolved in DMF (2 mL). (6-methoxy-2,4-dimethylpyridin-3-yl)boronic acid obtained in Preparation Example 24 (15 mg), Pd(PPh3)4 (4.8 mg), cesium carbonate (54 mg) and water (0.5 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 150° C. for two hours. The reaction mixture was returned to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a 5 N aqueous sodium hydroxide solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (3.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH:20]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:28][CH2:29]3)=[O:17])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: C1CCC(CN2CCNCC2)CC1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC3CCCCC3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with (1-cyclohexyl-methyl)piperazine to give 4-chloro-N-{4-[2-(4-cyclohexylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide, using general procedure A. Colorless amorphous solid. MS 461.0 ([M+H]+)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([O:16]C)=[O:15])[NH:10][CH:9]=[CH:8]2)=[O:4].C(O)C.[OH-].[Na+].Cl>O>[NH:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: COC(=O)c1cc2cc[nH]c2cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc[nH]c2cc1C(=O)O
Yield: 86.5 %

Procedure:
To a stirred solution of the dimethyl ester produced in step d (1.14 g, 4.9 mmol) in a 5:1 mixture of ethanol:water (12 ml) was added solid sodium hydroxide (0.49 g, 12.4 mmol). The solution was stirred at a gentle reflux for 3 h. The solution was acidifed on cooling to pH2 with hydrochloric acid and then evaporated. The residue was azeotroped with ethanol and then toluene and dried under vacuum. The residue was then extracted with hot acetone (5×20 ml) and the combined extracts were evaporated to leave the title compound (870 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7](Br)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([O:18][C:19](=[O:38])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[OH:37])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:10])[CH:7]([O:37][C:31]1[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=1[CH2:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][C:19]([O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:38])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(COc1ccc(Cl)cc1Cc1cc(Cl)ccc1O)OCc1ccccc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromopropionic acid tert-butyl ester (0.827 g, 3.95 mmol) in DMF (15 mL) is added [4-chloro-2-(5-chloro-2-hydroxy-benzyl)-phenoxy]-acetic acid benzyl ester (1.5 g, 3.60 mmol) and potassium carbonate (0.547 g, 3.95 mmol). The reaction mixture is stirred at RT overnight and the solvent is removed in vacuo. The crude product is dissolved in EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic portion is dried (MgSO4) and concentrated in vacuo to yield a yellow oil which is dried in a vacuum oven for 2 hours to afford the titled product which is used in the next step without purification.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].CCOC(C)=O>CN(C)C=O>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCSc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A stirred mixture of 4-(ethylthio)benzoic acid (0.36 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.670 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (hexanes/EtOAc, gradient, product eluted at ˜95% EtOAc). The product fractions were combined and concentrated to give 4-ethylsulfanyl-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.37 g, 61% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.03 min (99.73%); mp: 135-137° C.; 1H NMR (DMSO-d6) δ 1.27 (t, J=7.3 Hz, 3H), 1.89 (s, 3H), 1.95-2.11 (m, 1H), 2.53-2.61 (m, 2H), 2.61-2.77 (m, 1H), 3.06 (q, J=7.3 Hz, 2H), 4.61 (d, J=5.7 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.72-7.88 (m, 5H), 9.18 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 13.92, 21.02, 25.19, 28.57, 29.11, 42.58, 58.76, 121.60, 123.18, 126.32, 127.83, 129.59, 130.38, 131.38, 133.38, 141.22, 147.51, 165.86, 167.73, 167.88, 172.13, 172.19; LCMS: MH=466; Anal Calcd for C21H23N3O5S+0.3H2O: C, 61.21; H, 5.05; N, 8.92. Found: C, 61.27; H, 5.13; N, 8.80.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].[CH2:16]([CH2:26]S([O-])(=O)=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=C.O>CS(C)=O>[CH2:24]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:26]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCCCCCCS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Theobromine (3.45 g, 19.2 mmol) was added to a suspension (30 ml) of sodium hydride (461 mg, 19.2 mmol) in dimethylsulfoxide. After 15 minutes, the 9-decenylmesylate (2.25 g, 11 mmol) was added and the reaction stirred for 18 hours at 25° C., then for 40 minutes at 100° C. The mixture was then poured into water (100 ml) and extracted with three 50 ml aliquots of dichloromethane. The combined organic portions were washed with saturated salt solution (60 ml) and dried over magnesium sulfate. Evaporating the solvent under vacuum left a white solid residue. Recrystallization of the residue in ether produced 3.40 g of 1-(9-decenyl)-3,7-dimethylxanthine (56% yield). 1-(9-Decenyl)-3,7-dimethylxanthine (3.2 g, 10.1 mmol), 4-methylmorpholine-N-oxide (1.41 g, 12 mmol), 3 drops of 2.5% osmium tetroxide solution in t-butanol, acetone (40 ml) and water (10 ml) were stirred for 24 hours. Following addition of 5 ml of a saturated solution of sodium dithionite and a further 15 minutes of stirring, the reaction mixture was extracted with four 50 ml aliquots of 25% ethanol/dichloromethane. The combined organic portions were dried over sodium sulfate. Evaporating the solvents left a white solid residue, which upon recrystallization in ethanol produced 3.3 g of 1-(9,10-dihydroxydecyl)-3,7-dimethylxanthine (93% yield). 1-(9,10-Dihydroxydecyl)-3,7-dimethylxanthine (2.11 g, 6 mmol), prepared above, was stirred with hydrogen bromide (3.58 ml, 4.85 g of a 30% solution in acetic acid, 18 mmol) for 90 minutes. The mixture was then added to a flask containing 40 ml aqueous sodium bicarbonate solution (5 g) and 50 ml dichloromethane. After 10 minutes of vigorous stirring the layers were separated and the aqueous portion washed with two 50 ml aliquots of dichloromethane. The organic portions were combined, dried over sodium sulfate, and evaporating the solvent produced 2.72 g of a yellow oil, inventive compound no. 1583 (100% yield).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([Cl:24])=[CH:17][C:18]=3[Cl:23])[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[Cl:23][C:18]1[CH:17]=[C:16]([Cl:24])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:6]([CH3:25])[CH:7]=1)=[N:13]2
Reactant: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCBr
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethylphenyl]-5,7-dichloro-3H-quinazolin-4-one (0.44 g, 1.00 mmol) in anhydrous DMF (10 mL) was added pyrrolidine (0.28 g, 4.00 mmol). The reaction mixture was stirred at room temperature for 6 hours under nitrogen. Solvent was evaporated under reduced pressure. Water (50 mL) was added. The separated solid was filtered, washed with water (20 mL), and dried under vacuum. The crude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2 and 5% methanol (containing 7.0 M ammonia) in CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.31 g (72%). MP 209-210° C. 1H NMR (400 MHz, DMSO-d6): δ 12.39 (br s, 1H), 7.90 (s, 2H), 7.71 (d, J=1.95 Hz, 1H), 7.60 (d, J=1.95 Hz, 1H), 3.91 (t, J=5.85 Hz, 2H), 2.83 (t, J=6.05 Hz, 2H), 2.55 (m, 4H), 2.31 (s, 6H), 2.01 (m, 4H). MS (ES+) m/z 432.54 (100%), 434.49 (90%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:19]2[C:23]3=[N:24][CH:25]=[C:26]([C:28]4[N:29]=[N:30][N:31]([CH2:33][C:34](OCC)=[O:35])[CH:32]=4)[CH:27]=[C:22]3[N:21]=[CH:20]2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)(=[O:3])[CH3:2].[NH3:39]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:19]2[C:23]3=[N:24][CH:25]=[C:26]([C:28]4[N:29]=[N:30][N:31]([CH2:33][C:34]([NH2:39])=[O:35])[CH:32]=4)[CH:27]=[C:22]3[N:21]=[CH:20]2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1cc(-c2cnc3c(c2)ncn3-c2cc(NC(C)=O)cc(-c3ccc(F)cc3F)c2)nn1
Reactant: N
Solvent: CO
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC(N)=O)nn4)cnc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
To a mixture of the compound of Example 270 (100 mg, 0.19 mmol) in methanol was added methonalic ammonia at 0° C. and the mixture was stirred at RT for 16 h. The mixture was distilled completely and the crude product was purified by preparative HPLC to give the product in 13% yield (12 mg). δ 10.5 (s, 1H) 9.14-8.97 (d, 2H), 8.82 (s, 1H), 8.76 (d, 1H), 8.35 (s, 1H), 7.89 (d, 1H), 7.81-7.80 (m, 2H), 7.65-7.55 (m, 1H), 7.27 (m, 1H), 5.55 (s, 2H), 2.8 (s, 2H), 2.10 (s, 3H); LC-MS (ESI): Calculated mass: 515.5; Observed mass: 516.5 [M+H]+ (rt: 1.37 min).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C@H:4]1[CH2:6][O:5]1.[N-:9]=[N+:10]=[N-:11].[Na+].[NH4+].[Cl-]>CCO.O>[N:9]([CH2:6][C@@H:4]([OH:5])[CH2:3][C:2]([F:8])([F:7])[F:1])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NC[C@@H](O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
To a solution of (S)-2-(2,2,2-trifluoroethyl)oxirane (2.00 g, 16.0 mmol) in a mixture of EtOH (16 mL) and H2O (4 mL) were added NaN3 (2.06 g, 32.0 mmol) and NH4Cl (1.70 g, 32.0 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with H2O (50 mL), extracted with Et2O (2×75 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give (S)-1-azido-4,4,4-trifluorobutan-2-ol as an oil (2.26 g, 83% yield). NMR: 400 MHz 1H (CDCl3) 4.17 ppm, 1H, ddd, J=6.81, 3.74, 3.52 Hz; 3.48 ppm, 1H, m; 3.37 ppm, 1H, m; 2.35 ppm, 2H, m.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C@H:29]([CH3:36])[CH2:30][C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=2)=[O:21])[CH:3]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:36])[CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=2)=[O:21])[CH:3]=1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2cc(C)c3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)Nc3ccc(C(C)CC(=O)O)cc3)cc2o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A solution of ethyl (R) 3-{4-[2-(4-methyl-2-o-tolylaminobenzoxazol-6-yl)acetylamino]phenyl}butanoate [0.14 g, Reference Example 15(a)] in methanol (2 mL) was treated with aqueous sodium hydroxide solution (1.2 mL, 1M) and then stirred at 50° C. for 2 hours. The mixture was diluted with water and partially evaporated. The residue was washed with diethyl ether and then acidified to pH 4. The precipitated solid was filtered and sucked dry to give the title compound (0.07 g) as a tan solid. LC-MS: RT=3.38 minutes (100% by ELSD); MS (ES+), 458 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:12][C:11]([C@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[CH3:1])=[O:13]
Reactant: CO
Reactant: C[C@@H]1c2ccccc2C[C@@H]1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1Cc2ccccc2[C@H]1C
Yield: 91 %

Procedure:
cis-2,3-Dihydro-1-methyl-1H-indene-2-carboxylic acid methyl ester is prepared from cis-2,3-dihydro-1-methyl-1H-indene-2-carboxylic acid (see Example 4) by the standard methods using methanol and concentrated sulphuric acid. Yield 91%.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Sn:19](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:1]([O:8][N:9]1[C:13]([Sn:19]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=[N:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc(COn2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnn1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a solution of 1-benzyloxy-1H-pyrazole (1.17 g, 6.72 mmol) in THF (15 mL) at −78° C. was added dropwise n-BuLi (4.6 mL, 1.6M, 7.4 mmol). The mixture was stirred at −78° C. for 2 h before addition of Bu3SnCl (1.99 mL, 7.38 mmol). The mixture was kept at this temperature for 1 h and was then allowed to warm up to r.t. and stirred for 1 h. The mixture was concentrated in vacuo and hexanes was added. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo to afford 1-benzyloxy-5-tributylstannanyl-1H-pyrazole (3.3 g, 100%) as a yellow syrup.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[B:32]([O-])([O-:34])[O-:33]>C1COCC1.CCCCCC>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[B:32]([OH:34])[OH:33])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: [O-]B([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1ccc2ccccc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (11.0 g; 78 mmols) in THF (170 ml), at -78° C. and under nitrogen, a 1.6M solution of BuLi (56.1 ml; 89.7 mmols) in hexane is added slowly in order to maintain the temperature below -65° C. The mixture is stirred at -75° C. for 10 min and is then warmed to 0° C. within 30 min. After cooling again to -78° C., a solution of 1-tert-butoxycarbonylindole (15.6 g; 72 mmols) in THF (300 ml) is added, keeping the temperature below -65° C. The mixture is stirred 1 hour at -75° C. and a solution of trimrthyl borate (7.5 g; 72 mmols) in THF (200 ml) is added dropwise. The reaction is allowed to warm up to room temperature overnight. A 0.25N solution of Hcl (200 ml) is added and the THF is removed under vacuum. The residue is extracted with ethyl ether (3×150 ml) and the combined organic phases are washed with water (2×100 ml) and dried over sodium sulphate. The solution is then concentrated, cooled to 0° C. and filtered to obtain crystalline (1-tert-butoxycarbonylindol-2-yl)boronic acid (6.95 g; 26.6 mmols). Yield: 37%.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH3:8][C:9]([CH3:25])([CH3:24])[C:10]([O:12][C:13]1[C:14]([C:20]([O:22][CH3:23])=[O:21])=[N:15][CH:16]=[N:17][C:18]=1[OH:19])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH3:8][C:9]([CH3:25])([CH3:24])[C:10]([O:12][C:13]1[C:18](=[O:19])[N:17]([CH3:5])[CH:16]=[N:15][C:14]=1[C:20]([O:22][CH3:23])=[O:21])=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ncnc(O)c1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1ncn(C)c(=O)c1OC(=O)C(C)(C)C

Procedure:
Dimethyl sulfate (1.5 eq.) was added to a solution of the product of Step 3 (1 eq.) in THF containing cesium carbonate (1.5 eq.). The reaction was carried out at 50° C. for thirty minutes. The solvent was evaporated and the resulting oil was dissolved in ethyl acetate, washed with 1N HCl solution. The crude title compound was recovered as yellow solid and used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.Cl.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([NH:34][C@@H:32]([C:29]2[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[CH3:33])=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)nc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-(thiazol-2-yloxy)benzoic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C@@H:60]([OH:62])[CH3:61]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH2:59][C@H:60]([OH:62])[CH3:61])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: C[C@H](O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC[C@@H](C)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-aminopropan-2-ol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.1 Hz, 3 H) 1.12-1.41 (m, 3 H) 1.55-1.87 (m, 8 H) 1.70-1.88 (m, 4 H) 3.21 (q, J=6.3 Hz, 1 H) 3.32 (s, 3 H) 3.77 (m, 1 H) 3.94 (s, 3 H) 4.16 (t, J=13.0 Hz, 2 H) 4.49 (quin., J=12.1 Hz, 1 H) 7.53 (d, J=8.6 Hz, 1 H) 7.58 (s, 1 H) 8.14 (d, J=8.3 Hz, 1 H) 8.23 (s, 1 H) 8.41-8.47 (m, 1 H) 8.51-8.57 (m, 1 H). [M+H] calc'd for C25H32F2N6O4 519; found 519.