Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([Br:26])=[CH:21][CH:20]=4)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[Br:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:15]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]4[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=4)=[CH:28][CH:27]=3)[CH2:14][CH2:13]1)=[O:16])=[CH:25]2
Reactant: NCCc1ccc(NC2CCN(C(=O)c3cc4cc(Br)ccc4[nH]3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 38.8 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(5-bromo-1H-indol-2-yl)methanone (0.160 g, 0.363 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.15 g, 0.37 mmol) according to Procedure G to give the title compound (0.119 g, 0.141 mmol).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl.O>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH2:3][CH2:4]1)=[O:28]
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To a mixture of 4-piperazin-1-ylbenzonitrile hydrochloride (0.200 g, 0.890 mmol) in dichloromethane (15 mL) and triethylamine (0.452 g, 4.47 mmol) was added 2-trifluoromethylbenzoyl chloride (0.186 g, 0.890 mmol) at 0° C. The reaction mixture was warmed up to ambient temperature and stirred for 6 hours, then diluted with water, and extracted with dichloromethane. The organic phase was separated, washed with diluted HCl solution, sodium bicarbonate solution, brine, then dried over anhydrous MgSO4 and concentrated. The residue was purified by column chromatography and crystallization from n-hexane and the title compound was obtained as a white solid in 91% yield (0.294 g). 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=8.9 Hz, 1H), 7.54 (m, 4H), 7.36 (m, 1H), 6.84 (d, J=9.6 Hz, 2H), 3.94 (m, 2H), 3.33 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 167.5, 153.0, 134.3, 133.6, 132.4, 129.5, 127.6, 127.2, 125.4, 121.8, 119.7, 114.9, 101.5, 47.3, 46.4, 41.2. MS (ES+) m/z 360.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:38]
Reactant: CCOC(=O)CCCCCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Product: CCOC(=O)CCCCCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Yield: 98 %

Procedure:
Using the procedure of example 122, rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (example 121), was alkylated with ethyl 7-bromoheptanoate giving the title compound as a pale-yellow oil, in 98% yield.
Reaction SMILES: C([C:4]1[CH:8]=[C:7](Cl)[S:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=CC(CCO)=C[CH:15]=1)(=[O:12])=[O:11])(=O)C.[H-].[Na+].[CH3:25][O:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C>[CH3:25][O:26][CH2:27][CH2:28][CH2:29][N:13]1[CH:14]([CH3:15])[CH2:19][C:4]2[CH:8]=[CH:7][S:6][C:5]=2[S:10]1(=[O:11])=[O:12]
Reactant: CC(=O)c1cc(Cl)sc1S(=O)(=O)Nc1ccc(CCO)cc1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1C(C)Cc2ccsc2S1(=O)=O
Temperature: -20 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
The product from Step B (800 mg, 3.95 mmol) was dissolved in DMF (10 mL) and the solution was cooled to -20° C. Sodium hydride (236 mg of an oil dispersion, 5.91 mmol) was added followed by 3-methoxypropyl bromide (1.8 mL, 11.82 mmol) and this mixture was warmed to 0° C. and stirred for 4 hr. The reaction mixture was poured into ice/water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with water (2×50 mL) and brine (2×50 mL), dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 10% methanol/methylene chloride) to give the desired product (890 mg, 82%).
Reaction SMILES: [C:1]([OH:6])#[C:2][CH2:3][CH2:4][CH3:5].[Si:7](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:20]([Si:7]([O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCCC#CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A mixture of pentynol (8.0 g, 95 mmol), t-butyldiphenylsilylchloride (28 g, 114 mmol) and Et3N (14 g, 138 mmol) in CH2Cl2 is stirred at room temperature for 16 h, treated with 1M K2CO3 and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is purified by filtration on a silica pad to obtain 30 g of t-butylpent-4-ynyloxy diphenyl silane (yield: 98%
Reaction SMILES: C(O)(=O)C.[C:5]([C:7](=[N:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8]([NH2:10])=[NH:9])#[N:6].C(N(CC)CC)C.BrBr.[S-:27][C:28]#[N:29].[K+]>CO>[CH3:17][O:16][C:14]([CH2:13][O:12][N:11]=[C:7]([C:8]1[N:10]=[C:28]([NH2:29])[S:27][N:9]=1)[C:5]#[N:6])=[O:15]
Reactant: N#C[S-]
Reactant: COC(=O)CON=C(C#N)C(=N)N
Agent: BrBr
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CON=C(C#N)c1nsc(N)n1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a suspension of 2-cyano-2-methoxycarbonylmethoxyiminoacetamidine acetate (495 g) in methanol (4.95 l) was dropped triethylamine (512.6 g) at -10° C. under stirring and cooling, and further, bromine (357.3 g) was added to the above mixture at the same temperature. After the reaction mixture was stirred for 15 minutes, a solution of potassium thiocyanate (216 g) in methanol (2.16 l) was dropped thereto at -10° to -5° C. under stirring, which was continued for 30 minutes at 0° to 5° C. The resulting precipitates were collected by filtration, washed with water (5 l) and dried to give 2-methoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetonitrile (syn isomer) (430 g), which was recrystallized from aqueous methanol, mp. 225° to 227° C. (dec.).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])C.Br[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[CH:38][N:39]=3)[CH:36]=2)=[O:28])=[CH:22][CH:21]=1.BrC1C=CC(N)=CC=1>>[N:39]1[CH:38]=[CH:37][N:35]2[CH:36]=[C:31]([CH2:30][NH:29][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([C:8]4[CH:7]=[N:6][N:5]([CH2:1][CH2:2][CH3:4])[CH:9]=4)=[CH:21][CH:22]=3)=[O:28])[CH:32]=[CH:33][C:34]=12
Reactant: O=C(NCc1ccc2nccn2c1)Nc1ccc(Br)cc1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Nc1ccc(Br)cc1
Product: CCCn1cc(-c2ccc(NC(=O)NCc3ccc4nccn4c3)cc2)cn1

Procedure:
The title compound was prepared as described in Example 51A, substituting 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1-(4-bromophenyl)-3-(imidazo[1,2-a]pyridin-6-ylmethyl)urea for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.44 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.76 (s, 1H), 7.57-7.50 (m, 2H), 7.48-7.32 (m, 4H), 7.21 (dd, J=9.2, 1.7 Hz, 1H), 6.65 (t, J=5.9 Hz, 1H), 4.30 (d, J=5.8 Hz, 2H), 4.04 (t, J=6.9 Hz, 2H), 1.87-1.73 (m, 2H), 0.84 (t, J=7.3 Hz, 3H); MS (ESI(+)) m/e 375 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22]([OH:24])=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N>CN(C=O)C.O1CCOCC1>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([C:22]([NH2:30])=[O:24])([CH2:20][CH2:21]3)[CH2:18][CH2:19]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(N)=O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 200 mg of 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (Example 13) (0.515 mmol) in 5 ml of DMF was added 235 mg of HATU (0.618 mmol) and 0.4 ml of N,N-diisopropylethyl amine. Let stir at rt for 30 min. Added 2.1 ml of 0.5 M NH3 in dioxane (1.03 mmol) dropwise over 5 min. Let stir overnight added 0.5 eq. of 0.5M NH3 in dioxane (0.5 ml). Added EtOAc and 1N NaOH until pH=9 and washed with 10% citric acid, sat'd NaHCO3 and brine. Dried over NaSO4 and conc'd in vacuo to afford 80.9 mg (40%) of pure product (MH+=388.34).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl[C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[CH:24][C:23]=1[F:43])=[O:21]>ClCCl>[F:43][C:23]1[CH:24]=[C:25]([CH:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH:26]=[CH:27][C:22]=1[C:20](=[O:21])[NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:12]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)c2ccc(C3CCCN3C(=O)OCc3ccccc3)cc2F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of methyl 3-amino-2-hydroxybenzoate (3.4 g, 20.4 mmol) and pyridine in anhydrous dichloromethane (35 mL) was added dropwise a solution of benzyl 2-(4-(chlorocarbonyl)-3-fluorophenyl)pyrrolidine-1-carboxylate (8.87 g, 24.5 mmol) in anhydrous dichloromethane (90 mL). After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water, 1N HCl, brine, dried over anhydrous sodium sulfate, and concentrated, re-crystallized from ethyl acetate to give benzyl 2-(3-fluoro-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamyl)phenyl)pyrrolidine-1-carboxylate as white solid (8.20 g, yield 68%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.77-1.87 (m, 3H), 2.33-2.37 (m, 1H), 3.55-3.58 (m, 1H), 3.64-3.70 (m, 1H), 3.83 (s, 3H), 4.86-5.07 (m, 3H), 6.65 (s, 1H), 6.92 (s, 1H), 7.19-7.39 (m, 6H), 7.48-7.51 (m, 1H), 7.82-7.84 (m, 1H), 8.25-8.30 (m, 1H), 9.86 (br s, 1H), 10.99 (br s, 1H); LC-MS (ESI) m/z: 493 (M+1)+.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH:3]=[CH:2]1.C(=O)=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[C:26]1([C@H:32]2[CH2:36][O:35][C:34](=[O:37])[NH:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)CO.CN(C)C1C=CN=CC=1.C1COCC1.CC(OC)(C)C>[C:26]1([C@H:32]2[CH2:36][O:35][C:34](=[O:37])[N:33]2[C:4]([CH:1]2[CH:3]=[CH:2]2)=[O:6])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)C1C=C1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: COC(C)(C)C
Solvent: OCCO
Solvent: CCN(CC)CC
Product: O=C1OC[C@H](c2ccccc2)N1C(=O)C1C=C1
Reaction time: 1 h

Procedure:
A flame-dried 1 L round bottomed flask containing an MTBE solution of 6 (2.8 g, 33 mmol), and 800 mL of THF was chilled by a cold bath at −30° C. (dry ice/30% ethanol in ethylene glycol). The mixture was allowed to stir under nitrogen atmosphere. Distilled triethylamine (12.2 g, 17.0 mL, 120 mmol), and pivaloyl chloride (6.0 g, 6.2 mL, 50 mmol) were added sequentially, and stirring at −30° C. was continued for one hour. LiCl (7.0 g, 170 mmol) was added. After five minutes, (S)-4-phenyloxazolidinone (9.8 g, 60 mmol), and 4-dimethylamino pyridine (408 mg, 3.35 mmol) were added. The whole reaction mixture was allowed to stir overnight at room temperature. The solvents were removed under reduced pressure, and the residue was partitioned between 300 mL of CH2Cl2 and 300 mL water. The aqueous layer was extracted twice with 300 mL portions of CH2Cl2, and the combined organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on silica gel. The initial eluent was 1:1:9 CH2Cl2:ethyl acetate:hexane, followed by elution with 1:3:7 CH2Cl2:ethyl acetate:hexane. The yield of 7 was 7.20 g (31.5 mmol, 95%). Compound 7 is a white solid. mp=118-119° C., [α]D+140.0 (c 1.00, THF).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.O[N:12]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 162.6 %

Procedure:
A mixture of 6-aminopyridine-3-carboxylic acid (8.36 g), N-hydroxybenzotriazole (10.2 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.8 g) and 4-dimethylaminopyridine (8.12 g) in N,N-dimethylformamide (300 ml) was stirred at 0° C. for 15 minutes. (2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-ylamine (7.7 g) was added to the mixture. The solution was stirred at 0° C. for 2 hours and then at room temperature overnight. The mixture was evaporated in vacuo and the residue was diluted with water. The resulting precipitate was filtered and washed with water to give N-[(2E,4E)- and (2Z-4E)-4-methyl-2,4-heptadien-1-yl]-6-amino-3-pyridinecarboxamide (13.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[Cl:30]N1C(=O)CCC1=O>CN(C=O)C>[Cl:30][C:29]1[C:9]2[C:10](=[N:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:27][N:28]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3[nH]nc(Cl)c3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a solution of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.5 mmol, obtained in example 1) in DMF (5 mL), N-chlorosuccinimide (0.10 g, 0.8 mmol) was added under argon atmosphere and the mixture was heated to 60° C. for 5 h. It was washed with 1 N NaOH and extracted with CHCl3 and EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 171 mg of title compound (yield: 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.N1([C:15](=[O:25])[C@@H:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:17])CCOCC1.C(NC(C)C)(C)C.[Li]>C1COCC1.C1COCC1.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:15](=[O:25])[C@@H:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[CH3:17]
Reactant: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Reactant: Fc1ccc(F)cc1
Agent: [Li]
Solvent: CCCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(=O)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
1,4-Difluorobenzene (1.8 g; 15.8 mmol) and (2S)-1-Morpholin-4-yl-2-(tetrahydro-pyran-2-yloxy)-propan-1-one (3 g; 10.5 mmol) are dissolved in dry THF (15 ml). The mixture is cooled to 0° C. and then lithium diisopropylamine (7.9 ml of a 2M solution in THF/Heptane; 15.8 mmol) is added dropwise over a period of 20 minutes. The mixture is stirred for another 2 hours at 0° C. The reaction is then quenched with a saturated ammonium chloride solution. The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water and brine and then dried over magnesium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. The crude product is chromatographed over silicagel (eluent: Petrol ether/Ethyl acetate 50:1 to 30:1). 1.31 g of yellow crystalline material (yield 44.8%) is obtained with a HPLC purity of 96.2%. NMR: (CDCl3; 400 MHz): 7.53-7.47 (m; 1H); 7.24-7.16 (m; 1H); 7.15-7.07 (m; 1H); 5.10 (qd; J=7.2 Hz; 2.0 Hz; ½H); 4.85 (q; J=7.2 Hz; ½H); 4.74 (m; ½H); 4.64 (m; ½H); 3.89 (m; ½H); 3.71 (m; ½H); 3.51 (m; ½H); 3.34 (m; ½H); 1.90-1.48 (m; 6H); 1.47 (d; J=7.2 Hz; 1.5H); 1.42 (d; J=7.2 Hz; 1.5H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:24]=1[C:25](N(OC)C)=[O:26]>O1CCCC1>[F:22][C:23]1[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:24]=1[C:25]([C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(Br)n2)CC1
Reactant: CON(C)C(=O)c1cc(C)cnc1F
Solvent: C1CCOC1
Product: Cc1cnc(F)c(C(=O)c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate (898 mg, 2.52 mmol) in tetrahydrofuran (10 ml) at −78° C. was added a 2.5M solution of nbutyllithium in hexanes (1.01 ml, 2.52 mmol) dropwise maintaining the temperature at −78° C. After complete addition, the solution was stirred at −78° C. for a further 20 minutes. A solution of 2-fluoro-N-methoxy-N,5-dimethylnicotinamide (500 mg, 2.52 mmol) in tetrahydrofuran (5 ml) was added dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 hour. The reaction was quenched with a saturated solution of ammonium chloride. The mixture was stirred at room temperature for 20 minutes and extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 40 g column, 0-20% EtOAc/Petrol) to afford the title compound as a sticky green oil (906 mg, 87% yield).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[N:15]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:20][CH2:19][CH:18]([NH:21][C:22](N2C=CN=C2)=[O:23])[CH2:17][CH2:16]1>C(O)(C)C.C(Cl)Cl>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:22](=[O:23])[NH:21][CH:18]2[CH2:19][CH2:20][N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:16][CH2:17]2)[CH2:13][CH2:14]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)NC2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-N-Boc-amino-piperidine (0.396 g, 1.85 mmol) in iso-propanol (5 ml) is added imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (50 ml of a 10 mg/ml solution in DCM, 1.85 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and recrystallisation of the solid from methanol yields the title product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][C:14](=O)[C:13]3([CH3:20])C)=[CH:8][C:6]=2[N:7]=1.[N:27]1[N:28]=CN2CCNCC=12>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[CH:14]=[N:27][N:28]=[C:20]4[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC1(C)C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: c1nnc2n1CCNC2
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCn4cnnc4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3,3-dimethyl-piperazin-2-one using 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in place of 3,3-dimethyl-piperazin-2-one. The title compound was obtained as a white solid (115 mg, 84%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]3[CH2:10][CH2:11][CH:12]([CH3:14])[O:13][C:8]=3[CH:7]=2)[CH2:2]1.[NH2:17][CH:18]([CH3:20])[CH3:19]>>[CH3:14][CH:12]1[CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][C:6]([O:5][CH2:4][CH:3]([OH:1])[CH2:2][NH:17][CH:18]([CH3:20])[CH3:19])=[CH:7][C:8]=2[O:13]1
Reactant: CC(C)N
Reactant: CC1CCc2ccc(OCC3CO3)cc2O1
Product: CC(C)NCC(O)COc1ccc2c(c1)OC(C)CC2

Procedure:
Following the process of example 9 (a) and reacting 1,2-epoxy-3-(2-methyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-propane with 2-aminopropane, 1-(2-methyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-3-(1-methylethylamino)-2-propanol was obtained as a base (m.p. 79°-81° C.).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([C:7]([C@H:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C1CC[C@@H](C(=O)N2CCOCC2)N1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
The reaction vessel is charged with 30 g L-pyroglutamic acid and 4.71 g 1-hydroxybenzotriazole hydrate. The solids are then suspended in 190 ml anhydrous acetonitrile and the mixture is then heated to 45° C. Subsequently, 20.24 ml morpholine is added via a dropping funnel within 20 min, and the dropping funnel is then washed with 5 ml anhydrous acetonitrile. The resulting mixture is then heated to 65° C. and 29.32 g N—-N′-diisopropylcarbodiimide added within 1 h via a dropping funnel. After complete addition, the dropping funnel is washed with 5 ml anhydrous acetonitrile and the reaction mixture is stirred at 65° C. for an additional 30 min. The resulting suspension is then cooled to ambient temperature, filtered and the filter cake washed with 3×30 ml acetonitrile. The filtrate is concentrated under heating and reduced pressure to approx. ½ of its original volume and the residue is then seeded with 16 mg (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one. Concentration under reduced pressure is continued until approx ⅓ of the original volume of the filtrate is reached. While further concentrating the filtrate under reduced pressure and removing approx. 95 ml of distillate, simultaneously 210 ml 2-methyltetrahydrofuran is added. The suspension is then cooled to 0° C. and the solids are isolated by filtration. The filter cake is washed with 3×20 ml cooled 2-methyltetrahydrofuran and dried at 55° C. under vacuum to give 42.54 g of (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one as fine white crystals (98.0% purity by HPLC, ee (HPLC)>99.6% [4-a, R1=H; R4=morpholine]).