Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9]([C:14]3[CH:15]=[C:16]([NH:24][C:25](=[O:31])[CH2:26][C:27]([O:29]C)=[O:28])[CH:17]=[N:18][C:19]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:8][C:7]=2[C:6]([CH2:32][CH2:33][CH3:34])=[N:5]1>CO>[CH3:3][N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9]([C:14]3[CH:15]=[C:16]([NH:24][C:25](=[O:31])[CH2:26][C:27]([OH:29])=[O:28])[CH:17]=[N:18][C:19]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:8][C:7]=2[C:6]([CH2:32][CH2:33][CH3:34])=[N:5]1
Reactant: CCCOc1ncc(NC(=O)CC(=O)OC)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ncc(NC(=O)CC(=O)O)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 77.8 %

Procedure:
Sodium hydroxide (2 N, aq., 1 mL) was added to a solution of the title compound of Example 78 (79 mg, 0.18 mmol) in methanol (10 mL) and the resultant mixture stirred at room temperature for 19 h, concentrated in vacuo and the residue dissolved in water (20 mL). After washing with dichloromethane (20 mL), the aqueous phase was acidified to pH 2-3 with 2 M HCl and the resultant white precipitate removed by filtration and dried to afford the title compound (58 mg, 0.14 mmol).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:27]([F:28])=[CH:26][C:8]([O:9][C:10]2[CH:24]=[CH:23][C:13]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]3)=[O:15])=[CH:12][C:11]=2[F:25])=[C:7]([O:29][CH3:30])[CH:6]=1)[CH3:4].Br[CH2:32][C:33]([NH2:35])=[O:34].C(OCC)(=O)C>O1CCCC1.O>[CH2:3]([C:5]1[C:27]([F:28])=[CH:26][C:8]([O:9][C:10]2[CH:24]=[CH:23][C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:32][C:33]([NH2:35])=[O:34])[C:18](=[O:22])[CH2:17]3)=[O:15])=[CH:12][C:11]=2[F:25])=[C:7]([O:29][CH3:30])[CH:6]=1)[CH3:4]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCN(CC(N)=O)C(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in oil, 49 mg, 1.2 mmol) was added to a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoy]-piperazin-2-one (which may be prepared in accordance with the experimental described in Example 5, step 1; 400 mg, 1 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 15 minutes prior to the addition of 2-bromoacetamide (212 mg, 1.5 mmol). After stirring for 2 days at room temperature, the reaction mixture was diluted by addition of ethyl acetate (20 mL) and water (20 mL). After separation, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (2×20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98:2 to 95:5) as eluent. The title product was obtained as a white solid (300 mg, 65%).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][N:6]1[CH2:10][C@@H:9]2C[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:8]2[C:7]1=[O:16])C.[NH3:18]>CO>[O:16]=[C:7]1[C@H:8]2[C@@H:9]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:6]1[CH2:5][C:4]([NH2:18])=[O:17]
Reactant: N
Reactant: CCOC(=O)CN1C[C@@H]2CCCCC[C@@H]2C1=O
Solvent: CO
Product: NC(=O)CN1C[C@@H]2CCCC[C@H]2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
For example, trans-octahydro-1-oxo-cyclohexa[c]pyrrole-2(1H)acetic acid ethyl ester (V) (6.6 g, 0.031 mole) in methanol is saturated with anhydrous ammonia and the mixture is stirred at room temperature 24 hours. The solution is concentrated at reduced pressure to yield a solid. Recrystallization from acetonitrile yields pure trans-octahydro-1-oxo-2H-isoindole-2-acetic acid amide (VI).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[CH:26]=3)[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@@H:40]1[CH2:45][O:44][CH2:43][CH2:42][NH:41]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:41]2[CH2:42][CH2:43][O:44][CH2:45][C@H:40]2[CH3:39])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[CH:26]=3)[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1COCCN1
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccccc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccccc3F)cc21

Procedure:
Prepared from (2R,5R)-5-chloromethyl-4-{2-[6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and (R)-3-methyl-morpholine in a similar manner to General Procedure 6. MS: [M+H]+=610.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C@@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14]Cl)[CH:3]=1.[I-:22].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C@@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14][I:22])[CH:3]=1
Reactant: [I-]
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCI)c1ccccc1
Yield: 98.8 %

Procedure:
4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-5-fluorobenzonitrile (1.8 , 5.6 mmol) and sodium iodide (12.8 g, 100 mmol) were dissolved in acetone (50 ml) and heated under reflux for 24 h. The reaction mixture was cooled, filtered and evaporated. The semi-solid residue was dissolved in toluene, filtered and evaporated again to give 2.3 g of the crude product as a yellow oil. This was used without purification for the next step.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C.C(O)(=O)C>CO>[O:8]([CH:9]([C:22]1[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(C(=O)O)o1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole-5-carboxylic acid (281 mg, 6.673 mmol) was dissolved in a mixture of MeOH:toluene (4 mL: 10 mL), cooled to 0° C. and TMSCHN2 (2 M in hexanes, 3 equiv) was added dropwise under Ar. The reaction mixture was stirred at room temperature for 0.5 h before it was cooled to 0° C. and acetic acid was added dropwise until the solution turned from yellow to clear. The mixture was evaporated in vacuo and the resulting solid was dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO3, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude ester which was purified by flash chromatography (10-30% EtOAc/hexanes) to afford the pure ester as a clear oil (225 mg, 78%): 1H NMR (CDCl3, 500 MHz) δ 7.78 (s, 1H), 7.36-7.33 (m, 2H), 725-7.23 (m, 3H), 4.92 (t, 1H, J=7.0 Hz), 3.98 (s, 3H), 2.67 (t, 2H, J=7.5 Hz), 2.12-1.94 (m, 2H), 1.72-1.67 (m, 2H), 1.53-1.43 (m, 6H), 0.98 (s, 9H), 0.17 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 169.0, 158.5, 143.1, 142.6, 134.5, 128.8, 128.6, 126.0, 69.1, 52.5, 36.7, 36.3, 31.8, 29.5, 26.1, 26.1, 25.4, 18.6, −4.6, −4.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].C1(C)C=C(C)C=C(C)C=1S(O[NH2:26])(=O)=O>O1CCCC1>[NH2:26][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ccn(N)c2c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.735 g 6-methoxyindole and 5 ml tetrahydrofuran (THF) is added to a suspension of 0.44 g of 60% sodium hydride in 10 ml THF at 0° C. After 15 minutes a mixture 1.07 g O-mesitylsulfonyl-hydroxylamine and 15 ml THF is added. Stirring at 0° C. is continued for 1.5 hours. The mixture is poured into ice cold water, extracted with ethyl acetate, and purified by flash chromatography.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[C:10]([NH:13][C:14]1[S:15][C:16]([C:19]2[CH2:26][S:25][CH:24]3[N:21]([C:22](=[O:28])[CH:23]3[NH2:27])[C:20]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:17][N:18]=1)(=[O:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[C:10]([NH:13][C:14]1[S:15][C:16]([C:19]2[CH2:26][S:25][CH:24]3[N:21]([C:22](=[O:28])[CH:23]3[NH:27][C:7](=[O:8])[CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:20]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])=[CH:17][N:18]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Reactant: O=C(Cl)Cc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1

Procedure:
A solution of (thien-2-yl)-acetyl chloride (0.55 cc) in dry tetrahydrofuran (5 cc) is added, in 5 minutes, to a solution of 3-(2-acetamido-thiazol-5-yl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.27 g) in dry tetrahydrofuran (27.5 cc) at 2° C., and after 30 minutes a solution of triethylamine (0.63 cc) in dry tetrahydrofuran (5 cc) is added. After 1 hour's reaction at 2° C., the reaction mixture is filtered and the filtrate is diluted with a mixture of ethyl acetate (200 cc) and half-saturated sodium bicarbonate solution (200 cc). The organic layer is washed with water (100 cc) followed by a saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is chromatographed on a column (height: 30 cm; diameter: 5 cm) of silica (0.04-0.06 mm), elution being effected under 0.4 bar (40 kPa) with a 30:70 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 15 to 22, containing the pure product, are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 3-(2-Acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.92 g) is obtained in the form of a yellow powder.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3cccc(F)c3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2cccc(F)c2)cc1
Yield: 87.5 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((3-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0325 g, 0.056 mmol) and LiOH (0.013 g, 0.564 mmol) in 9:1 EtOH/H2O (2 mL0 was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((3-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0269 g, 0.049 mmol, 87% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.39 (dt, J=5.8, 7.9 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.16-7.23 (m, 2H), 7.01-7.10 (m, 4H), 5.95 (br. s., 1H), 5.12-5.19 (m, 2H), 3.62 (br. s., 1H), 2.88 (br. s., 1H), 2.65 (s, 3H), 2.23 (s, 3H), 1.24 (s, 9H), 0.87 (br.s., 3H), 0.67 (br. s., 3H). 6H of piperidine were not resolved. LCMS (M+H)=549.4.
Reaction SMILES: [C:1]([C:9]1[CH:34]=[C:33]([Br:35])[CH:32]=[CH:31][C:10]=1[C:11]([N:13]([CH2:25][CH:26]([OH:30])[CH2:27][CH2:28][CH3:29])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.Cl>CS(C)=O>[C:1]([C:9]1[CH:34]=[C:33]([Br:35])[CH:32]=[CH:31][C:10]=1[C:11]([N:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=1)[CH2:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(O)CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCCC(=O)CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
[Step 2] To a solution of 2-benzoyl-4-bromo-N-(2-hydroxypentyl)-N-(4-methanesulfonylbenzyl)benzamide (2.7 g) in DMSO (27 ml) was added triethylamine (11 ml), and pyridine sulfur trioxide complex (6.2 g) was added to the mixture at room temperature. The mixture was stirred for 1 hr. and added to water. 10% Hydrochloric acid was added to acidify the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxopentyl)benzamide (2.2 g).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11][C:27]([C:24]3([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:26][CH2:25]3)=[O:28])[C:4]2=[N:3][CH:2]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1
Yield: 79 %

Procedure:
Combine (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (570 mg, 2.86 mmol), 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (commercially available, 633.19 mg, 3.15 mmol), 1-hydroxybenzotriazole (464 mg, 3.43 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (658 mg; 3.43 mmol) in tetrahydrofuran (10 mL). Add diisopropylethylamine (599 μL, 3.43 mmol) and stir the reaction for approximately 16 hours at ambient temperature under nitrogen. Dilute the reaction with ethyl acetate, wash with dilute sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (25% EtOAc/hexanes to 85% EtOAc/hexanes) to give the title compound (860 mg, 79%) as a white solid: MS (m/z): 383 (M+1).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][C:11]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:10]=3[O:9][C:8]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH+]1C=CC=CC=1.Cl.CCOC(C)=O>O>[CH:1]1([N:7]2[CH2:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[O:9][C:8]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)OC(=O)N(C1CCCCC1)C2
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Oc2cc(O)ccc2CN1C1CCCCC1
Temperature: 220 °C

Procedure:
A mixture of 66 g of 3-cyclohexyl-7-methoxy-3,4-dihydro-benzo[e][1,3]oxazin-2-one and 200 g of pyridinium HCl are heated without solvent on a metal bath to 220° C. for 45 minutes whilst stirring. Evolving HCl gas is sucked off. The mixture obtained is cooled to RT, the melt obtained is dissolved in H2O and EtOAc and two phases obtained are separated. The aqueous layer obtained is extracted with EtOAc and washed with 1N HCl, dried and concentrated in vacuo. The concentration residue obtained is filtered over silica gel and the filtration residue obtained is concentrated. 3-Cyclohexyl-7-hydroxy-3,4-dihydro-benzo[e][1,3]oxazin-2-one is obtained in crystallized form. m.p. 193-196°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[C:18]1([NH:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:27][CH2:26][CH2:25][NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Reactant: NCCNc1ccccc1
Solvent: C1COCCO1
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1-c1cccs1

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile and N-phenylethylenediamine in dioxane. ES-MS m/e (%): 337 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25]>ClCCl>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:24](=[S:25])[N:23]([CH3:27])[CH3:22])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CN(C)C(=S)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OC(=S)N(C)C)ccc(C(C)=O)c1O
Yield: 41.4 %

Procedure:
Stir a mixture of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2 g, 10.3 mmol), triethylamine (1.6 mL 11.3 mmol), and dichloromethane (40 mL) at room temperature. Add dimethylthiocarbamoyl chloride (1.27 g, 10.3 mmol) and stir at room temperature overnight. Wash the mixture with 1M hydrochloric acid (25 mL), dry over magnesium sulfate, filter and concentrate. Purify the residue via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to afford dimethyl-thiocarbamic acid O-(4-acetyl-3-hydroxy-2-propyl-phenyl) ester (1.2 g, 41%) as a light yellow solid. Stir the yellow solid in tetradecane (10 mL) at 250° C. for an hour and purify by silica chromatography eluting with hexanes to 6:4 hexanes:ethyl acetate to give the title compound (1.08 g, 90%) as a white solid. LCMS (m/z) 280 m−1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH2:30]([O:37][CH2:38][C@@H:39]([NH:44][CH3:45])[CH2:40][CH:41]([CH3:43])[CH3:42])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][CH2:38][C@@H:39]([N:44]([CH3:45])[C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:25][CH:24]=1)[CH2:40][CH:41]([CH3:42])[CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN[C@H](COCc1ccccc1)CC(C)C
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C)[C@H](COCc3ccccc3)CC(C)C)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N—((S)-1-benzyloxymethyl-3-methyl-butyl)-N-methyl-amine as described for example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.[ClH:26]>O1CCOCC1>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:22]([F:24])([F:23])[F:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)nn1-c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc(C(F)(F)F)nn1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 46 %

Procedure:
In 9 mL of dioxane, tert-butyl (1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (501 mg, 1.39 mmol) was dissolved and hydrogen chloride in dioxane (2.27 mL, c=4 mol/L, 9.06 mml, 6.5 equiv.) was added. The reaction mixture was stirred overnight and filtered, the filter cake was washed with ether (2×15 mL) and dried to give (1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (188 mg, 46%).
Reaction SMILES: CN(C)C=O.C(N(CC)CC)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:23][CH3:24])[CH2:21][OH:22])=[CH:16][CH:15]=1.[I-].C[S+]=[C:28]1[S:32][CH2:31][CH2:30][S:29]1>C(OCC)C>[S:29]1[CH2:30][CH2:31][S:32][C:28]1=[N:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:23][CH3:24])[CH2:21][OH:22])=[CH:18][CH:19]=1
Reactant: CCC(CO)c1ccc(N)cc1
Reactant: C[S+]=C1SCCS1
Agent: [I-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CO)c1ccc(N=C2SCCS2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 450 ml of dimethylformamide containing 23.8 ml of triethylamine was added 11.4 g of 2-(4-aminophenyl)-butanol and to the resulting solution was added, in portions over 45 minutes, 21 g of methyl(1,3-dithiolan-2-ylidene)sulfonium iodide. The resulting hazy-yellow solution was stirred for 2 hours and then poured into ice water. The aqueous mixture was extracted 5 times with diethyl ether and the combined organic extracts were washed 7 times with 0.2 N hydrochloric acid, twice with water and once with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and the resulting crude residue was purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. The purified light-yellow oil obtained was immediately dissolved in warm diethyl ether and allowed to crystallize. The solid which formed was separated by filtration and dried to give 2-[4-(1,3-dithiolan-2-ylideneamino)phenyl]butanol as white spars melting at about 98.5°-100.5° C. This compound has the following structural formula ##STR3##
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].IC.[NH4+].[Cl-]>C1COCC1>[C:6]([NH:10][C:11]([C:13]1[C:18]([CH3:1])=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: [Li]CCCC
Reactant: CC(C)(C)NC(=O)c1cc(Cl)ccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Cl)ccnc1C(=O)NC(C)(C)C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 29 mL, 72 mmol) is added dropwise to N-tert-butyl-4-chloropyridine-2-carboxamide (7.00 g, 32.9 mmol) in THF (70 mL) at −78° C. After 1 h at −78° C. iodomethane (6.8 mL, 109 mmol) is added and stirring is continued for 1 h. Saturated NH4Cl (10 mL) is added and the organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-20% EtOAc/cyclohexane) to furnish N-tert-butyl-4-chloro-3-methyl-pyridine-2-carboxamide (5.7 g, 76%).