Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CO>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol) described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol), which was then concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) was added 4-fluorobenzyl bromide (2.3 μL, 0.019 mmol), which was stirred for 1 hour at room temperature. The reaction mixture was purified as is by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.1 mg, 39%) as a trifluoroacetic acid salt.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>CN(C=O)C>[CH2:3]([O:10][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([Br:11])[CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
NaH (60% in mineral oil) (40.9 g 1.0225 mol) in 800 mL of DMF was cooled to 0° C., and benzyl alcohol (105 mL 1.014 mol) was added slowly. The reaction mixture was stirred for 1 hour at 20° C., then 3,5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH4Cl (500 mL), diluted with 400 mL water and extracted with Et2O (5×300 mL). The combined Et2O extracts were washed with 50% brine (6×300 mL) and dried (MgSO4). The solvent was evaporated in vacuo and the crude product was recrystallized from Et2O to afford 161 g (72%) of the title product, mp 63-68° C. 1H NMR (CDCl3, 300 MHz) δ8.37-8.27 (m, 2H), 7.5-7.35 (m, 6H), 5.1 (s, 1H). MS (DCI/NH3) m/z 264, 266 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=S)[S:23]C)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>C(O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22](=[S:23])[NH:27][NH2:28])=[CH:18][CH:19]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CSC(=S)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=S)NN)cc1

Procedure:
A mixture of 1.53 g (4.1 mmole) of methyl N-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]dithiocarbamate, 796 μl (820 mg, 16.4 mmole) of hydrazine hydrate, and 10 ml of absolute ethanol was stirred at reflux under N2. After 2 hours the resulting solution was cooled and concentrated. The residual oil was chromatographed on a column of silica gel (elution with 99:1 and the 98:2 CH2Cl2) to give (after concentration and vacuum-drying) 1.15 g (79%) of a stiff, white foam, mp>45° C. (gradual); homogeneous by TLC in 19:1 CH2Cl2 -MeOH; mass spectrum (FAB) m/e 358 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1.[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4]1
Reactant: CCOC(=O)c1ccc2nc[nH]c(=O)c2c1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1ccc2ncn(Cc3cccc(Br)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
Into a round-bottom flask was added ethyl 4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.14 g, 0.63 mmol), 3-bromobenzyl bromide (0.24 g, 0.95 mmol), cesium carbonate (0.25 g, 0.76 mmol), acetonitrile (12 mL) and DMF (3 mL). The reaction mixture was stirred at rt for 16 h. The mixture was then concentrated and to the residue was added EtOAc and water. After separation, the aqueous phase was extracted with EtOAc (2×). The combined organic phases were then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Flash column chromatography (25% to 50% EtOAc/hexanes) afforded ethyl 3-(3-bromobenzyl)-4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.17 g, 68%) as a white solid. LC-MS: (FA) ES+ 388; 1H NMR (CDCl3, 300 MHz) δ 9.00 (d, J=1.70 Hz, 1H), 8.39 (dd, J=8.5, 1.9 Hz, 1H), 8.26 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.26 (m, 2H), 5.17 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[CH2:23]([NH2:28])[C:24]#[C:25][CH2:26][CH3:27]>O1CCCC1>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:28][CH2:23][C:24]#[C:25][CH2:26][CH3:27])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: CCC#CCN
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Solvent: C1CCOC1
Product: CCC#CCNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1

Procedure:
A mixture of 10.0 g. of 1,3-dihydro-7-(trifluoromethyl)-5-phenyl-2H-1,4-benzodiazepine-2-thione (V), 10.0 g. of 2-pentynylamine, and 150 ml. of dry tetrahydrofuran is stirred under nitrogen at ambient temperature for about 5 hours and then concentrated in vacuo. The residue thus obtained is recrystallized from methanol to give 7-trifluoromethyl-5-phenyl-2-(2-pentynylamino)-3H-1,4-benzodiazepine.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].[C:13]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1)=O.Cl>CN(C=O)C.O>[C:13]1(=[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:3][C:4]2=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
To a suspension of sodium hydride (6.0 g, 150 mmol, 60% in mineral oil) in 300 mL DMF was added oxindole (10.0 g, 75.1 mmol) in 50 mL DMF over 8 min. After stirring for 15 min at room temperature, a solution of phthalide (13.1 g, 97.6 mmol) in 50 mL DMF was added over 1 min. The mixture was stirred for 1.25 h, then poured into 1100 mL H2O. Addition of 4% aqueous HCl solution gave a yellow solid which was filtered and rinsed with H2O to give the title compound (8.75 g, 47%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C[C:16]1C=CC=[C:18](C)[C:17]=1[N+:23]([O-])=O.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([NH:23][CH:17]([CH3:18])[CH3:16])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CC(=O)O)c1[N+](=O)[O-]
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(CC(=O)NC(C)C)c1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To a slurry of 3-methyl-2-nitrobenzeneacetic acid (prepared by the method of H. Rapoport et al., J. Org. Chem., 1954, 77, 670-675 from 1,3-dimethyl-2-nitrobenzene, 0.70 g, 3.6 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.41 mL, 4.7 mmol) and two drops of N,N-dimethylformamide. The reaction mixture was stirred for 20 minutes, resulting in a solution. The volatiles were removed with a rotary evaporator. The residue was dissolved in 10 mL of dichloromethane. Half of this material was added dropwise at 0° C. to isopropylamine (1 mL) in 5 mL of dichloromethane. The reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution was added, and the reaction mixture was passed through a Celite® diatomaceous filter aid cartridge. The solvent was removed with a rotary evaporator to afford the title compound as an orange solid (0.40 g).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([S:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)([F:36])[F:37]
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Sc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.00 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 301 mg (60%) pale beige powder.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.Cl[C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1>C(#N)C>[NH2:29][C:27]1[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=[C:23]([N:5]2[CH2:6][CH2:7][C@H:2]([CH3:1])[C@H:3]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[CH2:4]2)[N:28]=1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: C[C@H]1CCNC[C@H]1C(=O)N1CCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CCN(c2ncc([N+](=O)[O-])c(N)n2)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a solution of cis-(4-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (1.7 g, 8.60 mmol) in acetonitrile (20 mL) was added triethylamine (3.65 mL, 26.02 mmol). The mixture was stirred for 10 min at room temperature. Then 2-chloro-5-nitropyrimidin-4-amine (1.19 g, 6.9 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and stirred for 1 h. Ice cold water was added and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (40-100% ethyl acetate in petroleum ether) to afford cis-(1-(4-amino-5-nitropyrimidin-2-yl)-4-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (1.6 g). MS (ES+) (M+H) 335.3.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26][C:27](=[CH2:29])[CH3:28].[OH-].[Na+]>O1CCOCC1>[CH2:6]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:23]([O:25][C:27]([CH3:29])([CH3:28])[CH3:26])=[O:24])[NH2:22])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
Into two separate 500 ml hydrogenation vessels each containing 100 ml of dioxane and 9.0 ml (160 mmol) of concentrated sulfuric acid was placed 11.0 gm (39.2 mmol) and 10.6 gm (37.8 mmol) of Nε-benzyloxycarbonyl-L-lysine. The two solutions were cooled to -78° C. and 140 ml of condensed (-78° C.) isobutylene was added to each vessel. The mixtures were then mechanically shaken (Parr shaker) at room temperature for 4 hours (26 psi). The reaction mixtures were combined and poured into 1000 ml (1.0 mol) of an ice cold solution of 1.0N aqueous sodium hydroxide and subsequently extracted three times with ether. The organic portions were combined (ca. 3000 ml), washed once with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 16.7 gm (64%) of t-butyl Nε-benzyloxycarbonyl-L-lysinate (IV-A) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([S:27]C(=O)C)[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([SH:27])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)SC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCC(S)CC1COc1c(F)ccc(F)c12
Reaction time: 4 h
Yield: 34.8 %

Procedure:
A solution of thioacetic acid S-[10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yl]ester (420 mg, 0.888 mmol) in MeOH (8 mL) was treated with 1N NaOH (2 mL) followed by THF (3 mL). After 4 h, the reaction mixture was concentrated in vacuo, diluted with 1N HCl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo. Flash chromatography (2→20% EtOAc/Hex) gave the disulfide of the title compound (133 mg, 17%): 1H NMR (CDCl3 400 MHz) δ 7.62 (d, J=8.8 Hz, 4H), 7.51 (d, J=8.8 Hz, 4H), 7.07 (m, 2H), 6.41 (m, 2H), 5.24 (dd, J=11.0, 2.9 Hz, 2H), 4.11 (d, J=11.0 Hz, 2H), 3.48 (m, 2H), 3.14 (d, J=13.2 Hz, 2H), 2.55 (m, 2H), 2.42 (m, 2H), 1.92-1.52 (m, 8H); followed by the title compound (169 mg, 44%): 1H NMR (CDCl3 400 MHz) δ 7.60 (dd, J=8.8, 1.5 Hz, 2H), 7.48 (dd, J=8.8, 1.5 Hz, 2H), 7.08 (m, 1H), 6.42 (m, 1H), 5.25 (dd, J=11.7, 2.2 Hz, 1H), 4.11 (d, J=11.0 Hz, 1H), 3.11 (m, 1H), 2.95 (d, J=12.5 Hz, 1H), 2.40-2.38 (m, 2H), 2.04-1.82 (m, 3H), 1.49 (m, 1H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[C:57](O)=[O:58].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(N(CC)CC)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:57]([C:48]1[CH:49]=[CH:50][C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=1)=[O:58])=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2ccc3ccccc3c2)s1
Reaction time: 8 h
Yield: 19.6 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (3.70 g) was dissolved in dimethylformamide (20 ml). Naphthalene-2-carboxylic acid (0.95 g) and diphenylphosphoryl azide (1.29 ml) were added under ice-cooling and dissolved in the solution. A solution of triethylamine (2.24 ml) in dimethylformamide was dropwise added, and the mixture was allowed to stand overnight at room temperature. Then, a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 0.53 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)naphthalene-2-caboxamide.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH:34]([CH3:35])[CH2:33][N:32]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=2)[CH2:31][CH:30]1[CH3:43])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH:30]([CH3:43])[CH2:31][N:32]([C:36]2[CH:37]=[N:38][C:39]([NH:42][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:40][CH:41]=2)[CH2:33][CH:34]1[CH3:35])=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC1CN(c2ccc(N)nc2)CC(C)N1C(=O)OC(C)(C)C
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)C(C)C4)cn3)ncc12
Temperature: 25 °C
Yield: 37.5 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 4-(6-amino-pyridin-3-yl)-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.14 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.620 g, 37.6%). 1H NMR δ (400 MHz, CDCl3) 8.79 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.99 (d, J=2.7 Hz, 1H), 7.36 (dd, J=2.7, 8.8 Hz, 1H), 5.99 (m, 1H), 4.28 (m, 2H), 3.30 (m, 2H), 2.93 (dd, J=4.4, 11.7 Hz 2H), 2.61 (s, 3H), 2.30 (m, 2H), 2.11 (m, 2H), 1.89 (m, 2H), 1.68 (m, 2H), 1.49 (s, 9H), 1.38 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]1([P:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH:18](=[N:11][CH2:10][CH2:9][CH2:8][P:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCP(c1ccccc1)c1ccccc1
Solvent: CCO
Product: C(=NCCCP(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 96.2 %

Procedure:
Under argon, a solution of 3-diphenylphosphino-propylamine (631.2 mg, 2.6 mmol) and benzaldehyde (278.1 mg, 2.6 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a white solid (822.3 mg, 2.5 mmol, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([F:13])([F:12])[F:11])=[O:9])=[CH:4][C:3]=1[O:14][CH3:15].C[Si](I)(C)C.[OH-].[Na+].Br[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([F:13])([F:12])[F:11])=[O:9])=[CH:4][C:3]=1[O:14][C:15]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc(C(=O)C(F)(F)F)ccc1F
Reactant: Brc1ccccc1
Agent: C[Si](C)(C)I
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccc(F)c(Oc2ccccc2)c1)C(F)(F)F

Procedure:
Trifluoromethyl 4-fluoro-3-phenoxyphenyl ketone may be prepared using the following procedure. Bromination of 2-fluoroanisole yields a mixture of bromo-2-fluoroanisole isomers from which 5-bromo-2-fluoroanisole is isolated. The Grignard reagent of 5-bromo-2-fluoroanisole is then prepared and is in turn reacted with N-methoxy-N-methyl-2,2,2-trifluoroacetamide in tetrahydrofuran, yielding trifluoromethyl 4-fluoro-3-methoxyphenyl ketone. This ketone is protected by formation of the corresponding ketal, which is in turn treated with trimethylsilyl iodide, sodium hydroxide, bromobenzene, and acid, yielding trifluoromethyl (4-fluoro-3-phenoxyphenyl) ketone.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[Cl:20]>C(O)C.Cl>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:14][C:13]=1[Cl:20]
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(F)c(Cl)c1
Yield: 15 %

Procedure:
A solution of 1.39 g of 3-amino-5,5-dimethyl-2-cyclohexen-1-one and 793 mg of 4-fluoro-3-chlorobenzaldehyde in 10 ml of absolute ethanol and 1 ml of 1M aqueous hydrochloric acid was heated at reflux under a nitrogen atmosphere for 18 hours. The cooled mixture was filtered and the residue was washed with 25 ml of cold diethyl ether. Crystallization from absolute ethanol/water gave 302 mg of 9-(4-fluoro-3-chlorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione as a pale yellow crystalline solid of melting point 274-275° C. (decomposition).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:36])[CH:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([F:37])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:38])=[O:3])=[CH:6][C:7]=3[F:37])=[O:36])=[C:28]3[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:22]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 7.2, 4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white oil. MS: m/e=510.3 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:15][CH2:14][O:13][C:12]2[CH:16]=[C:17]([O:20][C:21]3[CH:22]=[C:23]([C:33]([NH:35][C:36]4[CH:40]=[CH:39][N:38](C(OC(C)(C)C)=O)[N:37]=4)=[O:34])[CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)[CH:18]=[CH:19][C:11]=2[S:10]1(=[O:49])=[O:48]>C(Cl)Cl>[CH3:8][N:9]1[CH2:15][CH2:14][O:13][C:12]2[CH:16]=[C:17]([O:20][C:21]3[CH:22]=[C:23]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)[C:33]([NH:35][C:36]3[CH:40]=[CH:39][NH:38][N:37]=3)=[O:34])[CH:18]=[CH:19][C:11]=2[S:10]1(=[O:49])=[O:48]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)S3(=O)=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)S3(=O)=O)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 1,1-dimethylethyl 3-{[(3-[(2-methyl-1,1-dioxido-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate (50 mg, 0.08 mmol) in DCM (8 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo and DCM (20 mL). The mixture was washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL), brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (31 mg). 1H NMR δ (CDCl3): 1.33 (d, 3H), 2.80 (s, 3H), 3.40 (s, 3H), 3.51-3.61 (m, 2H), 3.71-3.73 (m, 2H), 4.17-4.22 (m, 2H), 4.57-4.65 (m, 1H), 6.72-6.74 (m, 1H), 6.79-6.84 (m, 2H), 6.86 (s, 1H), 7.20 (s, 1H), 7.41 (s, 1H), 7.49 (s, 1H), 7.78 (d, 1H), 9.59 (s, 1H), 10.20 (s, 1H); m/z 503 (M+H)+