Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.Cl.[NH2:41][O:42][CH3:43].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:43][O:42][N:41]=[C:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:6][CH2:7]1
Reactant: CON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=NOC)CC2)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), (aminooxy)methane hydrochloride (0.32 g) and pyridine (10 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 71%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[N:13]=[C:12]([NH2:14])[S:11][N:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:15](O)=[O:16]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[N:13]=[C:12]([NH:14][CH:15]=[O:16])[S:11][N:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1nsc(N)n1
Reactant: O=CO
Product: CON=C(C(=O)OC)c1nsc(NC=O)n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 67.6 %

Procedure:
Methyl 2-methoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetate (anti-isomer) (10 g, 0.046 mol) in 99% formic acid (50 g) was heated under stirring at 70° C. for 6 hrs. It was cooled to below 10° C. to separate crystals, which were collected by filtration, washed with methanol and dried to give methyl 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (7.6 g, yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:10])[CH:5]=1.[H-].[Na+].[F:14][C:15](I)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17]>CN(C=O)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:15]([F:14])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:5]=1
Reactant: COC(=O)c1cccc(S)c1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(SC(F)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
To a stirred solution of 3-mercaptobenzoic acid methyl ester (2.32 g, 13.8 mmol) in DMF (15 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 608 mg, 15.2 mmol) in small portions. After stirring for 10 min at 0° C., and a further 30 min at room temperature, perfluoroisopropyl iodide (2.16 mL, 15.2 mmol, 1.1) was added to the reaction. Following the addition, the reaction was stirred for 10 min at room temperature and then heated to 60° C. After 90 min at 60° C. the reaction was cooled to room temperature, diluted with ethyl ether (150 mL), washed with brine (2×200 mL), saturated aqueous NaHCO3 (200 mL), brine (100 mL), dried over MgSO4 and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% EtOAc in hexanes as an eluent to furnish 3-(1,2,2,2-tetrafluoro-1-trifluoromethylethylthio)benzoic acid methyl ester (3.13 g).
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4]>C(Cl)Cl.C(N(CC)CC)C.C(Cl)(=O)C>[C:3]([O:4][CH2:3][C:2]([NH:1][C:11](=[O:16])[CH3:10])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][CH3:7])(=[O:4])[CH3:2]
Reactant: CCCC(N)(CO)CCc1ccccc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CCCC(CCc1ccccc1OCc1ccccc1)(COC(C)=O)NC(C)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 129 %

Procedure:
To a solution of 2-amino-2-(2-(2-benzyloxyphenyl)ethyl)pentanol (1.1 g) in methylene chloride (35 ml), triethylamine (1.2 ml) and acetyl chloride (0.5 ml) were added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=1:1) to give the subject compound (0.90 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[O:17][C:18]([C:20](O)=[O:21])=[CH:19][C:13]=3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.[CH:41]1[CH:42]=[CH:43][C:44]2[N:49](O)N=[N:47][C:45]=2[CH:46]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:47][C:45]1[CH:46]=[CH:41][CH:42]=[CH:43][C:44]=1[NH:49][C:20]([C:18]1[O:17][C:14]2[CH2:15][CH2:16][N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:12][C:13]=2[CH:19]=1)=[O:21]
Reactant: Cc1ccc(S(=O)(=O)N2CCc3oc(C(=O)O)cc3C2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCc3oc(C(=O)Nc4ccccc4N)cc3C2)cc1
Reaction time: 8 h

Procedure:
To a solution of 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylic acid (1.0 eq) obtained from step II in DMF was added Et3N (2.2 eq.), EDCI (1.2 eq) and HOBt ((1.2 eq) and reaction was stirred for 1 h Phenylene diamine was added to reaction mass and stirred for overnight. Reaction was quenched with water and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([O:26][C:27]2[N:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)[CH:14]=[C:15]([C:17]([NH:19][C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)=[O:18])[CH:16]=1)[CH3:9])(C)C.Cl.[NH:39]1[CH2:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[N:39]1([C:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:13]3[CH:14]=[C:15]([CH:16]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][OH:6])[CH:12]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[N:32][CH:31]=2)=[O:34])[CH2:42][CH2:41][CH2:40]1
Reactant: C1CNC1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
A solution of 6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylic acid (0.20 g, 0.378 mmol), azetidine hydrochloride (0.106 g, 0.114 mmol), HATU (0.302 g, 0.794 mmol) and DIPEA (0.39 mL, 0564 mmol) in DMF (7 mL) was stirred at RT overnight. 3.5M Hydrochloric acid (0.5 mL) was added and the solution left to stir for 20 minutes. The solution was neutralised with saturated sodium bicarbonate solution. Water (20 mL) was added and the solution extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired product (27 mg). 1H NMR δ (CDCl3): 1.32 (d, 3H), 2.38 (quintet, 2H), 3.77 (m, 2H), 3.80 (s, 3H), 4.29 (d, 4H), 4.57 (sextet, 1H), 6.81 (d, 1H), 6.91 (t, 1H), 6.99 (d, 1H), 7.27 (m, 2H), 7.38 (m, 1H), 8.42 (d, 1H), 8.86 (s, 1H). m/z 452 (M+H)+
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]([CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:8][OH:9]>N1C=CC=CC=1>[CH3:1][S:2]([O:9][CH2:8][CH:7]([CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)(=[O:4])=[O:3]
Reactant: CC(CO)Cc1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(COS(C)(=O)=O)Cc1ccc2ccccc2c1
Yield: 66 %

Procedure:
11 g (0.1 mol) of methanesulphonyl chloride are added dropwise to 14 g (0.074 mol) of 2-methyl-3-β-naphthylpropanol (crude) in 80 ml of absolute pyridine at 0° C., with stirring, the mixture is stirred at room temperature for a further 16 hours. When the addition has ended, excess pyridine is removed by distillation in vacuo, the residue is taken up in water, the mixture is extracted several times with methylene chloride, the extract is dried over sodium sulphate and the solvent is removed in vacuo. 13.6 g (66% of theory) of 1-methanesulphonyloxy-2-methyl-3-β-naphthyl-propane are obtained as an oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][CH2:19]O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CCN(S(F)(F)[F:27])CC.ClCCl>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][CH2:19][F:27])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCC1CCC(C2CCC(OCCCO)CC2)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC1CCC(C2CCC(OCCCF)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
A mixture of 2.75 g (9.8 mmol) of 4-(4-propylcyclohexyl)-(3-hydroxypropyloxy)cyclohexane obtained in Example 4, 3.14 g (19.6 mmol) of DAST, and 25 ml of dichloromethane was stirred for 5 hours at a room temperature. The reaction product was put in 40 ml of an ice water and extracted with 40 ml of toluene. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The magnesium sulfate was separated, the solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to a silica gel column chromatography (eluate: toluene) to obtain 1.87 g of a crude 4-(4-propylcyclohexyl)-(3-fluoropropyloxy) cyclohexane. This product was recrystallized twice from 6 ml of ethanol in a freezer to obtain 1.60 g (yield 58%) of 4-(4-propylcyclohexyl)-(3-fluoropropyloxy)cyclohexane. Several kinds of spectra well supported its structure.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[NH:11][C:12]([C:14]1[NH:18][C:17]2[C:19]([Cl:23])=[C:20]([Cl:22])[S:21][C:16]=2[CH:15]=1)=[O:13].CCN(CC)CC.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38](Cl)=[O:39])[CH2:34][CH2:33]1>C(Cl)Cl>[Cl:22][C:20]1[S:21][C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@H:3]3[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]3[NH:1][C:38]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:39])=[O:13])[NH:18][C:17]=2[C:19]=1[Cl:23]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)N[C@H]2c3ccccc3C[C@@H]2NC(=O)c2cc3sc(Cl)c(Cl)c3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of N-[(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 9, 240 mg, 0.5 mmol) and Et3N (101 mg, 1.0 mmol) in DCM (4 mL) was added a solution of 4-methyl-1-piperazine carbonyl chloride (100 mg, 0.5 mmol) in DCM (1 mL). The reaction was stirred at ambient temperature for 2 hours, washed with saturated NaHCO3 (1 mL), water (1 mL), brine (1 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (110 mg, 45%) as a foam. MS m/z (M−H)− 491.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[O:26][CH3:27])[CH2:15][CH2:14]2)=[N:11][CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:34](=[O:36])[CH3:35])=[CH:21][C:20]=3[O:26][CH3:27])[CH2:15][CH2:14]2)=[N:11][CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN=C(Nc1cc(Cl)cc(Cl)c1)N1CCN(c2ccc(O)cc2OC)CC1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN=C(Nc1cc(Cl)cc(Cl)c1)N1CCN(c2ccc(OC(C)=O)cc2OC)CC1

Procedure:
A solution of 0.10 mole of N-[3,5-dichlorophenyl]-N'-methyl-4-[2-methoxy-4-hydroxy phenyl]-1-piperazine-carboxamidine, 0.12 mole of pyridine and 0.12 mole of acetic anhydride in 250 ml of dichloromethane was stirred 12 hours at room temperature and poured into 2 L water. The organic phase was separated, washed with cold water, dried on sodium sulfate and evaporated. The residue (oil) was purified by flash chromatography on silica gel (200 mesh) using ethylacetate (60)/methanol (40) as eluant. The first 250 ml of eluant were collected and evaporated, and the residue further purified by recrystallization, to give N-[3,5-dichlorophenyl]-N'-methyl-4-[2-methoxy-4-acetyloxy-phenyl]-1-piperazine-carboxamidine, m.p. 144° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C@@H:16]([O:18]C1CCCCO1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:25])([C@@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@H](OC1CCCCO1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@H](O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 55 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
In ethanol (4 ml) were dissolved (3S)-2-(2,4-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.22 g) and pyridinium p-toluenesulfonate (47 mg), which was stirred for two hours at 55° C. To the solution was further added pyridinium p-toluenesulfonate (10 mg), which was stirred for further two hours at 55° C. The reaction mixture was cooled, then the solvent was distilled off. To the residue was added ethyl acetate (30 ml), which was washed with a saturated aqueous sodium chloride solution (10 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. To the residue was added ethyl ether, then precipitating crystals were collected by filtration to obtain (2S,3S)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (60 mg). m.p. 115°-117° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]3[C:17](=[O:20])[NH:18][C:19]=1[C:6]=23.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:27][C:22]1[C:21]([C:4]2[C:5]3[O:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:7]4[C:17](=[O:20])[NH:18][C:19]([C:6]=34)=[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1noc(C)c1-c1cc(Br)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc(-c2ccccc2)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (9.0 mg, 0.021 mmol), phenylboronic acid (3.1 mg, 0.025 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (1:1) (0.9 mg, 0.001 mmol) and potassium carbonate (8.8 mg, 0.063 mmol) in 1,4-dioxane (0.1 mL), and water (0.07 mL) was heated at 80° C. for 3 h. The reaction mixture was diluted with MeOH and purified on by preparative LCMS using a pH 10 buffer to give the title compound. LCMS calc. for C26H22N3O3 (M+H)+: m/z=424.2. found: 424.0.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)Cc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 23.8 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), phenylacetyl chloride (53.5 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (31.0 mg, yield 24%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[CH3:17].O>O1CCOCC1.CO>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:10]2[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=2)=[CH:21][CH:20]=1)[CH3:17]
Reactant: OB(O)c1ccncc1
Reactant: CCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCOc1ccc(-c2ccncc2)cc1
Reaction time: 48 h

Procedure:
Under inert gas atmosphere 88 mg (0.12 mmol) PdCl2(dppf)xCH2Cl2, 13.6 mL (27.2 mmol) 2N sodium carbonate solution and 1.64 g (13.3 mmol) pyridine-4-boronic acid are added to 3.00 g (12.1 mmol) 1-ethoxy-4-iodo-benzene in 18 mL 1,4-dioxane and 6 mL methanol. The mixture is stirred for 2 d at reflux. After that time, water is added. The precipitate is filtered off, taken up in DCM and extracted with water. The organic layer is dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; gradient DCM:MeOH 100:0→95:5) to yield the desired product which is directly used in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].S(O)(O)(=O)=O.[CH3:16][NH:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:18]\[NH:17][CH3:16])/[CH3:9]
Reactant: CC(=O)c1ccccc1Cl
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN/N=C(/C)c1ccccc1Cl
Yield: 184.3 %

Procedure:
A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen and charged with 1-(2-chlorophenyl)ethan-1-one (3.80 g, 24.6 mmol, 1.20 equiv), methylhydrazine sulfate (3.00 g, 20.8 mmol, 1.00 equiv) and ethanol (30 mL). The resulting solution was heated to reflux overnight. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to provide 7.0 g (crude) of (Z)-1-[1-(2-chlorophenyl)ethylidene]-2-methylhydrazine as yellow oil. LCMS (ESI, m/z): 183 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12](Cl)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([N:25]4[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: CC1CCNCC1
Reactant: Clc1nc(Nc2cc(C3CC3)[nH]n2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1CCN(c2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of (5-cyclopropyl-1H-pyrazol-3-yl)-(2-chloro-quinazolin-4-yl)-amine (118 mg, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-methylpiperidine (0.49 mL, 4.1 mmol) and the reaction mixture heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (×2), and rinsed with Et2O (×2) to afford III-111 as a white solid (123 mg, 85%): mp 190° C.; 1H NMR (DMSO) δ 0.66 (2H, s), 0.93 (5H, br s), 1.07 (2H, d), 1.66 (3H, s), 1.91 (1H, s), 2.85 (2H, t), 4.72 (2H, d), 6.33 (1H, s), 7.06 (1H, t), 7.29 (1H, d), 7.52 (1H, t), 8.31 (1H, d), 9.95 (1H, s), 12.18 (1H, br s); IR (solid) 2925, 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, 1394; MS 349.2 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[CH:3][CH:2]=1.[OH:9][C:10]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])(O)=O.[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[OH:9][C:10]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:13]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Product: O=C(OCc1ccccc1)c1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
BnBr (1.20 mL, 8.325 mmol) was added to a solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (1.50 g, 7.277 mmol) in TBAF (10 mL, 1 M solution in THF) and the mixture was stirred at r.t. for 2 h. The reaction mixture was poured into NaHCO3 (saturated aqueous solution, 100 mL) and extracted with EtOAc (100 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→30% EtOAc/hexanes) to furnish 2.18 g of benzyl 2-hydroxy-4-(trifluoromethyl)benzoate (colourless oil, yield: quantitative).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])[O:3]1.[OH-].[Na+].Cl>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8]([CH:7]=[C:5]([OH:6])[C:4]([OH:21])=[O:3])=[O:9])=[CH:15][CH:16]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)O
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
A solution of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide (3.65 g, 11.8 mmol) in tetrahydrofuran (150 ml) was treated at 15° C. with 35 ml (35 mmol) of 1 M aqueous sodium hydroxide. After 30 minutes, the reaction mixture was acidified with 1N hydrochloric acid (65 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and evaporated in vacuo to give a white solid. Recrystallization from ethyl acetate and hexane gave 3.04 g (96% yield) of the title material as white needles; mp 129° C. (dec.). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.73 (3H, s), 4.84 (2H, s), 6.57 (1H, s), 7.07 (2H, mn), 7.34 (2H, m). 13CNMR (enol form) 125 MHz (DMSO-d6) δ (ppm): 47.08, 63.05, 93.35, 130.61, 130.83, 130.90, 132.86, 132.89, 133.14, 133.16, 161.02, 161.38, 163.32, 163.81, 170.97. Anal. calcd for C12H12FNO5: C, 53.53; H, 4.49; N, 5.20; Found: C, 53.78; H, 4.30; N, 4.90.