Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[N:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH2:60][CH2:61][NH-:62].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH2:60][CH2:61][NH-:62]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCc1ccccn1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 140 mg of Z-Phe-His-OH, 100 mg of H-Leu-Val-Ala-2-(2-pyridyl)-ethyl amide, 50 mg of HOBt and 66 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.26, Rf (B11)=0.45.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:4])=[O:3].C(O)(=[O:16])C.C(OC(=O)C)(=O)C>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:12][OH:16])[C:6]=1[CH3:13])(=[O:4])=[O:3]
Reactant: CC(=O)O
Reactant: Cc1c(S(C)(=O)=O)cc[n+]([O-])c1C
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: Cc1c(S(C)(=O)=O)ccnc1CO
Temperature: 80 °C

Procedure:
To a mixture of (4-Methanesulfonyl-2,3-dimethyl-pyridine)-1-oxide (24 g) and acetic acid (50 ml) was added acetic anhydride (28.2 ml), followed by heating to reflux and maintaining the same temperature for about 3 hrs. The reaction mass was cooled to 80° C. and methanol (25 ml) was added followed distilling off the solvent completely under vacuum. THF:methanol (125:25 ml), LiOH (7.5 g) was added to the crude at 25-30° C. followed by adding DCM (100 ml) to the reaction mixture and extraction with (2×150 ml) DCM. All the organic layers were combined and washed with saturated sodium chloride solution (25 ml). The organic layer was dried over sodium sulphate and distilled off completely under vacuum. Subsequently, n-hexane (100 ml) was added to the reaction mass, the compound filtered and washed with n-hexane (10 ml). The wet compound was then dried at 50-55° C. to yield 14 g of the title compound characterized by 1HNMR data (300 MHz): δ 2.58 (s, 3H), 3.13 (s, 3H), 4.62 (s, 1H), 4.80 (s, 2H), 7.86 (d, 1H), 8.68 (d, 1H) and mass [M]+: 202.06.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7]2)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7]2
Reactant: CC(C)(C)OC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Yield: 96.8 %

Procedure:
A 500 mL Par hydrogenation bottle was charged with compound 10 (5.80 g, 22.14 mmol), 10% Pd/C (0.6 g) and methanol/THF (150 mL, 1:4 v/v), and purged with hydrogen. The reaction mixture was shaken with 50 psi H2 over night. The catalyst was removed by filtration and the solvent was evaporated to give 4.98 g (97% yield) of the title compound 11 as brown solid. 1H NMR (DMSO), 11.42 (s, 1H), 7.18 (d, 1H, J=8.3 Hz), 6.83 (s, 1H), 6.71 (s, 1H), 6.67 (d, 1H, J=8.4 Hz), 1.62 (s, 9H). This product is unstable and therefore it was immediately used in the following step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]I.Br[C:14]1[C:15](=[O:26])[NH:16][C:17](=[O:25])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:14]2[C:15](=[O:26])[NH:16][C:17](=[O:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:2]1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]I
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1ccccc1
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of 4.9 g of indole in 50 ml of benzene was treated with 19 ml of a 3M solution of methylmagnesium iodide in diethyl ether and stirred under nitrogen for 15 minutes. 3.5 g of 3-bromo-4-phenyl-1H-pyrrole-2,5-dione were added and the mixture was stirred for 18 hours. The solvent was evaporated and the residue was dissolved in 250 ml of dichloromethane and 50 ml of 2M hydrochloric acid. The organic extracts were washed with water, dried and evaporated. The residue was purified on silica gel with ethyl acetate/petroleum ether. Trituration with dichloromethane and recrystallization from methanol yielded 1.40 g of 3-(3-indolyl)-4-phenyl-1H-pyrrole-2,5-dione, m.p. 256° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([F:32])[CH:26]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:23])[NH:29][C:28]1[CH:30]=[CH:31][C:25]([Br:24])=[CH:26][C:27]=1[F:32])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Br)cc1F

Procedure:
(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4.45 g, 12.9 mmol) was dissolved in 50 mL dry CHCl3 under an Ar atmosphere, added 4-bromo-2-fluoroaniline (2.45 g, 12.9 mmol), EEDQ (3.8 g, 15 mmol), and triethylamine (2.6 mL, 19.3 mmol). Reaction was refluxed for 6 hours, cooled and concentrated. Redissolved in EtOAc (250 mL), washed with 10% HCl (2×200 mL), 0.1M NaOH (2×200 mL), water, brine, dried with MgSO4, filtered and concentrated to yield title compound. (5.5 g, 82%) APCI (AP−): 515.1, 517.1 (M−H)−. Step 4: (2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[NH2:33][C@@:34]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][C:38]2([CH2:40][CH2:39]2)[C@@H:37]2[C@H:35]1[C@H:36]2[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([NH:33][C@@:34]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][C:38]2([CH2:40][CH2:39]2)[C@@H:37]2[C@H:35]1[C@H:36]2[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)CC21CC1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)(C(=O)OCC)CC21CC1
Temperature: 22.5 °C
Yield: 100 %

Procedure:
Charge tetrahydrofuran (45 mL, 10 volumes) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (3.4 g, 1.2 equivalents) to a reactor followed by N-methylmorpholine (1.96 mL, 1.2 equivalents) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (3.12 g, 1.2 equivalents). Stir the resulting thin slurry between 20-25° C. for at least 3 hours until the reaction is complete by HPLC. Charge diethyl (1S,2S,5R,6S)-2-aminospiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate hydrochloride (4.55 g, 14.81 mmol) in one portion between 20-25° C. followed by N-methylmorpholine (1.63 mL, 1.0 equivalents) over at least 10 minutes keeping the temperature between 20-25° C. Stir the resulting slurry between 20-25° C. for at least 2 hours until the reaction is complete by HPLC. Filter the resulting solids and wash the wet cake with tetrahydrofuran (2×10 mL, 2.2 volumes) to provide the title compound assuming 100% yield. Use the pale amber tetrahydrofuran solution of the title compound without further purification assuming a 100% yield. 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (s, 1H), 6.72 (d, J=7.9, 1H), 4.08-3.92 (m, 5H), 2.42-2.37 (m, 1H), 1.81-1.64 (m, 3H), 1.47 (dd, J=6.6, 3.1, 1H), 1.34 (s, 9H), 1.18-1.08 (m, 9H), 0.66-0.59 (m, 1H), 0.57-0.52 (m, 1H), 0.46-0.36 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([OH:3])=O.[C:12](C1NC=CN=1)([C:14]1[NH:15][CH:16]=[CH:17]N=1)=O.C(NCC)C.O>O1CCCC1>[CH2:14]([N:15]([CH2:16][CH3:17])[C:1](=[O:3])[C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=1)[CH3:12]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCNCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cccc(C=O)c1
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution of 3-carboxybenzaldehyde (5.0 g, 33.3 mmol) in 50 mL of tetrahydrofuran was added carbonyl diimidazole (5.67 g, 35.0 mmol) under Argon. After 1 h of stirring, diethylamine (4.87 g, 66.7 mmol) was added, and the reaction mixture was stirred for 18 h and then refluxed one hour. After cooling, water (50 mL) was added to the reaction flask, and the contents were concentrated on a rotary evaporator. The resulting mixture was extracted three times with dichloromethane (50 mL). These extracts were combined, washed twice with 1 N aqueous hydrochloric acid solution (50 mL) and twice with water (50 mL), dried (Na2SO4), and concentrated to give a yellow oil. This material was purified on flash silica gel (1% methanol-chloroform to 3% methanol-chloroform) to provide 4.68 g (68% yield) of N,N-diethyl(3-formyl)benzamide as a light green oil. MS (ES), m/z 206 (MH+). 300 MHz 1H NMR (CDCl3) δ1.13 (br s, 3H), 1.27 (br s, 3H), 3.26 (br d, J=5.5 Hz, 2H), 3.58 (br d, J=5.5 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.87-7.96 (m, 2H), 10.04 (s, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([I:15])[C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>O1CCOCC1>[I:15][C:7]1[C:8]([CH3:14])=[C:9]([CH:13]=[C:5]([S:2]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:4])=[O:3])[CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: Cc1c(I)cc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: C1CCNC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1c(I)cc(S(=O)(=O)N2CCCC2)cc1C(=O)O
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with 5-(chlorosulfonyl)-3-iodo-2-methylbenzoic acid (1.00 g, 2.77 mmol), pyrrolidine (0.278 mL, 3.33 mmol), 1,4-dioxane (4 mL) and pyridine (0.20 mL, 2.5 mmol). The mixture was stirred for 30 minutes. The solvent was removed and the residue was purified by flash chromatography to yield the compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(O)CO>O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(C(F)(F)F)c1
Solvent: OCCO
Solvent: O
Product: CCOC(=O)Cn1c(-c2cccc(C(F)(F)F)c2)nc2cccnc21
Yield: 88.3 %

Procedure:
A mixture of N-[3-[[3-(trifluoromethyl)benzoyl]amino]-2-pyridinyl]glycine ethyl ester (22.0 g, 0.06 mole) and ethylene glycol (100 ml) was heated at reflux for 40 minutes. The reaction mixture was poured into water (300 ml) and cooled. The solid was collected by filtration, washed with water (200 ml), and dried. The solid was recrystallized from isopropyl ether-tetrahydrofuran to give in 2 crops 18.4 g (0.053 mole) of crude 2-(3-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester. This solid together with potassium hydroxide pellets (4.7 g, 0.084 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed for 21/2 hrs. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (100 ml) and extracted with methylene chloride (2×30 ml). The aqueous portion was acidified with glacial acetic acid and filtered after precipitation was complete. The filter cake was suspended in water (200 ml) and filtered. Recrystallization from tetrahydrofuran-isopropyl ether gave 15.3 g (91%). A 1.6-g sample was recrystallized from tetrahydrofuran-isopropyl ether to give 1.0 g of an off-white solid, mp 240°-241.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[Cl:9][CH2:10][C:11](=O)[CH2:12]Cl>CCOC(C)=O>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:12]=1
Reactant: NC(=O)c1cccs1
Reactant: O=C(CCl)CCl
Solvent: CCOC(C)=O
Product: ClCc1coc(-c2cccs2)n1
Yield: 62.9 %

Procedure:
Thiophene-2-carboxamide (0.8 g, 6.29 mmol) and 1,3-dichloropropan-2-one (0.96 g, 7.55 mmol) were heated at 150° C. for 2.5 hours. The dark solid was dissolved in EtOAc and washed with aqueous NaHCO3, then the organic phase was dried over Na2SO4, filtered and evaporated to dryness. The dark brown oil was purified by flash chromatography (Petroleum ether/EtOAc=9/1) to obtain 4-(chloromethyl)-2-(thiophen-2-yl)oxazole (790 mg, 63% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4](P(OCC)(OCC)=O)[CH2:5][CH3:6].[H-].[Na+].[C:18]([O:22][C:23]([C:25]1[S:26][C:27]([CH:30]=O)=[CH:28][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([C:25]1[S:26][C:27](/[CH:30]=[C:4](/[C:3]([O:2][CH3:1])=[O:15])\[CH2:5][CH3:6])=[CH:28][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOP(=O)(OCC)C(CC)C(=O)OC
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)OC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2-(diethylphosphono)butyric acid methyl ester (46 g, 0.193 mol) was dissolved in tetrahydrofuran (300 mL), 60% sodium hydride (6.6 g, 0.165 mol) was added at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 5-formyl-2-thiophenecarboxylic acid tert-butyl ester obtained in Example 1, step 2(32.1 g, 0.15 mol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N-hydrochloric acid solution, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography to give the title compound (35.6 g, 0.12 mol, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>[Pd].CO.[H][H]>[NH2:21][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reaction time: 2 h
Yield: 110.2 %

Procedure:
To a mixture of N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide 66 (12 g, 37.0 mmol) and palladium on activated carbon (0.438 g, 3.70 mmol) in methanol (800 mL), hydrogen (gas) was bubbled through for 2 h. Excess of Pd/C (5 g) was added and stirred for additional 2 h. Filtered over decalite and concentrated to give N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (12 g, 88%). (m/z)=295 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=N)[O:11][CH2:12][CH3:13].[CH2:15]([OH:17])[CH3:16].[CH2:18]([O:20]CC)[CH3:19]>>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:20][CH2:18][CH3:19])([O:17][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOCC
Reactant: CCOC(=N)Cc1ccccc1F
Reactant: CCO
Agent: Cl
Product: CCOC(Cc1ccccc1F)(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A mixture of ethyl 2-(2-fluorophenyl)acetimidate hydrochloride (34.4 g, 0.158 mol) and absolute ethanol (50 mL) was stirred at ambient temperature for 18 hours. Diethyl ether (50 mL) was added to the mixture, and the solids were removed by suction filtration. The solids were rinsed with ether (2×25 mL), and the combined filtrates were spin evaporated in vacuo to give 34.7 g (86%) of 1-fluoro-2-(2,2,2,-triethoxyethyl)benzene as a semisolid; nmr (DMSO-d6): δ6.7-7.7 (complex multiplets, 4H, ArH), 3.48 (q, 6H, OCH2), 3.03 (s, 2H, CH2), 1.03 (t, 9H, CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]#[N:15])[CH:9]=[CH:10][C:11]=1[CH3:12].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:13][C:14]1[NH:23][N:22]=[N:21][N:15]=1
Reactant: Cc1ccc(CC#N)cc1OCc1c(C)cccc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(Cc2nnn[nH]2)cc1OCc1c(C)cccc1C
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-dimethylbenzyloxy)-4-methylphenyl)acetonitrile (Step B, 1.12 g, 4.2 mmol), sodium azide (0.400 g, 6.1 mmol) and ammonium chloride (0.350 g, 6.5 mmol) in dry DMF (15 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, diluted with water and extracted with EtOAc (30 ml×4). The combined organic layer was washed with brine, dried over Na2SO4, filtered concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5→92.5:7.5) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[C:9]([CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])[CH:10]=[CH:11][C:4]=2[NH:3]1.[OH-].[Na+].CC(O)=O>CCO.O>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[C:9]([CH:12]([CH3:18])[C:13]([OH:15])=[O:14])[CH:10]=[CH:11][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)OCC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)OCC(=O)N2
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of Ethyl 2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl)propanoate (80 mg, 0.321 mmol) in 90% aq. EtOH (5 mL) was added NaOH (64 mg, 1.60 mmol) at room temperature. The reaction mixture was stirred for 12 hrs at 50° C. then cooled to room temperature. The mixture was diluted with H2O (20 mL) and acidified with AcOH then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:3][CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:4]2[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C2CCCN2)cc1
Product: Cc1ccc(C2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound, white solid, m.p. 124° C. and MS: m/e=315 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-p-tolyl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: C(OC1C=C(C=C(OCC)C=1F)C[N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:10][CH2:9]1)C.[CH:34]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([O:46][CH:47]([CH3:49])[CH3:48])[CH:45]=1)[CH:41]=[O:42])([CH3:36])[CH3:35].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH:47]([O:46][C:44]1[CH:43]=[C:40]([CH:39]=[C:38]([O:37][CH:34]([CH3:36])[CH3:35])[CH:45]=1)[C:41]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:10][CH2:9]1)=[O:42])([CH3:49])[CH3:48]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1F
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CO)cc(C(=O)NC2CCN(C(=O)c3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxymethyl-5-methoxy-N-piperidin-4-yl-benzamide (example 217) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 471.1 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c12
Reactant: c1nc[nH]n1
Product: Cc1csc2nc(-n3cncn3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](F)=[O:5].[Cl-:12].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:12])=[O:5]
Reactant: [Cl-]
Reactant: O=C(F)c1ccc(F)cc1F
Agent: [Al+3]
Product: O=C(Cl)c1ccc(F)cc1F
Temperature: 90 °C

Procedure:
13.5 g (.085 mol) of 2,4-diflurobenzoylfluoride were cooled to about 5° C. Aluminum chloride (3.7 g; 0.028 mol) was added slowly over about 0.5 hour. The conversion to the aroyl chloride was 80% (as determined by Gas Chromatography). The reaction was warmed to 90° C. Complete conversion of the starting material resulted. The product was distilled at reduced pressure to yield 2,4-difluorobenzoylchloride as a colorless liquid. This material was not assayed but used directly in the reduction step.
Reaction SMILES: [C:1]([O:6]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8](OC)(=O)[CH:9]=[CH2:10].[C:14]1(C)[C:15](C)=[CH:16]C=[CH:18][CH:19]=1>>[CH2:10]=[CH:9][C:8]1[CH:16]=[CH:15][CH:14]=[CH:19][CH:18]=1.[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cc1ccccc1C
Reactant: C=C(C)C(=O)OC
Reactant: C=CC(=O)OC
Product: C=C(C)C(=O)[O-]
Product: C=Cc1ccccc1

Procedure:
By reference to JP-A-2008-146003, there was produced a pellet of methyl methacrylate/methyl acrylate copolymer (P-1) by use of 0.0294 parts by mass of 1,1-di-t-butyl-per-oxy-3,3,5-trimethyl cyclohexane and 0.115 parts by mass of n-octyl mercaptan along with a monomer mixture including 89.2 parts by mass of methyl methacrylate, 5.8 parts by mass of methyl acrylate, and 5 parts by mass of xylene. In addition, there was produced a pellet of styrene/methacrylate copolymer (P-2) by use of as a photopolymerization initiator, 1,1-tert-butyl per oxy-3,3,5-trimethyl cyclohexane while taking, as a fluid preparation, 75.2 mass % of styrene, 4.8 mass % of methacrylate, and 20 mass % of ethyl benzene.