Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:25]3[C:20](=[C:21]([F:26])[CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]=[CH:18][CH:17]=[C:16]2[O:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([CH2:8][NH2:7])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1

Procedure:
tert-Butyl-N-({trans-4-[(8-fluoroquinolin-4-yl)oxy]cyclohexyl}methyl)carbamate (950 mg, 2.54 mmol) was dissolved in dichloromethane (7.0 mL) and trifluoroacetic acid (2.0 mL, 25.4 mmol) was added at room temperature. After one hour at room temperature the reaction mixture was concentrated by evaporation and was then coevaporated with toluene. The residue was taken up in ammoniacal methanol solution (7 N) and concentrated by evaporation again to dryness. After chromatography, the desired product was obtained at 68% yield (470 mg).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:9][CH:8]=[C:7]([C:10](=[O:13])[CH2:11][CH3:12])[CH:6]=1)=[O:4].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20][NH2:21]>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20][NH:21][C:3]([C:5]1[NH:9][CH:8]=[C:7]([C:10](=[O:13])[CH2:11][CH3:12])[CH:6]=1)=[O:4]
Reactant: CCC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: NCc1ccc(F)c(F)c1
Solvent: CN(C)C=O
Product: CCC(=O)c1c[nH]c(C(=O)NCc2ccc(F)c(F)c2)c1
Reaction time: 24 h

Procedure:
To a solution of compound 3 (1 equivalent) in DMF, at ambient temperature, was added 3,4-difluorobenzyl amine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 6 was used without purification.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>N1C=CC=CC=1>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1ccc2[nH]nc(O)c2c1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Methyl 3-hydroxy-1H-indazole-5-carboxylate (1.60 g, 8.33 mmol) was suspended in pyridine (10 mL). Ethyl chloroformate (0.90 mL, 9.3 mmol) was added slowly and the reaction was stirred at room temperature for 1 hour. Additional ethyl chloroformate (0.30 mL, 3.1 mmol) was added and the reaction was stirred for another 30 minutes. The reaction was poured into water (65 mL) and cooled in a refrigerator for 3 hours. The brown solid was collected by filtration, rinsed with water, and dried under vacuum to give the title compound (1.75 g, 80%). +ESI (M+H) 265.1; 1H NMR (400 MHz, CDCl3, δ): 8.56 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.13 (br. s., 1H), 4.59 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 1.56 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:48][CH2:49]2)[CH:36]=1)[O:23][C:21](=[O:22])[CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(CCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(CCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
(S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-phenyl)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)-3,5-dichloropyridine 1-oxide (40 mg, 0.05 mmol) was dissolved in DCM (1.5 ml), then HCl 4M in Dioxane (1 ml, 4 mmol) was added, and the mixture was stirred at RT for 5 hours. The reaction was diluted with DCM and washed with water. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to yield 20 mg of final product (Yield: 62%).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC2CCCCO2)cc1

Procedure:
A mixture of 7 g. (19.4 m moles) 4-(hexadecylamino)benzoic acid, 2 g. (23.8 m moles) dihydropyran and 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and condensed. The residue is crystallized from methylcyclohexane to white crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C=O.[CH3:18]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(I)cc2)CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CN1CCC(C#N)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of the crude 4-(4-iodo-phenyl)-piperidine-4-carbonitrile (˜4.7 mmol) in ClCH2CH2Cl (100 mL) was added formaldehyde (1.92 mL of a 37% solution in H2O, 23.65 mmol, 5 eq.) and HOAc (1 mL, 1% v/v). The mixture was stirred for 0.5 h at room temperature and then NaBH(OAc)3 (1.48 g, 7 mmol, 1.5 eq.) was added. The reaction mixture was stirred for 16 h and then quenched by the addition of saturated aqueous NaHCO3 solution (50 mL). The resulting mixture was extracted with EtOAc (200 mL) and the organic layer was washed with saturated aqueous NaHCO3 solution (50 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carbonitrile (1.5 g, 97%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.84 (dd, 2H), 7.36 (dd, 2H), 3.08 (dt, 2H), 2.60 (m, 2H), 2.50 (s, 3H), 2.20 (m, 4H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1)#[N:2].[H][H].[ClH:21]>[Pd].C(O)(C)C>[ClH:21].[NH2:2][CH2:1][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: C=C(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(C(=O)OC(C)(C)C)c1ccc(CCN)cc1
Reaction time: 8 h

Procedure:
t-Butyl p-(cyanomethyl)-phenylacrylate (6.0 g) is combined with 600 mg 10% palladium on carbon in 80 ml isopropanol and 24 ml 1N HCl and treated with hydrogen at room temperature. After 8 hours at 3 atmospheres pressure, the catalyst is filtered off and the filtrate concentrated under vacuum. The residue is triturated with ether, filtered and dried under vacuum to afford t-butyl p-(2-aminoethyl)-phenylpropionate hydrochloride as a white solid. The hydrochloride salt is partitioned between ethyl acetate and 1N NaOH. The ethyl acetate extract is washed with a saturated NaCl solution and dried over MgSO4. Filtration and concentration of the filtrate affords t-butyl p-(2-aminoethyl)-phenylpropionate as a yellow oil; NMR (CDCl3): 7.1 (4H,s), 2.98 (2H,t), 2.89 (2H,t) 2.73 (2H,t), 2.5 (2H,t), 2.02 (2H,s), 1.42 (9H,s).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13]Cl)[S:10][CH:9]=1)=[O:7]>CN(C=O)C.[Na+].[Cl-]>[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][C:1]#[N:2])[S:10][CH:9]=1)=[O:7]
Reactant: COC(=O)c1csc(CCl)c1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1csc(CC#N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 105.1 %

Procedure:
A solution of potassium cyanide (3.2 g, 48.5 mmol) in DMF (25 mL) is treated with 5-chloromethyl-thiophene-3-carboxylic acid methyl ester (4.4 g, 23.1 mmol) in DMF (30 mL). After stirring for 14 h at room temperature the mixture is warmed to 50° C. for 0.5 h. After cooling, the solution is diluted with saturated aq NaCl and extracted with CHCl3 (3×). The combined organic layers are dried over MgSO4, filtered and concentrated in vacuo to give 5-cyanomethyl-thiophene-3-carboxylic acid methyl ester (4.4 g, 100%). 1H NMR (CDCl3, 300 MHz) δ 8.00 (s, 1 H), 7.44 (s, 1 H), 3.90 (s, 2 H), 3.84 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([F:10])[C:3]=1[Cl:11].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([F:10])[N:5]=[C:6]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]=1[F:8]
Reactant: CC(C)(C)N
Reactant: Fc1nc(F)c(Cl)c(Br)c1F
Solvent: CC#N
Product: CC(C)(C)Nc1nc(F)c(Cl)c(Br)c1F
Yield: 103.2 %

Procedure:
To 40 ml of acetonitrile was dissolved 10.2 g of 4-bromo-3-chloro-2,5,6-trifluoropyridine and 10.5 g of t-butylamine, and the mixture was heated under reflux for 1 hour and the solvent and the like were distilled off under reduced pressure. To the residue was added 80 ml of chloroform and the mixture was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 12.8 g of the title compound as reddish orange oil.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=1.[CH3:14][O:15][Si:16](OC)([O:19][CH3:20])[O:17][CH3:18]>O1CCCC1>[CH3:10][N:9]([C:8]1[CH:12]=[CH:13][C:5]([Si:16]([O:19][CH3:20])([O:17][CH3:18])[O:15][CH3:14])=[CH:6][CH:7]=1)[CH3:11]
Reactant: CN(C)c1ccc(Br)cc1
Reactant: CO[Si](OC)(OC)OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CO[Si](OC)(OC)c1ccc(N(C)C)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
In a 200 ml two-necked flask equipped with a dropping funnel were put 1.01 g (41.5 mmol) of magnesium, 50 ml of tetrahydrofuran (THF), and a small amount of iodine in a nitrogen stream, and a solution of 8.32 g (41.6 mmol) of p-bromo-N,N-dimethylaniline in 50 ml of THF was added thereto dropwise at room temperature over a 40-minute period while stirring. After the addition, the mixture was stirred at room temperature for 75 minutes, and a solution of 6.40 g (42.0 mmol) of tetramethoxysilane in 60 ml of THF was further added thereto, followed by stirring at room temperature overnight. The solvent was removed under reduced pressure, and the residue was suspended in 100 ml of toluene and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound in a yield of 75%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25](C=O)[CH2:24][CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:38])=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:25][CH2:24][CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:38])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 70.4 %

Procedure:
To a solution of (−)-8-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (2.92 g) in methanol (75 ml) was added 3N hydrochloric acid (29.1 ml), after which the mixture was stirred at 80° C. for 7 hours. After diluting with water at 0° C., the product was neutralized with potassium carbonate. After extracting with ethyl acetate, the reaction product was washed with aqueous saturated solution of sodium bicarbonate and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified with a basic silica gel column chromatography (methanol:ethyl acetate=1:67) to give (−)-8-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (1.97 g) (Compound 30) as a yellow amorphous material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=1>C(#N)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:20]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)CCCc1ccc(CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)CCCc1ccc(CN2CCN(c3ccncc3)CC2)cc1
Temperature: 30 °C

Procedure:
1-(4-Pyridyl)piperazine (1.63 g) was dissolved in warm acetontrile (25 ml), the solution cooled to 30° C. and with stirring, a solution of methyl 4-(4-bromomethylphenyl)butyrate in acetonitrile (5 ml) added. After 30 minutes the resulting precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow oil. Purification by flash chromatography on silica, eluting with 0 to 4% v/v methanol/dichloromethane gave a solid. Trituration with ether and removal of the insoluble solid gave a clear solution. Concentration of this solution gave the title compound, 0.90 g, as a white fluffy solid: m.p. 126°-127° C.; NMR (d6DMSO) δ8.14(2H,d), 7.24(2H,d), 7.14(2H,d), 6.77(2H,d), 3.59(3H,s), 3.48(2H,s), 3.30(4H,t), 2.59(2H,t), 2.47(4H,t), 2.32(2H,t), 1.63(2H,m); m/e 354 (M+H)+ ; calculated for C21H27N3O2 0.25H2O: C, 70.4; H, 7.7; N, 11.7. found: C, 70.6; H, 7.6; N, 11.7%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=O)[CH2:11][C:12](O)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13](OCC)=[O:14])[CH:7]=[CH:6][N:5]=1)[CH3:2].Cl.[NH2:26][NH2:27]>C(O)C>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13](=[O:14])[NH:26][N:27]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1nccc(C(=O)CC(O)(C(=O)OCC)C(=O)OCC)n1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCNc1nccc(-c2cc(C(=O)OCC)c(=O)[nH]n2)n1
Temperature: 130 °C

Procedure:
A mixture of 2 g of diethyl 2-[2-(2-ethylaminopyrimidin-4-yl)-2-oxo-ethyl]-2-hydroxy-malonate, 485 mg of hydrazine hydrochloride and 20 ml of ethanol is stirred under reflux for 24 hours. After cooling while stirring, the precipitate is filtered off with suction, heated in 4 ml of N-methylpyrrolidinone (NMP) at 130° C. for 3 hours and, after cooling, mixed with 15 ml of n-heptane and stirred. The precipitate is then filtered off with suction and stirred with methylene chloride, again filtered off with suction and dried.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[C:19]([CH3:25])=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:26][CH3:27])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:28].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[C:19]([CH3:25])[C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([F:28])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:26][CH3:27])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncnc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1C
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 4.0 g (10.2 mmol) 4-[5-(6-amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 1.29 g (30.7 mmoL) LiOH in 40 mL water and 200 mL THF. The reaction mixture is stirred over night at 50° C. The THF is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and MeOH. After drying 1.25 g (32%) of the desired product is obtained a solid material.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:9][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(Br)c(C)cc1O
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: COc1cc(Br)c(C)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2-methoxy-5-methylphenol (500 mg, 0.002 mol), phenylboronic acid (0.70 g, 0.0058 mol), TEA (1.9 mL, 0.014 mol), cupric acetate (0.67 g, 0.0037 mol) and DCM (30 mL) were added to a 100 mL oven dried flask and the reaction mixture was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=2.27 (s, 3H), 3.79 (s, 3H), 6.84 (s, 1H), 6.88-6.96 (m, 2H), 7.00-7.08 (m, 1H), 7.15 (s, 1H), 7.23-7.33 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:9][N:8]([C:10](OCC)=O)[CH2:7][CH2:6][C:5]2[S:15][CH:16]=[CH:17][C:4]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][CH:3]1[CH2:9][N:8]([CH3:10])[CH2:7][CH2:6][C:5]2[S:15][CH:16]=[CH:17][C:4]1=2
Reactant: CCOC(=O)N1CCc2sccc2C(OC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COC1CN(C)CCc2sccc21

Procedure:
Prepared analogously to Example 60a from ethyl 4-methoxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-carboxylate (US 2006/0003990) by reduction with lithium aluminum hydride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[C:13](Cl)=[N:14][CH:15]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]([Br:9])=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 117.8 %

Procedure:
Hydroxy-acetic acid methyl ester (46 mg, 0.50 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (40 mg, 1.0 mmol) was added thereto at room temperature. After stirring for 30 minutes, 5-bromo-2-chloro-3-nitro-pyridine (100 mg, 0.42 mmol) dissolved in 1 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow solid (144 mg, 99%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3Br)[C:12](=[O:22])[NH:11][C:10](=[O:23])[CH:9]=2)[CH2:3]1.[I:24]C1C=CC=CC=1CCl>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[I:24])[C:12](=[O:22])[NH:11][C:10](=[O:23])[CH:9]=2)[CH2:3]1
Reactant: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2Br)C1
Reactant: ClCc1ccccc1I
Product: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2I)C1

Procedure:
The title compound was prepared by the procedure described in the preparation of compound 8, except that 2-iodobenzyl chloride was used as the benzylating reagent. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.76 (d, J=7.6 Hz, 1 H), 7.21 (t, J=7.3 Hz, 1 H), 6.89 (t, J=7.2 Hz, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 5.26 (s, 1 H), 4.79-4.92 (ABq, J=34.1, 6.7.0 Hz, 2H), 3.27 (m, 1 H), 3.13 (s, 1 H), 2.85 (d, J=11.6 Hz, 1 H), 2.70 (m, 1 H), 2.41 (m, 1 H), 2.02 (m, 1 H), 1.60 (m, 1 H), 1.45 (m, 2 H). MS (ES) [m+H] calc'd for C16H20IN4O2, 427.1; found, 427.1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-])=O)[CH3:2].Cl>C(O)C>[CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[NH2:12])[CH3:2]
Reactant: CCNCc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCNCc1cc(Br)ccc1N
Reaction time: 1 h

Procedure:
Stannous chloride dihydrate (22.5 g, 0.1 M) was added in one portion to a stirred mixture of N-ethyl-5-bromo-2-nitrobenzylamine (8.5 g, 32.8 mmol) and 36% hydrochloric acid (20 ml, 0.22M) in ethanol (250 ml) at ambient temperature. There was an exothermic reaction (50° C.) and a yellow solution formed, which was stirred for 1 hour allowing it to cool. The solvent was evaporated at reduced pressure and the residue dissolved in ethanol (100 ml) and stirred while diluting with ether (200 ml) until crystallisation occurred. The yellow solid was filtered off and washed with ether to give N-ethyl-5-bromo-2-aminobenzylamine as a salt, from which the free base was isolated by stirring with 2N sodium hydroxide solution (150 ml) and extracting into ether. The organic layer was dried over anhydrous magnesium sulphate and evaporated to give an oil (4.2 g).