Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:11]([CH2:14][C@H:15]([NH:19][C@@H:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:21]([F:24])([F:23])[F:22])[C:16](O)=[O:17])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:57][C@@H:58]([CH2:67][CH3:68])[CH:59]([OH:66])[C:60]([NH:62][CH:63]1[CH2:65][CH2:64]1)=[O:61].CCN(C(C)C)C(C)C>ClCCl>[CH:63]1([NH:62][C:60](=[O:61])[CH:59]([OH:66])[C@@H:58]([NH:57][C:16](=[O:17])[C@@H:15]([NH:19][C@@H:20]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:21]([F:23])([F:24])[F:22])[CH2:14][S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)(=[O:13])=[O:12])[CH2:67][CH3:68])[CH2:64][CH2:65]1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)C[C@H](N[C@@H](c2ccc(F)cc2)C(F)(F)F)C(=O)O)c1
Reactant: CC[C@H](N)C(O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@H](CS(=O)(=O)c1cccc(S(C)(=O)=O)c1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
A solution of (R)-3-((3-(methylsulfonyl)phenyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-amino)propanoic acid (7.3 g; 15 mmol) and HATU (6.84 g; 18.0 mmol; 120 mole %) in anhydrous dichloromethane (200 mL) was stirred at ambient temperature for 5 minutes, then (3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide hydrochloride (35.0 mmol; 233 mole %) was added and the mixture stirred for 5 minutes. The reaction mixture was then cooled to 0-5° C. and treated with the dropwise addition of DIPEA (7.8 mL; 5.8 g; 45 mmol; 300 mol %). After the addition was complete, the cooling bath was removed and the reaction was stirred for 2.5 h at ambient temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed in sequence with a solution of 10% aqueous potassium hydrogensulfate, water, 10% aqueous sodium bicarbonate, water, and finally saturated aqueous sodium chloride. The organic phase was dried (MgSO4), and concentrated almost to dryness. The residue was triturated with diethyl ether then some hexane was added. The resulting solid was filtered and washed with hexane to give 8.6 g (96%) of (3S)—N-cyclopropyl-2-hydroxy-3-((R)-3-((3-(methylsulfonyl)phenyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanamido)pentanamide as an off-white solid. LC-MS, positive ion mode: m/z=638 [M+H]+ (100%); negative ion mode: m/z=636 [M−H]− (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. No. 7,488,848.
Reaction SMILES: N[C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[I:16]CI.N(OCCC(C)C)=O>C(#N)C.CCCCCC>[C:7]([C:6]1[C:2]([I:16])=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:4][C:5]=1[S:9][CH3:10])#[N:8]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1N
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCCCCC
Product: CCOC(=O)c1sc(SC)c(C#N)c1I
Temperature: 40 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
Ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate (10 g, 41.3 mmol) was dissolved in acetonitrile (50 mL) under an atmosphere of argon. Diiodomethane (11.6 mL, 0.144 mol) was added and the mixture was heated at 40° C. Isoamyl nitrite (12.1 g, 0.103 mol) was added and the reaction was allowed to cool to room temperature and stirred for 2 hours. Mixture was cooled down at 0° C., diluted with hexane (50 mL) and the precipitate was filtered off, washed with 10:1 hexane-acetonitrile mixture (10 mL), 3:1 hexane-ether (10 mL) and hexane (10 mL). The precipitate was dried to afford ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (6.90 g, 45%). LCMS: (FA) ES+ 354. 1H NMR (400 MHz, d1-chloroform) δ: 4.38 (q, 2H), 2.70 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2].CS(O[CH2:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)cc1CC
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)cc1CC

Procedure:
The parent phenolic compound, ethyl 3-(2-ethyl-4-hydroxylphenyl)propionate (10.4 g, 50 mmol) and 120 ml acetonitrile were added into a 250 ml single neck flask, and stirred. Then the parent sulfonate compound, 2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethyl methanesulfonate (15 g, 50 mmol) and potassium carbonate (K2CO3) (100 mmol) were added. The mixture was heated for 16 hours under reflux. After the reaction was completed, the product was filtered. The filter cake was washed with ethyl acetate (3×50 ml) and then discarded. The filtrates were combined, and the solvent was distilled off under reduced pressure, to obtain crude ethyl 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)propionate. The crude ethyl 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)propionate, without purification, was dissolved with 120 ml ethanol. 10% NaOH (30 ml) was added at room temperature, and the stirring was maintained for 3 hours at room temperature. After the reaction was completed, the product was acidified by adding 10% dilute hydrochloric acid, to obtain a solid precipitate. It was filtered by suction filtration, to obtain crude 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)propionic acid. The crude product was crystallized by ethyl acetate-petroleum ether, to obtain 12.3 g white solid, with a yield of 62% from the 2 steps.
Reaction SMILES: C([N:3]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11][CH2:10][N:9]([CH:23]([CH2:30][CH2:31][CH:32]([N:39]2[CH2:50][CH2:49][N:48]([CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])[CH2:47][CH2:46][N:45](C=O)[CH2:44][CH2:43][N:42]([CH2:61][C:62]([O:64]C(C)(C)C)=[O:63])[CH2:41][CH2:40]2)[C:33]([O:35]C(C)C)=[O:34])[C:24]([O:26]C(C)C)=[O:25])[CH2:8][CH2:7][N:6]([CH2:69][C:70]([O:72]C(C)(C)C)=[O:71])[CH2:5][CH2:4]1)=O.O.[Li+].[OH-].Cl>C(O)C>[C:52]([CH2:51][N:48]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43][N:42]([CH2:61][C:62]([OH:64])=[O:63])[CH2:41][CH2:40][N:39]([CH:32]([CH2:31][CH2:30][CH:23]([N:9]2[CH2:8][CH2:7][N:6]([CH2:69][C:70]([OH:72])=[O:71])[CH2:5][CH2:4][NH:3][CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]2)[C:24]([OH:26])=[O:25])[C:33]([OH:35])=[O:34])[CH2:50][CH2:49]1)([OH:54])=[O:53]
Reactant: CC(C)OC(=O)C(CCC(C(=O)OC(C)C)N1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1)N1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCN(C(CCC(C(=O)O)N2CCN(CC(=O)O)CCNCCN(CC(=O)O)CC2)C(=O)O)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In a 250 mL RB flask the ester of Example 4 (1.77 g, 1.63 mmol) was dissolved in ethanol (30 ml) and water was added until the solution turned slightly turbid. The temperature was elevated to 100° C. and 1N LiOH (13 mL) was added. After maintaining the mixture at 100° C. for 7 hours, the reaction was stirred at 50° C. for a further 18 hours. The solution was adjusted to pH 0.5 with 5N HCl (aq), and the mixture was refluxed for 1.5 hours and stirred at ambient temperature for an additional 18 hours. The material was loaded onto a bed of AG5OW-X8 [80 mL, (H+ -form)] strongly acidic cation exchange resin. After rinsing with water (1100 mL), the target material was eluted from the bed using 0.25N NH4OH solution. The fractions containing the title product were combined and evaporated to afford 0.79 g (79%) as a glassy solid. 1H NMR (D2O) δ 3.81 (br, 2H), 3.58-2.78 (br, 40H), 2.135 (br, 2H), 1.85 (br, 2H). 13C NMR (D2O): 22.5, 23.1, 40.6, 46.4, 48.6, 54.5, 62.6, 170.3, 175.7. MS (FAB): m/e 719.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccncc2)cc1
Reaction time: 20 h
Yield: 90.5 %

Procedure:
A mixture of 4-(4-nitrophenyl)pyridine (274 mg, 1.37 mmol) and Pd—C(10%, 80 mg) in MeOH (10 mL) was hydrogenated under balloon H2 for 20 h. The mixture was then filtered through celite. The filtrate was concentrated in vacuo to give 4-(pyridin-4-yl)aniline as a solid (211 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][NH:5][C:6](=[O:8])[CH:7]=1.Br[CH:12]([CH3:16])[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][N:5]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:6](=[O:8])[CH:7]=1
Reactant: N#Cc1c[nH]c(=O)cc1Br
Reactant: CC(Br)C(=O)O
Product: CC(C(=O)O)n1cc(C#N)c(Br)cc1=O

Procedure:
1.0 g (purity 77%, 3.87 mmol) of 4-bromo-6-oxo-1,6-dihydropyridin-3-carbonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 35-45° C. After aqueous work-up, the crude product was triturated with cyclohexane/dichloromethane, and the solid was filtered off and dried under high vacuum. Yield: 648 mg (purity 66%, 41% of theory)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([Cl:20])[N:3]=1.Cl.[CH2:22]([NH2:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:20][C:4]1[N:3]=[C:2]([NH:24][CH2:22][CH3:23])[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 100 °C
Yield: 13 %

Procedure:
A suspension of 626 mg (2.0 mmol) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 2), 244 mg (2.4 mmol) ethylamine hydrochloride and 689 mg (5.0 mmol) K2CO3 in DMF (6 ml) was heated to 100° C. for 3 d. Then the RM was poured into ice water (10 ml), followed by extraction with EtOAc (3×15 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 84 mg (0.26 mmol, 13%) 6-chloro-2-ethylamino-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:34][C:35]([F:53])([F:52])[C:36]([C:39]1[CH:48]=[CH:47][C:46]2[CH2:45][C@H:44]([C:49]([OH:51])=O)[CH2:43][CH2:42][C:41]=2[N:40]=1)([CH3:38])[CH3:37].Cl.[NH2:55][C@@H:56]([C:58]1[C:63]([F:64])=[CH:62][C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])=[C:60]([CH3:70])[CH:59]=1)[CH3:57]>CN1CCCC1=O>[F:64][C:63]1[CH:62]=[C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[C:60]([CH3:70])=[CH:59][C:58]=1[C@H:56]([NH:55][C:49]([CH:44]1[CH2:43][CH2:42][C:41]2[N:40]=[C:39]([C:36]([CH3:38])([CH3:37])[C:35]([F:53])([F:34])[F:52])[CH:48]=[CH:47][C:46]=2[CH2:45]1)=[O:51])[CH3:57]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 45.9 %

Procedure:
A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (19.8 mg, 0.0522 mmol) and N,N-diisopropylethylamine (28 uL, 0.16 mmol) in N-methylpyrrolidinone (300 uL) was added to (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (15 mg, 0.052 mmol) in a 2 mL vial, and the mixture stirred at room temperature for 1 h, before a solution of (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (18 mg, 0.063 mmol) in N-methylpyrrolidinone (200 uL) was added. After 18 h the mixture was filtered and purified by reverse-phase HPLC (30-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (12.3 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.41 (app dd, J=7.7, 12.0 Hz, 1H), 7.53 (app dd, J=3.3, 8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.6 Hz, 1H), 5.09 (app hextet, J=7.3 Hz, 1H), 3.01 (s, 3H), 2.92-2.78 (m, 4H), 2.71-2.61 (m, 1H), 2.26 (s, 3H), 2.06-1.97 (m, 1H), 1.87-1.69 (m, 1H), 1.53 (s, 3H), 1.35 (d, J=7.1 Hz, 3H); m/z=516.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)CCl>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([O:20][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Under argon, 10 g (20.11 mmol) of (−)-3-(2-benzyloxy-5-iodophenyl)-2(S)-tert-butoxycarbonylaminopropionic acid (Example (−)-6A) are dissolved in 200 ml of acetonitrile. To this are added 246 mg (2.01 mmol) of 4-dimethylaminopyridine and 4.16 ml (40.22 mmol) of benzyl alcohol. The mixture is cooled to −10° C., and 4.63 g (24.13 mmol) of EDC are added. The mixture is allowed slowly to reach RT and is stirred overnight. After about 16 h, the mixture is concentrated on a rotary evaporator in vacuo, and the residue is purified by column chromatography on silica gel (mobile phase: dichloromethane). Yield: 10.65 g (88% of theory).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH:8]([O:12][CH3:13])[CH2:9][NH:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CC1CCCO1>[Cl:1][CH2:2][C:3]([N:10]([CH2:9][CH:8]([O:12][CH3:13])[O:7][CH3:6])[CH3:11])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCC(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: COC(CN(C)C(=O)CCl)OC

Procedure:
195 ml chloroacetyl chloride in 200 ml 2-methyltetrahydrofuran are added dropwise at 2° C. within one hour to a mixture of 300 ml (methylamino)-acetaldehyde dimethylacetal, 1200 ml 2-methyltetrahydrofuran and 1200 ml saturated potassium carbonate solution. After 40 min 1450 ml of water are added and the phases are separated. The aqueous phase is extracted with 600 ml 2-methyltetrahydrofuran. The combined organic phases are dried on sodium sulphate and evaporated down. 451 g product remain.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[C:9](=[O:15])[C:8](O)=[CH:7][C:6]2=[O:17])[CH3:2].S(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:9](=[O:15])[C:10]2[C:5]([C:6](=[O:17])[CH:7]=1)=[CH:4][C:3]([CH2:1][CH3:2])=[C:12]([CH2:13][CH3:14])[CH:11]=2
Reactant: CCc1cc2c(cc1CC)C(=O)C(O)=CC2=O
Reactant: O=S(Cl)Cl
Product: CCc1cc2c(cc1CC)C(=O)C(Cl)=CC2=O

Procedure:
A solution of 6,7-diethyl-2-hydroxy-1,4-naphthoquinone (22 g; 0.096 mole) in thionyl chloride (250 ml) was refluxed for 12 hours and the solvent removed in vacuo. Repeated evaporation with dry benzene gave an orange solid which after recrystallisation from ethanol in the presence of charcoal weighed 18.04 g (76%) and had m.p. 90°-92° C. (Found; C, 67.21; H, 5.39; Cl, 14.21; C14H13ClO2 requires; C, 67.61; H, 5.27; Cl, 14.26%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([NH:12][C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28]>CN(C=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([N:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C[C@@H](N(Cc2ccccc2Cl)c2ccc(C#N)c(Cl)c2)CC1=O
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
NaH (60% in mineral oil, 0.010 g, 0.26 mmol) was added to a solution of 2-chloro-4-{[(3S)-1-methyl-5-oxo-3-pyrrolidinyl]amino}benzonitrile (0.06 g, 0.24 mmol) in DMF (2 mL) at 0° C. under a N2 atmosphere. After stirring for 10 min, 1-(bromomethyl)-2-chlorobenzene (0.054 g, 0.26 mmol) was added and the reaction mixture was stirred at 0° C. for 15 min. The reaction was quenched with H2O and then partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via column chromatography with 5% EtOAc in hexane grading to 100% EtOAc in hexane to yield the titled compound (0.03 g, 37%) as a clear oil. 1H-NMR (CDCl3) δ: 2.486 (1H, m), 2.797 (1H, m), 2.866 (3H, s), 3.383 (1H, m), 3.785 (1H, m), 4.563 (2H, m), 4.281 (1H, m), 6.519 (1H, dd, J=8.8 Hz, 2.8 Hz), 6.717 (1H, d, J=2.8 Hz), 6.757 (1H, dd, J=7.6 Hz, 1.2 Hz), 7.264 (2H, m), 7.420 (2H, m). LC-MS (ES) m/e 374.2 (M+H)+.
Reaction SMILES: [I-].[Ca+2].[I-].[C:4]([O:7][CH:8]=[CH2:9])(=[O:6])[CH3:5]>C(O)(=O)C>[C:4]([O:7][CH:8]([O:7][C:4](=[O:6])[CH3:5])[CH3:9])(=[O:6])[CH3:5]
Reactant: C=COC(C)=O
Agent: [Ca+2]
Agent: [I-]
Solvent: CC(=O)O
Product: CC(=O)OC(C)OC(C)=O
Reaction time: 6 h
Yield: 18027.3 %

Procedure:
The procedure of Example 9 was repeated except that 10 g of calcium iodide was used in place of methyl iodide and the reaction was carried out for 6 hours. GC analysis showed that 0.083 g of vinyl acetate and 12.7 g of ethylidene diacetate were formed with considerable amount of acetic acid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:11][N:10]=1>C(O)(=O)C>[C:1]([N:11]1[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([OH:8])=[N:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c[nH]nc1O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C(C)=O)nc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.2 mL, 12.8 mmol) is added to a suspension of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (2.0 g, 12.8 mmol) in 30 mL of acetic acid. The reaction mixture is stirred at RT for 2 h. The solvent is removed in vacuo, and the remaining solid is washed with water, collected by vacuum filtration, and dried in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (1H, s), 8.27 (1H, bs), 4.38 (2H, q), 2.64 (3H, s), 1.38 (3H, t).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[O:16]=[C:11]1[C:10](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:22]=2[CH2:21][CH2:20][NH:19][C:18]3=[O:17])[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12]1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(-c3ccccc3)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-phenyl-1,3-dihydro-indol-2-one (41.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [Br-].C1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)C=CC=CC=1.[Li]CCCC.[O:27]=[C:28]1[NH:33]C2C=C(C=O)C=CC=2[S:30][CH2:29]1>C1COCC1>[CH:8]([C:9]1[CH:10]=[CH:11][C:12]2[S:30][CH2:29][C:28](=[O:27])[NH:33][C:13]=2[CH:14]=1)=[CH2:15]
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a stirred suspension of triphenylmethylphosphonium bromide (20.0 mmole) in dry THF (40 mL) at RT was added 2.5 M n-BuLi (7.5 mL, 3.0 mmole). After 3 h, 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (1.93 g, 10.0 mmole) was added and the reaction contents were stirred at RT overnight. The reaction solution was filtered and the filtrate concentrated, dissolved in EtOAc and washed with 1 M HCl (20 mL). The organic solution was dried (Na2SO4) and concentrated under vacuum. Purification on silica (EtOAc/hexanes, 1:4) afforded the title compound (1.20 g, 63%) as light yellow solid: LC-MS (ES): m/e 192 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[N:7][CH:6]=1.[Se](=O)=[O:33].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19](=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[N:7][CH:6]=1
Reactant: CCC(C)Oc1cccc(Cc2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(C)Oc1cccc(C(=O)c2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Temperature: 85 °C
Yield: 82.7 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester (200 mg, 0.47 mmol) in ethyl acetate (4 mL) was added selenium dioxide (65 mg, 0.59 mmol). The reaction mixture was heated at 85° C. for 1 hr. The solvent was evaporated and afford a crude product. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded [1-(3-sec-butoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester as a light brown oil (170 mg, 83% yield).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Br)cc2)CC1
Reactant: ON=C1CCCCCC1
Product: Brc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-bromophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-bromophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][C:7]([C:9]1[NH:31][C:12]2[CH2:13][C@@:14]3([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29]C)[CH:24]=4)[C@H:19]([CH2:20][C:11]=2[C:10]=1[CH3:32])[CH2:18][N:17]([CH2:21][CH3:22])[CH2:16][CH2:15]3)=[O:8])[CH:3]([CH3:5])[CH3:4].B(Br)(Br)Br>>[ClH:1].[CH2:2]([O:6][C:7]([C:9]1[NH:31][C:12]2[CH2:13][C@@:14]3([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=4)[C@H:19]([CH2:20][C:11]=2[C:10]=1[CH3:32])[CH2:18][N:17]([CH2:21][CH3:22])[CH2:16][CH2:15]3)=[O:8])[CH:3]([CH3:5])[CH3:4]
Reactant: CCN1CC[C@@]2(c3cccc(OC)c3)Cc3[nH]c(C(=O)OCC(C)C)c(C)c3C[C@@H]2C1
Agent: BrB(Br)Br
Agent: Cl
Product: CCN1CC[C@@]2(c3cccc(O)c3)Cc3[nH]c(C(=O)OCC(C)C)c(C)c3C[C@@H]2C1

Procedure:
0.56 g of (±)-trans-2-(i-butoxycarbonyl)-6-ethyl-3-methyl-8a-(3-methoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline hydrochloride were treated with 0.68 ml (7.26 mmol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (AcOEt/MeOH/conc. NH4OH 75:25:2.5) and then crystallised from AcOEt yielding 0.1 g of the title compound. M.p.=196°-198° C.