Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:20]2[CH2:19][CH:18]([C:21]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])([C:23]([O:25][CH3:26])=[O:24])[CH3:22])[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([N:36]([CH3:38])[CH3:37])[CH:13]=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:26][O:25][C:23](=[O:24])[C:21]([S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH:18]1[CH2:17][CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([N:36]([CH3:37])[CH3:38])[CH:13]=3)[NH:8][C:20]=2[CH2:19]1)[CH3:22]
Reactant: COC(=O)C(C)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(N(C)C)cc23)C1)S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(C1CCc2c([nH]c3ccc(N(C)C)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 4.6 %

Procedure:
To 42 mg (9.3 mmol) of (RS,SR)-2-(-1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-6-dimethylamino-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester in 1 ml of CH2Cl2 were added 0.06 ml of TFA at 0° C. The solution was stirred at RT for 5 h, a NaHCO3 solution was added, and the inorganic phase was extracted with CH2Cl2, washed with brine and dried over Na2SO4. Column chromatography on ISOLUTE Flash NH2 (Separtis, aminopropyl-modified silicagel) with EtOAc/heptane 2:1, followed by tituration with ether/heptane yielded 190 mg (56%) of (RS,SR)-2-benzenesulfonyl-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester as light green amorphous material, MS: 441 (MH+).
Reaction SMILES: CN[C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:10])=[O:4].[Li]CCCC.C1C[O:19]CC1.C(#N)C1C=CC(OC)=CC=1>C1COCC1>[CH3:10][C:6]1[S:7][CH:8]=[CH:9][C:5]=1[C:3]([OH:19])=[O:4]
Reactant: CNC(=O)c1ccsc1C
Reactant: C1CCOC1
Agent: COc1ccc(C#N)cc1
Agent: [Li]CCCC
Product: Cc1sccc1C(=O)O
Temperature: -70 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of N-methyl-2-methylthiophene-3-carboxamide (36.0 g) in THF (500 ml) was added dropwise 2.5M n-BuLi/THF solution (200 ml) at −70° C. The reaction solution was stirred at −70° C. for 2 hr. followed by the addition of anisonitrile (31.0 g) at once. After the dry ice/acetone bath was removed, the reaction mixture was back to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, and then the mixture was further stirred for 1 hr. The resulting white precipitates were collected by filtration, washed with water, ether and n-hexane in this order, and then dried, to give the title compound (17.9 g, yield; 30%).
Reaction SMILES: [NH2:1][C:2](=[O:14])[CH2:3][O:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][C:6]=1[C:11](O)=[O:12].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[Br:10][C:9]1[C:5]2[O:4][CH2:3][C:2](=[O:14])[NH:1][C:11](=[O:12])[C:6]=2[S:7][CH:8]=1
Reactant: NC(=O)COc1c(Br)csc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C1COc2c(Br)csc2C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a solution of 3-(2-amino-2-oxoethoxy)-4-bromothiophene-2-carboxylic acid (50.5 g), 1-hydroxybenzotriazole 1 hydrate (24.4 g) and DMF (500 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (34.5 g), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (34.5 g), and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (34.5 g), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and water (500 mL) was added to the residue to give the title compound (38.8 g, 82.2%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[N:3]1[CH2:8][CH2:7][C:6]([NH:11][CH3:12])([C:9]#[N:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O1CCCC1>[C:9]([C:6]1([N:11]([CH3:12])[C:31](=[O:32])[CH2:30][C:23]2[C:22]([CH3:21])=[CH:27][C:26]([CH3:28])=[CH:25][C:24]=2[CH3:29])[CH2:7][CH2:8][N:3]([N:2]([CH3:1])[CH3:13])[CH2:4][CH2:5]1)#[N:10]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CNC1(C#N)CCN(N(C)C)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CC(=O)N(C)C2(C#N)CCN(N(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
1.2 g 1-Dimethylamino-4-methylamino-piperidine-4-carbonitrile (from Step 1), 1.67 g triethylamine and 10 mg N,N-Dimethyl-4-aminopyridine are dissolved in 35 ml tetrahydrofuran. The mixture is cooled in an ice bath and a solution of 1.3 g (2,4,6-trimethylphenyl)-acetyl chloride in 20 ml tetrahydrofuran is added. The temperature is kept around 0° C. during addition. Then the mixture is allowed to warm to room temperature and stirred for 18 hours. Then saturated aqueous sodium bicarbonate is added, the mixture is extracted with t-butyl methyl ether, dried over sodium sulfate, and the solvent evaporated. The residue is purified by chromatography on silica gel, using ethyl acetate/acetone (3:1) as a solvent. 1.3 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-N-methyl-2-(2,4,6-trimethylphenyl)-acetamide is obtained. 1H-NMR (CDCl3): 6.85 ppm (s, 2H), 3.65 ppm (s, 2H), 3.10 ppm (s, 3H), 3.00 ppm (m, 2H), 2.78 ppm (m, 2H), 2.50 ppm (m, 2H), 2.38 ppm (s, 6H), 2.23 ppm (s, 3H), 2.18 ppm (s, 6H), 1.96 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].Cl.[CH3:31][O:32][C:33]([C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH3:31][O:32][C:33]([C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=3)=[O:11])=[CH:21][C:22]=2[F:29])[CH2:37][CH2:36]1)=[O:34]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3Cl)cc2F)CC1

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a light yellow foam, MS (ESI+): m/z=553.3 [M+H]+.
Reaction SMILES: O1CCCC1.Cl.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=3[C:16]([CH:27]=[CH:28][O:29]C)=[N:15]2)=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=3[C:16]([CH2:27][CH:28]=[O:29])=[N:15]2)=[CH:31][CH:32]=1
Reactant: COC=Cc1nn(Cc2ccc(OC)cc2)c2cccc(C(=O)OC)c12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c(CC=O)nn2Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a −78° C. cooled suspension of (methoxymethyl)triphenylphosphonium chloride (119 g, 347 mmol) in tetrahydrofuran (1000 mL) was carefully added a solution of lithium bis(trimethylsilyl)amide (1.0M in THF, 347 mL, 347 mmol). The resulting dark red mixture was stirred at −40° C. for 30 min. To this was added a solution of methyl 3-formyl-1-(4-methoxybenzyl)-1H-indazole-4-carboxylate (45 g, 139 mmol) in tetrahydrofuran slowly and the mixture was stirred for 30 min. The reaction was quenched with sat. aqueous sodium chloride (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (4×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude oil was purified by column chromatography (silica gel, 5 to 30% ethyl acetate in hexanes) to afford methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 82%) as a yellow oil. A mixture of tetrahydrofuran (950 mL) and 6N hydrochloric acid (30 mL) was added to methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 114.5 mmol) and the resulting biphasic mixture was heated to reflux for 2.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (1500 mL). The organic layer was separated and washed with brine (4×500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indazole-4-carboxylate (30 g, 77%) as a yellow solid: 1H NMR δ (300 MHz, DMSO-d3) 9.78 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.2, 0.6 Hz, 1H), 7.48 (dd, J=8.7, 7.5 Hz, 1H), 7.22-7.19 (m, 2H), 6.88-6.85 (m, 2H), 5.61 (s, 2H), 4.26 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H); MS (ESI+) m/z 339 (M+H).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[N:8]=[C:9]([Si](C)(C)C)[S:10][CH:11]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]4[C@:34]([C:36](OC)=[O:37])([CH2:35][C:26]=3[CH:25]=[N:24]2)[CH2:33][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:30]4)=[CH:19][CH:18]=1.Cl>CCOCC.CCOCC.O1CCCC1.C(#N)C.C(OCC)(=O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]4[C@:34]([C:36]([C:7]5[N:8]=[CH:9][S:10][CH:11]=5)=[O:37])([CH2:35][C:26]=3[CH:25]=[N:24]2)[CH2:33][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:30]4)=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)c1nc(Br)cs1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cscn2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A suspension of isopropylmagnesium chloride (2M in tetrahydrofuran, 1.755 ml, 3.51 mmol) in dry ether (4.5 mL) at 0° C. was treated dropwise with a solution of 4-bromo-2-(trimethylsilyl)thiazole (0.829 g, 3.51 mmol) in dry ether (2.5 mL) and the resulting suspension stirred at 0° C. for 1 hour. The suspension was then treated dropwise with a solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (0.5 g, 1.17 mmol) in dry ether:tetrahydrofuran (4:1, 5 mL total volume) and the resulting suspension stirred at 0° C. for 15 minutes. The reaction mixture was then allowed to warm to room temperature, and the solution stirred for a further 3 hours. The reaction mixture was cooled to 0° C., and ice water (50 mL) added dropwise. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic extracts washed with brine (50 mL) and dried over magnesium sulphate. The solvent was removed to give an orange oil. This was dissolved in acetonitrile (12 mL) and treated dropwise with 1M aqueous HCl (1171 μl, 1.171 mmol) and the resulting solution stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate (150 mL) and washed sequentially with brine (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL), and further brine (50 mL). The organic layer was dried over magnesium sulphate and the solvent removed. The crude product was purified by column chromatography on silica gel (gradient: 5-95% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (238 mg) as a pale yellow gum. LCMS (Method F, ES-API): RT 2.55 min, m+H=481.2.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:12][O:11][CH:10]2[CH:5]([C@:6]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][CH:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:26])[CH2:17]5)[C@@H:8]3[CH2:9]2)[CH3:7])[O:4]1.[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[CH2:31]Br)[CH3:28].O>O1CCCC1>[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[CH2:31][O:26][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][CH:10]3[O:11][CH2:12][CH2:3][O:4][CH:5]32)[CH2:17]1)[CH3:28]
Reactant: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CO[C@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1)OCC
Reaction time: 2 h

Procedure:
To a suspension of 5.5 g of NaH (60% dispersion in mineral oil) in 400 ml of dry tetrahydrofuran 8.5 g of 17-ethylenedioxy-androstan-3β-ol were added at room temperature under nitrogen atmosphere. The mixture was kept at 40° C. for 2 hrs, then 26 ml of bromoacetaldehyde diethylacetal were added and the suspension was kept at the same temperature for 4 hrs; 50 ml of water were added cautiously, and the tetrahydrofuran was distilled under reduced pressure. The residue was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 7.5 g of 3β-(2,2-diethoxyethoxy)-17-ethylenedioxy-androstane as a thick oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:21]([O:26]CC1OC1)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CO>[C:21]([O:26][CH:3]([N:2]([CH2:23][CH2:22][CH2:21][OH:25])[CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: CCCCCCCCCCCCCCCCCCNC
Solvent: CO
Product: C=C(C)C(=O)OC(CCCCCCCCCCCCCCCCC)N(C)CCCO

Procedure:
Equimolar quantities of N-methyl-N-octadecyl amine and glycidyl methacrylate were reacted together in methanol to form methacryloyloxyhydroxypropyl methyl octadecyl amine. 14.3 grams of the resultant amine were dissolved in 20 grams of dimethyl formamide and 4.2 grams of dimethyl sulfate were added slowly with stirring. After 10 days' standing at 25° C, 9 grams of crystalline material was isolated, washed with ether, and dried. The sulfate band in the crystalline product was identified in the I.R. spectrum.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH2:5]([O:8][CH2:9][CH:10]=[CH2:11])[CH:6]=[CH2:7]>>[CH2:1]([O:2][CH2:11][CH2:10][CH2:9][O:8][CH2:5][CH:6]=[CH2:7])[CH:3]=[CH2:4]
Reactant: C=CC=O
Reactant: C=CCOCC=C
Product: C=CCOCCCOCC=C

Procedure:
GC revealed that peaks assigned to carbonyl compounds such as acrolein, 3-allyloxy-1-propionaldehyde and 3-hydroxy-1-propionaldehyde were not detected (these carbonyl compounds showed GC detection limit of 10 ppm or less in this example), but diallyl ether and 1,3-diallyloxypropane were produced.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](Br)[CH2:22][CH2:23][CH3:24]>CN(C)C=O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14][CH2:21][CH2:22][CH2:23][CH3:24])=[O:13])[CH:8]=2)[CH:3]=1
Reactant: CCCCBr
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccc2cc(O)ccc2c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The mixture of 2-hydroxy-6-naphthoic acid of 18.8 g, N,N-dimethylformamide of 150 g and anhydrous sodium carbonate of 13.3 g was heated to 70° C., and n-butyl bromide of 16.4 g was dropwise added thereto in one hour. After finishing dropwise adding, the suspension was further stirred at 70° to 80° C. for 6 hours. The reaction mixture was cooled down to room temperature and filtrated off the inorganic salt. Then the filtrate was discharged into water of 1000 g. The deposited solid was separated, and sludging was carried out in n-hexane, whereby n-butyl 2-hydroxy-6-naphthoate of 22.0 g was obtained in the form of brown crystal.
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1>C(O)CC#C>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:4]=[C:5]([CH2:6][CH2:7][OH:8])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Agent: C#CCCO
Product: O=C(c1ccc(Cl)cc1)c1cc(CCO)on1
Yield: 245.5 %

Procedure:
A solution of 12 g of 4-chlorophenylglyoxylohydroxamyl chloride in 30 g of 3-butyn-1-ol was refluxed under N2 for 2.5 hours. Concentration of the product on a rotovapor under high vacuum gave 17 g of an oil. Purification by high pressure liquid chromatography with 5% ethyl acetate/CH2Cl2 yielded 11.8 g (85%) of an oil which solidified on standing, m.p. 59°-62°.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C@H:11]([C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=1)[O:16][CH2:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1C(OC(C)(C)C)=O)[OH:12])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C@H:11]([C:13]1[CH:32]=[CH:31][CH:30]=[C:15]([O:16][CH2:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:14]=1)[OH:12]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCC[C@@H](O)c1cccc(OC[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pyrrolidine-1-carboxylate (0.3 g, 0.66 mmol) in DCM (10 mL) was added HCl/dioxane (3 mL) at 0° C. and the reaction mixture was stirred at rt for 2 h. After completion of the reaction the solvent was removed in vacuo. The residue was purified by prep HPLC to give (R)-3-Amino-1-(3-((S)-pyrrolidin-2-ylmethoxy)phenyl)propan-1-ol (Example 22) as a white solid. Yield (0.18 g, 89%); 1H NMR (400 MHz, CD3OD) δ 7.31 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 4.83-4.82 (m, 1H), 4.35 (dd, J=10.4, 3.2 Hz, 1H), 4.17-4.12 (m, 1H), 4.05-4.03 (m, 1H), 3.39-3.36 (m, 2H), 3.14-3.01 (m, 2H), 2.32-2.18 (m, 1H), 2.16-2.08 (m, 2H), 2.06-1.87 (m, 3H). MS: m/z 251.28 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.OC1CCC(C(OCC)=O)CC1.[Cr](O)(O)(=O)=O.C(O)(C)C>CC(C)=O>[O:1]=[C:2]1[CH2:12][CH2:11][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=[Cr](=O)(O)O
Agent: CCOC(=O)C1CCC(O)CC1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C1CCC(=O)CC1
Temperature: 0 °C

Procedure:
Ethyl 4-hydroxybenzoate is reduced to ethyl 4-hydroxycyclohexanecarboxylate according to the procedure described in R. A. Finnegan and P. L. Bachman, Journal of Organic Chemistry, Volume 30, pages 4145-4150 (1965). The crude material obtained in this reduction (190 g) is dissolved in 1200 ml of reagent grade acetone. The solution is cooled to 0° C. and 152 ml of a 8 N chromic acid solution (prepared from concentrated sulfuric acid and chromium trioxide) is added dropwise to the mechanically stirred reaction mixture. Enough isopropanol is added to the mixture to discharge its red color and it is then filtered through Celite. The salts are washed with several portions of acetone. The filtrate is evaporated in vacuo. The residue is dissolved in 750 ml of diethyl ether and washed with sodium bicarbonate and brine solutions. After drying, the solvent is evaporated and the residue is distilled to yield the title compound; bp12 125 ° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](Cl)(=O)[CH2:12][CH3:13]>O1CCOCC1.CN(C)C=O>[OH:9][C:6]1[N:7]2[N:8]=[C:11]([CH2:12][CH3:13])[N:1]=[C:2]2[N:3]=[C:4]([CH3:10])[CH:5]=1
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: CCC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCc1nc2nc(C)cc(O)n2n1

Procedure:
Intermediate 1 (0.4 g, 2.85 mmol) was allowed to react with propionyl chloride (ALDRICH, 0.372 mL, 4.28 mmol) in a mixture of 1,4-dioxane (8 mL) and N,N-dimethylformamide (2 mL) overnight under refluxing conditions. The reaction was concentrated under vacuum and the residue was purified (silica gel column, eluting with DCM:MeOH mixtures from 100:0 to 90:10%) to obtain 7-hydroxy-2-ethyl-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 4) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1csc(C(=O)O)c1
Product: Cc1csc(C(=O)Cl)c1

Procedure:
220 cc of thionyl chloride were progressively added to 50 gm of 4-methyl-thiophene-2-carboxylic acid [prepared by process in Beil, Vol. 18, p. 294] and the mixture was heated to reflux for 1 hour. Excess thionyl chloride was evaporated off under reduced pressure and the residue was distilled under reduced pressure to obtain 51 gm of 4-methyl-thiophene-2-carboxylic acid chloride boiling at 112°-114° C. at 18 mm Hg. which was used as is for the next step. The light yellow liquid was soluble in ether.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][C:19]([Cl:31])=[C:20]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(OCc1ccccc1)N1CCC(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(c2cc(C(=O)N3CCCCCC3)c(Cl)s2)CC1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
4-[4-(Azepane-1-carbonyl)-thiophen-2-yl]-piperidine-1-carboxylic acid benzyl ester (0.037 g, 0.087 mmol) was dissolved in acetic acid. N-chlorosuccinimide (0.09 mmol) was added and the reaction heated to 100° C. for 2.5 minutes using microwave irradiation. The product was purified by HPLC, eluting with 20%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.027 g). LCMS m/z 461.24 [M+H]+ RT=13.23 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.4-7.25 (m, 5H), 6.6 (m, 1H), 5.1 (s, 2H), 4.3 (m, 2H), 3.65 (m, 2H), 3.35 (t, 2H), 2.9-2.8 (m, 3H), 2.0-1.9 (m, 2H), 1.85-1.75 (m, 2H), 1.7-1.6 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[C:11]([C:12]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C2(C#N)CCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2cccc(C(=O)O)c2Cl)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
Methyl 2-chloro-3-(1-cyanocyclobutyl)benzoate (710 mg, 2.84 mmol) was dissolved in a mixed solvent of tetrahydrofuran (9 mL)/methanol (3 mL)/water (3 mL), lithium hydroxide monohydrate (192 mg, 4.56 mmol) was added, and the mixture was stirred at room temperature for 19 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid (5 mL) was added dropwise to the residue. The precipitate was collected by filtration, and washed with water to give the title compound (435 mg, 65%) as a white powder.