Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[C:8]=1[F:18])(=O)=O.[C-:19]#[N:20].[Na+].O>CS(C)=O>[Cl:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:17])[CH3:16])=[C:8]([F:18])[C:7]=1[CH2:6][C:19]#[N:20]
Reactant: [C-]#N
Reactant: CC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(Cl)c(CC#N)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 3-acetamido-6-chloro-2-fluorobenzyl methanesulfonate (1.31 g, 3.54 mmol) in DMSO (10 mL) was treated with sodium cyanide (0.868 g, 17.72 mmol), stirred at RT overnight, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-chloro-3-(cyanomethyl)-2-fluorophenyl)acetamide (630 mg, 78% yield) as a yellow solid. MS (ESI) m/z: 227.0 [M+H]+.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=[O:4].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([O:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-Boc-Gly (3.0 g) in methylene chloride (100 ml) was added benzyl alcohol (1.6 ml), EDC (4.4 g) and a catalytic amount of DMAP. After 2 hours, the mixture was poured into 1N HCl and extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated to give N-Boc-Gly-OBn (4.5 g). To a solution of N-Boc-Gly-OBn (1.32 g) in THF (10 ml) was added potassium bis(trimethylsilyl)amide (1.19 g) in THF (20 ml) at -78° C. After 30 minutes at -78° C. allyl bromide (0.52 ml) was added to the reaction mixture slowly. The resulting mixture was slowly warmed up to room temperature and stirred for an additional 12 hours. The mixture was poured into 1N HCl and extracted with ether, the combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatotron (hexanes/ethyl acetate=10/1) to give desired product (585 mg). ##STR91##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>CC#N.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]#[N:12])[CH2:9][CH2:10]2)=[CH:6][C:7]=1[Br:20]
Reactant: N#CC1(c2ccc(N)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CC1(c2ccc(N)c(Br)c2)CC1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 1-(4-amino-phenyl)-cyclopropanecarbonitrile (96 mg, 0.60 mmol) in MeCN (3 mL) at 0° C. was added NBS (108 mg, 0.60 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with EtOAc (25 mL) and was then washed with saturated aqueous NaHCO3 (1×25 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give 114 mg (80%) of 1-(4-amino-3-bromo-phenyl)-cyclopropanecarbonitrile. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12](=[O:19])[C:13]3[S:17][CH:16]=[C:15]([CH3:18])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[N:4][CH:3]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O.C(O)(=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12](=[O:19])[C:13]3[S:17][CH:16]=[C:15]([CH3:18])[CH:14]=3)[C:7](=[O:11])[N:8]2[C:20]([NH2:21])=[O:26])=[N:4][CH:3]=1
Reactant: Cc1csc(C(=O)C2C(=O)Nc3cc(F)cnc32)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1csc(C(=O)C2C(=O)N(C(N)=O)c3cc(F)cnc32)c1

Procedure:
The title compound was prepared from 6-fluoro-3-(4-methyl-2-thenoyl)-4-azaoxindole (Example 36) according to the procedure of Example 2C, using 6-fluoro-3-(4-methyl-2-thenoyl)-4-azaoxindole (614 mg, 2.22 mmol), N-chlorosulfonyl isocyanate (0.30 mL, 3.45 mmol) and acetonitrile (10 mL). The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO (4 mL) overnight in a flask open to the air. The product was isolated by dilution with water, filtration, and recrystallization from acetic acid. Yield: 249 mg (35%). M.p.>250°.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CN1CCOCC1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO.O1CCOCC1.O>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:16])=[CH:15][CH:14]=2)=[O:13])[CH2:28][CH2:27]1
Reactant: Cc1ccc(N2CCCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(N2CCCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16, 1-(2,4-dimethylphenyl)-[1,4]diazepane hydrochloride (253 mg) described in Preparation Example 93 and N-methylmorpholine (0.12 mL) was dissolved in a solution of methanol (2 mL), 1,4-dioxane (2 mL) and water (0.5 mL), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (349 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (223 mg).
Reaction SMILES: O=[C:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][C:5]([O:7]CC(C)C)=[O:6].[BH4-].[Na+].O.C(OCC)(=O)C>C(O)C>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:2]1[O:7][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CCCCCCC(=O)CCC(=O)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCC1CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 200 ml of 99.5% ethanol, was dissolved 24.2 g (0.10 mol) of isobutyl 4-oxodecanoate. Thereto was added 4.2 g (0.11 mol) of sodium borohydride in small quantities, and then the mixture was stirred for 10 minutes at 25° C. The solution was poured into 1 L of water, and 1 L of ethyl acetate was further added thereto followed by stirring to thereby extract the product into the ethyl acetate phase. Ethyl acetate was distilled off followed by vacuum distillation, yielding γ-decalactone (a compound in which R61 represents an n-pentyl group in the above formula (39)). Gas chromatographic analysis showed that the yield of γ-decalactone relative to isobutyl 4-oxodecanoate was 93%. In the resulting γ-decalactone, a plastic-like flavor or acid taste was not observed at all, but it had a good peach-like aroma.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)/[C:18](=[CH:22]\[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)/[C:17]([CH3:31])=[C:16]2[CH2:32][N:33]=[C:34]=[O:35]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)/[C:18](=[CH:22]\[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)/[C:17]([CH3:31])=[C:16]2[CH2:32][NH:33][C:34]([N:3]([OH:4])[CH3:2])=[O:35]
Reactant: CSc1ccc(/C=C2/C(C)=C(CN=C=O)c3cc(F)ccc32)cc1
Reactant: CNO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ccc(/C=C2/C(C)=C(CNC(=O)N(C)O)c3cc(F)ccc32)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of N-methyl hydroxylamine hydrochloride (9.82 g, 117.6 mmol) in THF (150 mL) at room temperature there was added triethylamine (16.3 mL, 117.6 mmol) and the mixture stirred for 10 minutes. There was added, over 15 minutes, a solution of the isocyanate from Step 1 in THF (100 mL). After 2 hours of stirring at room temperature, the THF was evaporated and the residue, on trituration with water, afforded a yellow solid which was filtered. This solid was stirred in ether (150 mL) and filtered again. This crude material was chromatographed on silica gel eluting with 5% ethanol in methylene chloride. The more polar component of the mixture was stirred with methylene chloride (50 mL) for 2 hours and filtered and the solid crystallized from ethyl acetate to afford the pure title product as yellow crystals, mp 190-192° C. dec.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Reactant: OC1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(OC3CCCCC3)c2C#N)o1

Procedure:
From 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 299 (M+H+, 50), 217 (M+H—C6H10+, 100).
Reaction SMILES: [ClH:1].[P:2]([O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([NH:35][C:36]3[S:37][C:38]([CH2:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=4)=[O:43])=[CH:39][N:40]=3)=[N:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:52][CH3:53])([O:9]C(C)(C)C)([O:4]C(C)(C)C)=[O:3]>O1CCOCC1>[ClH:1].[ClH:1].[P:2]([OH:4])([OH:9])([O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([NH:35][C:36]3[S:37][C:38]([CH2:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=4)=[O:43])=[CH:39][N:40]=3)=[N:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:52][CH3:53])=[O:3]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4cccc(F)c4)s3)ncnc2cc1OCCCN1CCC[C@H]1COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4cccc(F)c4)s3)ncnc2cc1OCCCN1CCC[C@H]1COP(=O)(O)O
Reaction time: 20 h
Yield: 97 %

Procedure:
Hydrochloric acid (10.4 ml of a 4.0 N solution in 1,4-dioxane, 41.5 mmol) was added, dropwise to a solution of di(tert-butyl) ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl phosphate (4.49 g, 5.92 mmol) in 1,4-dioxane (180 ml) upon which a light yellow solid precipitated from the reaction mixture. The resulting heterogeneous reaction mixture was stirred for a further 20 hours before the precipitate was collected, washed with 1,4-dioxane (80 ml) and acetonitrile (2×100 ml) and dried in vacuo to yield ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl dihydrogen phosphate bis-hydrochloride as a light yellow solid (4.40 g, 97% yield):
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH3:13])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3]1[N:22]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:21][C:2]=1[CH2:11][CH2:12][CH3:13])[CH3:9]
Reactant: NC(=O)c1ccccc1
Reactant: CCCC(Br)C(=O)CC(=O)OCC
Product: CCCc1oc(-c2ccccc2)nc1CC(=O)OCC

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from ethyl 4-bromo-3-oxo-heptanoate (2.83 g, 11.4 mmol) and 5.51 g (45 mmol) of benzamide to give 820 mg of Intermediate IC: TLC Rf=0.70 (2/1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ7.98 (m, 2H), 7.43-7.4 (m, 3H), 4.18 (q, 2H, J=7.2), 3.56 (s, 2H), 2.66 (t, 2H, J=7.5), 1.76-1.68 (m, 2H), 1.27 (t, 3H, J=7.2), 0.99 (t, 3H, J=7.2); low resolution MS (ES+)m/e 274.1 (MH+).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[O:87]=[C:88]1[CH2:92][CH2:91][CH2:90][N:89]1[CH2:93][C:94](O)=[O:95]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:95])[CH2:93][N:89]1[CH2:90][CH2:91][CH2:92][C:88]1=[O:87])[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)CN1CCCC1=O
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(2-oxopyrrolidin-1-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 655.5 (M+H)+, 1.99 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=7.9 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 6.77 (s, 1H), 5.29 (d, J=4.7 Hz, 1H), 4.75 (d, J=1.3 Hz, 1H), 4.63 (s, 1H), 3.97-3.85 (m, 2H), 3.58-3.51 (m, 2H), 2.65-2.54 (m, 2H), 2.47 (t, J=8.0 Hz, 2H), 2.38 (dd, J=8.4, 12.5 Hz, 1H), 2.17-2.07 (m, 3H), 1.95-1.85 (m, 1H), 1.83-1.74 (m, 2H), 1.73 (br. s., 1H), 1.70 (s, 3H), 1.68-1.62 (m, 1H), 1.60-1.43 (m, 8H), 1.42-1.22 (m, 6H), 1.13 (br. s., 1H), 1.09 (s, 3H), 1.01 (s, 6H), 0.94 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11](/[C:15](/[CH2:19][CH3:20])=[CH:16]/[CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4]>[Si:1]([O:8][C:9]1[CH:10]=[C:11](/[C:15](/[CH2:19][CH3:20])=[CH:16]/[CH:17]=[O:18])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC/C(=C\CO)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Mn+4]
Agent: [O-2]
Product: CC/C(=C\C=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
In a manner analogous to example 1j, by reaction of 6.7 g (23 mmol) of (E)-3-[3-(tert-butyldimethylsilanyloxy)phenyl]pent-2-en-1-ol with 10 g (115 mmol) of manganese dioxide. A yellow oil is obtained (m=4.7 g; Y=71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[N:6][C:5]=1Cl.C([O-])=O.[NH4+]>[Pd]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1cc(F)c(C)nc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: COC(=O)c1cnc(C)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A flask containing 10% Pd/C (0.20 g, 0.19 mmol) and 2-chloro-5-fluoro-6-methyl-nicotinic acid methyl ester (0.410 g, 2.01 mmol) is placed under an atmosphere of Ar. The atmosphere of the vessel is evacuated and refilled with Ar three times. To this is added MeOH (30 mL) followed by ammonium formate (1.0 g, 16 mmol). The mixture is stirred at room temperature for 1 h. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide a solid. The material is washed with EtOAc and filtered to remove insoluble material. The filtrate is concentrated under reduced pressure to provide 0.210 g (61.6%) of 5-fluoro-6-methyl-nicotinic acid methyl ester as a solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Cl:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COC(=O)c1ccc(OC)cc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OC)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c(Cl)c1

Procedure:
Compound of example 6 (1.0 g, 3.2 mmol) in dry DMF (25 mL) was reacted with methyl 2-chloro-4-methoxybenzoate (1.29 g, 6.4 mmol) in the presence of NaH (50%, 0.776 g, 16 mmol) as described in example 16 to obtain the title compound.
Reaction SMILES: [C:1]([O:9]C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C[Si](C)(C)[O-].[K+:16]>O1CCCC1>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[K+:16]
Reactant: COC(=O)c1cccnc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C([O-])c1cccnc1
Yield: 90.9 %

Procedure:
The procedure of Example 1 was followed using methyl nicotinate (2.74 g, 20 mmol), potassium trimethylsilanolate (2.56 g, 20 mmol), dry tetrahydrofuran (50 mL), and a 5 h reaction time. Potassium nicotinate (2.93 g, 90% yield) was isolated as a white solid: 1H NMR (D2O, DSS) δ 7.55 (ddd, J=1.0, 5.3, 8.3 Hz, Ar--H, 1H), 8.25 (dt, J=1.9, 8.3, Ar--H, 1H), 8.93 ppm (m, Ar--H, 1H). Anal. Calcd. for C6H4KNO2 : C, 44.70; H, 2.50; N, 8.96; K, 24.26. Found: C, 42.28, 42.51, 44.97; H, 2.95, 2.74, 2.83; N, 8.54; K, 24.57.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:10][CH2:11][N:12](C(OCC)=O)[CH2:13][CH2:14][C:15]=3[C:6]=2[CH:5]=[C:4]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:3]=1.[OH-].[K+].Cl>C(O)CO.COCCOC.O.CO>[ClH:1].[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]=3[C:6]=2[CH:5]=[C:4]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:3]=1
Reactant: CCOC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)CCNCC3
Temperature: 100 °C
Yield: 31.4 %

Procedure:
The product of step E (35 mg, 0.08 mmol) was dissolved in a mixture of ethylene glycol (0.5 mL) and DME (0.5 mL) then treated with 20% KOH solution (0.5 mL). The reaction mixture was heated to 100° C. for 36 h. After cooling to ambient temperature, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by semi-preparative HPLC to give the free base which was treated directly with 1.25 M HCl in methanol solution. Concentration in vacuo afforded 7-chloro-9-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepine hydrochloride (5 mg, 15%, AUC HPLC>99%) as a white solid: 1H NMR (CD3OD, 300 MHz) δ 8.18 (d, J=2.0 Hz, 1H), 8.00 (d, J=7.4 Hz, 2H), 7.90 (d, J=1.7 Hz, 1H), 7.68-7.52 (m, 3H), 3.60-3.51 (m, 4H), 3.42-3.35 (m, 2H), 3.23-3.15 (m, 2H); APCI MS m/z 362 [M+H]+.
Reaction SMILES: C[C@@H]([C@@H]1[C@@]2(C)CCC3[C@@]4(C)CCC(OC([Cl:29])=O)CC4=CCC3C2CC1)CCCC(C)C.[CH2:32]([O:39][CH:40]([CH2:43][OH:44])[CH2:41]O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(Cl)Cl.N1C=CC=CC=1.O>[CH2:32]([O:39][CH:40]([CH2:43][OH:44])[CH2:41][Cl:29])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: OCC(CCl)OCc1ccccc1
Yield: 135.4 %

Procedure:
A solution of 10.2 g of cholesteryl chloroformate in 130 ml of methylene chloride is treated under argon while stirring with 4.6 g of 2-O-benzylglycerol in 120 ml of methylene chloride and 2 ml of pyridine, taken up in 500 ml of water and 50 ml of 1N HCl after 1 hour and extracted with methylene chloride. The organic phase is dried and concentrated at 50° C. After chromatography over SiO2 with n-hexane:ether (1:1) there are obtained 6.17 g of (RS)-2-(benzyloxy)-3-hydroxypropyl chloride 5-en-3β-ylcarbonate, MS: 595 (M+H+), the starting material of Example 13.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C1COCC1.[O:14]=[C:15]1[N:21]2[C@H:17]([CH2:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:35][Si](CC)(CC)CC)[CH:29]=3)=[C:20]2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[C@H:16]1[C@H:43]([O:45][Si](CC)(CC)CC)[CH3:44].C(=O)([O-])O.[Na+]>O>[OH:45][C@@H:43]([C@H:16]1[C:15](=[O:14])[N:21]2[C@@H:17]1[CH2:18][C:19]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][OH:35])[CH:29]=1)=[C:20]2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH3:44]
Reactant: C=CCOC(=O)C1=C(c2cccc(CO[Si](CC)(CC)CC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 1 h

Procedure:
Anhydrous trifluoromethanesulfonic acid was added to THF (7 ml) and water (4 ml), and the solution was adjusted to pH2.2. To the solution was added at 0° C. allyl (5R,6S)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-3-(3-{[(triethylsilyl)oxy]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (520 mg). After stirring for 1 hour, thereto was added a saturated aqueous sodium hydrogencarbonate solution, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate. This product was used in the next step without further purification.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([S:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].[OH-].[Ca+2].[OH-]>ClCCl>[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([S:33]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:6])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:20][CH:21]3[CH2:22][CH:23]([CH2:24][CH:25]([CH2:27]3)[CH2:26]1)[CH2:28]2)=[O:16]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(SC2CCNCC2)ccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(S(=O)C2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
m-Chloroperoxybenzoic acid (166 mg) was added to a solution of 2-chloro-5-(piperidin-4-ylsulfanyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.35 g, Example 55c) in dichloromethane (5 ml). After 2 h calcium hydroxide (0.20 g) was added and 30 min. later the salts removed by filtration. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 0-25% ethanol in dichloromethane). The residue was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the solution was concentrated under reduced pressure and triturated with diethyl ether to yield the title compound as the hydrochloride salt (0.030 g).