Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]([CH3:18])[CH2:10]2.Br[Zn][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]([CH3:18])[CH2:10]2
Reactant: CC1Cc2cc(Br)ccc2C(=O)O1
Reactant: Br[Zn]CC1OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Temperature: 110 °C

Procedure:
A sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.124 mmol) and tri-t-butylphosphine-BF4 complex (0.072 g, 0.249 mmol) and sealed. The tube was evacuated and refilled with nitrogen before DMF (12.44 ml) and 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (0.75 g, 3.11 mmol) were added followed by bromo(1,3-dioxolan-2-ylmethyl)zinc (6.22 ml, 3.11 mmol). The tube was heated to 110° C. in the microwave for 75 minutes, after which it was cooled, diluted with EtOAc, filtered, concentrated and purified via MPLC (20-50% E/H) to afford 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one. 1H NMR (500 MHz; CDCl3): δ 8.04 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 5.11 (t, J=4.7 Hz, 1H), 4.68 (m, 1H), 3.96 (m, 2H), 3.88 (m, 2H), 3.03 (d, J=4.9 Hz, 2H), 2.93 (m, 2H), 1.54 (d, J=6.4 Hz, 3H); LC-MS (IE, m/z): 249 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:21]=1[CH2:22][N:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:26](=[O:34])(=[O:33])[N:25](CCC2C(C)=NOC=2C)[C:24]1=[O:44]>CN(C=O)C>[F:19][C:20]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:21]=1[CH2:22][N:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:26](=[O:34])(=[O:33])[N:25]([CH2:2][C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH3:12])[N:4]=2)[C:24]1=[O:44]
Reactant: Cn1nc(CCl)c2ccccc21
Reactant: Cc1noc(C)c1CCN1C(=O)N(Cc2c(F)cccc2F)c2ccccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(CN2C(=O)N(Cc3c(F)cccc3F)c3ccccc3S2(=O)=O)c2ccccc21

Procedure:
The title compound (11 mg, 0.02 mmol) was prepared from (IntE3) (50 mg, 0.154 mmol), 3-(chloromethyl)-1-methyl-1H-indazole (69.6 mg, 0.39 mmol), KI (5.1 mg, 0.03 mmol) and K2CO3 (53.3 mg, 0.39 mmol) in DMF (3 mL) in a CEM Discover microwave reactor (100° C., 1 h) using the methods of (120).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:13](O)(C)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CCOC(=O)C1C(=S)NCC1C
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)OC(=O)C1C(=S)NCC1C

Procedure:
To 5.0 g of ethyl 4-methyl-2-thioxopyrrolidine-3-carboxylate were added 300 ml of isopropyl alcohol and 11.4 g of titanium tetraisopropoxide. The resulting mixture was heated under reflux for 24 hours. After distilling off the excessive isopropyl alcohol under reduced pressure, water and chloroform were added to the residue and insoluble matters were filtered off. The chloroform layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the chloroform, 5.0 g of the title compound was obtained.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (0.18 g, 1.65 mmol) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (Starting Material 1 supra) (0.3 g, 0.82 mmol) using (Ph3P)2PdCl2 (28.8 mg) and CuI (7.8 mg) as catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 85° C. for 18 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 0.23 g, 72%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([C:9]1([OH:32])[C:29]2[CH:28]=[C:27]3[N:15]([CH2:16][C:17]4[C:18]3=[N:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH:26]=4)[C:14](=[O:30])[C:13]=2[CH2:12][O:11][CH:10]1[OH:31])[CH3:8]>O.C(O)(=O)C>[CH:10]([O:11][CH2:12][C:13]1[C:14](=[O:30])[N:15]2[C:27](=[CH:28][C:29]=1[C:9](=[O:32])[CH2:7][CH3:8])[C:18]1=[N:19][C:20]3[C:25]([CH:26]=[C:17]1[CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:31]
Reactant: CCC1(O)c2cc3n(c(=O)c2COC1O)Cc1cc2ccccc2nc1-3
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)c1cc2n(c(=O)c1COC=O)Cc1cc3ccccc3nc1-2
Temperature: 0 °C

Procedure:
A solution of sodium metaperiodate (14 g, 65 mmol) in water (140 ml) is added dropwise to a suspension of 4-ethyl-3,4-dihydroxy-1,3,4,12-tetrahydro-14H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-14-one (13.4 g, 38 mmol) in glacial acetic acid (720 ml) and the resultant solution is agitated for one hour at ambient temperature. The reaction mixture is then poured into an ice/water mixture (650 ml) and the resultant suspension is then agitated for half an hour then filtered and washed successively with water, isopropyl alcohol and diethyl ether, which allows the sought product (11.5 g) to be obtained, after drying under reduced pressure, in the form of a pale yellow solid m.p. >200° C. (d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:43]=[C:44]([N:48]=[C:49]=[O:50])[CH:45]=[CH:46][CH:47]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:49]([NH:48][C:44]5[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=5)=[O:50])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Reactant: O=C=Nc1cccc(F)c1
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)Nc4cccc(F)c4)nc3)n2)cc1
Yield: 35.9 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (Example 190, Step 4, 0.156 g, 0.293 mmol) and 3-fluorophenyl isocyanate (0.084 mL, 0.73 mmol) in THF (3 mL) was stirred at rt for 5 h. The resulting precipitate was collected to give 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-(3-fluorophenyl)urea (0.0707 g) as a yellow solid. The filtrate and wash were concentrated and purified by silica gel chromatography (25 g, eluent: EtOAc in hexanes 0%-30%) to give a second batch of the product (0.1218 g). The combined yield was 0.1925 g (98%). 1H NMR (300 MHz, CDCl3) δ 11.77-11.96 (m, 2H); 8.80-8.93 (m, 1H); 8.43 (br. s., 1H); 8.32 (br. s., 1H); 7.93 (br. s., 1H); 7.45-7.63 (m, 2H); 7.27-7.35 (m, 2H); 7.15-7.24 (m, 4H); 6.66-6.95 (m, 7H); 4.85 (br. s., 4H); 3.79 (d, J=10.08 Hz, 6H); 2.62 (s, 3H). m/z (ESI, +ve ion) 672.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][NH:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[NH2:28])[CH:10]=1.[C:35]([O:39][C:40](=[O:54])[CH2:41][CH2:42][S:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[NH:28][C:48]([C:47]2[CH:46]=[C:45]([CH:53]=[CH:52][CH:51]=2)[CH2:44][S:43][CH2:42][CH2:41][C:40]([O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:54])=[O:49])[CH:10]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(OC2CCOCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(OC3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(tetrahydro-2H-pyran-4-yloxy)phenyl)isonicotinamide (270 mg, 0.52 mmol, 1.00 equiv, 90%) in dichloromethane (10 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (339 mg, 0.92 mmol, 2.00 equiv, 80%), EDC HCl (220 mg, 1.15 mmol, 2.00 equiv), and 4-dimethylaminopyridine (140 mg, 1.15 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 150 mL of dichloromethane and was washed with 1×20 mL of aqueous NH4Cl, 1×20 mL of 10% sodium bicarbonate, and 1×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1)˜dichloromethane:methanol (20:1). The product was obtained as 190 mg (42%) of a brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[F:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:11][C:12]1[N:17]=[CH:16][C:15]([O:10][C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:13]=1
Reactant: OCCc1cccc(O)c1
Reactant: OB(O)c1ccc(F)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: OCCc1cccc(Oc2ccc(F)nc2)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 3-(2-hydroxyethyl)phenol (142.5 mg) in chloroform (5 ml), 279 mg of (6-fluoro-3-pyridinyl)boronic acid, 0.043 ml of triethylamine, 681 mg of copper acetate, and 500 mg of 4A molecular sieve were added, and the reaction solution was stirred at room temperature for 6 days. The reaction solution was filtered through Celite, and the filtrate was diluted with water, extracted with chloroform, and dried over anhydrous magnesium sulfate. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-50:50-75/25)) to afford the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:23][C:24]1[N:25]([C:2]2[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:6]=2)[CH:26]=[CH:27][N:28]=1
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-chloro-4-(4-trifluoromethylphenyl)-5-oxazolepropionate (1.33 g), 2-methylimidazole (1.33 g), potassium carbonate (2.00 g), and N-methylpyrrolidone (10 ml) was stirred at 110° C. for 2 hours. The reaction mixture was poured into ice water (100 ml). The precipitated crystals were filtered, washed with water and air-dried to give crystals of methyl 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropionate. Recrystallization from ethyl acetate-hexane gave pale yellow prisms (1.07 g, 71%). Melting point 94-95° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1.CC1C=CC=C(C)N=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[C:32]([N:15]1[CH2:16][CH2:17][C@H:13]([O:12][C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=2)[CH2:14]1)(=[O:35])[CH:33]=[CH2:34]
Reactant: O=c1[nH]nc(-c2cc3ccc(F)cc3c(O[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Temperature: -40 °C
Yield: 22.2 %

Procedure:
To (S)-3-(7-fluoro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5 (4H)-one (60 mg, 1.61 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (51 mg, 0.475 mmol). The mixture was cooled to −40° C. Acryloyl chloride (17 mg, 0.20 mmol) was added and the mixture was warmed to 0° C. over a 30 minute period. The reaction was subsequently quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (16.4 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 11.82 (s, 1H), 8.17-8.13 (t, J=8 Hz, 1H), 8.05 (s, 1H), 7.88-7.85 (d, J=12 Hz, 1H), 7.78-7.76 (t, J=8 Hz, 1H), 6.50-6.70 (m, 1H), 6.19-6.13 (m, 2H), 5.73-5.67 (dd, J1=12 Hz, J2=4 Hz, 1H), 4.11-4.08 (m, 0.5H), 3.87-3.82 (m, 2H), 3.69-3.65 (m, 1.5H), 2.38-2.25 (m, 2H); ESI-MS m/z [M+H]+ 370.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:13]S(C(C)(C)C)=O)[CH3:12])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[ClH:20].O1CCOCC1>CO>[ClH:20].[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: C[C@H](NS(=O)C(C)(C)C)c1ccnc(S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1ccnc(S(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-ethyl]amide (29.9 g, 98.2 mmol) in methanol (160 mL) was added a solution of 4 N HCl in dioxane (25.8 mL, 103 mmol). After 1 hour, the solution was concentrated to half the original volume and diluted with toluene (100 mL), and concentrated. The crude material was diluted with toluene (3×100 mL) and concentrated in vacuo and dried in vacuo for 18 hours to afford the title compound as an off-white solid which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].O.[Li+].[OH-]>O1CCOCC1>[CH3:26][CH:23]1[CH2:22][CH2:21][CH:20]([C:18]([N:10]([CH:11]2[CH2:12][CH2:13][C:14](=[O:17])[CH2:15][CH2:16]2)[C:9]2[CH:8]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:19])[CH2:25][CH2:24]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCC(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (34 mg, 0.075 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (375 ul, 0.375 mmol) was added. After 3 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 17 mg (52%) of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 13).
Reaction SMILES: Cl[C:2]([F:26])([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH2:19][CH3:20])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C(O)C.[Pd]>[F:26][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH2:19][CH3:20])[C:4]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1OCC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1OCC
Reaction time: 18 h
Yield: 47.8 %

Procedure:
A mixture of 5.0 g (0.012 mol) of product of Example 19, 1.72 ml (0.012 mol) of triethylamine and 0.75 g of 10% Pd-C in 65 ml of ethanol was hydrogenated at 40° C. under 522 kPa of H2 pressure for 18 hours. The reaction mixture was filtered through celite and concentrated. The residue was taken up in ether, washed with 10% HCl (aq), dried (MgSO4) and concentrated in vacuo to 3.28 g of yellow solid, which was recrystallized in hot hexane to give 2.13 g (47.4%) of product as a light yellow solid, mp 59°-61° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15].OS(O)(=O)=O>C(Cl)Cl.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCc2ccccc2O1

Procedure:
Chroman-2-carboxylic acid (35.6 g, 0.2 mol) prepared according to the method of Augstein et al., J. Med. Chem., v. 11, pp. 844-848, 1968) and absolute ethanol (24.3 g, 0.6 mol) were combined in 300 ml of CH2Cl2. H2SO4 (0.6 ml, 96%) was added and the mixture gently refluxed for 21 hours, then cooled and diluted with 500 ml H2O. The organic layer was separated, washed with saturated NaHCO3 and then H2O, dried (MgSO4) and stripped to yield present title product as an oil; 38.6 g (93%); 1H-NMR (CDCl3), 300 MHz) delta 7.12 (t, 1H), 7.02 (d, 1H), 6.92 (d, 1H), 6.85 (t, 1H), 4.71 (q, 1H), 4.25 (q. 2H), 2.80 (m, 2H), 2.22 (m, 2H), 1.29 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:19]2[CH2:22][CH2:21][CH2:20]2)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (100 mg, 0.389 mmol) in DCE (11 mL) was added azetidine (33 mg, 0.578 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (132 mg, 0.623 mmol) was added and stirring was continued for 2 h. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (102 mg, 88%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:22])[C:14]3[N:15]([N:17]=[C:18]([CH2:20]O)[CH:19]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:29])CC)C>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:22])[C:14]3[N:15]([N:17]=[C:18]([CH2:20][F:29])[CH:19]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cn3nc(CO)cc3c(=O)[nH]2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cn3nc(CF)cc3c(=O)[nH]2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A suspension of 149 mg (0.50 mmol) 6-(4-tert-butyl-phenyl)-2-hydroxymethyl-5H-pyrazolo[1,5-a]pyrazin-4-one in 1.25 ml dichloromethane is cooled to −78° C. Then 264 μl (2.00 mmol) diethylaminosulfurtrifluoride are added. The reaction mixture is allowed to reach room temperature over 30 minutes. The reaction mixture is evaporated and the residue is treated with water and saturated sodium hydrogen carbonate solution. The solids are filtered off and chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 6-(4-tert-butyl-phenyl)-2-fluoromethyl-5H-pyrazolo[1,5-a]pyrazin-4-one as white powder; HPLC/MS 2.80 min (B), [M+H] 300; 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.03 (s, 1H), 7.73-7.64 (m, 2H), 7.55-7.46 (m, 2H), 7.15 (d, J=2.0 Hz, 1H), 5.52 (d, J=48.1 Hz, 2H), 1.32 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:20]([F:28])[CH:21]=1
Reactant: Brc1cccc2[nH]ncc12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1cc(-n2ncc3c(Br)cccc32)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60.3 %

Procedure:
To a solution of 4-bromo-1H-indazole (4.32 g, 21.9 mmol) in dichloromethane (100 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (10.8 g, 43.9 mmol), pyridine (3.5 mL, 43.3 mmol), copper acetate (5.9 g, 32.6 mmol) and powdered 4A molecular sieves (5 g). The reaction mixture was stirred at room temperature in the presence of air for 5 days. Celite was added to the reaction mixture and the mixture stirred for 5 minutes. The mixture was then filtered through a pad of celite and washed with dichloromethane and then the filtrate concentrated in vacuo. The residue was diluted in dichloromethane and water. After separation of the layers, the aqueous phase was extracted with dichloromethane (×4). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 10-80% dichloromethane in hexane to yield the title compound (D38) (5.25 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([OH:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][CH2:33][Cl:34].O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:21][CH2:31][CH2:32][CH2:33][Cl:34])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2]
Reactant: C#Cc1cc(Nc2ncnc3cc(OC)c(O)cc23)ccc1F
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)ccc1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a suspension of 4-((3-ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (3.90 g), K2CO3 (4.36 g) in DMF (30 mL) was added 1-bromo-3-chloropropane (3.80 mL) at rt, the mixture was stirred at 40° C. overnight. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (3.30 g, 68.00%).