Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:13]1([S:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]nc(Sc2ccccc2)c2ccccc12
Yield: 83.3 %

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (2.1 g, 12 mmol), thiophenol (2.6 g, 23 mmol), and K2CO3 (2.4 g, 17 mmol) in DMF (40 mL) was microwaved at 125° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, concentrated, and triturated with Et2O to give the title compound (2.5 g, 10 mmol): 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.28 (dd, J=7.8, 1.1, 1H), 8.06-7.99 (m, 1H), 7.98-7.92 (m, 1H), 7.92-7.85 (m, 1H), 7.44 (d, J=1.2, 2H), 7.38 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[C:11]=2[NH2:16])=[CH:6][CH:5]=1.[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([NH:24][C:25]([NH:16][C:11]1[C:12]([CH3:15])=[N:13][O:14][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: O=C=NCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 0.040 g, 1.00 mmol) was added to a solution of 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine (0.170 g, 0.67 mmol) in DMF, and the mixture was stirred for 5 minutes at room temperature. Benzyl isocyanate (0.08 mL, 0.67 mmol) was added, and the reaction was stirred at 80° C. for 2 hours. After aqueous workup, the crude material was used directly in the coupling step.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:30][NH2:31])[CH2:9][C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]2[CH2:25][O:24]C(C)(C)[O:22]2)=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:30][NH2:31])[CH2:9][C:10]([CH3:28])([CH3:29])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([OH:22])[CH2:25][OH:24])=[CH:15][CH:14]=1
Reactant: CC(C)(CCc1ccc(OC[C@@H]2COC(C)(C)O2)cc1)C[C@@H](CN)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CCc1ccc(OC[C@@H](O)CO)cc1)C[C@H](N)CN

Procedure:
A solution of {(S)-1-Aminomethyl-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-3,3-dimethyl-pentyl}-carbamic acid tert-butyl ester (0.13 g, 0.28 mmol) and TFA (1 ml) in DCM (5 ml) is stirred at room temperature for 1 hour, then loaded onto an SCX-2 cartridge which has been pre-eluted with MeOH. The cartridge is eluted with MeOH (2×5 ml), followed by 7M NH3 in MeOH (2×5 ml) to yield (S)-3-[4-((S)-5,6-Diamino-3,3-dimethyl-hexyl)-phenoxy]-propane-1,2-diol in 80% purity as a colourless oil; [M+H]+ 311
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[OH-].[Na+]>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
To a well-stirred solution of L-proline (5.75 g, 0.05 mmole) in 2N NaOH (25 ml), 4N NaOH (12.5 ml) and benzoyl chloride (5.8 ml, 0.05 mole) were added dropwise from different drop funnels, maintaining the temperature near 0°-4° C. The mixture after 15 minutes was acidified with 1N HCl. The resulting oil was extracted with CHCl3, the combined organic extract was dried (MgSO4), and the solvent was removed. Ether was added to the residue and the mixture was allowed to stand overnight at 0° C. The crystals of N-benzoyl-L-proline were separated. Yield 3.42 g (60%), m.p. 152°-154° C., [α]D20 -68.5° (c 0.4; CHCl3); Rf 0.13 (Kiesel-gel, CHCl3 --CH3OH, 9:1). Analysis Calcd. for C12H13NO3 : C, 65.73; H, 5.99; N, 6.39. Found: C, 65.64; H, 6.03; N, 6.54.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>CC#N.CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:30][CH:29]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCCC2)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCCC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 68.6 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol), (4-pyrrolidin-1-ylphenyl)amine (0.081 g, 0.500 mmol) and TEA (0.070 ml, 0.500 mmol) in MeCN (2 ml) and DMF (1 ml) was heated in a microwave reactor at 120° C. for 45 mins. TEA (0.070 ml, 0.500 mmol) was added and the mixture was heated at 120° C. for 15 mins. The precipitate from the reaction mixture was isolated by filtration and washed with MeCN. The crude product was dissolved in MeOH and purified by silica gel column chromatography using 15-100% EtOAc in petroleum ether 40-60° C. as eluent, to give the title compound (0.146 g, 69%). 1H NMR (500 MHz, CDCl3): δ 7.22-7.02 (m, 5H), 6.55 (d, 2H), 6.14 (d, 2H), 3.15-3.10 (m, 4H), 1.99-1.92 (m, 4H), 1.77 (s, 9H); 13C NMR (125 MHz CDCl3): δ 160.8, 149.9, 131.6, 129.7, 128.5, 127.9, 125.5, 124.7, 123.9, 111.2, 108.8, 61.8, 47.9, 27.9, 25.6; Mass Spectrum: M+H+ 426.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)([OH:15])[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6]1)[CH3:3].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]([CH2:4][CH:5]1[C:14]([OH:15])([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6]1)[CH3:3]
Reactant: COc1cccc(C2(O)CCC3(CC2CN(C)C)OCCO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCC(=O)CC2CN(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54081.6 %

Procedure:
78 g (0.24 mmole) 7-dimethylaminomethyl-8-(3-methoxy-phenyl)-1,4-dioxaspiro[4.5]decan-8-ol (65) were dissolved in a 500 ml tetrahydrofuran and cooled to a temperature between 0° C. and 5° C. 200 ml of aqueous hydrochloric acid (2:1 concentrated hydrochloric acid/water) were added over 30 minutes. The mixture was stirred for 12 hours at room temperature and was subsequently cooled to a temperature between 0° C. and 5° C. After adding 250 ml of concentrated aqueous sodium hydroxide solution the product was extracted three times with ether and dried over sodium sulphate. After removing the solvent by distillation, the residue (66 g) was introduced on to a silica gel column and eluted successively with diisopropyl ether, 1:1 diisopropyl ether/ether and 1:1 ethyl acetate/methanol. 36 g base (66) (48%% theoretical) were obtained as a light yellow, viscous oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][CH:9]=[CH2:10])[CH2:6][O:5][CH2:4]1)[CH3:2].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.B1C2CCCC1CCC2.[C:40]1([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[N:51]=[C:50]([C:52]3[CH:53]=[C:54]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH:55]=[CH:56][CH:57]=3)[N:49]=[C:48]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66](Br)[CH:65]=3)[N:47]=2)[CH:41]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:40]1([C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[N:51]=[C:50]([C:52]3[CH:53]=[C:54]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH:55]=[CH:56][CH:57]=3)[N:49]=[C:48]([C:64]3[CH:65]=[CH:66][CH:67]=[C:68]([CH2:10][CH2:9][O:8][CH2:7][C:3]4([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]4)[CH:69]=3)[N:47]=2)[CH:41]=1
Reactant: Brc1cccc(-c2nc(-c3cccc(-c4ccccc4)c3)nc(-c3cccc(-c4ccccc4)c3)n2)c1
Reactant: C=COCC1(CC)COC1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC1(COCCc2cccc(-c3nc(-c4cccc(-c5ccccc5)c4)nc(-c4cccc(-c5ccccc5)c4)n3)c2)COC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
13.1 g (92 mmol) of 3-ethyl-3-vinyloxymethyloxetane and 11.3 g (60.8 mmol) of 9-BBN dimer are dissolved in 200 ml of toluene at room temperature under protective gas and stirred for 20 h. During the reaction, the suspension of 9-BBN slowly dissolves. 50 g (92 mmol) of 2,4-bis-biphenyl-3-yl-6-(3-bromophenyl)-1,3,5-triazine and 50 ml of a 1 M NaOH solution are subsequently added to the reaction solution. The reaction mixture is carefully degassed, 200 mg of tetrakistriphenylphosphino-palladium are added, and the mixture is heated under reflux for 20 h. The solution is cooled to room temperature, and the phases are separated. The aqueous phase is extracted three times with toluene, the combined organic phases are subsequently washed twice with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo. The residue is recrystallised from ethanol/toluene 3:1, giving 54 g (89 mmol) (97%) of a white solid in a purity of 99:8%.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][CH:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@@H:5]([OH:12])[C@@H:4]1[OH:13].[C:14](O)(=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[C:14]([O:10][CH2:9][C@H:7]1[O:8][CH:3]([O:2][CH3:1])[C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]1[OH:11])(=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCC(=O)O
Product: CCCCCCCCCC(=O)OC[C@H]1OC(OC)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 59 %

Procedure:
Methyl-D-glucopyranoside (a 2:3 mixture of the α- and β-anomers) (24 g, 0.12 mol, prepared according to Example 6) was esterified with decanoic acid (43 g, 0.25 mol) by the procedure described in Example 1 using 2.4 g of an immobilized lipase (derived from Candida antarctica). After 17 hours the enzyme was removed by filtration (at 80° C.) HPLC analysis of the crude product showed 77% of the title compound, 15% diesters and 8% methyl-D-glucopyranoside. Part of the crude product was purified by chromatography, yielding 39.4 g (59%) of the title compound which was identified by NMR spectroscopy.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][OH:9].[C:10]([C:12]1([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:15][CH2:14][CH2:13]1)#[N:11]>CCO>[CH3:20][C:19]([CH3:22])([S:17]([NH:16][C:12]1(/[C:10](=[N:8]/[OH:9])/[NH2:11])[CH2:13][CH2:14][CH2:15]1)=[O:18])[CH3:21]
Reactant: CC(C)(C)S(=O)NC1(C#N)CCC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)S(=O)NC1(/C(N)=N/O)CCC1
Temperature: 60 °C
Yield: 52.4 %

Procedure:
Potassium carbonate (1.38 g, 9.98 mmol) was added to a stirring solution of hydroxylamine hydrochloride (347 mg, 4.99 mmol) and N-(1-cyanocyclobutyl)-2-methylpropane-2-sulfinamide (500 mg, 2.50 mmol) in EtOH (8 ml) at rt. The reaction was then heated to 60° C. for 16 h. The mixture was then concentrated and the resulting residue was diluted with EtOAc and washed with H2O followed by sat NaCl (aq). The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product (Z)-1-(1,1-dimethylethylsulfinamido)-N′-hydroxycyclobutanecarboximidamide (305 mg, 1.31 mmol, 52% yield) as a white solid consistent by LCMS and NMR. LC-MS retention time: 0.456 min; m/z (MH+): 234. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 5.60 (s, 1H), 5.10 (s, 2H), 2.35-2.30 (m, 1H), 2.27-2.17 (m, 1H), 2.10-2.03 (m, 1H), 1.99 (s, 1H), 1.80-1.75 (m, 1H), 1.73-1.62 (m, 1H), 1.13 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]=[C:13]=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]>O1CCCC1>[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:13]([NH:12][C:4]3[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=3)=[O:14])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]
Reactant: O=C=Nc1cc(F)cc(C(F)(F)F)c1
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(F)cc(C(F)(F)F)c3)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.8 %

Procedure:
0.061 cm3 (0.426 mmol) of 3-fluoro-5-trifluoromethylphenyl isocyanate is added at room temperature to a suspension of 100 mg (0.387 mmol) of 2-acetylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide in 5 cm3 of anhydrous tetrahydrofuran. The reaction medium is stirred at room temperature for 24 hours, cooled in a water-ice bath and then filtered on sintered glass. The solid collected is washed with a small amount of dichloromethane and cyclohexane and then dried under vacuum. 75 mg of 2-acetylamino-4-{4-[3-(3-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide are obtained in the form of a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10](=[O:26])[CH:11]=[CH:12][N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[C:14]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([F:27])[CH:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:8][C:6]1[CH:7]=[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH:3]=[C:4]([F:27])[C:5]=1[C:9]1[C:10](=[O:26])[CH:11]=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: OB(O)c1cncnc1
Reactant: O=c1ccn2c(-c3ccc(F)cc3)cccc2c1-c1c(F)cc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=c1ccn2c(-c3ccc(F)cc3)cccc2c1-c1c(F)cc(-c2cncnc2)cc1F
Temperature: 90 °C

Procedure:
To a solution of 1-(4-bromo-2,6-difluorophenyl)-6-(4-fluorophenyl)-2H-quinolizin-2-one Example 44, 74 mg, 0.17 mmol) in toluene (5 mL) was added pyrimidin-5-ylboronic acid (42 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (196 mg, 0.017 mmol), EtOH (0.5 mL) and 2N Na2CO3 (0.5 mL), and heated to 90° C. for 12 h. After cooling the reaction to room temperature, the mixture was concentrated. The crude residue was dissolved in EtOAc and washed with water, brine, dried over MgSO4, and concentrated. The crude material was purified using silica gel chromatography (CH2Cl2/EtOAc/MeOH) to give title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C@@H:20]([NH:22][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)N)c1
Reactant: CC(C)(C)C(=O)Cl
Product: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)NC(=O)C(C)(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (73 mg, 0.18 mmol) and pivaloyl chloride (0.088 ml, 0.72 mmol). Yield 75 mg (85%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:27][CH:28]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccc(OCCBr)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCOc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 145 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(2-bromoethoxy)-4-chlorobenzene and conditions outlined in procedure V. LCMS: 456 [M+H]; Rt=1.07 min.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][C:5]1[NH:10][C:9](=O)[C:8]2[CH:12]=[CH:13][O:14][C:7]=2[CH:6]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>>[Cl:18][C:9]1[C:8]2[CH:12]=[CH:13][O:14][C:7]=2[CH:6]=[C:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[N:10]=1
Reactant: CN(C)CCc1cc2occc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCc1cc2occc2c(Cl)n1
Temperature: 110 °C
Yield: 94.2 %

Procedure:
A mixture of 6-[2-(dimethylamino)ethyl]furo[3,2-c]pyridin-4(5H)-one (3.9 g, 18.9 mmole) and phosphorus oxychloride (5.0 g, 32.6 mmole) was heated, under an argon atmosphere, at 110° C. for 2.0 hours. The cooled blackish liquid was poured onto crushed ice and the solution made basic with sodium hydroxide solution. The alkaline mixture was extracted into methylene chloride (4×100 ml). The combined extracts were washed with water (1×25 ml), brine (2×25 ml) and dried (MgSO4). Solvent removal gave 4.0 g of an oil (88%, yield). The compound was used as is in the following step. A small sample was purified further using a preparative thin layer chromatography plate and eluting with a 25% methanol/74% chloroform/1.0% ammonium hydroxide mixture. The sample was removed from the plate using methylene chloride and treated with excess hydrogen chloride in ethanol. The ethanol was removed via vacuum and the resulting clear oil triturated with diethyl ether to give white crystals, mp: 212°-213° C.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=12.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:11][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH:4]=[N:3][C:2]=2[Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc2c(I)ncn2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(C)ccc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask, 1-iodo-6-methyl-imidazo[1,5-a]pyridine (97 mg, 0.38 mmol) was dissolved in THF (3 ml). The solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0M solution in THF, 0.23 ml, 0.46 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (0.12 ml, 0.44 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to provide 6-methyl-1-tributylstannanyl-imidazo[1,5-a]pyridine as a brown oil which was used without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:13][C:14](=O)[CH3:15])(=[O:12])[CH3:11].[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N+:23]([O-])C(C)=[CH:25][CH:26]=1)=[O:20].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][C:15]([CH2:14][O:13][C:10](=[O:12])[CH3:11])=[CH:25][CH:26]=1)=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(COC(C)=O)nc1
Temperature: 120 °C
Reaction time: 2.25 h
Yield: 48 %

Procedure:
N,N-Diisopropylethylamine (2.2 mL, 13 mmol) and acetic anhydride (3.5 mL, 38 mmol) were added to a solution of 6-methylpyridine-3-carboxylic acid methyl ester N-oxide (Reference Compound No. 8-1, 2.1 g, 13 mmol) in acetic acid (14 mL), and then the reaction mixture was stirred at 120° C. for 135 minutes. After cooling, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added thereto, and then sodium hydrogen carbonate was added until foam formation was ended. The whole was extracted with ethyl acetate (100 mL, 50 mL), the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and then the resulting solid was collected by filtration with hexane and ethyl acetate to give 1.2 g of the title reference compound as a pale yellow solid. (Yield 48%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[N:7]=[C:6]1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[F:40])#[N:30].C([O-])([O-])=O.[Na+].[Na+].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>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[C:32]([F:40])[CH:33]=2)[N:7]=[C:6]1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:16][CH2:15]1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)c(Cl)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Yield: 35 %

Procedure:
A mixture of [2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-4,5-dichloro-6-oxo-6H-pyrimidin-1-yl]-acetic acid methyl ester (5.76 g, 13.2 mmol), 4-cyano-3-fluoro benzeneboronic acid (2.24 g, 16.1 mmol), Pd(PPh3)4 (306 mmol, 0.26 mmol) and Na2CO3 (2.8 g, 26.5 mmol) in DMF:H2O (50 mL:10 mL) was stirred at 65° C. overnight under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by silica chromatography (1:20 to 1:0, EA:PE) to give 2.4 g of the title product (43%). 1H NMR (400 MHz, CDCl3): δ 1.27-1.37 (m, 2H), 1.45 (s, 9H), 1.99-2.02 (m, 2H), 2.99-3.06 (m, 2H), 3.68-3.76 (m, 1H), 3.78 (s, 3H), 4.42-4.52 (m, 3H), 4.90 (s, 2H), 7.63-7.66 (m, 1H), 7.67-7.71 (m, 2H). [M+H] Calc'd for C24H27ClFN5O5, 520. Found, 520.