Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24].[C:28](Cl)(=[O:31])[CH2:29][CH3:30].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:28](=[O:31])[CH2:29][CH3:30])=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:24])[CH3:25]
Reactant: CCC(=O)Cl
Reactant: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(O)cc3)n2C)ccc1Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g (4.7 mmoles) of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-hydroxyphenylimino)-3-methyl-4-thiazoline is suspended in 40 ml of dry chloroform. 0.4 g (4.7 mmoles) of propionyl chloride (dissolved in 10 ml of chloroform) and 1.4 g (18 mmoles) of pyridine are added in that order. A slightly exothermic reaction produces, temporarily, a solution from which a yellow solid precipitates. After stirring for 3 hours at room temperature, a further 0.4 ml of propionyl chloride is added. The resulting yellow solution is allowed to stand for 3 days at room temperature and then evaporated to dryness in vacuo, the residue is distributed between water and ethyl acetate, the organic phase is dried and evaporated and the residue is recrystallized from isopropanol. Colorless crystals of m.p. 155°-159° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13].C(O)(=[O:33])C.OO>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)(=[O:33])=[O:13]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc(CCc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1
Agent: OO
Solvent: ClCCl
Product: O=C(O)c1ccc(CCc2ccc(S(=O)(=O)Cc3ccc4ccccc4n3)cc2)cc1
Temperature: 25 °C

Procedure:
To 3 mmol of the sulfinyl compound from Step A in acetic acid (40 mmol) is added 30% hydrogen peroxide (2 ml). The mixture is stirred at ambient temperature and assayed by TLC. Upon disappearance of the sulfinyl starting compound, the reaction mixture is diluted with dichloromethane, washed with dilute aqueous sodium bisulfite and water, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfonyl)phenethyl)benzoic acid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[Cl-].[C:17]([CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:19])=[O:18].O1CCCC1.CC(C)([O-])C.[K+]>O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[CH2:20][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(-n2ccccc2=O)cc1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C/C=C/c1ccc(-n2ccccc2=O)cc1
Temperature: -50 °C
Reaction time: 10 h
Yield: 77 %

Procedure:
3.00 g of 4-(1,2-dihydro-2-oxo-1-pyridyl)benzaldehyde and 6.15 of β-carboxyethyltriphenyl phosphonium chloride were suspended into 30 ml of tetrahydrofuran, cooled to -50° C. and stirred. 20 ml of a tetrahydrofuran solution of 3.72 g of potassium-tert-butoxide was dropped and the temperature was gradually raised to 0° C. After 10 hours, iced water was added and the aqueous layer was washed with ether. The aqueous layer was adjusted to about pH 3 with concentrated hydrochloric acid, and deposited crystals were collected by filtration to obtain 2.96 g of the above-captioned compound as pale brown yellow powder (yield: 77%). Melting point (°C.): 218.5-221.5
Reaction SMILES: [I:1]I.[CH2:3]([N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+].CCOCC>O>[I:1][C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=1
Reactant: CCCCN(CCCC)c1ccccc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCN(CCCC)c1ccc(I)cc1
Temperature: 12.5 °C
Yield: 70.7 %

Procedure:
Iodine (7.88 g, 31 mmol) was added portionwise to a mixture of N,N-dibutylaniline (7 g, 34 mmol) and NaHCO3 (2.87 g, 34 mmol) in water (25 mL) with stirring at 10-15° C. After 1 h the mixture was poured into Et2O (200 mL), washed with water (100 mL), Na2S2O3 (2×100 mL), water (2×100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexane as eluent. The first fraction was collected and the solvent removed under reduced pressure to give the title compound (7.26 g, 71%) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(CCCC#N)=NCCCC#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccc(Br)cc21
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccc(Br)cc21

Procedure:
6-Bromophthalide (5.85 gms; 0.0275 mole), N-bromosuccinimide (4.89 gm; 0.0275 mole) and azobisbutyronitrile (0.1 gm) were gently refluxed in dry carbon tetrachloride (200 ml.) for 2 hours. On cooling, the succinimide was filtered off and the solvent removed in vacuo to give an oil, which was used immediately.
Reaction SMILES: [F:1][C:2]([F:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C1COCC1.CO.[Pt](=O)=O>[F:27][C:2]([F:1])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(C(F)(F)c4ccccc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(C(F)(F)c4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
Platinum(IV) oxide (14 mg) was added to a solution of 9-{4-[difluoro(phenyl)methyl]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (49 mg) in THF (dry) (10 mL) and MeOH (10 ml). The mixture was stirred at room temperature under hydrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (18.8 mg) as colorless crystals.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:26][C:25]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39].CI>O1CCCC1>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]([CH3:1])[C:25]([C:31]3[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=3)([C:27]([F:30])([F:28])[F:29])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2C)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (0.24 ml) in dry tetrahydrofuran (8 ml) stirred under argon at 0° C., was added n-butyl lithium (“n-BuLi”) (2.5 M in hexane) (0.74 ml). The solution was stirred at 0° C. for 30 minutes then was cooled to −85° C. To this solution was added a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (made as described in EP 1,731,512) (500 mg) in dry tetrahydrofuran (3 ml). The reaction mixture was stirred at −85° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added methyl iodide (0.14 ml) and the reaction mixture was stirred at −85° C. for 1 hour. More methyl iodide (0.08 ml) was added and the reaction mixture was stirred at −85° C. for a further 30 minutes. Then the reaction was quenched by addition of aqueous ammonium chloride (saturated) at −85° C. The mixture allowed to warm to ambient temperature and was then extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 85:15) to give 4-[5-(3,5-dichloro-phenyl)-4-methyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (290 mg) as a white foam. 1H-NMR (CDCl3, 400 MHz): 7.98-7.92 (m, 1H), 7.58-7.38 (m, 5H) 4.22-4.05 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H), 1.58-1.56 (m, 3H), 0.94-0.92 (m, 3H) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:17][CH2:18][CH:19]=[C:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]=2[CH2:24][O:23][C:22]2[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:34][C:21]1=2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH:19]=[C:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[N:30][C:25]=3[CH2:24][O:23][C:22]3[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:34][C:21]2=3)[CH2:8][CH2:7]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: Clc1ccccc1OC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(Oc3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
4-(2-Chloro-phenoxy)-piperidine hydrochloride (0.067 g, 0.268 mmol) was dissolved in a mixture of acetonitrile (1.32 mL) and water (0.17 mL). To this mixture was added 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.050 g, 0.134 mmol) and potassium carbonate (0.074 g, 0.536 mmol). The mixture was stirred at room temperature for 24 hrs and then concentrated in vacuo. The resulting white solid was suspended in ethyl acetate (5 mL) and an equal volume of water was added. The product was extracted into ethyl acetate (2×5 mL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford an oil. The residue was purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient) to afford the title compound (46 mg, 68%).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[O:22]=[S:23]1(=[O:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:28][CH:25]3[CH2:26][CH2:27][S:23](=[O:29])(=[O:22])[CH2:24]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: NC1CCS(=O)(=O)C1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)NC1CCS(=O)(=O)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 24.5 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), 1,1-dioxidotetrahydrothien-3-ylamine (10.4 mg, 0.077), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (5.1 mg, 24.3%). 1H NMR (400 MHz, CD3OD) δ 0.93 (dd, J=6.57, 1.26 Hz, 3 H) 1.05 (dd, J=6.32, 3.79 Hz, 3 H) 2.06-2.28 (m, 1 H) 2.40-2.59 (m, 2 H) 2.98 (td, J=12.57, 7.45 Hz, 1 H) 3.04-3.18 (m, 1 H) 3.21-3.29 (m, 1 H) 3.35-3.53 (m, 1 H) 4.51-4.66 (m, 1 H) 4.95-5.12 (m, 2 H) 5.40 (dd, J=19.20, 13.39 Hz, 1 H) 7.83-7.89 (m, 1 H) 8.17 (dd, J=3.28, 1.52 Hz, 1 H). [M+H] calc'd for C18H21FN4O4S, 409; found, 409.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([OH:17])=O)[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:54][NH:55][O:56][CH3:57].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([N:55]([CH3:54])[O:56][CH3:57])=[O:17])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H](CC1CCCCC1)C(=O)N(C)OC
Reaction time: 0.05 h

Procedure:
To 0.5 mL CH2Cl2 was added 48.6 mg (200 μmole) of EtOCO-Cha, 34.8 μL (200 μmole) DIEA, and 88.4 mg (200 μmole) BOP. After 3 min, 19.4 mg (200 μmole) N,O-dimethyl-hydroxylamine.HCl and 34.8 μL (200 μmole) DIEA were added. The reaction was monitored by TLC, and after 90 min it was diluted with CH2Cl2, washed 2× with dilute HCl and 2× with saturated NaHCO3. The organic layer was dried with Na2SO4, filtered, and the filtrate evaporated by rotary evaporation to give the title compound. NMR (300 MHz, CDCl3): a 4.72 (br m, Cha-α, 1H), 4.04 (q, CH3CH2OCO, 2H), 3.72 (s, N(CH3)OCH3, 3H), 3.13 (s, N(CH3)OCH3, 3H), 1.17 (t, CH3CH2OCO, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8](O)[CH3:9])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[O:15][CH3:16].OS(C(F)(F)[F:22])(=O)=O.COCCN(S(F)(F)F)CCOC.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([F:22])[CH3:9])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[O:15][CH3:16]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)c1nc(C(C)O)cc(N)c1OC
Agent: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(C(C)F)cc(N)c1OC
Temperature: -10 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a −10° C. (ice+NaCl) suspension of methyl 4-amino-6-(1-hydroxyethyl)-3-methoxypicolinate (0.3 g, 1.326 mmol) in Chloroform (6.63 ml) was added dropwise Triflic Acid (0.141 ml, 1.591 mmol) followed by Deoxo-Fluor® (0.257 ml, 1.392 mmol). The suspension was stirred at −10° C. (LC monitoring). After 2 h, the reaction mixture was poured into saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (ISCO, SiO2 24 g, hexane/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-amino-6-(1-fluoroethyl)-3-methoxypicolinate (175 mg, 0.767 mmol, 57.8% yield) as a white solid. ESIMS m/z 227 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 6.91 (s, 1H), 5.59 (dq, J=47.6, 6.3 Hz, 1H), 4.53 (s, 2H), 3.97 (s, 3H), 3.87 (s, 3H), 1.62 (dd, J=24.6, 6.4 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −176.20.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][C:15]=3[CH3:24])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]>CO.C(O)C.[Pd]>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:15]([CH3:24])=[CH:16][C:17]([NH2:21])=[CH:18][C:19]=3[CH3:20])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1cc(N)cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1

Procedure:
11.95 g (36.85 mmol) of nitro compound from Example XIV are hydrogenated in 500 ml of methanol/ethanol mixture using 550 mg of palladium/active carbon (10%) at 3 bar. The mixture is filtered through kieselguhr, the solvent is removed in vacuo and the product is purified by chromatography (toluene/ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O.OS(O)(=O)=O.O.[N+]([O-])([O-])=O.[Cu+2].O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[CH2:16]2)=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC1CCc2ccc(OCc3ccccc3)cc2C1
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC1CCc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of acetic acid 7-benzyloxy-1,2,3,4-tetrahydronaphthalen-2-yl ester (5.77 g, 19.5 mmol) in AcOH (30 mL) is added a solution of 90% HNO3 (3.0 mL, ca. 64 mmol) in AcOH (5 mL), copper(II) nitrate hemipentahydrate (3.71 g, 19.8 mmol) and conc. H2SO4 (3 drops) at room temperature. The mixture is stirred at room temperature for 1.5 h and partitioned between EtOAc and aq. KOH. The organic layer is dried over MgSO4, concentrated and chromatographed to afford acetic acid 7-benzyloxy-6-nitro-1,2,3,4-tetrahydronaphthalen-2-yl ester with some impurities. Crystallization from DCM-hexanes yields a precipitate, which is quickly rinsed with Et2O-hexanes to afford pure acetic acid 7-benzyloxy-6-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl ester: 1H NMR (CDCl3) δ 7.66 (s, 1H), 7.48-7.29 (m, 5H), 6.80 (s, 1H), 5.22-5.15 (m, 1H), 5.19 (s, 2H), 3.10 (dd, J=16.0, 8.0 Hz, 1H), 2.95-2.72 (m, 3H), 2.05 (s, 3H), 2.05-1.95 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][NH:17]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2cc[nH]c2c1
Product: Fc1cnc(Cl)nc1Nc1ccc2cc[nH]c2c1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted to provide 2-chloro-5-fluoro-N4-[(1H)-indol-6-yl]-4-pyrimidineamine. LCMS: purity: 92%; MS (m/e): 263 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1>>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]3[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=3[CH:23]=2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Product: Cc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:11])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[Cl:21].C(O)(=O)C.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[C:14]([Cl:21])[CH:15]=1)=[O:5]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 0.2 g, 1.27 mmol) was dissolved in methanol (5.5 mL), followed by addition of 4-fluoro-3-chlorobenzaldehyde (0.201 g, 1.27 mmol) and stirred at 25° C. for 10 min. After this time, 5.2 M acetic acid (0.245 mL) was added, stirred at 25° C. for 5 min before placing in an ice-bath. Once at 0° C., sodium borohydride (0.203 mg, 3.2 mmol) was added portionwise after which time the mixture was allowed to warm to 25° C. and continued to stir for 17 h. The reaction mixture was quenched by pouring into saturated aqueous sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-80% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-(3-chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (256 mg, 0.898 mmol, 70% as a yellow oil, containing residual ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 1.55-1.97 (m, 6H), 2.86 (dd, 1H, J1=14.2 Hz, J2=7.0 Hz), 3.19 (dd, 1H, J1=13.1 Hz, J2=6.9 Hz), 3.62 (s, 3H), 3.64 (d, 2H, J=6.2 Hz), 6.96 (t, 1H, J=8.5 Hz), 7.04-7.08 (m, 1H), 7.26-7.28 (m, 1H). LC-MS (ESI) calcd for C14H17ClFNO2 285.09, found 286.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[C:24]([F:26])[C:21]([C:22]#[N:23])=[C:20]([Cl:27])[CH:19]=2)=[N:14]1>>[Cl:27][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])[CH3:28])[N:14]=2)[CH:25]=[C:24]([F:26])[C:21]=1[C:22]#[N:23]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)c[nH]1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1

Procedure:
The title compound was prepared according to the method of Example 247 starting from 2-methyl-1H-imidazole-4-carboxylic acid and (S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chloro-6-fluorobenzonitrile (which can be prepared according to Example 34(c)). The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-98:2) to give the product, which was triturated in diethyl ether at RT to afford the title compound. 1H NMR (400 MHz, DMSO-d6): 1.06 (3H, d), 2.31 (3H, s), 4.28 (1H, distorted dd), 4.35-4.45 (2H, m), 7.02 (1H, d), 7.42 (1H, s), 7.86 (1H, d), 7.93 (1H, dd), 8.00 (1H, d), 8.07 (1H, d), 12.11 (1H, s).
Reaction SMILES: Br[CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3]1.C(O)C.[Na].[CH3:17][SH:18]>O>[CH3:17][S:18][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3]1
Reactant: O=C1c2ccccc2OCC1Br
Reactant: CS
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CSC1COc2ccccc2C1=O
Reaction time: 2 h
Yield: 17 %

Procedure:
After 10.4 g of 3-bromo-4-chromanone [synthesized in accordance with procedures described in W. S. Johnson, et al., J. Am. Chem. Soc., vol.66, p.218 to 220 (1944)] was dissolved into 42 ml of ethanol, 21.3 ml of a 15% aqueous solution of a sodium salt of methylmercaptan was added dropwise thereto. After the stirring for 2 hours at room temperature, the reaction mixture was poured into 300 ml of cold water. An organic layer was extracted with 200 ml of ether, and the ether layer was sequentially washed with a sodium chloride aqueous solution and water. After the ether layer was dried with magnesium sulfate, the solvent was removed by evaporated under vacuum. The residue was isolated and purified through a silica gel column (elute: hexane/ethyl acetate=3/1) to provide 1.52 g of 3-methylthio-4-chromanone (yield: 17%).