Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].C(OC)(C)(C)C>C(O)(C)C>[ClH:10].[C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CC(N)c1ccccc1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
At room temperature 122 g of (R)-1-phenylethylamine (1.0 mol) was dissolved in 30 mL of isopropanol. The solution was stirred and cooled to 0° C. Then, a previously prepared solution of 100 mL of 37% hydrochloric acid (118 g, 1.2 mol) in 320 mL of isopropanol was added during 1 h. The solution was stirred at 0° C. for an additional 40 min, and then it was concentrated on a rotary evaporator (16 mbar, bath 45° C.) to a volume of 300 mL. The translucent gel which had formed was transferred into a 1.5 l flask, then, under stirring, 250 mL of tert-butyl-methyl-ether was slowly added. Crystals started to form and the suspension was stirred at 0° C. for 3 h. The product was collected by filtration, washed with 100 mL of tert-butyl-methyl-ether and dried at 30° C./16 mbar for 4 hours to give 133 g (84%) of 1-phenylethylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[N:13]O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[NH2:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: ON=C1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
Add 1-(4-chlorobenzyl)-4-piperidone oxime (1.87 mmol) to a solution of lithium aluminum hydride (2.5 mL of a 1 M solution in tetrahydrofuran) and place under a nitrogen atmosphere. Heat at reflux for 2 hours, cool and pour into dilute aqueous sodium hydroxide. Extract with a mixture of ethyl ether/ethyl acetate (2×), wash with aqueous sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][C:10](=O)[CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].Cl.[Br:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)N)=[CH:17][CH:16]=1.C(O)(=O)C.C(Cl)(=O)C>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[C:22]3[C:23](=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:9]([CH2:8][C@@H:2]([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[C:10]2[CH3:11])=[CH:17][CH:16]=1
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Reactant: COC(=O)C[C@H](C)CCC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H](C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of ketone from Step 3 (92 mg, 0.3 mmol), N-(4-bromobenzyl)-N-(4-methoxyphenyl))hydrazine (52 mg, 0.3 mmol) from Example 1, Step 5, acetic acid (36 mg, 0.6 mmol) and toluene (3 mL) was stirred at room temperature for 1.5 h. The solvent was evaporated and replaced by ethanol (3 mL). Then acetyl chloride (110 mg, 5 eq) was added and the mixture was heated at 60° C. for 45 min. After evaporation of the ethanol, the mixture was chromatographed on silica gel, eluting with a 1:3 mixture of EtOAc and hexane, to afford the product as an oil which solidified (80 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:20]4[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]4[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:62](Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64].Cl>ClCCl>[C:23]([O:22][C@@H:21]1[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[O:46][C@H:20]1[O:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:7][CH:6]=2)[NH:16][N:17]=1)(=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(4-hydroxyphenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (1.6 g) in dichloromethane (20 mL) were added triethylamine (0.44 mL) and pivaloyl chloride (0.31 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =2/1−1/1) to give the title compound (1.76 g).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:18][C:19]([CH3:21])=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:3]=1[C:4]([O:6][CH2:20][C:19]([CH3:21])=[CH2:18])=[O:5]
Reactant: C=C(C)COc1ccc(F)c(F)c1C(=O)O
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COC(=O)c1c(OCC(=C)C)ccc(F)c1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2,3-difluoro-6-(2-methylallyloxy)benzoic acid (732) (1.45 g, 6.35 mmol), 3-chloro-2-methylpropene (0.77 mL, 7.62 mmol), and potassium carbonate (1.76 g, 12.7 mmol) in anhydrous DMF was stirred at 65° C. under N2 overnight. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by flash column chromatography eluting with hexanes-EtOAc (4:1) to provide 2-methylallyl 2,3-difluoro-6-(2-methylallyloxy)benzoate (733) (1.55 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.14 (q, J=9.5 Hz, 1H), 6.63-6.60 (m, 1H), 5.09 (s, 1H), 5.06 (s, 1H), 4.98 (s, 2H), 4.78 (s, 2H), 4.45 (s, 2H), 1.81 (s, 3H), 1.79 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](N)=[CH:37][CH:36]=1)=[O:34]>CN(C=O)C>[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])[CH3:32].[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: CC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The D-biotin (1 g, 4.1 mmol) is solubilized in 45 ml of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (590 μl, 5.33 mmol) and isobutyl chloroformate (840 μl, 6.60 mmol) are successively added. The mixture is kept stirred for 30 min, and then 4-aminoacetophenone (824 mg, 6.10 mmol) is added. The solution is maintained stirred at 0° C. for 2 h, and then evaporated to dryness. The residue is taken up in 50 ml of water. The precipitate obtained is filtered, washed with water and then with 50 ml of MeOH in the hot state. The white precipitate is dissolved in DMF while heating and then the solution obtained is filtered and washed with MeOH. The filtrate is recovered and evaporated to dryness to give 888 mg of 1b (2.46 mmol, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:15])([O-])[CH3:13].[K+].ClCC1CC1>CS(C)=O>[CH2:11]1[CH2:13][CH:12]1[CH2:15][O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: OCCc1ccc(O)cc1
Agent: ClCC1CC1
Agent: [K+]
Solvent: CS(C)=O
Product: Oc1ccc(CCOCC2CC2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A reaction flask was charged with 4-Hydroxyphenethyl alcohol (1) (100 g, 0.72 mol), Potassium tert-butoxide (243 g, 2.17 mol), and 500 mL of DMSO. The mixture was stirred under nitrogen at 50° C. for 30 minutes. A solution of (Chloromethyl)cyclopropane (100 g, 1.10 mol) in 500 mL of DMSO was added dropwise to the reaction mixture. The mixture was then stirred at 50° C. for one hour and then cooled to room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](O)[N:6]=1)=[O:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][C@H:40]3[CH3:45])[N:36]=[C:35]([N:46]3[CH2:50][CH2:49][CH2:48][C@H:47]3[CH3:51])[N:34]=2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.CC(N(C)C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:42]2[CH2:43][CH2:44][N:39]([C:37]3[CH:38]=[C:33]([C:30]4[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=4)[N:34]=[C:35]([N:46]4[CH2:50][CH2:49][CH2:48][C@H:47]4[CH3:51])[N:36]=3)[C@H:40]([CH3:45])[CH2:41]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C)c(O)n1
Reactant: C[C@@H]1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc(C)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCC[C@H]4C)n3)[C@H](C)C2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a cold solution (0° C.) of 6-hydroxy-5-methyl-pyridine-2-carboxylic acid methyl ester (Adamczyk et. al. (2002) Tetrahedron 58:6951-6963) (167 mg, 1.0 mmol) in CHCl3 (15 mL), add trifluoroacetic anhydride (423 mg, 1.5 mmol) dropwise followed by TEA (202 mg, 2.0 mmol). Stir the mixture for 1 h. Dilute with CHCl3, wash with sat. NaHCO3, dry the organic layer (Na2SO4) and concentrate under reduced pressure. Mix the residue with 4-(4-fluoro-phenyl)-6-(2-(R)-methyl-piperazin-1-yl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidine (426 mg, 1.2 mmol) and DIEA (129 mg, 1.0 mmol) in DMA. Heat the mixture at 100° C. for 16 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:5) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([OH:8])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:43]([O:47][C:48]([C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][CH2:56]O)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][CH2:56][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[I:9])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCO
Reactant: Oc1cc(Cl)ccc1I
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCOc1cc(Cl)ccc1I
Reaction time: 0.33 h

Procedure:
5-Chloro-2-iodophenol (801 mg, 3.15 mmol) and PPh3 (1.15 g, 4.41 mmol) were dissolved in THF (25 mL). DIAD (0.91 mL, 4.62 mmol). was added dropwise and the solution was stirred for 20 min. A solution of 1-(2-hydroxy-ethyl)-pyrrolidine-2-(S)-carboxylic acid tert butyl ester (816 mg, 3.79 mmol) in THF (4 mL) was added via canulation. The mixture was stirred for 40 min at 0° C. then for 1.5 h at room temperature and finally for 3 h at 50° C. The mixture was diluted with heptanes (100 mL), washed with water (4×25 mL), dried over Na2SO4 and evaporated onto silica gel. After flash chromatography using silica gel, eluting with heptanes/EtOAc, 9:1, the title compound was obtained as a colorless oil (1.023 g, 72%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[OH:6][C@@H:7]1[C@@H:31]([N:32]2[CH2:37][CH2:36][O:35][C:34]([CH3:39])([CH3:38])[CH2:33]2)[CH2:30][C@@:29]2([CH3:40])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:41])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:24])[CH2:18]OS(C)(=O)=O)[CH2:8]1.O>C(O)C>[C:1]([O:4][CH2:18][C:17](=[O:24])[C@@H:16]1[C@:25]2([CH3:41])[C@H:13]([C@H:12]3[C@H:28]([CH2:27][CH2:26]2)[C@:29]2([CH3:40])[C@H:9]([CH2:8][C@H:7]([OH:6])[C@@H:31]([N:32]4[CH2:37][CH2:36][O:35][C:34]([CH3:39])([CH3:38])[CH2:33]4)[CH2:30]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)COS(C)(=O)=O)CC[C@@H]43)C[C@@H]2O)CCO1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3CC[C@]12C
Yield: 35.4 %

Procedure:
Anhydrous potassium acetate (470 mg) was added to (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-21-[(methylsulfonyl)oxy]pregnan-20-one (1.0 g) in ethanol (15 ml) and the solution was heated under reflux for 1.5 h. The reaction mixture was poured into water (150 ml) and the precipitated solid was filtered off, washed with water and the solid was dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel. The purified product was crystallised from methanol to give (2β,3α,5α)-21-(acetyloxy)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnan-20-one (330 mg). m.p. 174°-175° C.; [α]D +13.9° (c 0.5).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CS(O[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]1)(=O)=O.O>CN(C)C=O>[CH3:15][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][N+:11]=1[O-:14]
Reactant: Cc1cc(-c2ccc(O)cc2)cc[n+]1[O-]
Reactant: C[C@H]1CCCN(CCCOS(C)(=O)=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccc(OCCCN3CCC[C@H](C)C3)cc2)cc[n+]1[O-]
Temperature: 25 °C

Procedure:
A A mixture of 4-(4-hydroxyphenyl)-2-methylpyridine 1-oxide (55 mg), potassium carbonate (187 mg) and (3S)-1-(3-methanesulfonyloxypropyl)-3-methylpiperidine hydrochloride in N,N-dimethylformamide (3 mL) is heated at a temperature close to 65° C. overnight and cooled back to room temperature. Water (5 mL) is added; the solution is washed with methylcyclohexane (twice 10 mL) and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (eluent dichloromethane/methanol from 95/5 to 80/20). Fraction containing the expected product are pooled and concentrated under reduced pressure. The crude base is diluted in ethanol, oxalic acid (7 mg) is added and solvent is removed under reduced pressure to give 32 mg of (3S)-2-methyl-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide, oxalate as a brown crystalline material.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:11][C:6]1[S:5][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[N:3][C:2]=1[CH3:1]
Reactant: CC(=O)Nc1nc(C)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(C)c(Br)s1

Procedure:
N-(4-Methyl-thiazol-2-yl)-acetamide (Example 17a) (4.0 g, 25.6 mmol) is dissolved in glacial acetic acid (100 ml) at room temperature. This solution is then treated portionwise with N-bromosuccinimide (4.6 g, 25.6 mmol). After 48 hours the reaction mixture is poured into water (1000 ml) and extracted with ethyl acetate (3×250 ml). The combined organic layers are washed with water (200 ml), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in toluene (100 ml) followed by the removal of the solvent in vacuo. This is repeated twice more and the resulting solid is dried in vacuo at 40° C. to give N-(5-bromo-4-methyl-thiazol-2-yl)-acetamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:40])[CH2:9][CH2:10][CH:11]1[CH2:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[C:14]2=[C:24]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:25]3[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[CH:29][C:30]=3[N:13]2[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][CH:43]([O:51][CH3:52])[CH2:44][N:45]([CH3:50])[S:46]([NH2:49])(=[O:48])=[O:47].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:34]1([C:24]2[C:25]3[CH:26]=[CH:27][C:28]([C:31]([NH:49][S:46]([N:45]([CH2:44][CH:43]([O:42][CH3:41])[O:51][CH3:52])[CH3:50])(=[O:48])=[O:47])=[O:32])=[CH:29][C:30]=3[N:13]3[CH2:12][CH:11]([CH2:10][CH2:9][N:8]([CH3:40])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:17][C:16]4[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=4[C:14]=23)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: COc1ccc2c(c1)CC(CCN(C)C(=O)OC(C)(C)C)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(CCN(C)C(=O)OC(C)(C)C)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)CC(OC)OC)cc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 6-{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}-13-cyclohexyl-3-methoxy-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid in DCM (0.07M), N-(2,2-dimethoxyethyl)-N-methylsulfamide (2 eq, Example 1, Step 1), EDC (3 eq) and DMAP (5 eq) were added. The mixture was stirred at 40° C. for 3 h, then diluted with EtOAc and washed with 1N HCl, 1N NaOH solution and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo and the residual material was used in the next step without purification. (ES+) m/z 727 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH2:24][CH2:23][CH2:22][C:21]([C:33](O)=[O:34])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:48]([N:51]1[C:55]([CH2:56][S:57]([C:59]2[CH:65]=[CH:64][C:62]([NH2:63])=[CH:61][CH:60]=2)=[O:58])=[CH:54][N:53]=[CH:52]1)[CH2:49][CH3:50]>ClCCl.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH2:24][CH2:23][CH2:22][C:21]([C:33]([NH:63][C:62]4[CH:61]=[CH:60][C:59]([S:57]([CH2:56][C:55]5[N:51]([CH2:48][CH2:49][CH3:50])[CH:52]=[N:53][CH:54]=5)=[O:58])=[CH:65][CH:64]=4)=[O:34])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3Cc2cnn(C)c2)cc1
Reactant: CCCn1cncc1CS(=O)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3Cc2cnn(C)c2)cc1
Reaction time: 1 h

Procedure:
(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartarate monohydrate (620 mg) was dissolved in ethyl acetate (10 ml) and 1N hydrochloric acid (3.16 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (3.16 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) twice. The organic layers were combined and washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, after which the solvent was distilled off again under reduced pressure to give (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 8-(4-(2-butoxyethoxy)phenyl)-1-((1-methylpyrazol-4-yl)methyl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (350 mg) in dichloromethane (10 ml) was added a drop of DMF, and then oxalyl chloride (0.081 ml) was added, and the mixture was stirred under nitrogen atmosphere for 1 hour. The resulting solution was added dropwise to a solution of (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and triethylamine (2.6 ml) in dichloromethane (10 ml) at 0° C. under nitrogen atmosphere. The mixture was returned to room temperature and stirred for 3 hours, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous acetic acid solution twice, with aqueous saturated sodium bicarbonate solution twice, and with saturated brine once, after which the resultant was dried with magnesium sulfate. After distilling off the solvent under reduced pressure, the resultant was separated and purified with a basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9) to give (−)-8-[4-(2-butoxyethoxy)phenyl]-1-((1-methylpyrazol-4-yl)methyl)-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (98.3 mg) (Compound 34) as a yellow amorphous material.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[O:31][C:32]([F:35])([F:34])[F:33])=[N+]=[N-].Cl.C(Cl)Cl>C1COCC1.[OH-].[NH4+].[OH-].[Na+].CCOCC.CO>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([O:31][C:32]([F:33])([F:34])[F:35])=[C:24]([CH:29]=1)[CH2:23][NH2:20]
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1OC(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cc(Cl)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
Triphenylphosphine (0.99 g, 3.8 mmol) was added to a solution of the azide (0.86 g, 3.4 mmol) in THF (25 mL) at 0° C. After 5 min, the mixture was warmed to room temperature. After 18 h, the reaction was diluted with ammonium hydroxide (10 mL). After 3 h, the reaction was diluted with 3 M NaOH and stirred for 1 h. The reaction was acidified to pH 2 with 4 N HCl. The solution was then diluted with Et2O and the layers were separated. The aqueous layer was extracted with Et2O and then basified with 2 N NaOH. The basic aqueous solution was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to yield an oily solid. The crude solid was diluted with Et2O (50 mL) and filtered. The filtrate was concentrated in vacuo to yield a pale yellow oil. Silica gel column chromatography using 20:1 CH2Cl2:MeOH as an eluent yielded 0.64 g (83%) of 5-chloro-2-trifluoromethoxy-benzylamine as a colorless oil. The product was not stable at room temperature and was used for the next step immediately.