Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][S:18][CH3:19].ClN1C(=O)CCC1=O.C[O-].[Na+].CO>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([N:15]=[S:18]([CH3:19])[CH3:17])[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(OCc2ccccc2)ncc1F
Reactant: CSC
Agent: C[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(C)=Nc1nc(OCc2ccccc2)ncc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
A 10 mL oven-dried Schlenk flask was charged with 2-(benzyloxy)-5-fluoropyrimidin-4-amine (101 mg, 0.462 mmol), CH2Cl2 (2 mL), and dimethylsulfide (75.0 μL, 1.02 mmol) and was cooled to 0° C. in an ice bath. N-Chlorosuccinimide (122 mg, 0.914 mmol) was added and the resulting mixture was allowed to stir at 0° C. for 45 minutes, and then at room temperature for 30 minutes. A solution of NaOMe in MeOH (25%, 360 μL, 1.35 mmol) was added. After 20 minutes, the reaction was quenched with water (3 mL) and allowed to stir for 1 hour. The crude reaction mixture was then diluted with CH2Cl2 and washed with water (50 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation and then on high vacuum to give the title compound (120 mg, 93%) as an off white solid: mp 125-129° C.; 1H NMR (300 MHz, DMSO-d6): δ 7.70 (d, J=3.9 Hz, 1H), 7.25-7.44 (m, 5H), 5.21 (s, 2H), 2.75 (s, 6H); MS (ESI) m/z 281.1 (M+H)+. *Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 4128-4129.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[N:7]=[CH:8][CH:9]=2)[N:4]([CH3:15])[CH:3]=1
Reactant: COc1nccc2c(I)c[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c(I)cn(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
3-Iodo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.75 g, 2.74 mmol) in dimethylformamide (10 mL) was treated with 60% sodium hydride in mineral oil (0.219 g, 5.47 mmol) at room temperature for 20 minutes. To this solution was added methyl iodide (0.505 g, 3.56 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 10% ethyl acetate/hexanes to give 0.75 g (95%) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[H-].[Na+]>>[CH2:1]([C:8]1[N:9]([CH2:17][CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)[nH]c(Cc2ccccc2)n1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(=O)n(CCOc2ccc(C=O)cc2)c(Cc2ccccc2)n1
Yield: 20.5 %

Procedure:
The title compound (2.0 g, 20.6%) was prepared from 2-benzyl-4-methyl-1,6-dihydro-6-pyrimidone (5.6 g, 28.0 mmol), 4-[2-bromoethoxy]benzaldehyde (17.05 g, 30.1 mmol) in the presence of 95% NaH (873 mg, 35.0 mmol) as base by a similar procedure to that described in preparation 1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4]2[N:5]([CH:19]=[CH:20][N:21]=2)[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.[I:24]Cl>>[I:24][C:19]1[N:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=3)[CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[C:4]2=[N:21][CH:20]=1
Reactant: ClI
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Yield: 98 %

Procedure:
Prepared from 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 10) (4.44 g, 14 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a yellow solid (5.803 g, 98%). MS (ISP) 458.2 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:34])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:34])[NH:15][C:9]=2[CH:10]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M47) (270 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (129 mg).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](OC)(OC)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[CH3:31][C@@H:32]([OH:36])[C@H:33]([OH:35])[CH3:34].CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CC1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[O:36][C@H:32]([CH3:31])[C@@H:33]([CH3:34])[O:35]1
Reactant: COC(Cn1cncn1)(OC)c1ccc(Cl)cc1Cl
Reactant: C[C@@H](O)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[C@H]1OC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O[C@@H]1C
Yield: 50 %

Procedure:
A mixture of 9.5 parts of 1-[2(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-1H-1,2,4-triazole 4-methylbenzenesulfonate, 2 parts of (2R, 3R)(-)-2,3-butanediol, 1 part of 4-methylbenzenesulfonic acid and 90 parts of methylbenzene is stirred and refluxed for 3 days. The reaction mixture is cooled and alkalized with a sodium hydroxide solution 20%. The whole is poured onto water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using ethyl acetate as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'oxybispropane and petroleumether (1:1 by volume). The product is filtered off and dried, yielding 3.2 parts (50%) of (-)-(4R,trans)-1-[2-(2,4-dichlorophenyl)-4,5-dimethyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole; mp. 82.5° C.; [α]D =-30.26° (c=0.5% CHCl3)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[N:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][OH:13])=[N:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(C=O)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2ncc(F)c(CO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To an ice-chilled suspension of 3-fluoro-6-methoxy-[1.5]naphthyridine-4-carbaldehyde (5 g, 24.25 mmol; prepared as in WO 2006/032466) in MeOH (180 mL) was added NaBH4 (1.03 g, 26.68 mmol, 1.1 eq.) in one portion. After 30 min, the reaction mixture was warmed to rt. Water (180 mL) was added and the volatiles were removed under reduced pressure. The residue was filtered off and washed with water. The aq. filtrate was extracted twice with EA (2×100 mL). The combined org. layers were washed with brine (120 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to afford a yellow solid. The residue was purified by CC (Hept-EA 1:1) to give the title intermediate as a pale yellow solid (4.01 g, 79% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCOCC.I[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>C1COCC1.[Cl-].[Cl-].[Zn+2]>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: c1cocn1
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1coc(-c2ccc3[nH]ccc3c2)n1
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a stirred solution oxazole (0.1 g, 1.45 mmol) in anhydrous THF (3 mL), n-BuLi (1.6 mL, 1.6 mmol) was added at −78° C. and stirred for 30 minutes. The reaction mixture was brought to 0° C., ZnCl2.Et2O (4.35 mL, 4.35 mmol) was added and stirred for 1 h. 5-iodo-1H-indole (0.352 g, 1.45 mmol) and (Ph3P)PdCl2 (0.050 g, 0.072 mmol) were added and stirred at 80° C. for 1 h. The reaction mixture was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography to give 2-(1H-indol-5-yl)oxazole (0.060 g, 22%); MS: 185.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=S)[C:8]3([CH2:11][NH:12][C:4]=2[CH:3]=1)[CH2:10][CH2:9]3.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[C:16]([CH3:17])=[N:19][N:20]=[C:7]3[C:8]3([CH2:10][CH2:9]3)[CH2:11][NH:12][C:4]=2[CH:3]=1
Reactant: CC(=O)NN
Reactant: S=C1Nc2ccc(Br)cc2NCC12CC2
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)cc1NCC21CC1
Yield: 52.9 %

Procedure:
A solution of 7-bromo-4,5-dihydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2(1H)-thione (500 mg, 1.77 mmol) and acetohydrazide (1.05 g, 14.2 mmol) in n-butanol (15 mL) was heated to 130° C., and maintained at the same temperature for 12 hours. The reaction mixture was concentrated, extracted with ethyl acetate (15 mL), washed with water (25 mL*2). The organic phase was separated, dried by sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=30:1) to afford 8-bromo-1-methyl-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane] (286 mg, 53%). 1H NMR (300 MHz, d6-DMSO): δ 7.31-7.28 (m, 2H), 7.11 (dd, J=6.0 Hz, J=2.4 Hz, 1H), 5.80-5.78 (m, 1H), 3.36-3.35 (m, 2H), 2.37 (s, 3H), 0.88-0.86 (m, 2H), 0.77-0.73 (m, 2H). LRMS (M+H)+: calcd 304.03. found 304.
Reaction SMILES: CC1[N:3]=[CH:4][NH:5]C=1CSCCN.[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].CSC(=N)[NH2:20]>O>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[NH2:3][C:4]([NH2:5])=[NH:20]
Reactant: CSC(=N)N
Reactant: Cc1nc[nH]c1CSCCN
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)N

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (19.0 g.) and S-methylisothiourea sulphate (15.1 g.) in water (100 ml.) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[(4-methyl-5-imidazolyl)methylthio)ethyl]guanidine sulphate (13.0 g.) m.p. 230°-235° (from aqueous methanol).
Reaction SMILES: CC1(C)[O:17][CH:5]2[CH:6]([O:13][CH2:14][O:15][CH3:16])[CH2:7][C:8]3[CH:9]([CH2:10][O:11][N:12]=3)[CH:4]2[O:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C>[OH:3][CH:4]1[CH:9]2[CH2:10][O:11][N:12]=[C:8]2[CH2:7][CH:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]1[OH:17]
Reactant: COCOC1CC2=NOCC2C2OC(C)(C)OC12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOC1CC2=NOCC2C(O)C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
4,5-(Dimethylmethylenedioxy)-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (257 mg) was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 1N hydrochloric acid was added, followed by stirring the mixture at room temperature for 4 hours. The reaction mixture was diluted with diethyl ether, and neutralized with a sodium hydrogen carbonate aqueous solution. The organic layer was washed with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 167 mg of 4,5-dihydroxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:21])=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1.CC1(C)C2C=CC=CC=2I([C:32]([F:35])([F:34])[F:33])O1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][C:32]([F:35])([F:34])[F:33])=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Reactant: O=S(=O)(Nc1cc(Cl)ccc1S)c1cc2ccccc2o1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Cl)ccc1SC(F)(F)F)c1cc2ccccc2o1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of benzofuran-2-sulfonic acid (5-chloro-2-mercapto-phenyl)-amide (332 mg, 0.98 mmol) in CH2Cl2 (10 ml) at −78° C. was added 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (CAS #: 887144-97-0, 354 mg, 1.07 mmol) and the reaction was stirred for 1 h, and was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2) to give the title compound (375 mg, 94%).
Reaction SMILES: O[NH:2][C@H:3]([C:8](N)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(Cl)(Cl)=[O:12]>C1COCC1.C1(C)C=CC=CC=1>[NH2:2][C@H:3]([C:8]([OH:9])=[O:12])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](NO)C(N)=O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](N)C(=O)O
Temperature: 50 °C
Yield: 90 %

Procedure:
HO-Leu-NH2 (10.0 g, 76.2 mmol) was suspended in 150 mL of anhydrous THF and heated to 50° C. Phosgene (20% in toluene) (76.0 mL, 152.4 mmol) was added to the amino acid suspension. The amino acid dissolved over the course of approx. 1 hr, forming a clear solution. The solution was concentrated on the rotovap, transferred to a beaker, and hexane was added to precipitate the product. The white solid was isolated by filtration and dissolved in toluene. The solution was filtered over a bed of Celite to remove any insoluble material. An excess of hexane was added to the filtrate to precipitate the product. The NCA was isolated by filtration and dried in vacuo. 9.0 g (75% yield) of Leu NCA was isolated as a white, crystalline solid. 1H NMR (d6-DMSO) δ 9.13 (1H), 4.44 (1H), 1.74 (1H), 1.55 (2H), 0.90 (6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])[CH2:13][CH3:14]>>[CH3:11][C:10]1[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH2:12][CH2:13][CH3:14])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([NH2:6])=[O:5]
Reactant: Cc1cccc(C(N)=O)c1N
Reactant: CCCOc1ccccc1C(=O)Cl
Product: CCCOc1ccccc1C(=O)Nc1c(C)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-methylbenzamide and 2-n-propoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as a colourless solid (71%), m.p. 140-142° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:19][C:20]1[C:24]([C:2]2[C:3]([CH3:18])=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[O:6][CH:5]3[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Cc1c(Br)ccc2c1C(c1ccccc1)OC2=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: [Na+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1C)C(c1ccccc1)OC2=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 5-Bromo-4-methyl-3-phenyl-3H-isobenzofuran-1-one (100 mg, 0.33 mmol), 3,5-dimethylisoxazole-4-boronic acid (93 mg, 0.66 mmol, 2 eq.), 1N Na2CO3 (0.66 mL, 0.66 mmol) and Pd(PPh3)4 (62 mg, 0.033 mmol, 0.1 eq.) in dioxane (20 mL) is stirred at 90° C. for 16 hours. After cooled to room temperature, the mixture is evaporated in vacuo. The residue is purified by preparative-TLC using a petrol ether ethyl acetate mixture to afford the desired compound as a white solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:12])[CH3:11].[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:40][CH3:41])=[CH:30][C:31]=3[O:33][CH2:34][C@H:35]3[CH2:39][CH2:38][CH2:37][NH:36]3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[F:21]>C(Cl)Cl>[C:10]([N:36]1[CH2:37][CH2:38][CH2:39][C@@H:35]1[CH2:34][O:33][C:31]1[CH:30]=[C:29]([O:40][CH3:41])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([F:21])=[C:15]([Cl:14])[CH:16]=1)=[N:24][CH:25]=[N:26]2)(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: COc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC[C@H]2CCCN2C(C)=O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 1 h
Yield: 83 %

Procedure:
N,N-Diisopropylethylamine (52 μl) and acetyl chloride (21 μl) were added sequentially, each in one portion, to a stirred mixture of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (100 mg) in DCM (2 ml) at room temperature. The reaction mixture was stirred for 1 hour and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow solid, which was purified by column chromatography using 24% methanol in DCM as eluent, followed by trituration with ether to give the title compound as a white solid (92 mg, 83%); NMR Spectrum (DMSO-d6) 9.90 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.25 (m, 1H), 3.95 (s, 3H), 3.50 (m, 1H), 3.30 (s, 3H), 2.0-1.85 (m, 5H); Mass spectrum MH+ 445.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][C@H:20]1[CH2:22][O:21]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:21]1[CH2:22][C@H:20]1[CH2:19][O:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc(-c2cccc3cccnc23)c1
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OC[C@@H]2CO2)cc(-c2cccc3cccnc23)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(quinolin-8-yl)phenol (221 mg, 1 mmol) and (R)-2-(chloromethyl)oxirane (114.6 mg, 1.2 mmol) in CH3CN (10 mL) had K2CO3 (690 mg, 5 mmol) added to it. The reaction mixture was then stirred at 80° C. for 4 h. The solid was removed by filtration, the filtrate concentrated, and the crude product used in the next step without further purification. ESI-MS (m/z): 278.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=1>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[C:6]([NH:29][CH:27]([CH3:28])[CH2:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=2)[N:7]=1
Reactant: CC(C)c1nc(N)nc(Cl)n1
Reactant: CC(N)CCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(CCc1ccc(F)cc1)Nc1nc(N)nc(C(C)C)n1

Procedure:
2.6 g (0.015 mol) of 2-amino-4-chloro-6-isopropyl-1,3,5-triazine and 2.1 g (0.015 mol) of K2CO3 are initially introduced in 50 ml of acetonitrile. 2.5 g (0.015 mol) of 1-(4-fluorophenyl)-3-butylamine, dissolved in 20 ml of acetonitrile, are added dropwise to this solution. It is then heated to reflux for 3 hours. The solid constituents are then filtered off with suction and the filtrate is concentrated in a rotary evaporator. The residue is purified by means of column chromatography (eluent: ethyl acetate). Yield: 4.1 g (90% of theory).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
The 4-(N-Boc amino)-1-piperidineethanol (13 g, 53.2 mmol) was treated with TFA (26 mL) for 90 mL. The TFA was removed (reduced pressure) and the TEA salt was converted to the HCl salt by treatment with 20% HCl/methanol (130 mL) at ambient temperature for 30 min. The HCl/methanol was evaporated (reduced pressure) and the residue dissolved in H2O (10 mL). The solution was cooled in an ice-bath and NaOH (10M, 35 mL) added to pH >10. The solution was warmed to RT and stirred for 15 min prior to evaporating to dryness. The residue was triturated with ether/isopropanol (2:1), filtered and evaporated to dryness. The trituration process was repeated until no salt was present in the oil (5×) to yield 6.7 g (87%) of an off-white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C:21]2[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH:31]=O)=[O:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:35][O:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][NH:43][CH2:44]2)=[CH:39][CH:38]=1.ClCCl>ClCCCl>[CH3:35][O:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][N:43]([CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:25](=[O:26])[C:24]3[CH:33]=[CH:34][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][CH:23]=3)[CH2:44]2)=[CH:39][CH:38]=1
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc2c(c1)CNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Sodium triacetoxyborohydride (4.66 g, 22 mmol) was added to a stirred mixture of 4-(4-phenylbenzoylamino)butyraldehyde (3.92 g, 15 mmol) and 7-methoxy-1,2,3,4-tetrahydroisoquinoline [Daniel J. Sall et al., J. Med. Chem., 1987, 30, 2208] (2.40 g, 14.7 mmol) in 1,2-dichloroethane (200 ml) at room temperature. After stirring for 16 h, dichloromethane (100 ml) was added and the mixture was then washed with saturated aqueous K2CO3 (2×100 ml) and brine (100 ml). Drying (Na2SO 4) and evaporation in vacuo afforded a viscous oil which was chromatographed on silica gel, eluting with ethyl acetate, to give the title compound as a pale pink solid (5.04 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([CH3:21])[N:15]=1.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[NH2:13][C:14]1[N:19]=[C:18]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH2:8]2)[CH:17]=[C:16]([CH3:21])[N:15]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: COc1ccc2c(c1)CCCN2
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CCCN2c1cc(C)nc(N)n1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A flask containing 6-methoxy-1,2,3,4-tetrahydroquinoline (1.33 g), 2-amino-4-chloro-6-methylpyrimidine (1.00 g), sulfuric acid (0.6 g), and 100 mL of water was heated on a steam bath for 2 hours. The solution was then cooled to room temperature and treated with ammonium hydroxide until the solution was basic (pH 8-9). The resultant solid, which precipitated from solution, was collected by filtration and recrystallized from ethyl alcohol to give 2-amino-4-(6-methoxy-3,4,-dihydro-2H-quinolin-1-yl)-6-methylpyrimidine (0.93 g), m.p. 175.2-175.9° C.