Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:35][C:36]1[C:41](B(O)O)=[CH:40][C:39]([CH3:45])=[CH:38][N:37]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.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:32][C:13]1[C:12]2[O:11][C:10]3[C:19](=[CH:20][C:7]([C:41]4[C:36]([F:35])=[N:37][CH:38]=[C:39]([CH3:45])[CH:40]=4)=[CH:8][CH:9]=3)[C@@:18]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:17]=2[CH:16]=[C:15]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:14]=1
Reactant: Cc1cnc(F)c(B(O)O)c1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(N3CCOCC3)cc12
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: Cc1cnc(F)c(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(N4CCOCC4)cc(F)c2O3)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A resealable vial was charged with (S)-2-amino-4′-fluoro-2′-morpholino-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (130 mg, 0.258 mmol; prepared as described in Method BB40), tetrakis(triphenylphosphine)palladium(0) (29.8 mg, 0.026 mmol), 2-fluoro-5-methylpyridin-3-ylboronic acid (64.0 mg, 0.413 mmol), DMF (1.3 mL) and 2 M aqueous sodium carbonate (387 μL, 0.775 mmol). The vial was sealed and the mixture stirred for 2 hr at 85° C. The mixture was cooled and diluted with EtOac (6 mL) and water (2 ml). The organic layer was filtered through celite, concentrated, and purified by reverse phase HPLC (Gilson, 15-90% MeCN in 0.1% aq. TFA). The fractions containing product were concentrated in vacuo, neutralized with saturated sodium bicarbonage and extracted with ethyl acetate. Organic layer was washed with brine, and concentrated. The residue was redissoved in ˜1 mL 1:1 MeCN/water and liophilized to afford (S)-4′-fluoro-7′-(2-fluoro-5-methylpyridin-3-yl)-2′-morpholino-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH2:17])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH:17][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccnc(CN)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccnc(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 4-(t-butyloxycarbonylaminomethyl)-2-aminomethyl-pyridine(600 mg, 2.63 mmol), NMM (341 ml, 3.03 mmol), 4-DMAP (920 mg, 0.16 mmol) and benzyl chloroformate (433 ml, 3.30 mmol) in methylene chloride (15 ml) was stirred at room temperature overnight. The mixture was diluted with methylene chloride (50 ml) and then washed with water and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give an oil. The crude product was purified by MPLC using 70% ethyl acetate in hexane as eluting solvent to give the title compound 844 mg (100%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:29]=CC(C(OC)=O)=C[CH:21]=3)=[C:14]([F:30])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB(C2C=[N:41][C:42]([NH2:45])=[N:43]C=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[NH2:45][C:42]1[N:43]=[CH:21][C:20]([C:19]#[C:18][C:15]2[CH:16]=[CH:17][C:12]([N:8]3[CH2:7][C@H:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]3=[O:11])=[CH:13][C:14]=2[F:30])=[CH:29][N:41]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COC(=O)c1ccc(C#Cc2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)NC[C@H]1CN(c2ccc(C#Cc3cnc(N)nc3)c(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A solution of Example 1F (41 mg) in degassed DME (1.3 mL) was treated with 5-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-pyrimidin-2-ylamine (41.5mg, prepared according to the procedure described in Tetrahedron Letters, 1997, 38, 3447-3450), tetrakis(triphenylphosphine)palladium (12 mg) and a degassed 2 N solution of potassium carbonate in water (0.2 mL). The tube was sealed, heated to 70° C., and stirred for 20 hours. The reaction mixture was then cooled to room temperature, concentrated, and diluted with dichloromethane (4 mL). The precipitate was removed by filtration and washed with water (10 mL) and then cold acetone (3 mL) to provide the desired product. MS (ESI(+)) m/e 370 (M+H)+; 1H NMR (300 MHz, MeOH) δ 8.49 (s, 2H), 7.61 (dd, J=2.1, 12 Hz, 1H), 7.57 (t, J=8.4 Hz, 1H), 7.32 (dd, J=2.1, 8.7 Hz, 1H), 4.8 (m, 1H), 4.16 (t, J=9 Hz, 1H), 3.83 (dd, J=6.3, 9.6 Hz, 1H), 3.56(d, J=5.4 Hz, 2H), 1.96 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=[O:25].Cl>O.CN(C=O)C>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccccc1Oc1cccc(CO)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 130.1 %

Procedure:
3-Hydroxybenzyl alcohol (31.0 g) was ground finely and stirred with potassium carbonate (34.6 g), 2-bromophenylacetic acid (26.9 g) and cuprous chloride (large spatula full) under nitrogen. The mixture was warmed to 140° C., and stirred vigorously for 31/2 hours. DMF (60 ml) was then added to the stirred melt and the solution was allowed to cool, poured into water and acidified with dilute hydrochloric acid. The aqueous layer was extracted with ether, and the ether extracts were washed with water, dried and evaporated to give 2-(3-hydroxymethylphenoxy)phenylacetic acid as a brown oil (42.03 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5].[CH3:14][N:15]=[C:16]=[O:17]>C1C=CC=CC=1>[C:4]([C:3]1[C:6]([O:12][CH3:13])=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[NH:1][C:16]([NH:15][CH3:14])=[O:17])#[N:5]
Reactant: COc1ccc(N)c(C#N)c1OC
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)Nc1ccc(OC)c(OC)c1C#N
Yield: 35.6 %

Procedure:
To 2-amino-5,6-dimethoxybenzonitrile (3.4 g, 19.0 mmol) dissolved in 50 ml of benzene, was added 30 mmol of methylisocyanate in benzene. The resultant mixture was refluxed for 0.75 hours and the tan precipitate which formed was collected by filtration. Recrystallization of the crude product from 2-propanol gave 1.59 g (34%) of the analytical urea, mp 236°-237.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)O)=[CH:4][CH:3]=1.C([Cl:27])(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[Cl:27])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1cccc(F)c1
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(c2ccc(F)cc2)c2cccc(F)c2)cc1
Reaction time: 12 h

Procedure:
Bis(4-fluorophenyl)-3-fluorophenylmethanol (999 mg, 3.18 mmol) was added to a 20% solution of acetyl chloride in dichloromethane (10 mL) at rt. The resulting purple solution was stirred for 12 h after which the solvent was removed by evaporation. Toluene (20 mL) was added to the residue and then evaporated affording crude bis(4-fluorophenyl)-3-fluorophenylchloromethane which was used in the next step without purification.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].N1CCCCC1>C(O)C>[C:17]([C:19]1[C:20](=[O:21])[NH:22][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH2:9]2)#[N:18]
Reactant: CC(=O)C1CC(c2ccncc2)CCC1=O
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccncc1)CC2
Yield: 34.7 %

Procedure:
2-Acetyl-4-(4-pyridyl)cyclohexanone (1.65 g) and cyanoacetamide (0.64 g) were dissolved in ethanol, and a small amount of piperidine was added. The reaction mixture was heated under reflux for 7 hours. After the reaction was completed, deposited crystals were filtered out to obtain 0.7 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].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.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=1[O:34][CH3:33])=[N:3][CH:4]=[C:5]2[F:32])(=[O:14])=[O:13]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)ncc(F)c3c2)c(OC)c1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP; 0.041 g, 0.083 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.027 g, 0.125 mmol), Pd(PPh3)4 (9.59 mg, 8.30 μmol), and potassium carbonate (0.057 g, 0.415 mmol). Dioxane (0.415 mL) and water (0.138 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (12 g, gradient elution 0 to 100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature after which time the reaction was concentrated and triturated with diethyl ether. The solids were filtered, washed with diethyl ether, and vacuum dried to afford 4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.008 g, 0.017 mmol, 19.94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.00 (s, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.51 (d, J=1.4 Hz, 1H), 7.99 (dd, J=1.7, 8.9 Hz, 1H), 7.79 (dd, J=1.8, 9.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.55-7.46 (m, 2H), 7.31 (d, J=4.6 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 484.2 (M+H)+.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20]CC2C=CC=CC=2)[C@H:10]1[O:28]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl>C(Cl)Cl>[OH:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][OH:20])[C@H:10]1[OH:28]
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)C[C@@H]2O1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)C[C@@H]2O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of (3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)hexahydrobenzo[d]oxazol-2(3H)-one (7.35 g, 15.5 mmol) in DCM (80 mL) at −78° C. was added a solution of BCl3 in DCM (1.0 M, 53 mL, 53 mmol). The mixture was slowly warmed up to 0° C. and stirred at this temperature for 4 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (50 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 5%-15% MeOH in DCM to give the product of (3aR,4R,5R,6R,7aS)-4,5-dihydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazol-2(3H)-one (2.99 g, 95%) as a white solid. 1H NMR (400 MHz, MeOD) δ 4.68-4.71 (m, 1H), 3.72 (dd, J=10.8 Hz, 3.4 Hz, 1H), 3.64 (dd, J=10.8 Hz, 5.2 Hz, 1H), 3.46 (t, J=7.2 Hz, 1H), 3.32 (t, J=8.7 Hz, 1H), 3.19 (t, J=9.4 Hz, 1H), 2.17-2.25 (m, 1H), 1.64-1.75 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].C(O[C:15](=N)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(O)(=O)C>C(OCC)C>[CH2:20]([O:19][C:17]([CH2:16][C:15]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1)=[O:18])[CH3:21]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2[nH]1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of 3,4-diaminobenzoic acid (9.4 g, 62 mmol), ethyl 3-ethoxy-3-iminopropionate and glacial acetic acid (15 mL) was stirred 30 minutes at 110° C. under nitrogen. The mixture was poured over crushed ice (50 mL) and stirred 30 minutes to give a dark yellow oil. The mixture was stirred while diethyl ether (25 mL) was added to give a gray precipitate. The precipitate was isolated by filtration, washed several times with diethyl ether and dried under vacuum to provide 2-ethoxycarbonylmethyl-1H-benzoimidazole-5-carboxylic acid (12.6 g, 83% yield); 1H-NMR (300 Mhz, DMSO-d6): 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J=7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J=7.1 Hz).
Reaction SMILES: [N:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:9][OH:10].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15].O>CN(C=O)C>[CH2:15]([O:8][CH2:7][C:6]1[N:1]=[C:2]([CH2:9][OH:10])[CH:3]=[CH:4][CH:5]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: OCc1cccc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCc1cccc(CO)n1
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A solution of 2,6-pyridinedimethanol (5.0 g, 35.9 mmol) in DMF (30 mL) at 0° C. was treated with sodium hydride (1.44 g, 35.9 mmol), stirred for 30 min, treated with allyl bromide (3.42 ml, 39.5 mmol), stirred for 16 h at room temperature, poured into water (150 mL), extracted with EtOAc (3×30 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1 to 1:1)] to give the title compound (1.56 g, 24%) as a colourless oil: NMR δH (400 MHz, CDCl3) 7.69 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz), 6.04-5.93 (1H, m), 5.38-5.21 (2H, m), 4.74 (2H, d, J 5.0 Hz), 4.65 (2H, s), 4.15-4.09 (2H, m) and 3.76 (1H, t, J 5.0 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>>[N:49]1[CH:50]=[CH:51][CH:52]=[C:47]([CH2:46][O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:9][CH:10]=2)[CH:48]=1
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3cccnc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate [Example 55 (b)] with 3-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-4-{4-[2-(pyridin-3-ylmethoxy)-ethoxy]-phenyl}-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[NH2:22][CH2:23][CH:24]([OH:26])[CH3:25]>O1CCOCC1>[OH:26][CH:24]([CH3:25])[CH2:23][NH:22][C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1
Reactant: CC(O)CN
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Solvent: C1COCCO1
Product: CC(O)CNc1nnc(C#N)c(N2CCc3ccccc3CC2)n1

Procedure:
In analogy to the procedure as described in example 4 the 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile was reacted with (RS)-1-amino-2-propanol in dioxane at 120° C. overnight to give (RS)-3-(2-hydroxy-propylamino)-5-(1,2,4,5 -tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a white solid; MS: 325 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([N:33]=[C:34]=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:26]([NH:33][C:34](=[O:35])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCN=C=O
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, n-heptyl isocyanate (505 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8h as solid. Yield: 0.600 g, 75.6%.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[CH2:2][CH2:3][CH3:4].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][CH2:25][O:26][CH2:27][C:28]([NH2:30])=[NH:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:30][C:28](=[NH:29])[CH2:27][O:26][CH2:25][CH2:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[F:16])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(Cl)c(C(=O)O)c1
Reactant: N=C(N)COCCc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cc(F)ccc2F)c1

Procedure:
In analogy to the procedure described in example 78.3, 5-butyl-2-chloro-nicotinic acid (example 126.3) was reacted with 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 78.2) in the presence of TBTU and DIPEA to give 5-butyl-2-chloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=410.1 [M+H+].
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)[CH:32]=[C:31]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:30]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: COCOc1cc(B2OC(C)(C)C(C)(C)O2)cc(N2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCCC2)c1
Temperature: 150 °C

Procedure:
A microwave flask was charged with 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (705 mg, 1.71 mmol, following the general procedures described in these Examples), 1-[3-methoxymethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine (570 mg, 1.71 mmol), and K2CO3 (591 mg, 4.28 mmol). Dioxane (13 ml) and water (3.2 ml) were added, and the solution was vacuum degassed under argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (140 mg, 0.17 mmol) was added, and the reaction mixture was heated (150° C.) in a microwave reactor for 45 minutes. The reaction mixture was filtered through a plug of celite using ethyl acetate. The filtrate was transferred to a reparatory funnel and shaken with water (60 ml). The organic phase was collected and the aqueous phase back extracted with ethyl acetate (2×50 ml). The organic phases were combined, dried (MgSO4), filtered and stripped to provide a viscous semi-solid. This material was purified by preparative TLC, eluting with 24% ethyl acetate in hexanes to afford 492 mg of 1-[2-(3-Methoxymethoxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a red-brown viscous oil.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[O:21][N:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl.CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:6]([C:5]4[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=4)=[O:7])[CH2:25]3)[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(-c2noc(C3CCCNC3)n2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1)N1CCCC(c2nc(-c3ccc(F)cc3)no2)C1
Yield: 30 %

Procedure:
The compound was prepared following the procedure described in the Example 3 (D), using 4-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (already prepared before in the Example 4 (B)). Yield: 30% (white powder); mp=82-83° C.; Rf=0.25 (DCM/MeOH:98/2);