Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C[Al](C)C.[F:27][C:28]([F:47])([F:46])[C:29]([NH:31][C:32]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][N:39]=2)[S:34][C:33]=1[C:41](OCC)=[O:42])=[O:30]>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:20]([C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:41]([C:33]2[S:34][C:35]3=[N:36][CH:37]=[CH:38][N:39]=[C:40]3[C:32]=2[NH:31][C:29](=[O:30])[C:28]([F:27])([F:47])[F:46])=[O:42])[CH:3]=1)=[O:22])([CH3:19])[CH3:18])#[N:21]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: CCOC(=O)c1sc2nccnc2c1NC(=O)C(F)(F)F
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1NC(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (25 mg, 0.085 mmol) and trimethylaluminum (0.170 mL, 0.341 mmol) in toluene (1 mL) was stirred for 30 min. Ethyl 7-(2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxylate 10 (27.2 mg, 0.085 mmol) in toluene (1 mL) was added and stirred overnight at 60° C. Poured in NaHCO3 solution and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated. Purification by chromatography (20->80 ethylacetate in CH2Cl2) gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-(2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxamide 44 (10 mg, 20%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 7.29 (d, J=8.2 Hz, 1H), 7.58-7.66 (m, 2H), 7.76 (d, J=8.2 Hz, 1H), 7.91-7.98 (m, 2H), 8.05 (s, 1H), 8.85 (s, 1H), 8.94 (s, 1H), 10.20 (br s, 1H), 10.38 (s, 1H), 11.80 (br s, 1H). (m/z)=567 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([S:10][CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:46])C=1>O>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:24]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([S:10]([CH2:11][CH3:12])=[O:46])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc(SCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc(S(=O)CC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 77.4 %

Procedure:
500 mg of product obtained in Example 5 with 5 cm3 of methylene chloride and 215 mg of meta chloroperbenzoic acid is agitated for 2 hours at ambient temperature. The mixture is poured into 50 cm3 of water, extracted 3 times with 50 cm3 of methylene chloride, the extracts are dried, filtered and brought to dryness under reduced pressure. The residue (675 mg) is chromatographed on silica (eluant: methylene chloride - acetone (6-4)). 400 mg of the desired product is obtained.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18]C)=[O:17])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (3.30 g; 12.25 mmol), 1 N LiOH (15 mL), and methanol (60 mL) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification. 1H NMR (CDCl3): δ0.89 (t, 3H); 1.21, 1.24 (s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H); 3.22 (d, 1H); 3.42(m, 1H); 5.31 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=CC(O[CH2:48][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:48][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1 H) 8.15(m, 1 H) 8.07 (m, 1 H) 7.97 (m, 1 H) 7.88 (t, J=8.0 Hz, 1 H) 7.66 (s, 1 H) 7.23 (d, J=8.36 Hz, 1 H) 7.16 (d, J=8.36 Hz, 1 H) 4.44 (t, J=5.8 Hz, 2 H) 3.72 (t, J=8.0 Hz, 2 H) 3.43 (q, J=7.32 Hz, 2 H) 3.03 (s, 6 H) 2.41 (m, 2 H) 1.34 (t, J=7.32 Hz, 3 H). [M+H] calc'd for C24H27ClN3O3S, 472; found, 472.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[O:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[C@H:6]([CH3:24])[CH2:7][C@H:8]([NH:23][C:30](=[O:31])[CH2:29][CH2:28][C:27]([OH:32])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Reaction time: 2 h
Yield: 21.6 %

Procedure:
To a stirred solution of (S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (200 mg, 0.52 mmol) and dihydrofuran-2,5-dione (68 mg, 0.68 mmol) in 8 ml CH2Cl2 was added pyridine (0.17 ml, 2.1 mmol) and the solution was stirred for 2 hours. The reaction mixture was acidified to pH=3 with 1M HCl. Solvent was removed under reduced pressure and the residue was purified by preparatory HPLC (DAICEL CHIRALCEL OD-H 21×250 mm column, 18 ml/min, 90% heptane 10% EtOH+0.1% TFA), collected a peak at 3.9 minutes, to give 50 mg (2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. MS m/z 446.3 (M+H), 444.3 (M−H). LC/MS (Condition A): 1.52 min. 1H NMR (400 MHz, DMSO-d6): 1.04-1.05 (d, J=7.07 Hz, 3H), 1.09-1.13 (t, J=7.07 Hz, 3H), 1.34-1.42 (m, 1H), 1.72-1.79 (m, 1H), 2.24-2.29 (m, 2H), 2.36-2.40 (m, 2H), 2.64-2.74 (m, 2H), 3.33 (s, 1H), 3.86-3.93 (m, 1H), 3.95-4.01 (q, J=7.33 Hz, 14.40 Hz, 2H), 7.25-7.27 (m, 2H), 7.39-7.41 (m, 1H), 7.46-7.50 (t, J=7.58 Hz, 1H), 7.61-7.64 (m, 3H), 7.70 (t, J=1.77 Hz, 1H), 7.75-7.77 (d, J=8.59 Hz, 1H), 12.08 (br s, 2H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10][C@H:9]2[C:27](O)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([NH2:32])[CH3:31]>>[CH2:30]([NH:32][C:27]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[OH:26])=[O:15])[CH2:12][N:8]1[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:28])[CH3:31]
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Reactant: CCN
Product: CCNC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1

Procedure:
(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethylamide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid and ethylamine in an analogous manner to example 1. MS calcd. for C25H34N3O3 [(M+H)+] 424.0, obsd. 424.0.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C(O)(=O)C>C(O)C.C([O-])(=O)C.[NH4+]>[C:10]([C:12](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=Cc1ccc(O)cc1
Temperature: 0 °C
Yield: 121.8 %

Procedure:
30 g of 4-hydroxybenzaldehyde, 31.7 g of ethyl cyanoacetate, 4.5 ml of acetic acid and 1.9 g of ammonium acetate were refluxed in 100 ml of ethyl alcohol for 4 hours with heating. After the reaction, the reaction solution was poured into 500 ml of ice water to separate crystals. The resulting crystals were recrystallized from 400 ml of methyl alcohol to obtain 65 g of ethyl 2-cyano-3-(4-hydroxyphenyl)acrylate having a melting point of 89° to 91° C. 10.9 g of the resulting compound and 4.3 g of pyridine were dissolved in 100 ml of tetrahydrofuran, and 4.5 g of acryloyl chloride was added dropwise thereto. The reaction was carried out for 2 hours while maintaining the reaction temperature below 40° C. After the reaction, the reacting solution was poured into ice water to separate crystals, and the resulting crystals were recrystallized from 100 ml of methyl alcohol to obtain 11 g of the desired compound having a melting point of 82° to 85° C. The identification of the compound was carried out using IR spectrum, NMR spectrum and elemental analysis.
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][N:16](C([O:21][CH2:22][C:23]3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.O.C([OH:32])C>C(O)(=O)C.[C].[Pd]>[C:22]([OH:32])(=[O:21])[CH3:23].[NH:16]1[CH2:15][CH2:14][CH:13]([C:1]2[N:2]=[N:3][N:4]3[C:9]=2[C:8]2[CH:10]=[CH:11][NH:12][C:7]=2[N:6]=[CH:5]3)[CH2:18][CH2:17]1
Reactant: CCO
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: c1cc2c(ncn3nnc(C4CCNCC4)c23)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
5% Palladium-carbon (0.87 g) was added to benzyl 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (4.88 g, 13.0 mmol) obtained in Synthetic Examplea 26 in a mixture of acetic acid (60 mL), water (6 mL) and ethanol (10 mL), and after then the reaction system was flushed with hydrogen, the reaction mixture was stirred at room temperature for one day and then filtered. The filtrate was concentrated, and the resulting yellow solid was washed with ethanol to give the title compound as a colorless solid (3.30 g, yield 84%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.[OH-].[Li+]>C1COCC1.CO>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
220 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate (Example 20A; 0.524 mmol, 1 equivalent) were dissolved in 7 ml of THF/methanol 1:1, 2.6 ml of 1 N aqueous lithium hydroxide solution (2.6 mmol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was acidified with 1N aqueous hydrochloric acid. The solid obtained was stirred, filtered off, washed with water and dried under reduced pressure. This gave 120 mg of the title compound (60% of theory).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:31]([Cu])#[N:32].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:31]#[N:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Temperature: 120 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of 1-bromo-4-hydroxy-6-(4-propoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (315 mg, 0.664 mmol), CuCN (66 mg, 0.730 mmol), and N-methylpyrrolidinone (2 mL) was stirred at 120° C. for 4 h. After cooling to room temperature the mixture was poured into EtOAc (20 mL) and saturated ammonium hydroxide solution (˜1 mL) was added. The mixture was rapidly stirred for 2 min. Then it was acidified with concentrated HCl, washed with water, and saturated NaCl solution before it was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give title compound (206 mg). ESI MS (m/z): 421 (M+H+).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:13]([O:15][C:16](=[O:39])[CH2:17][S:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH2:28])[C:22]([C:29](=[O:38])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:21][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16](=[O:39])[CH2:17][S:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH:28][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=2)[C:22]([C:29](=[O:38])[NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[CH:21][N:20]=1)[CH3:14]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCN)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)c2ccc(N=[N+]=[N-])cc2)n1
Reaction time: 8 h
Yield: 15.6 %

Procedure:
4-Azidobenzoyl chloride (67 mg, 0.37 mmol) was added to a solution of [4-(2-aminoethylamino)-5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid ethyl ester (145 mg, 0.37 mmol) in DMF (2.0 mL). DIPEA (100 μL, 0.55 mmol, 1.5 eq) was then added to the reaction mixture and the acylation was allowed to proceed overnight at ambient temperature. The reaction mixture was concentrated by rotary evaporation and purified using flash chromatography (4 g silica gel, 10 mL/min flow rate) to yield the titled product (31 mg, 16%) as a clear glass. 1H NMR: (d6-DMSO) δ 10.23 (s, 1H), 8.67 (m, 1H), 8.55 (s, 1H), 7.81 (d, 2H), 7.62 (m, 2H), 7.13 (m, 3H), 4.07 (q, 2H), 3.97 (s, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 1.14 (t, 3H); HPLC: Rt=4.36 min; MS (ESI): m/z 537.31 (M−H)−; IR (KBr): 2126 cm−1.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][CH:15]1[CH2:20][CH:19]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH:17]([CH3:26])[CH:16]1[OH:27].C(O)(C)C>CC(C)=O>[CH3:14][CH:15]1[CH2:20][CH:19]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH:17]([CH3:26])[C:16]1=[O:27]
Reactant: CC(C)CCC1CC(C)C(O)C(C)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(C)CCC1CC(C)C(=O)C(C)C1
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Jones reagent (150 mL) was added dropwise at room temperature to a solution of 2,6-dimethyl-4-(3-methylbutyl)cyclohexanol (100 g, 0.5 mol, produced according to Example 4) in acetone (3,000 mL). The reaction mixture was stirred for 1 h and isopropanol added to decompose excess Jones reagent. The salts were removed by filtration and the solution concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with water (400 mL), 5% sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was dried, the solvent evaporated, and the residue fractionated to yield 71 g of the ketone, bp 96°-100° C. (3 mm). NMR (CDCl3) δ0.8-1.1 (12H, m), 1.1-3.2 (12H, m). IR (film) 1725, 1140, 990 cm-1. MS (m/e) 196 (M+), 69, 82, 97, 41.
Reaction SMILES: [CH2:1]([CH:4]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH:29]1[N:38]=[C:39]=[O:40])[CH2:35]2>C(Cl)Cl>[CH:30]12[CH2:36][CH:34]3[CH2:33][CH:32]([CH2:37][CH:28]([CH2:35]3)[CH:29]1[NH:38][C:39]([N:9]1[CH2:10][CH2:11][C:6]3([C:12]4[C:17](=[CH:16][CH:15]=[CH:14][C:13]=4[Cl:18])[CH:4]([CH2:1][CH:2]=[CH2:3])[O:5]3)[CH2:7][CH2:8]1)=[O:40])[CH2:31]2
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: C=CCC1OC2(CCNCC2)c2c(Cl)cccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1OC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Cl)cccc21
Reaction time: 19 h
Yield: 69.3 %

Procedure:
To a stirred solution of 3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine] (0.0190 g), and DIEA (0.5 mL) in CH2Cl2 (2 mL) was added 2-adamantyl isocyanate (0.0138 g, 0.0778 mmol) at rt. After 19 h, the solvents were removed in vacuo and the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 4 min, flow rate 25 mL/min) to afford N-(2-adamantyl)-3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxamide (0.0220 g, 97%). LC-MS Method 1 tR=2.33 min, m/z 443, 441 (MH+); 1H NMR (400 MHz, CDCl3) δ=7.24-7.20 (m, 2H), 7.09-7.05 (m, 1H), 5.87-5.77 (m, 1H), 5.25 (t, J=5.7 Hz, 1H), 5.15-5.08 (m, 2H), 3.98 (br s, 1H), 3.94-3.88 (m, 2H), 136-3.28 (m, 2H), 2.66-2.38 (m, 4H), 1.95-1.25 (m, 16H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][S:36]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)(=[O:38])=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2ccccc2C1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 64 h
Yield: 83 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (0.17 ml) was dissolved in dichloromethane (40 ml) at room temperature under nitrogen. Triethylamine (0.19 ml) was added, followed by 4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylic acid benzyl ester (500 mg) as a solution in dichloromethane (1.5 ml). The reaction was left to stir for 64 h then diluted with dichloromethane (60 ml), washed with 10% citric acid solution (2×50 ml), water (2×50 ml), saturated sodium bicarbonate solution (2×50 ml) and brine (50 ml). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound (506 mg, 83%) as a yellow oil.
Reaction SMILES: [OH-].[NH4+:2].C([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:10]1)=O)C>C(O)C>[C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:10]1)(=[O:5])[NH2:2]
Reactant: CCOC(=O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Concentrated ammonium hydroxide (10 ml, S.G. 0.880) was added to a solution of 1-ethoxycarbonylmethyl-3-(1-imidazolylmethyl) indole (0.50 g) in ethanol (5 ml) and the mixture was stirred at room temperature for 2 hours. The solid was filtered off, washed with water, dried and crystallised from ethanol/petrol (b.p. 60°-80° C.) to give 1-carbamoylmethyl-3-(1-imidazolylmethyl)indole (0.24 g), m.p. 211°-212° C. Found: C, 65.65; H, 5.58; N, 21.69. C14H14N4O requires: C, 66.12; H, 5.55; N, 22.04.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:20][C:21](=[O:34])[CH:22]([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Br)(Br)(Br)[Br:36]>C1COCC1>[CH2:13]([O:20][C:21](=[O:34])[C:22]([Br:36])([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(CCOCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(Br)(CCOCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 47.6 %

Procedure:
n-Butyllithium (2.5M in hexanes, 1.01 mL, 2.54 mmol) was added to a solution of diisopropylamine (0.376 mL, 2.658 mmol) in THF (10 mL) at −30° C. under a nitrogen atmosphere. Stirring at −30° C. was continued for 45 min, and the reaction mixture was cooled to −78° C. A solution of 4-benzyloxy-2-methylbutyric acid benzyl ester (0.721 g, 2.416 mmol) in THF (8 mL) was added over 5 min and stirring at −78° C. was continued for 1 h. A solution of carbon tetrabromide (CBr4) (1.20 g, 3.62 mmol) in THF (2 mL) was added and the mixture was slowly warmed to 0° C. over 3.5 h. The reaction mixture was quenched by addition of a saturated solution aqueous of NH4Cl and then extracted with EtOAc (×2). The combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 3-18% EtOAc in cyclohexane) affording 4-benzyloxy-2-bromo-2-methylbutyric acid benzyl ester (0.434 g), used in the following step without further purification.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:34])[C@H:11]([N:15]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[OH:8][NH:9][C:10](=[O:34])[C@H:11]([N:15]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOCc2ccccc2)C(C)C)cc1
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NO)C(C)C)cc1

Procedure:
N-Benzyloxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide (see example 29a) is reacted with hydrogen in the presence of 10% palladium on charcoal catalyst at room temperature and atmospheric pressure to yield N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide. After conversion to the hydrochloride salt, a white solid is obtained, m.p. 169°-170° C. (dec).