Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[C:14]([O:18][C:19](=[O:33])[C@H:20]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]I)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:14]([O:18][C:19](=[O:33])[C@H:20]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][N:7]1[C:3](=[O:13])[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]1=[O:8])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
Sodium hydride (0.522 g,13.05 mmol) is added to a solution of phthalimide (2.33 g, 15.84 mmol) and 18-crown-6 (0.01 g) in 20 mL of N,N-dimethylformamide (DMF). After stirring at RT for 20 min, a solution of the title F compound, (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester (4.61 g,11.55 mmol) in 5 mL of DMF is added, and the solution is stirred at RT for 30 min, then at 60° C. for 8 h. The solvent is removed under reduced pressure, and the residue is partitioned between 300 mL of ethyl acetate and 225 mL of 0.05M aqueous HCl. The organic phase is washed with 100 mL water and 50 mL of brine, dried over anhydrous Na2SO4 and concentrated to give 4.83 g (100%) of (2R)-(t-butyloxycarbonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester as a tan solid: NMR(CDCl3) 1.43 (s, 9H), 1.45 (s, 9H), 1.60-1.88 (m, 4H), 3.71 (t, 2H, J=6.6), 4.18-4.26 (m, 1H), 5.06 (br d, 1H, J=7.9), 7.70-7.73 (m, 2H), 7.83-7.86 (m, 2H); IR 1712, 1500, 1155; ESI-MS 290 (M++1).
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[NH:7])[NH2:6].CCO/[CH:21]=[C:22](/[CH:24]=O)\[CH3:23].C[O-].[Na+]>CO>[CH3:24][C:22]1[CH:21]=[N:7][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:23]=1
Reactant: COC(=O)c1cccc(C(=N)N)c1
Reactant: CCO/C=C(\C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(-c2ncc(C)cn2)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
2.41 g (10 mmol) of methyl 3-carbamimidoylbenzoate acetate are suspended in 40 ml of methanol, 1.31 ml (11 mmol) of 3-ethoxymethacrolein and 2.04 ml of 30% sodium methoxide in methanol are added, and the mixture is stirred at 50° C. for 15 h. The reaction mixture is evaporated to dryness, and 100 ml of water are added. The precipitate formed is filtered off with suction and dried in vacuo. The crude product is reacted further without further purification; product: 1.65 g; ESI: 229 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)[C:42]3(C4C=CC(O)=C[C:51]=4[O:50][CH2:49]3)C2=O)C=CC=CC=1>>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([O:25][CH2:42][CH2:49][O:50][CH3:51])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(O)cc12
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(O)ccc12
Product: COCCOc1ccc2c(c1)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2.68 and making non-critical variations using 1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 1′-(diphenylmethyl)-5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.44-7.25 (m, 10H), 7.15-7.07 (m, 1H), 7.04 (s, 1H), 7.00-6.90 (m, 2H), 6.58-6.44 (m, 3H), 6.41-6.33 (m, 1H), 4.86 (ABq, 2H), 4.15-3.98 (m, 2H), 3.75-3.66 (m, 2H), 3.41 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[F:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccccc1OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a mixture of 3-fluoroisonicotinic acid (2.20 g, 15.6 mmol), 2-(benzyloxy)aniline (2.84 g, 14.2 mmol) and BOP (6.94 g, 15.6 mmol) in DMF (20.0 mL) was added TEA (4.4 mL, 31.2 mmol). The reaction mixture was stirred at room temperature for 20 min and poured into water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to a quarter volume. The resulting solid was found to be the desired compound. The filtrate was concentrated in vacuo to dryness. The residue was triturated in 30% ethyl acetate in hexanes and the 2 solids were combined to afford compound 24 (4.45 g, 97%) as a white solid. LRMS (ESI): (calc) 322.11 (found) 323.2 (MH)+.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[C:14]1([CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[N:15]=[N:16][N:17]2[C:22]=1[C:21]1[CH:23]=[CH:24][NH:25][C:20]=1[N:19]=[CH:18]2.O>O1CCCC1>[C:14]1([CH:26]2[CH2:31][CH2:30][C:29](=[CH:3][C:1]#[N:2])[CH2:28][CH2:27]2)[N:15]=[N:16][N:17]2[C:22]=1[C:21]1[CH:23]=[CH:24][NH:25][C:20]=1[N:19]=[CH:18]2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Diethyl (cyanomethyl)phosphonate (37.0 μL, 0.235 mmol) in tetrahydrofuran (1 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 10.0 mg, 0.235 mmol) under cooling with ice and then stirred for 30 minutes. The reaction mixture was mixed with 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanone (20.0 mg, 0.0783 mmol) obtained in Synthetic Examplea 82 and then stirred at room temperature for 30 minutes. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2→1/1→1/0 (v/v)) to give the title compound as a colorless solid (20.0 mg, yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCOCC1
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 72 %

Procedure:
As described for example 19b, 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (98 mg, 0.3 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (89 mg, 72%) which was obtained as a white foam. MS: m/e=413.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:19]=1[N+:35]([O-:37])=[O:36]>CN(C)C(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:18]2[C:19]([N+:35]([O-:37])=[O:36])=[C:20]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)[N:21]=[CH:22][N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
(S)-3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.65 mmol, 131 mg) and sodium hydride (1.3 mmol, 31 mg) were dissolved in N,N-dimethyl acetamide (1.5 mL) and stirred for 30 minutes at room temperature. Then, (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.26 mmol, 84 mg) was added. The reaction was stirred at 70° C. for 30 minutes. Its progress was monitored by thin layer chromatography and LCMS. Sodium hydride was quenched with water and the desired compound was extracted in ethyl acetate. Organic solvents were evaporated in vacuo. Flash chromatography (Silica gel 60; 50/50 EtoAc/Hexanes) provided Compound A17 as a yellow solid (26 mg, 15%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.22 (s, 1H), 8.41 (s, 1H), 7.97 (d, 2H), 7.87 (d, 2H), 4.52 (m, 2H), 3.49 (m, 2H), 3.09 (s, 3H), 2.75 (m, 1H), 1.97 (m, 2H), 1.67 (m, 2H), 1.49 (s, 9H). LCMS (ESI), m/z 394.1 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH2:38][CH:33]([O:32][CH3:31])[CH2:34][CH2:35]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: COC1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methoxy-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-methoxy-piperidine following General Procedure B.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]3[N:24]([CH:32]([CH3:34])[CH3:33])[C:23]2=[O:35])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[CH3:31][C:29]1[CH:30]=[C:25]2[N:24]([CH:32]([CH3:33])[CH3:34])[C:23](=[O:35])[N:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:21][CH:20]=3)[C:26]2=[N:27][CH:28]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (198 mg) and 3-(4-hydroxyphenyl)-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (177 mg) in DMF (1.5 ml) was added NaH (40.0 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (125 mg) as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[C:6]([O:31][CH3:32])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[C:17]([C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:18]=1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), morpholine (29 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (35 mg, yield 64%).
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[OH:1][C:2]1([CH3:20])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:21](=[O:23])[CH3:22])=[C:13]([O:18][CH3:19])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1O
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg of 3-hydroxy-3-methyl-7-(p-hydroxy-m-methoxyphenyl)-5-heptanolide in 1 ml of pyridine was added 1 ml of acetic anhydride and the mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. Evaporation of the solvent from the extract yielded the desired compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[F:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[F:48])[C:41](=O)[CH2:42]Br>>[F:35][C:33]([F:34])([F:36])[C:24]1[CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:42]=[C:41]([C:40]2[CH:45]=[CH:46][C:47]([F:48])=[C:38]([F:37])[CH:39]=2)[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:18])([CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(-c3ccc(F)c(F)c3)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3,4-difluorophenacyl bromide.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:12])([O-:11])[O-:10])=[C:5]([CH:13](Br)[CH3:14])[C:4]=1CC)C.Cl[C:19]1C=CC=C[C:20]=1Cl>>[CH2:19]([O:10][P:9]1(=[O:12])[C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=2[CH:13]([CH3:14])[O:11]1)[CH3:20]
Reactant: CCc1ccc(P(=O)([O-])[O-])c(C(C)Br)c1CC
Reactant: Clc1ccccc1Cl
Product: CCOP1(=O)OC(C)c2ccccc21
Yield: 55 %

Procedure:
A mixture of diethyl-2-(1-bromoethyl)phenylphosphonate (12 g, 0.037 mole) in 25 ml. of 1,2-dichlorobenzene was refluxed for 2 hours. The reaction mixture was vacuum distilled to yield 1-ethoxy-3-methyl-1,3-dihydro-2,1-benzoxaphosphole-1-oxide (4.3 g, 55% yield) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>[Pt].C.O1CCOCC1.C(N(CC)CC)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1
Reactant: NC(=O)c1ccc(C2CCC(=CCC3OCCO3)CC2)cc1
Agent: [Pt]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc([C@H]2CC[C@H](CCC3OCCO3)CC2)cc1

Procedure:
A mixture of 500 mg of 4-[4-[2-(1,3-dioxolan-2-yl)ethylidene]cyclohexyl]benzamide and 20 ml of dioxan/triethylamine (vol. 9:1) was hydrogenated in the presence of 500 mg of 10 percent platinum-charcoal for 2 hours. The reaction mixture was then filtered and the filtrate was evaporated. Recrystallization of the evaporation residue from 40 ml of dioxan gave 230 mg of 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]benzamide as colorless crystals.
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1.Cl.[CH3:23][N:24](C)C=O>>[C:23]([C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1)#[N:24]
Reactant: CN(C)CCC=C1c2cc(I)ccc2CCn2cccc21
Reactant: CN(C)C=O
Agent: Cl
Product: CN(C)CCC=C1c2cc(C#N)ccc2CCn2cccc21
Reaction time: 0.5 h

Procedure:
A stirred mixture of 1 gm. of 9-iodo-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine, 1 gm. of cuprous cyanide, and 5 ml. of dimethylformamide is heated to reflux for 5 hr. The mixture is then poured into a solution of 4 gm. of ferric chloride hydrate in 25 ml. of 2 N hydrochloric acid. After stirring the resulting mixture at 60° for 30 min., it is extracted with 3 × 50 ml. of ethyl acetate. The aqueous acidic solution is then basified with sodium hydroxide and extracted with 3 × 50 ml. of ether. The combined ether extracts are then dried and evaporated to yield 9-cyano-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)#[N:3].CO[C:14](=[CH2:17])[C:15]#[N:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[NH2:16][C:15]1[CH:14]=[CH:17][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2)[N:11]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: C=C(C#N)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#Cc1ccc(-n2ccc(N)n2)cc1

Procedure:
Suspend 4-cyanophenyl hydrazine hydrochloride (5 g, 29.58 mmol) in tert-butanol (60 mL). Add methoxyacrylonitrile (2.458 g, 29.58 mmol) and potassium tert-butoxide (3.975 g, 35.49 mmol) and heat the mixture at 90° C. overnight. Concentrate in vacuo and partition the residue between EtOAc/water. Extract the organic phase with 10% hydrochloric acid. Neutralize the aqueous phase with saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain a solid that was washed with ether/hexane. Filter and dry the solid in vacuo to obtain the desired intermediate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:23]([F:22])([CH3:27])[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(F)CNC1
Agent: Cl
Product: CC1(F)CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1
Yield: 24 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with 3-fluoro-3-methylazetidine hydrochloride (CAN 1427379-42-7, 10.6 mg, 84.4 μmol) to obtain the title compound (6 mg, 24%) as off-white solid, MS (ESI): m/e=356.2 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[C:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reaction time: 96 h
Yield: 70.9 %

Procedure:
In pre-dried apparatus, held under a CaCl2 guard tube, 2,5-dibromopyridine (0.524 g), tert-butyl piperazine-1-carboxylate (0.824 g) and sodium carbonate (0.234 g) were combined in anhydrous 1-methyl-2-pyrrolidinone (10 ml) and heated in an oil bath held at 100° C. for 4 days. The mixture was then cooled, poured onto water (350 ml) and extracted with diethyl ether (3×50 ml). The combined organic extracts were washed with 2% citric acid solution (2×25 ml), water (2×25 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was then purified by silica gel column chromatography, with 30% diethyl ether/hexane as eluent, to provide the title compound as a white solid (0.537 g, 71%).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:19][C:20](Cl)=[O:21]>C(#N)C>[CH2:1]([N:8]1[C:20](=[O:21])[CH2:19][O:11][CH2:10][C@H:9]1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
A 5 L 3-neck round bottom flask was charged with (S)-(+)-N-benzylserine (229 g, 1.17 mol), sodium hydroxide (58.7 g, 1.47 mol), and water (1 L). The resulting solution was cooled to 0° C. and chloroacetyl chloride (170.4 g, 1.5 mol) added dropwise at a rate to maintain the temperature below 4° C. After addition was complete the reaction was stirred at 0° C. for 30 minutes. The cold bath was then removed and a solution of 30% sodium hydroxide (350 mL) added. An exotherm was observed and the reaction temperature reached 29° C. The reaction mixture was further heated to 33° C. and maintained at this temperature for 2 hours. Cooling to room temperature followed by acidification to pH 1 with 37% hydrochloric acid resulted in the formation of a thick white precipitate, which was isolated by filtration. The filter cake was slurried in acetonitrile (1 L), filtered, and the filtrate concentrated. Drying of the resulting solid afforded 68.1 g (25%) of (S)-(+)-4-benzylmorpholin-5-one-3-carboxylic acid as a crystalline white solid.