Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([N+:13]([O-])=O)[CH2:7][CH2:8][C:9](OC)=[O:10]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:7][CH2:8][C:9](=[O:10])[NH:13]1.[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:7][CH2:8][C:9](=[O:10])[NH:13]1
Reactant: COC(=O)CCC(CCC(=O)OC)(CCC(=O)OC)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCC1(CCC(=O)O)CCC(=O)N1
Product: COC(=O)CCC1(CCC(=O)OC)CCC(=O)N1

Procedure:
A solution of 160 g of crude γ-carbomethoxyethyl-γ-nitropimelic acid dimethyl ester in 800 ml of methanol is hydrogenated at approximately 50 psi using 2 g of 20% Pd/C as catalyst. The resulting slurry is filtered to remove the catalyst and the filtrate is concentrated at reduced pressure to yield crude 5-oxo-2,2-pyrrolidinedipropanoic acid dimethyl ester and 5-oxo-2,2-pyrrolidinedipropanoic acid monomethyl ester. The crude esters are dissolved in 100 ml of methanol and 100 ml of water and are treated with 120 g of 50% sodium hydroxide solution. The reaction mixture is stirred and is heated to 100° C. with distillation of methanol. The solution is cooled, neutralized with 130 ml of concentrated hydrochloric acid, and concentrated at reduced pressure. The residue containing 5-oxo-2,2-pyrrolidinedipropanoic acid is heated at 98°-100° C. for 24 hours with 204 gm of acetic anhydride. The sodium chloride from the neutralization is removed by filtration after the acetic anhydride reaction. The filtrate is then concentrated at reduced pressure and 200 ml of toluene is added and concentration is repeated. The resulting oil is crude tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)propanoic acid anhydride with acetic acid. The oil is stirred vigorously with water or is reacted with water in acetonitrile and the tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-propanoic acid is isolated by filtration. The tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-propanoic acid may be recrystallized from tetrahydrofuran for purification giving product with a melting point of 179°-181° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:10]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1Cl
Reactant: COCCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCCNC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 250 mg (0.88 mmol) of [(tert-butoxycarbonyl)amino](2-chlorophenyl)acetic acid, 177 mg (1.31 mmol) of HOBt, 252 mg (1.31 mmol) of EDC and 72 mg (0.96 mmol) of 2-methoxyethanamine in 6.3 ml of DMF was stirred at RT for 2 h. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 269 mg (90% of theory) of the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:39])[CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=[O:39])[CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3cccc(Cl)c3)cc2)S1
Yield: 47.2 %

Procedure:
To a stirring solution of phosphorus pentoxide (0.38 g, 1.30 mmol) in DCM (8 ml) at 0° C. was added a solution of 5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.25 g, 0.66 mmol) in DCM (8 ml) followed by dimethyl sulfoxide (0.23 mL, 3.30 mml). After stirring for 15 minutes N,N-diisopropylethylamine (0.34 mL, 2.00 mmol) was added. After 45 minutes the reaction was poured into cold sat'd NaHCO3 and the mixture was extracted with EtOAc (×2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-15% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 117 mg (47%) of a white solid. MS (ESI−) for C18H14ClNO4S m/z 374.1 (M−H)−.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:15][NH:14][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: NO
Reactant: O=C1CCc2ccccc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: ONC1CCc2ccccc2CC1
Reaction time: 8 h

Procedure:
To 6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-one (2.56 g, 16 mmol) and hydroxylamine hydrochloride (2.2 g, 32 mmol) in 27 mL of water is slowly added a solution of sodium carbonate (1.69 g, 16 mmol) in 14 mL of water. The mixture is stirred overnight. The solid is then filtered off, washed with water, and dried at 50° C. under reduced pressure to give 6,7,8,9-tetrahydro-N-hydroxy-5H-benzocyclohepten-7-amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C@H:11]1[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]1)[N:17]=[C:18]2[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
7.5 g of (−)-cis-N-[2-(3,4-dimethoxyphenyl)cyclohexyl]-3,4-dinitrobenzamide (compound A1) are dissolved in 120 ml of acetonitrile or toluene and 3.5 ml of phosphorus oxychloride and the solution is stirred overnight at 80° C. The reaction mixture is concentrated under reduced pressure and the residue is extracted with satd. sodium hydrogencarbonate solution and ethyl acetate. The organic phases are dried using sodium sulfate and concentrated. The residue is recrystallized from ethyl acetate. M.p.: 162-165° C.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:11][OH:12]>F[B-](F)(F)F.C[N+](C)(C)C>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:12][CH3:11])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)N1CCCCCC1
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCCCN1C(C)=O
Yield: 90.3 %

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 23.2 g of N-acetylhexahydroazepine and 57.7 g of methanol in the presence of 0.26 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of N-acetylhexahydroazepine the current is switched off. The calculated mean cell voltage is 40.8 volts. Work-up of the electrolysis solution gives 25.4 g of 1-acetyl-2-methoxyhexahydroazepine (boiling point 53° C./0.06 mbar; nD25 =1.4775), which corresponds to a product yield of 90.1% and a current efficiency of 71.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22](OC)=[O:23])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[CH2:12][CH2:13][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1.O.O1[CH2:36][CH2:35][CH2:34]C1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=4[Cl:21])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([C:22]([CH:34]2[CH2:35][CH2:36]2)([CH:26]2[CH2:28][CH2:27]2)[OH:23])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1Cl
Solvent: O
Product: OC(c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a solution of methyl 8-chloro-1-(2,4-dichlorophenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole-5-carboxylate (100 mg, 0.25 mmol) in tetrahydrofuran (2.5 mL) was added a solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.0 M, 1.5 mL, 1.5 mmol) at 0° C. The mixture was stirred at 60° C. for 1.5 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through the silica gel pad eluting with ethyl acetate and recrystallized from ethyl acetate to give the title compound (64.4 mg, 0.144 mmol, 57%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C1CCN2C(=NCCC2)CC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:31][C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][C:37]=1[Cl:38]>C(#N)C>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:6][C:2]([CH3:3])([CH3:1])[C:4]#[CH:5])=[CH:36][C:37]=1[Cl:38]
Reactant: C#CC(C)(C)O
Reactant: Oc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C#CC(C)(C)Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Methyl-but-3-yn-2-ol (1.68 g, 20 mmol) in acetonitrile (10 ml) was treated with DBU (20 mmol) and trifluoroacetic anhydride (20 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 20 mins and then transferred to the solution of 3,4-dichlorophenol in acetonitrile (15 ml) with DBU (22 mmol) and CuCl2.H2O (10 mg) at the same temperature over a period of about 10 mins. The reaction mixture was stirred for 2 h and then quenched with H2O. Ethyl acetate was added to extract the product twice. Organic layer was washed with brine, dried and concentrated to yield the title compound as a colorless liquid.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1)[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][O:30][C:31](=[O:41])[CH2:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35](Br)[CH:34]=1>>[CH3:29][O:30][C:31](=[O:41])[CH2:32][C:33]1[CH:34]=[C:35]([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[CH2:9][N:3]([C:4]([CH:6]2[CH2:7][CH2:8]2)=[O:5])[CH2:1][CH3:2])[CH:36]=[C:37]([Cl:39])[CH:38]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)C1CC1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: cyclopropanecarboxylic acid ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]amide and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:36])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12]
Reactant: Cn1nccc1-c1ccc(F)c([C@@]2(C)NC(=O)COC(C)(C)C2(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(F)c([C@@]2(C)NC(=S)COC(C)(C)C2(F)F)c1
Yield: 122.4 %

Procedure:
The reaction of (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-2H-pyrazol-3-yl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one (133 mg, 364 μmol) with Lawesson's reagent (120 mg, 292 μmol) in 1,4-dioxane (12 ml) yielded the (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-2H-pyrazol-3-yl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-thione (137 mg, 98% yield) as a colorless oil. MS (ISP): m/z=384.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.[B:27](OCC)([O:31]CC)[O:28]CC.Cl>C1COCC1.CCCCCC>[C:16]1([C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]([B:27]([OH:31])[OH:28])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: -80 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
An amount of 14 g (42 mmol) of 9-bromo-10-phenylanthracene was dissolved in dehydrated THF and cooled to −80° C. Then, 31.2 ml (49 mmol) of a solution of n-butyllithium in n-hexane was added dropwise. Forty minutes later, 13 g (89 mmol) of triethyl borate was added. After two-hour reaction, a diluted hydrochloric acid solution was added and allowed to stand for 12 hours. Then, the separated organic layer was recrystallized to obtain 10 g (33.6 mmol) of 10-phenylanthracene-9-boronic acid. The yield was 75.2%.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][NH2:8])#[CH:3].CN1CCOCC1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35](O)=[O:36])=[C:29]([C:38]([F:41])([F:40])[F:39])[CH:28]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][NH:8][C:35](=[O:36])[CH:34]=[CH:33][C:30]1[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][C:29]=1[C:38]([F:40])([F:39])[F:41])#[CH:3]
Reactant: COc1cc(C(F)(F)F)c(C=CC(=O)O)cn1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)C=Cc2cnc(OC)cc2C(F)(F)F)cc(F)c1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 79.5 %

Procedure:
To a suspension of 3-ethynyl-5-fluoro-4-methansulfonylaminobenzylamine hydrochloride (67 mg, 0.24 mmol) m THF (2 mL) was added N-methylmorpholine (40 μL, 0.36 mmol). After stirring for 5 minutes, 3-(6-methoxy-4-trifluoromethylpyridin-3-yl)acrylic acid (50 mg, 0.20 mmol) dissolved in THF (3 mL) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 67 mg, 0.24 mmol) were added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexane to give N-(3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl)-3-(6-methoxy-4-trifluoromethylpyridin-3-yl)acrylamide (75 mg, 66.2%) as a solid.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>ClCCCl>[F:31][C:27]1[CH:26]=[C:25]([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:10]3[CH:15]([CH2:16][N:8]([C:33]([O:35][CH:36]=[CH2:37])=[O:34])[CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CN(Cc3ccccc3)CC12
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1

Procedure:
A solution of (3aRS,7aRS)-2-benzyl-7,7-bis(3-fluorophenyl)perhydro-4-isoindolone (92.2 g) in 1,2-dichloroethane (860 cc) is treated with vinyl chloroformate (26.3 cc) and heated to reflux for 3 hours, then concentrated under reduced pressure (2.7 kPa). The residue is chromatographed (in two runs) on silica gel (particle size 0.04-0.063 mm, columns 8 cm in diameter and 35 cm high), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (75:25). The meringue-like product obtained is crystallized in isopropyl ether to give (3aRS,7aRS)-7,7-bis(3-fluorophenyl)-2-vinyloxycarbonylperhydro-4-isoindolone (50.3 g). M.p. 152° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].[H-].[Na+].[CH2:49](I)[CH3:50].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH2:49][CH3:50])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:26]=3)[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)N1c2ccc(O)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OCC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (207 mg) is dissolved in N,N-dimethylformamide (3 ml), then thereto is added sodium hydride (62.7%, 15 mg) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. After addition of ethyl iodide (50 μl) under ice-cooling, the mixture is stirred at room temperature for 2 hours. Water and ethyl acetate are added to the mixture, the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-ethoxy-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (141 mg). MS (m/z): 683 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH:25]([N:27]1C(=O)C2=CC=CC=C2C1=O)[CH3:26].C(Cl)(Cl)Cl>C(O)C.O.NN>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH:25]([NH2:27])[CH3:26]
Reactant: CC(c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(N)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Yield: 84.3 %

Procedure:
In a solution of 0.40 g of N-[1-[2-chloro-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl]ethyl]phthalimide in 10 mL of ethanol, 1.0 mL of 80% hydrazine monohydrate aqueous solution was added, and stirred under reflux with heating for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 20 mL of chloroform was added therein and insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The procedure comprising adding 20 mL of chloroform in the residue, filtering off insoluble material and distilling off the solvent under reduced pressure was repeated twice to obtain 0.26 g of the aimed product as yellow resinous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[C:16]=2[CH:15]=[CH:14]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[C:16]=2[CH:15]=[CH:14]1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3[nH]ccc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Product: Cl
Product: O=S(=O)(c1ccc(F)cc1Cl)n1ccc2c(N3CCNCC3)nccc21

Procedure:
2-Chloro-4-flourobenzenesulfonyl chloride (29.5 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (2.4 mg). LC/MS RT: 1.361 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 90%. MS: 396 (M+1)
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([N:21]([C:23](=[O:25])[CH3:24])[CH3:22])[C:18]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:16]=1[NH2:30]>O1CCOCC1>[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([N:21]([C:23](=[O:25])[CH3:24])[CH3:22])[C:18]([C:26]([F:27])([F:29])[F:28])=[CH:17][C:16]=1[NH:30][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(N(C)C(C)=O)c(C(F)(F)F)cc1N
Solvent: C1COCCO1
Product: COC(=O)c1cc(N(C)C(C)=O)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-chlorophenyl chloroformate (26 mg, 1.1 eq.) is slowly added to a solution of 5-(acetyl-methyl-amino)-2-amino-4-trifluoromethyl-benzoic acid methyl ester (36 mg, 0.12 mmoles) in dioxane (0.2 ml). The solution is stirred at 80° C. for 2 hours. The solution is evaporated to yield 5-(acetyl-methyl-amino)-2-(4-chloro-phenoxycarbonylamino)-4-trifluoromethyl-benzoic acid methyl ester after repeated trituration with hexane. Used tel quel for the next step.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])(=O)C.[OH-].[K+]>CO.O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 87.1 %

Procedure:
A solution of 7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (1.50 g, 3.73 mmol) and KOH (2 g) in MeOH (190 mL) and H2O (10 mL) is heated under reflux for 30 min, and the solvent volume is reduced to give 7-amino-4-(3-bromoanilino)-6-nitroquinazoline (1.17 g, 87%). 1H NMR (DMSO) δ10.17 (1H, brs), 9.43 (1H, s), 8.43 (1H, s), 8.15 (1H,m brs), 7.86 (1H, d, J=7.1 Hz), 7.42 (2H, brs), 7.40-7.31 (2H, m), 7.12 (1H, s).