Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=O.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1.[F:19][C:20]([F:25])([F:24])[CH2:21][CH2:22][NH2:23]>>[F:19][C:20]([F:25])([F:24])[CH2:21][CH2:22][NH:23][C:6]([C:5]1[CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[O:12][CH3:13])[N:18]([CH2:17][CH:14]2[CH2:16][CH2:15]2)[C:3]=1[CH3:2])=[O:12]
Reactant: NCCC(F)(F)F
Reactant: NCC1CC1
Reactant: COc1ccc(F)cc1C(=O)CBr
Product: COc1ccc(F)cc1-c1cc(C(=O)NCCC(F)(F)F)c(C)n1CC1CC1

Procedure:
The title compound was synthesized in analogy to Example 68, using 5-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-1-(5-fluoro-2-methoxy-phenyl)-ethanone as compound of formula S, cyclopropanemethylamine as R3—(CH2)m—NH2 and 3,3,3-trifluoro-N-propylamine as R1R2NH, MS (ISP) 399.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[S-:12][C:13]#[N:14].[NH4+:15]>CC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:14][C:13]([NH:15][CH2:10][CH2:11][CH2:3][CH2:4][CH2:5][CH3:6])=[S:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N#C[S-]
Reactant: [NH4+]
Solvent: CC(C)=O
Product: CCCCCCNC(=S)NC(=O)c1ccc(C#N)cc1
Reaction time: 16 h
Yield: 146.5 %

Procedure:
4-Cyanobenzoyl chloride (12.5 g) was added to a solution of ammonium thiocyanate (5.8 g) in acetone (125 ml) at room temperature, followed by heating under reflux for 15 minutes. The reaction mixture was ice-cooled, and after removal of the insoluble substance by filtration, the filtrate was evaporated under reduced pressure. To the resulting residue were added toluene (125 ml) and n-hexylamine (11 ml) successively, followed by stirring for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (ethyl acetate:methylene chloride=4:96) to give 1-(4-cyanobenzoyl)-3-n-hexylthiourea (16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[C@H:10]3[C:4]=2[CH:3]=1.[OH-].[K+].C(OCC)(=[O:26])C>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]([CH2:13][NH:12][CH3:14])[C@H:10]([C:11]([OH:15])=[O:26])[C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@@H]2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C(=O)O
Yield: 52 %

Procedure:
To a solution of cis-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (V) (2 gram, 6.7 mmol) in ethanol (20 mL), was added potassium hydroxide (3.8 g, 67 mmol). The reaction mixture was heated to reflux for 5 hours. The reaction mixture was evaporated and water was added (50 mL). The water phase was washed with diethyl ether (2×25 mL). The aqueous phase was acidified with concentrated hydrochloric acid to a pH between 5 and 6, resulting in a gum precipitate. Ethyl acetate was added (25 mL), which slowly dissolved the gum and resulted in the formation of fine crystals of the product. The crystals were filtered and dried to give trans-8-chloro-10,11-dihydro-11-[(methylamino)methyl]-dibenz[b,f]oxepin-10-carboxylic acid (I) (1.1 g, 52%); mp 154.4° C.; 1H-NMR (399.87 MHz in MeOD relative to TMS) δ 2.09 (s, 3H), 2.45 and 2.66 (2×m, 2H), 3.23 (s, 1H), 3.50 (m, 1H), 3.92 (d, 1H), 6.96-7.20 (m, 6H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[C:22]3[C:23]4=[C:24]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)OC(=O)[C:4]=1[C:26]([O:28][CH3:29])=[O:27].[C:30]1([N:36]2[CH:44]=[C:43]3[C:38]([CH2:39][CH2:40][CH2:41][C:42]3=O)=[N:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[C:22]3[C:23]4=[C:24]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[C:41]2[CH2:40][CH2:39][C:38]3[C:43](=[CH:44][N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:37]=3)[C:42]=2[C:4]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2ccc3ccc4cccc5ccc2c3c45)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc3ccc4cccc5ccc2c3c45)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-(pyren-1-yl)-2H-pyran-3-carboxylate (400 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 8 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 58% of methyl 8-(methylthio)-2-phenyl-6-(pyren-1-yl)-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate. Yellow solid; mp-174-176° C.; 1H NMR (300 MHz, CDCl3) δ 2.49 (s, 3H, CH3), 2.60-2.67 (m, 2H, CH2), 2.71-2.77 (m, 2H, CH2), 4.08 (s, 3H, OCH3), 7.27-7.36 (m, 2H, ArH), 7.47 (t, J1=8.28 Hz, J2=7.50 Hz, 2H, ArH), 7.65-7.72 (m, 2H, ArH), 7.73-7.81 (m, 1H, ArH), 7.90 (d, J=7.77 Hz, 1H, ArH), 7.99-8.09 (m, 3H, ArH), 8.14 (s, 2H, ArH), 8.18-8.29 (m, 3H, ArH); MS (ESI) m/z551 (M++1).
Reaction SMILES: [C:1]([CH2:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[S:11][CH:12]=1)=[O:7])(=[O:3])[NH2:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:14][CH:15]([O:17][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:16]2)[S:11][CH:12]=1)=[O:7])(=[O:3])[NH2:2].[C:1]([CH2:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:16][CH:15]([O:17][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:14]2)[S:11][CH:12]=1)=[O:7])#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N(CC(N)=O)C(=O)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CC#N)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Product: CC(C)N(CC(N)=O)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Yield: 17 %
Yield: 22 %

Procedure:
To a solution of 1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]-3-hydroxyazetidine (2.35 g, 7.88 mmol) (obtained as described in Reference Example 49(4)) in methylene chloride (120 ml) were added methanesulfonyl chloride (0.91 ml, 11.8 mmol) and triethylamine (1.66 ml, 11.8 mmol) in an ice bath. The reaction mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (516 mg, yield 17%) as a pale yellow solid and 1-[4-(cyanomethyl-isopropyl-carbamoyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (634 mg, yield 22%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([PH:24](=[O:28])[O:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23]>C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:11]([P:24]([CH2:20][CH2:21][CH2:22][CH3:23])(=[O:28])[O:25][CH2:26][CH3:27])[OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[PH](=O)OCC
Reactant: CC(C)(C)OC(=O)NCC(C=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CCCCP(=O)(OCC)C(O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A material of 283 mg of 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-propionaldehyde, 150 mg of ethyl n-butyl-phosphinate and 101 mg of triethylamine is heated to 100° C. for 21/2 hours. The mixture is cooled to room temperature and the volatile components are removed in high vacuum. Chromatography of the residue on silica-gel affords ethyl 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl-(n-butyl)phosphinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Cl[CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)=[O:8]
Reactant: ClCc1ccco1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of Example 340A (0.15 g, 0.53 mmol) in 5 mL DMF was added sodium hydride (0.016 g, 0.67 mmol, 95%). After the solution was allowed to stir at ambient temperature for 30 min, 2-(chloromethyl)furan (0.08 g, 0.67 mmol) was added. The reaction was held at ambient temperature overnight and then quenched with water. The crude was extracted with ethyl acetate and the organics washed with water, then dried over MgSO4, filtered, and concentrated. Flash chromatography over silica gel (50% ethyl acetate/hexane) gave 0.075 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.26 (d, J=1.36 Hz, 3H) 3.80 (s, 3H) 5.18 (s, 2H) 6.54 (s, 1H) 7.12 (d, J=8.81 Hz, 1H) 7.29 (d, J=1.36 Hz, 1H) 7.46 (dd, J=8.81, 2.71 Hz, 1H) 7.64 (t, J=1.70 Hz, 1H) 7.67-7.76 (m, 2H). m/z 363.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccoc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccoc1
Yield: 85 %

Procedure:
6.30 g of ethyl 2-[2-(4-fluorophenyl)-5-(3-furyl)-4-oxazolyl]acetate, 70 ml of methanol, 7 ml of water and 1.5 g of sodium hydroxide are treated in the same manner as described in Example 16. 4.88 g of 2-[2-(4-fluorophenyl)-5-(3-furyl)-4-oxazolyl]acetic acid are obtained. Yield: 85%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][C:14]1[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:17]3[N:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1cnc(-c2ccc3[nH]ccc3c2)cn1
Temperature: 90 °C
Yield: 41.2 %

Procedure:
Nitrogen was bubbled through a solution of 5-indolylboronic acid (340 mg, 2.11 mmol), 2-amino-5-bromopyrazine (245 mg, 1.41 mmol), sodium carbonate (493 mg, 4.65 mmol), dimethoxyethane (12 mL), and water (4 mL) for 15 min. After this time, the solution was treated with dichlorobis(triphenylphosphine)palladium(II) (98 mg, 0.14 mmol), and the resulting reaction mixture was heated at 90° C. for 2 d. The reaction was then poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 35/65 hexanes/ethyl acetate) afforded 5-(1H-indol-5-yl)-pyrazin-2-ylamine (122 mg, 41%) as a brown solid: EI-HRMS m/e calcd for C2H10N4 (M+) 210.0905, found 210.0901.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3[NH:15][CH:16]=[CH:17][C:7]=3[C:6]=2[CH:5]=1)=O.[CH2:18]([C:20]([O-:22])=[O:21])[CH3:19].[ClH:23]>O1CCCC1.C(OCC)C>[CH3:1][NH:3][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3[NH:15][CH:16]=[CH:17][C:7]=3[C:6]=2[CH:5]=1.[ClH:23].[CH2:18]([C:20]([OH:22])=[O:21])[CH3:19]
Reactant: CCC(=O)[O-]
Reactant: O=CNc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)O
Product: CNc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
0.41 mL (0.41 mmol) of a 1M solution of a borane-tetrahydrofuran complex in tetrahydrofuran is added to a solution of 45 mg (0.15 mmol) of 8-formylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 0.5 mL of anhydrous tetrahydrofuran. The reaction mixture is stirred overnight at room temperature then for 8 hours under reflux before further addition of 0.3 mL of a 1M solution of a borane-tetrahydrofuran complex in tetrahydrofuran. The reaction mixture is then stirred for 3 hours under reflux. The solvent is evaporated under reduced pressure, and the residue is taken up in 1 mL of anhydrous ethanol and 0.76 mL (1.52 mmol) of 2M hydrochloric acid in diethyl ether. The solution is stirred at 70° C. for 3 hours. The precipitate is filtered, washed with ethanol then with diethyl ether to give 24 mg (50%) of 8-methylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride in the form of a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[C:13]([C:35]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH:36]=2)[CH:12]=1)([CH3:10])[CH3:9])(C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[CH3:41][C:38]1([CH3:42])[CH2:39][CH2:40][C:35]([C:13]2[CH:12]=[C:11]([C:8]([CH3:9])([CH3:10])[CH2:7][OH:6])[CH:16]=[CH:15][C:14]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[CH:36][CH2:37]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2cc(C(C)(C)CO)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 2.20 g, 3.45 mmol) and tetrabutylammonium fluoride hydrate (4.52 g, 17.3 mmol) in 25 mL of THF was stirred at 50° C. for 3 h. After cooling to RT, the mixture was treated with 100 mL of EtOAc and washed with saturated aqueous NH4Cl (20 mL), H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-4% MeOH/DCM) to afford the title compound (1.25 g, 92%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C23H28N4O2, 393.2 (M+H). found 393.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.ClCC(OC(=O)CCl)=O.[CH2:19]([N:21](CC)CC)[CH3:20].O>C1C=CC=CC=1>[NH2:21][CH2:19][CH2:20][NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ccc(N)cn1
Reactant: CCN(CC)CC
Agent: O=C(CCl)OC(=O)CCl
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(NCCN)cn1
Reaction time: 3 h

Procedure:
5-amino-2-methoxypyridine(3.18 g), chloroacetic anhydride(6.56 g), and triethylamine(7.09 ml) were stirred in benzene(55 ml) for 1 hour while being cooled with ice. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. To the solution of the residue in dimethylformamide(20 ml) was added potassium phthalimide(5.21 g) and then the mixture was refluxed with stirring for 3 hours. After a large amount of water was added thereto, the depositing crystal was collected by filtration. The solution of the crystal in ethanol(120 ml), with hydrazine monohydrate(2.56 ml) was refluxed with stirring for 2 hours and then concentrated under a vacuum. The residue, with water added thereto, was acidified with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. The solution of the residue in tetrahydrofuran(40 ml) was dropped into the suspension of lithium aluminium hydride(2.63 g) in tetrahydrofuran(40 ml) while being cooled with ice and the mixture was stirred at room temperature for 2 hours. A small amount of water was added thereto and the resulting deposit was filtrated out. The filtrate was concentrated under a vacuum, thereby yielding 2.12 g of the aimed compound.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C:16]1[C:17]([CH3:40])=[CH:18][C:19]([F:39])=[C:20]([CH:38]=1)[NH:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34]CCO)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:5]([O:4][CH2:1][CH2:2][O:34][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:21][C:20]3[CH:38]=[C:16]([O:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:17]([CH3:40])=[CH:18][C:19]=3[F:39])=[N:23][CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33])(=[O:7])[CH3:6]
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCOC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Acetic anhydride (55 ml, 0.58 mmol) was added to a mixture of 4-(5-benzyloxy-2-fluoro-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (233 mg, 0.52 mmol), triethylamine (80 ml, 0.57 mmol) and 4-(N,N-dimethylamino)pyridine (5 mg) in ethyl acetate (50 ml). The mixture was stirred for 2 hours at ambient temperature, water was added, the organic layer separated, washed with water and brine and dried (MgSO4). Most of the solvent was removed by evaporation and hexane added. The precipitated product was collected by filtration to give 7-(2-acetoxyethoxy)-4-(5-benzyloxy-2-fluoro-4-methylanilino)-6-methoxyquinazoline (110 mg, 43%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]([C:15]([O:17]CC)=O)=[C:6]([CH:20]=[CH2:21])[N:5]=1)[CH2:2][CH3:3].[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.C(N(C(C)C)C(C)C)C.O>CC(N(C)C)=O>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([N:22]2[CH2:21][CH2:20][C:6]3[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=3[C:15]2=[O:17])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=Cc1nc(CCC)c(C(=O)OCC)cc1C(=O)OCC
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 135 °C
Reaction time: 4.5 h
Yield: 72.7 %

Procedure:
A mixture of diethyl 2-propyl-6-vinylpyridine-3,5-dicarboxylate (9.00 g), tert-butyl 4-aminopiperidine-1-carboxylate (7.42 g) and N-ethyl-N-isopropylpropan-2-amine (8.09 mL) in DMA (45 mL) was stirred at 130 to 140° C. for 4.5 hours. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with brine twice, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through a silica gel-pad (hexane/ethyl acetate), and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10.0 g).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.O>CN(C)C=O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: OCCCO
Reactant: Clc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOc1nc2ccccc2o1

Procedure:
To a stirred solution of 1,3-propanediol (65 g) in dimethylformamide (60 ml) was added sodium hydride (3.0 g, 60% dispersion in oil) portionwise. The mixture was stirred until effervescence had ceased. A solution of 2-chlorobenzoxazole (11.4 g) in dimethylformamide (30 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight. The mixture was added to water (600 ml) and extracted with ethyl acetate (3×300 ml). The combined organic extracts were washed with water (2×300 ml), brine (2×300 ml), dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as an oil following chromatography on silica gel in 3% methanol in dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[OH:12][NH2:13].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][OH:12])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115.4 %

Procedure:
4-Methoxybenzaldehyde (10.0 g, 73.4 mmol) was dissolved in 200 mL of ethanol. A solution of hydroxyamine hydrochloride (6.38 g, 91.8 mmol) in 50 mL of H2O was added followed by a solution of sodium acetate (12.1 g, 146.8 mmol) in 50 mL of H2O. The mixture was stirred at room temperature under N2 for 12 h. The ethanol was removed in vacuo and the aqueous mixture was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, and concentrated to afford 12.8 g of light yellow oil. 1H NMR showed it was 80% pure (92% yield). This material was taken into the next step without further purification. (CDCl3): δ2.15 (s, 1H); 3.83 (s, 3H); 6.92 (d, 2H); 7.50 (d, 2H); 8.10 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[Br:8][C:9]1[CH:14]=[CH:13]C=[CH:11][C:10]=1CCC(O)=O.B(F)(F)F.CCOCC>CC(OC)(C)C.O>[Br:8][C:9]1[CH:14]=[CH:13][C:5]([CH2:4][CH2:3][CH2:7][OH:6])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCc1ccccc1Br
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Sodium borohydride (119.12 g) and THF (5 L) were charged into reactor 1 and temperature adjusted to −20° C. 3-(bromophenyl)propionic acid (1 kg) was charged into reactor 2 with THF (3 L) and stirred at 25° C. until all the solids dissolved. This solution in reactor 2 was transferred to reactor 1 maintaining reactor 1 contents at <0° C. BF3.Et2O (991.4 g) was slowly added into reactor 1 maintaining reactor 1 contents at −20 to −10° C. After addition, the mixture was stirred at −20 to −10° C. for 1 h. The reaction is analysed for completion (3-(bromophenyl)propionic acid <2.5%). Water (2 L) was slowly added into reactor 1 to quench the reaction. (gas evolution). MTBE (5 L) was charged into reactor 1 and phases separation was carried out. The upper layer was collected and lower layer was washed with MTBE (5 L). The upper layer was collected and combined with the layer from the previous step. Adjusted pH value of the organic layer to 8-9 by adding 1N NaOH solution. The organic layer was washed with saturated NaCl solution (2 L) and the upper layer was collected. The organic layer was evaporated down to a colourless oil.