Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:26])[C:21]2[CH:20]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:19]3[O:18][C:17]=2[CH2:16][CH2:15][CH2:14]1.[C:27](=O)([O:30]C)[O:28][CH3:29]>O1CCCC1>[O:26]=[C:13]1[C:21]2[CH:20]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:19]3[O:18][C:17]=2[CH2:16][CH2:15][CH:14]1[C:27]([O:28][CH3:29])=[O:30]
Reactant: COC(=O)OC
Reactant: O=C1CCCC2=C1C1CCCCC1O2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CCC2=C(C1=O)C1CCCCC1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.56 mL, 39.0 mmol) in tetrahydrofuran (20 mL) was cooled to −78° C. and then treated with n-butyllithium (15.60 mL, 39.0 mmol) added dropwise. The mixture was stirred at this temperature for 30 minutes. The solution was transferred by cannula needle into a solution of the product from Example 1A, (3,4,5a,6,7,8,9,9a-octahydrodibenzo[b,d]furan-1(2H)-one, 2.5 g, 13.00 mmol) in tetrahydrofuran (40 mL) precooled to −78° C., and the resulting mixture was stirred for 30 minutes at −78° C. Then, dimethyl carbonate (11.71 g, 130 mmol) was added and the dry ice bath was removed. The mixture was stirred and allowed to warm to ambient temperature with stirring continued for 16 hours. The mixture was quenched with hydrochloric acid (1N, 40 mL) and diluted with ether (200 mL). The organic layer was separated and the aqueous layer was extracted with additional ether. The organic layers were combined and washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 10-30% ethyl acetate in hexanes to provide the title product: 1H NMR (CDCl3) δ 1.23-1.30 (m, 1H), 1.42-1.56 (m, 3H), 1.72-1.84 (m, 1H), 1.87-2.04 (m, 3H), 2.17-2.26 (m, 1H), 2.31-2.49 (m, 3H), 2.56-2.67 (m, 1H), 3.00-3.10 (m, 1H), 3.32-3.40 (m, 1H), 3.75 (d, J=2.45 Hz, 2H), 4.67-4.75 (m, 1H); MS (DCl/NH3) m/z 251 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: N#Cc1ccc(B(O)O)cc1
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: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)OCC
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A mixture of 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (1.19 g, 2.39 mmole), 4-cyanophenylboronic acid (702 mg, 4.77 mmole), cesium carbonate (2.33 g, 7.16 mmole) and tetrakis(triphenylphosphine)palladium (221 mg, 0.19 mmole) in dioxane (8 ml) was refluxed for 18 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (448 mg). MS: (+) m/z 524.30 (M+H+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:32][CH2:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=1)(=O)=O>CN(C)C=O>[CH3:45][O:44][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)[CH:39]=[C:38]([O:40][CH3:41])[C:37]=1[O:42][CH3:43]
Reactant: COc1cc(CCOS(C)(=O)=O)cc(OC)c1OC
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)cc(OC)c1OC
Temperature: 70 °C

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.8 g, 0.022 mole), K2CO3 (11.0 g) and 2-(3,4,5-trimethoxyphenyl)ethyl methanesulfonate (7.53 g, 0.026 mole) in 120 ml dimethylformamide was heated at 70° C. for 4.5 hours.
Reaction SMILES: [C:1]([O:12]C)(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-:6])=O.C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[NH2:55][C@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][C@H:57]1[OH:62].C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[OH:62][C@H:57]1[CH2:58][CH2:59][CH2:60][CH2:61][C@H:56]1[N:55]1[C:1](=[O:12])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: COC(=O)c1ccccc1C(=O)[O-]
Reactant: N[C@H]1CCCC[C@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCCC[C@@H]1O
Reaction time: 0.67 h
Yield: 96.5 %

Procedure:
Under a nitrogen atmosphere, a solution of monomethyl phthalate (1.31 g, 7.31 mmol) and N,N-diisopropylamine (1.72 ml, 7.31 mmol) in tetrahydrofuran (10 ml) was added dropwise to a solution of benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (3.77 g, 7.31 mmol) in tetrahydrofuran (10 ml) over a period of 15 minutes at room temperature. After 40 minutes, the solution thus prepared was slowly dropped into a solution of cis-2-aminocyclohexanol hydrochloride (1.0 g, 6.65 mmol) and triethylamine (1.01 ml, 7.31 mmol) in tetrahydrofuran (10 ml). After 3 hours, p-toluenesulfonic acid (35 mg) was added thereto, and the resulting mixture was refluxed. After 5 hours, water was added thereto and the resulting mixture was poured into a saturated aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) and purified again by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain cis-2-(2-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.5746 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].O[CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][C:50]1=[O:54].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:36][C:29]1[CH:30]=[C:31]([O:35][CH2:47][CH2:48][N:49]2[CH2:53][CH2:52][CH2:51][C:50]2=[O:54])[CH:32]=[C:33]([CH3:34])[C:28]=1[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=2)[CH:23]=1
Reactant: O=C1CCCN1CCO
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.2 g, 1.89 mmol), 1-(2-hydroxyethyl)pyrrolidin-2-one (0.23 mL, 2.08 mmol) and tributylphosphine (0.75 mL, 2.84 mmol) in tetrahydrofuran (25 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.74 g, 2.84 mmol) under stirring at room temperature, and the mixture was stirred for 14 hr. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-ethyl acetate) to give the title compound (0.91 g, yield 65%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.0 g, 5.8 mmol, 1.0 eq.) and ethyldiisopropylamine (17 mL, 3.0 eq.) in methylene chloride (4 mL) at 0° C. was added dropwise MsCl (0.46 mL, 1.0 eq.) and the resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched by addition of sat. NaHCO3 and the separated aqueous phase was extracted with 3× methylene chloride and 4×EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to give a crude methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-ylmethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([CH3:27])[O:26][CH2:25][CH2:24][O:23]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=1.[F:28][C:29]([F:36])([F:35])[C:30](OCC)=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3([CH3:27])[O:23][CH2:24][CH2:25][O:26]3)=[CH:20][CH:21]=2)[CH:5]=[C:6]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][N:10]([C:30](=[O:31])[C:29]([F:36])([F:35])[F:28])[CH2:9]2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C4(C)OCCO4)cc3)c2)CCNC1
Reactant: CCOC(=O)C(F)(F)F
Product: COC1(c2cc(F)cc(Sc3ccc(C4(C)OCCO4)cc3)c2)CCN(C(=O)C(F)(F)F)C1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in the third paragraph of the portion of Example 5 which is concerned with the preparation of starting materials, 3-{5-fluoro-3-[4-(2-methyl-1,3-dioxolan-2-yl)phenylthio]phenyl}-3-methoxypyrrolidine was reacted with ethyl trifluoroacetate to give 3-{5-fluoro-3-[4-(2-methyl-1,3-dioxolan-2-yl)phenylthio]phenyl}-3-methoxy-1-(trifluoroacetyl)pyrrolidine as a gum in 58% yield.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:21]([C:24]4([C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)[CH2:26][CH2:25]4)=[CH:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1>>[N:23]1[CH:3]=[C:1]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([C:21]([C:24]5([C:27]6[CH:28]=[C:29]7[C:34](=[CH:35][CH:36]=6)[N:33]=[CH:32][CH:31]=[CH:30]7)[CH2:25][CH2:26]5)=[CH:22][N:23]=4)[N:20]=3)=[CH:11][CH:10]=2)[CH:16]=[N:17][CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Product: c1cnc2ccc(C3(c4cnc5ncc(-c6ccc(-c7cncnc7)cc6)nn45)CC3)cc2c1

Procedure:
This compound was prepared as a TFA salt starting from 6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline using procedures analogous to those for Example 94. LCMS: (M+H)=442.1.
Reaction SMILES: C(O[C:9]([N:11]1[C@H:15]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][C:12]1=[O:27])=O)C1C=CC=CC=1.N1C(=O)CC[C@H]1C(N)=O.[Li+].[B-](CC)(CC)CC>C1COCC1>[CH2:18]([NH:17][C:16]([C@@H:15]1[CH2:14][CH2:13][CH:12]([OH:27])[N:11]1[CH3:9])=[O:26])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(NCCc1ccccc1)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: CC[B-](CC)CC
Agent: NC(=O)[C@@H]1CCC(=O)N1
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(O)CC[C@H]1C(=O)NCCc1ccccc1
Reaction time: 0.25 h

Procedure:
A THF solution of 11A pyroglutamide (3.9 g, 11 mmol) is chilled to −78° C. After 15 minutes, 1 M super-hydride solution (13 mL, 13 mmol) is slowly added. After 1 hour, it is carefully quenched with saturated bicarb and added 4 mL 30% hydrogen peroxide and concentrated to half volume and reconstituted with ethyl acetate, then washed with saturated bicarb and brine and dried over anhydrous sodium sulfate, filtered and concentrated to a clear oil. LCMS characterization ES+369.1 (m+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]#[N:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[OH-:29].[K+]>C(O)(C)(C)C.O>[O:28]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([NH2:26])=[O:29])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC#N)c2c1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC(N)=O)c2c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-propionitrile (150 mg, 0.38 mmol), and powdered potassium hydroxide (172 mg, 3.07 mmol) in tert-butanol (8 mL) was heated with stirring under reflux for 1.5 hours. After being cooled to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (eluting with 5% methanol in dichloromethane) to afford 125 mg of the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=O>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:10]1[C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:14]
Reactant: Nc1ccccc1S
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Nc1ccccc1-c1nc2ccccc2s1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 80.4 %

Procedure:
2-Aminothiophenol (137.7 g) was heated to 110° C., and isatoic anhydride (C8H5NO3, 203.9 g) was added portionwise over a 1 h period while taking care to avoid foaming. Thereafter the temperature was raised to 140° C., and heating was continued for about 2 to 4 h until the starting material 2-aminothiophenol was consumed. The melt was poured into an enamel cuvette and after cooling, the cold material was crushed, then boiled in aqueous NaOH solution (12 g of NaOH solved in 3.5 L of water) for 2 to 3 h. The precipitate was filtered off and the filter cake was washed with cold water until the pale blue fluorescence disappeared in the washings. The precipitate was dried at 80° C. to afford 2-(benzo[d]thiazol-2-yl)phenylamine (200 g). The product was used without further purification in the next stage of preparation.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH2:24][CH3:25])=[N:11][C:12]=2[CH2:22][CH3:23])[N:7]=1>O.Cl>[CH2:22]([C:12]1[N:11]=[C:10]([CH2:24][CH3:25])[CH:9]=[C:8]2[C:13]=1[CH:14]=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6](=[O:2])[NH:7]2)[CH3:23]
Reactant: O=N[O-]
Reactant: CCc1cc2nc(N)c(-c3ccccc3)cc2c(CC)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1cc2[nH]c(=O)c(-c3ccccc3)cc2c(CC)n1
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A solution of sodium nitrite (3.2 g) in water (64 ml) was added dropwise over 45 minutes to a solution of compound B (2.0 g) in 2M hydrochloric acid (150 ml). The mixture was stirred for a further 1 hour and then the suspended white solid was collected by filtration and dried under vacuum to give 5,7-diethyl-3-phenyl-1,6-naphthyridin-2(1H)-one (1.0 g); m.p. >260° C.; NMR (d6 -DMSO): 1.32(t, 3H), 1.33(t, 3H), 3.07(q, 2H), 3.47(q, 2H), 7.41(s, 1H), 7.43-7.55(m, 3H), 7.74-7.85(m, 2H), 8.31(s, 1H); mass spectrum (+ve FAB, methanol/NBA): 279 (M+H)+ ; microanalysis, found: C, 76.9; H, 6.6; N, 9.7%; C18H18N2O.0.25H2O requires: C, 76.4; H, 6.5; N, 9.9 %.
Reaction SMILES: [CH2:1]([N+](CCCC)(CCCC)CCCC)CCC.[C:18]([O:23]CCN(C)C)(=[O:22])[C:19]([CH3:21])=C.[C:29]([O:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:33])[C:30]([CH3:32])=[CH2:31].C(O[Si](C)(C)C)(=O)C(C)=C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO>[C:29]([O:34][CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:33])[C:30]([CH3:32])=[CH2:31].[CH3:1]/[CH:21]=[CH:19]/[C:18]([OH:23])=[O:22]
Reactant: C=C(C)C(=O)OCCN(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C=C(C)C(=O)OCCc1ccccc1
Agent: C=C(C)C(=O)O[Si](C)(C)C
Agent: [F-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C/C=C/C(=O)O
Reaction time: 9 h

Procedure:
To a solution of 4.86 g (5.52 mL, 21.0 mmol) of 1-(2-dimethylamino-ethoxy)-1-trimethyl-siloxy-2-methyl-1-propene, 0.1 mL of tetrabutylammonium biacetate hexahydrate (0.04M in THF) in 30 mL of THF was added a mixture of 6.6 g (7.1 mL, 42 mmol) of 2-dimethylaminoethyl methacrylate (purified by distillation and passage over a column of basic alumina under argon), and 31.6 g (31.6 mL, 168 mmol) of 2-phenylethyl methacrylate (purified by passage over a column of basic alumina under argon) from an addition funnel. The temperature of the reaction mixture rose to 62° C. during the course of the addition, and an ice bath was used to moderate the temperature rise. When, following the conclusion of the addition, the temperature was 26° C., the dropwise addition of 43.2 g (49 mL, 273 mmol) of trimethylsilyl methacrylate was begun. During the course of the addition the temperature of the reaction mixture rose to 45° C. while a total of 1.25 mL of tetrabutylammonium biacetate hexahydrate (0.04M in THF) was added in 9 additions. Analysis of an aliquot of the solution by 1H NMR showed that there was no residual monomer present. After addition of 55 mL of THF, 56 mL of methanol, and 0.086 g (2.7 mmol) of tetrabutylammonium fluoride trihydrate the solution was refluxed for 9 hr. Then 50 mL of THF was added, and refluxing was continued for an additional 9 hr. The solution was evaporated under reduced pressure with a rotary evaporator. The solid residue was dried in a vacuum oven at 80° C. for 8 hr to give 57 g of poly ω-2-β-dimethylaminoethyl isobutyrate(2-dimethylaminoethyl methacrylate [9 mol %]-co-2-phenylethyl methacrylate [35 mol %]-b-methacrylic acid [56 mol %]) 1H NMR analysis of the polymer showed that virtually no trimethylsilyl groups remained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=23)[N:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([NH2:26])[CH3:25])=[N:22][CH:23]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:9]=[N:10][N:11]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=34)[N:3]=2)[CH3:25])=[N:22][CH:23]=1
Reactant: Clc1ccnc(-c2cnn3ccncc23)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ccnc(-c2cnn3ccncc23)n1)c1ccc(F)cn1
Yield: 4.4 %

Procedure:
A solution of 3-(4-chloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 31, 170 mg, 0.61 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (85 mg, 0.61 mmol, prepared as described in WO2006/82392A1) and diisopropylethylamine (122 μL, 0.70 mmol) in N,N′-dimethylformamide (5 mL) was heated to 150° C. in a microwave oven for 75 min. The solvent was then removed under reduced pressure and the residue was partitioned between 4% aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give a crude which was purified by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 5% to 50%) to give the title compound (9 mg, 4%) as an oil. The corresponding fumarate salt was prepared by adding a solution of fumaric acid (3.1 mg, 0.027 mmol) in ethanol (0.5 mL) to a solution of the title compound (as free base, 9 mg, 0.027 mmol) in ethanol (2 mL) followed by evaporation of the solvent. The resulting solid was dried in an oven under vacuum to give 11 mg of the desired fumarate salt.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][N:4]=[C:5]([C:13](=NC1C=CC=CC=1)[CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[O:24]1CCCC1>>[F:1][CH:2]([F:22])[O:3][N:4]=[C:5]([C:13](=[O:24])[CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: C1CCOC1
Reactant: CC(=Nc1ccccc1)C(=NOC(F)F)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)C(=NOC(F)F)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 2-difluoromethoxyimino-3-phenyliminobutyrate (0.76 g) in tetrahydrofuran (3.8 ml) was added 1N hydrochloric acid (3.64 ml) under ice-cooling. After being stirred at 20° C. for 1.5 hours, the mixture was extracted with ethyl acetate. The separated organic layer was washed with water three times, dried over magnesium sulfate and concentrated under reduced pressure to give tert-butyl 2-difluoromethoxyimino-3-oxobutyrate (0.55 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.[OH-].[Na+].[CH3:23]I.[Na+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCOC(C)=O.O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][O:20][CH3:23])([CH3:18])[CH2:13]1
Reactant: CI
Reactant: C[C@]1(CO)CCCN(C[C@H]2COc3ccccc3O2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC[C@@]1(C)CCCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.3 %

Procedure:
A mixture of {(S)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-yl}methanol (134 mg, 0.48 mmol), tetrabutylammonium bromide (0.031 mg, 0.10 mmol) and 50% NaOH solution (2 ml) in toluene (2 ml) was stirred at room temperature for 15 min. Methyl iodide (0.24 ml, 3.86 mmol) was added drop wise and the mixture was stirred for 6 h 45 min. Saturated NaCl, water and EtOAc were added and the phases were separated. The aqueous phase was extracted twice with EtOAc and combined organic phases were washed with water and saturated NaCl. The organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified with flash chromatography using gradient of heptane and EtOAc as eluent to give 27 mg of the title compound.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:71])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:69])[C:57]4[CH:62]=[C:61]([O:63][CH3:64])[C:60]([O:65][CH3:66])=[C:59]([O:67][CH3:68])[CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:70])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:71])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:69])[C:57]4[CH:58]=[C:59]([O:67][CH3:68])[C:60]([O:65][CH3:66])=[C:61]([O:63][CH3:64])[CH:62]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:70])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(OC)c(OC)c(OC)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COc1cc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc(OC)c1OC
Yield: 83 %

Procedure:
The compound of example 144 was prepared analogous to compound of example 98 by hydrolysis of compound of example 143.