Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:43]=[CH:42][C:12]([CH2:13][N:14]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:26]CC3C=CC(OCC4C=CC=CC=4)=CC=3)=[N:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([OH:26])=[N:15]2)=[CH:42][CH:43]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A mixture of ethyl(E)-3-[1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-yl]propenoate (6.61 g), 5% palladium-carbon (13.00 g), ethanol (150 ml), and tetrahydrofuran (150 ml) was stirred for one hour at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to yield ethyl 3-[1-(4-hydroxybenzyl)-3-hydroxy-1H-pyrazol-4-yl]propionate (2.98 g, yield: 89%). This was recrystallized from ethyl acetate-hexane. Melting point: 143–144° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH:7]([NH:23][C:24](=[O:45])[CH:25]([NH:30]CC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.[O:53]1CCCC1>>[C:1]([O:5][C:6](=[O:46])[CH:7]([NH:23][C:24](=[O:45])[CH:25]([NH:30][CH:50]1[CH2:51][CH2:52][O:53][CH2:48][CH2:49]1)[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCNCC1
Reactant: C1CCOC1
Reactant: CC(C)CC(NCC1c2ccccc2-c2ccccc21)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Product: CC(C)CC(NC1CCOCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
A solution of [S-(R*,R*)]-3-(4-benzyloxy-phenyl)-2-{2-[(9H-fluoren-9-ylmethyl)-amino]-4-methyl pentanoylamino}-propionic acid tert-butyl ester (12.2 g, 20.0 mmol) in 500 mL of tetrahydrofuran was treated with piperidine (80 mL). The resulting solution was stirred at room temperature for 48 hours. The reaction mixture was concentrated and the residue purified by chromatography (SiO2, gradient elution EtOAc - 15% EtOH/EtOAc). The resulting yellow solid was broken up in heptane to give the title compound as a white solid (6.77 g, 77%).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[CH2:6][C:7](=O)[CH3:8].S(=O)(=O)(O)O>O1CCCC1>[CH2:7]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH2:6]1.[CH3:4][C:5]1([CH3:10])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH3:1])([CH3:8])[CH2:6]1
Reactant: C[Mg]Br
Reactant: CC(=O)CC(C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)c2ccccc21
Product: c1ccc2c(c1)CCC2
Temperature: 25 °C
Yield: 85.5 %

Procedure:
Methyl magnesium bromide (3M solution in diethyl ether, 22.2 mL, 66.6 mmol) was added slowly to a solution of 4-methyl-4-phenyl-pentan-2-one (Compound 40, 7.8 g, 44.3 mmol) in 50 mL of tetrahydrofuran (THF) at 0° C. After stirring and warming to room temperature for 2 h, the mixture was quenched with water at 0° C., extracted with ethyl acetate (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure to give a light yellow oil. The crude oil was then added slowly to 80% concentrated sulfuric acid at 0° C. and the resulting brown mixture was stirred at 0° C. for 1 h. The mixture was then slowly diluted with ice water, extracted with pentane (3×15 mL) and washed with brine (1×15 mL). After the extract was dried (MgSO4) and concentrated at reduced pressure, high-vacuum distillation of the residue afforded indan the title compound (3.3 g, 43% yield) as a colorless oil:
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].C(O)CC#C.CCCCC>C(Cl)Cl>[O:12]([CH2:2][CH2:3][C:4]#[CH:5])[S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Agent: C#CCCO
Solvent: ClCCl
Solvent: CCCCC
Product: C#CCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.6 %

Procedure:
The compound was prepared following a procedure of Hummel et al. Liebigs Ann. Chem. 746, 211-213 (1971). Anhydrous pyridine (20.0 mL, 19.6 g, 0.248 mol) was added to a stirred solution of trifluoromethanesulfonic anhydride (70.0 g, 0.248 mol) in anhydrous CH2Cl2 (500 mL) at 0° C. over a dry nitrogen atmosphere in an oven-dried apparatus. A heavy white precipitate formed immediately, and the resulting slurry was stirred for 15 min at 0° C. A solution of 3-butyn-1-ol (16.6 g, 0.236 mol) in anhydrous CH2Cl2 (80 mL) was added dropwise at 0° C. The slurry was warmed to room temperature and stirred for 2 h. Pentane (1000 mL) was added and the precipitated salts were filtered and washed with pentane. Fractional distillation of the combined filtrates gave 39.9 g (84% yield) of 3-butynyl triflate as a colorless liquid:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(Nc1cc(-c2cnccn2)ccc1[N+](=O)[O-])N1CCCC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(-c2cnccn2)cc1NC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 1 N-(2-nitro-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.11 g, 0.35 mmol) in methanol (6 mL) and THF (6 mL) was added Pd/C (0.04 g, 0.94 mmol, 0.33 equiv.). The reaction mixture was degassed then stirred at room temperature under H2 atmosphere for 1 h. The reaction was filtered through celite and concentrated. The crude solid was washed with ether, and dried under reduced pressure to obtain of pure N-(2-amino-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.07 g, 70% yield). ESI+ MS: m/z 284([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.30 (s, 1H), 8.55 (s, 1H), 8.40-8.39 (m, 1H), 7.88 (s, 1H), 7.71-7.69 (m, 1H), 7.53 (s, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.31 (s, 2H), 3.40-3.37 (m, 4H), 1.86 (m, 4H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC([Cl:35])=CC=2)=CSC=1C(OC)=O.C([O:47][CH2:48]C)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[Cl:35][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([O:47][CH3:48])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1scc(-c2ccc(Cl)cc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: COc1ccc(N)cc1
Product: COc1ccc(-n2cnc3c(-c4ccc(Cl)cc4)csc3c2=O)cc1
Yield: 70 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylate (100 mg, 0.373 mmol), triethyl orthoformate (2 ml), p-anisidine (85.56 mg, 0.70 mmol), and acetic acid (0.1 ml) were used to give 97 mg (0.26 mmol, 70% yield) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[Ca:36].C(C(CCCC)C([O-])=[O:41])C>CC(CC(C)C)=O.O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[OH2:41].[OH2:5].[Ca+2:36]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reactant: [Ca]
Reactant: CCCCC(CC)C(=O)[O-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Product: [Ca+2]
Temperature: 5 °C
Reaction time: 24 h

Procedure:
Pseudomonic acid (10.00 g, 20 mmole) was dissolved in isobutyl methyl ketone (100 ml) at 40° C. Calcium-2-ethyl-hexanoate (3.32 g, 10 mmole) was suspended in water (50 ml). (It is possible to obtain a solution by using a larger amount of water or an alcohol/water mixture). The solution of pseudomonic acid was added to the calcium-2-ethyl-hexanoate suspension, and the two phase system were stirred for 24 hours. The two phases were then separated, isobutyl methyl ketone (25 ml) was added to the aqueous phase, and stirred for 10 minutes. The two resulting phases were separated, and any traces of isobutyl methyl ketone was evaporated from the aqueous phase. The aqueous mupirocin calcium suspension was cooled in a refrigerator at 5° C. The solid mupirocin calcium dihydrate was filtered, washed with water (20 ml) and dried under vacuum at 35° C. for 14 hours. The mass of product was 7.95 grams. Assay 97.72%, water: 3.45%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25](O)=[O:26])=[CH:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:30]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([NH2:30])=[O:26])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Temperature: 150 °C

Procedure:
A mixture of 1.65 g 1-(4-fluorophenyl)-1,4-di-hydro4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylic acid, 2.2 g of 1,1'-carbonyldiimidazole and 15 ml dimethylformamide (DMF) was heated at 150° C. for 1.5 hrs. The reaction mixture was poured into 50 ml concentrated ammonium hydroxide. The product was extracted with methylene dichloride and recovered therefrom to give 2.2 g 1-(4-fluorophenyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide which was converted to its monomethanesulfonate salt hemihydrate, m.p. 301°-303° C. (decompn.). The free base, prepared from the salt with potassium carbonate solution, had m.p. 315°-317° C. when recrystallized from DMF.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([O:32][CH2:33][CH2:34]Cl)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:34][CH2:33][O:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: COc1ccc(OCCCl)cc1OC
Product: COc1ccc(OCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(3,4-dimethoxyphenyloxy)-ethyl chloride analogously to Example 3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.O>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 110.5 %

Procedure:
Indole-5-carboxylic acid (1.00 g, 6.21 mmol) was dissolved in DMF (10 mL) and the solution was added with EDCI (2.38 g, 12.4 mmol), HOBT monohydrate (839 mg, 6.21 mmol) and 1-(tert-butoxycarbonyl)piperazine (1.73 g, 9.29 mmol), followed by stirring at room temperature for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, 1 mol/L hydrochloric acid, and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5-[4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indole (2.26 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:15])([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:23][C:24]([C:26]2[N:27]=[N:28][C:29]([CH2:45][CH2:46][CH2:47][CH3:48])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:34][CH:33]=3)[CH:31]=2)=O)=C(F)C(F)=C(F)C=1F>ClCCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:15][C:24]([C:26]2[N:27]=[N:28][C:29]([CH2:45][CH2:46][CH2:47][CH3:48])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:34][CH:33]=3)[CH:31]=2)=[O:23])([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CO)C1
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCCc1nnc(C(=O)NC2(CO)CCN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 mmol, 0.21 g) in anhydrous DCE (2 mL), 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.5 mmol, 0.26 g) and TEA (0.5 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with NaOH (0.5 M) solution, water, and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (7:3) to provide 3-{[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+]([O-])=O)=[CH:6][CH:5]=1)=O.[N-]=[N+]=[N-].C(N([CH:22]([CH3:24])[CH3:23])CC)(C)C.[C:25](OCC)(=O)C.CO>CN(C=O)C>[CH:24]1[CH:22]=[CH:23][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][C:4]=2[OH:3])[CH:25]=1
Reactant: CCOC(C)=O
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Agent: [N-]=[N+]=[N-]
Solvent: CO
Solvent: CN(C)C=O
Product: Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.6 mgs of p-nitrophenyl formate was added to a stirred solution of 22.4 mgs of the amine (i) and 7 microliters of diisopropylethyl amine in 2 ml of DMF. The resulting mixture was stirred overnight at room temperature, partitioned between ethyl acetate and water. Aqueous workup and purification of the crude reaction product by column chromatography on silica gel using ethyl acetate/methanol (10:1) as the eluant gave the desired formamide (ii) (15.8 mg) as a white solid. FABMS MH+, 653.2.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccccc1B(O)O
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: COc1ccccc1-c1nnc(N)nc1-c1ccccc1
Yield: 48.5 %

Procedure:
6-(2-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (108 mg, 48%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 2-methoxyphenyl boronic acid (0.137 g, 0.90 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].[CH3:8][CH:9]1OC(C)OC(C)O1.[CH:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].P(=O)(O)(O)O>O.C(O)=O>[CH2:8]([C:5]1[S:4][C:3]([CH:1]([NH:26][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)[CH3:2])=[CH:7][CH:6]=1)[CH3:9]
Reactant: CCc1cccs1
Reactant: CC(C)c1ccc(C(N)=O)cc1
Reactant: CC1OC(C)OC(C)O1
Agent: O=P(O)(O)O
Solvent: O=CO
Solvent: O
Product: CCc1ccc(C(C)NC(=O)c2ccc(C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
2-Ethylthiophene (5.60 g, 0.05 mol), paraldehyde (2.20 g, 0.017 mol) and 4-isopropylbenzamide (1.63 g, 0.01 mol) were added to a mixture of formic acid (6 ml) and 85% phosphoric acid (3 ml) and stirred at a room temperature for four hours. Water (50 ml) was added to the reaction mixture. The mixture was extracted with chloroform (50 ml) and subjected to a silica gel column chromatography (eluent: chloroform) to obtain the entitled compound (2.5 g) as a viscous yellow brown liquid. Yield: 83.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.BrC1C=C2C3(CCNC3)CN(C(NC3SC(Cl)=CN=3)=O)C2=CC=1.[C:47]([CH2:49][C:50](O)=[O:51])#[N:48]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:50](=[O:51])[CH2:49][C:47]#[N:48])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: N#CCC(=O)O
Agent: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Product: N#CCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 23, with the exceptions that the 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 39 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that cyanoacetic acid was used instead of formic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[F:14][C:15]([F:27])([F:26])[O:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH2:25])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO.O>[F:14][C:15]([F:26])([F:27])[O:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH:25][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.7 %

Procedure:
4-Trimethylsilanyl-benzaldehyde (178 mg, 1 mmol), 2-(3-trifluoromethoxy-phenyl)-ethyl-amine hydrochloride (241 mg, 1.1 mmol) and triethyl amine (151 mg, 1.5 mmol) were dissolved in methanol (5 ml) and the solution was stirred at rt for 5 min. Sodium borohydride (37 mg, 1 mmol) was added under nitrogen and the reaction mixture was stirred at rt for 1 h. Water was added and methanol was evaporated in vacuo. The reaction was extracted twice with diethyl ether and the combined organic layers were washed once with water and once with sat. aq. NaCl solution, dried with sodium sulfate, filtered off and concentrated in vacuo to yield [2-(3-trifluoromethoxy-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine (370 mg, 100%) as a colorless oil. MS (ISP) 368.2 (100) (M+H)+.
Reaction SMILES: N.[Li].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15]CC2C=CC=CC=2)[CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(C)(C)C>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
In a flask purged with ammonia gas, about 150 mL of liquid ammonia is collected with ammonia condenser at −78° C. To the liquid ammonia is added portion wise lithium metal (116 mmol; 805 mg) at the same temperature. To the deep blue solution is added a solution of (2R,4R)-4-benzyloxy-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (29.1 mmol; 8.90 g) and tert-butanol (58.2 mmol; 4.31 g) in THF (30 mL). After stirring for 2 hours, the reaction mixture is quenched with MeOH, and then warmed to ambient temperature. The mixture is diluted with water, then aqueous 1M HCl is added to reach pH 8-9. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to give (2R,4R)-4-hydroxy-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6.25 g, 99.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[Cl:29][CH2:30][CH2:31][CH2:32][C:33]#[CH:34]>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][Cl:29])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: C#CCCCCl
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#CCCCCl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
Ethyl 6-chloro-8-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 73, Step 2) (1.50 g, 3.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.174 mmol), copper(I)iodide (0.066 g, 0.347 mmol), and triethylamine (1.05 g, 10.4 mmol) were dissolved in toluene (50 mL). 5-Chloro-1-pentyne (0.53 g, 5.20 mmol) was added via syringe and the mixture stirred for 18 hours at room temperature. The reaction was diluted with diethyl ether (50 mL), extracted with 0.5 N HCl (2×25 mL), and water (2×25 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield an orange oil. The crude material was purified by flash chromatography in 2% ethyl acetate in hexane. Recrystallization from hexane afforded the ester as a white solid (0.96 g, 68%): mp 84.8–85.9° C. 1H NMR (CDCl3/300 MHz) 7.61 (s, 1H), 7.33 (d, 1H, J=2.6 Hz), 7.14 (d, 1H, J=2.6 Hz), 5.79 (q, 1H, J=6.7 Hz), 4.37−4.29 (m, 2H), 3.75 (t, 2H, J=6.7 Hz), 2.67 (t, 2H, J=6.7 Hz), 2.11–2.03 (m, 2H,), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 424.1 (M+NH4+). ESHRMS m/z 424.0694 (M+NH4+, Calc'd. 424.0694). Anal. Calc'd. for C18H15Cl2F3O3: C, 53.09; H,3.71;, Cl,17.41. Found: C, 53.02; H, 3.90; Cl, 17.63.