Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([NH:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([OH:12])[C@@H:8]2[OH:13])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H].CO.[CH:24](Cl)(Cl)Cl>C(O)(C)C.[Ni].C(O)=O>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([C@@H:7]3[CH2:11][CH2:10][C@H:9]([OH:12])[C@@H:8]3[OH:13])[CH:24]=[N:17][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@@H]1CC[C@H](O)[C@@H]1O
Agent: [Ni]
Solvent: CO
Solvent: O=CO
Solvent: CC(C)O
Product: O[C@@H]1[C@H](n2cnc3cc(Cl)c(Cl)cc32)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(±)-(1S*,2R*,3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclopentanediol (3.77 g, 12.3 mmol) in isopropanol (250 mL) was shaken in a Parr shaker with Raney nickel (Aldrich, prewashed with water until neutral, ca. 1 tsp) under hydrogen (50 psi) for 2 hours, at which point uptake of hydrogen had ceased. TLC (silica gel, methanol:chloroform/1:10) shows one spot at lower Rf than starting material. The catalyst was filtered off (Celite) and volatiles evaporated to leave a glass which was refluxed in formic acid (65 mL) for 40 minutes. The formic acid was evaporated and the residual oil dissolved in ethanol (50 mL) and adjusted to pH 13 with 5N sodium hydroxide. After stirring at ambient temperature for 18 hours, the pH was adjusted to 7 with hydrochloric acid and the volatiles removed by evaporation in vacuo. The residue was triturated with methanol. The methanol solution was evaporated to dryness to give white solid which contained product and some salts (7.41 g). A portion of this solid (1.05 g) was chromatographed on silica gel and product was eluted with 6-8% methanol-chloroform as white powder, after solidification from ethanol (350 mg), m.p. 180°-182° C.; 1H-NMR(DMSO-d6) δ: 8.46, 8.08, and 7.93 (all s, 1 each, 3 aromatic CH), 4.96 (d, J=4.7 Hz, 1, OH), 4.92-4.85 (m, 1, NCH), 4.81 (d, J=5.9 Hz, 1, OH), 4.19-4.11 (m, 1, OCH), 4.08-3.93 (m, 1, OCH), 2.38-2.04 (m, 2, CH2), 2.03-1.72 (m, 2, CH2); mass spectrum(CI): 287 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(OCC)(OCC)=O.[Cl-].[CH3:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH3+:41])[CH2:37][CH2:36]1.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(N(CC)CC)C>[CH3:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:19]([CH:18]=[CH:17][CH:16]=[CH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([O:22][CH3:23])[CH:11]=2)=[O:21])[CH2:37][CH2:36]1
Reactant: C[C@H]1CC[C@H]([NH3+])CC1
Reactant: COc1cc(C=CC=CC(=O)O)ccc1OCc1ccccc1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1

Procedure:
Using 4g of 4-(4-benzyloxy-3-methoxyphenyl)-l,3-butadiene-1-carboxylic acid, 3 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 150 ml of methylene chloride, 2.2 g of trans-4-methylcyclohexylammonium chloride, and 0.5 g of -dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 3.62 g of N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-l-carboxamide (a compound of the present invention) was obtained as a pale yellowhish brown oil, which had the following physiochemical properties:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Product: O=C(Cc1cccc(Oc2ccccc2)c1)Nc1cccc2c1cnn2CCN1CCCC1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine and (3-phenoxy-phenyl)-acetic acid were processed as described in Example 3 to provide the title compound. MS (DCI/NH3) MS m/z 441 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (m, 2 H), 2.01 (m, 2 H), 3.04 (m, 2 H), 3.52 (m, 2 H), 3.71 (q, J=5.72 Hz, 2 H), 3.79 (s, 2 H), 4.76 (t, J=6.24 Hz, 2 H), 6.90 (m, 1 H), 7.03 (m, 3 H), 7.15 (m, 2 H), 7.39 (m, 5 H), 7.66 (m, 1 H), 8.34 (s, 1 H), 9.67 (br s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.Cl[C:30]1[C:35]([CH2:36][C:37](O)=[O:38])=[CH:34][CH:33]=[CH:32][N:31]=1>C(O)CCCC>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:14]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:35]3[CH2:36][C:37]2=[O:38])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccnc1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCCCCO
Solvent: O
Product: O=C1Cc2cccnc2N1c1ccc(OCc2ccccc2)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
A mixture of 4-(benzyloxy)aniline hydrochloride (2.21 g), 4-methylbenzenesulfonic acid hydrate (0.178 g), and (2-chloropyridin-3-yl)acetic acid (Journal of Medicinal Chemistry, 1990, 33, 2697-2706.) (1.61 g) in 1-pentanol (15 mL) was stirred at 140° C. for 24 h. After cooling to room temperature, the mixture was added to SiO2, and the mixture was concentrated and purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.39 g) as a pale yellow solid.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]3[NH:15][C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH:6]=[C:5]([Cl:22])[N:4]=1.[CH3:23][OH:24]>>[Cl:22][C:5]1[CH:6]=[C:7]([C:9]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]3[NH:15][C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH:8]=[C:3]([O:24][CH3:23])[N:4]=1
Reactant: CO
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Agent: [Na]
Product: COc1cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)cc(Cl)n1

Procedure:
Under a nitrogen atmosphere 0.21 g (9.3 mmol) sodium were added batchwise to 50 mL MeOH. After the sodium had dissolved completely, 1.0 g (3.1 mmol) of 6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one were added and the mixture was refluxed for 5 h. Then the reaction mixture was evaporated down i. vac., the residue was combined with 50 mL water and the precipitated solid was suction filtered. This was washed with a little water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[CH3:10])=[O:4].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[CH2:10][Br:12])=[O:4]
Reactant: COC(=O)c1scc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1scc(Br)c1CBr
Yield: 56.7 %

Procedure:
4-Bromo-3-methyl-thiophene-2-carboxylic acid methyl ester (3.0 g, 12.8 mmol), example 31-a, N-bromosuccinimide (2.33 g, 13.1 mmol), and benzoyl peroxide (310 mg, 1.28 mmol) were suspended in 32 mL of benzene and heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-40% ethyl acetate in hexanes to produce 2.28 g of a yellow solid. 1H NMR (CDCl3, 200 MHz): δ=7.48 (s, 1H), 4.91 (s, 2H), and 3.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.C=O.[F:36][C:37]1[CH:45]=[C:44]2[C:40]([CH:41]=[CH:42][NH:43]2)=[CH:39][CH:38]=1>CO.O1CCOCC1>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:41]3[C:40]4[C:44](=[CH:45][C:37]([F:36])=[CH:38][CH:39]=4)[NH:43][CH:42]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4cc(F)ccc34)CC1)O2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.3 %

Procedure:
A mixture of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (170 mg, 0.564 mmol, Intermediate 1, free base), AcOH (0.051 ml, 0.90 mmol), and HCHO (35% in H2O, 0.07 ml, 0.847 mmol) in MeOH (12 ml) and dioxane (3 ml) was stirred at RT for 20 min and then treated with 6-fluoro-1H-indole (100 mg, 0.734 mmol). The resulting solution was stirred at 50° C. for 1 h. The solvent was then evaporated, the residue dissolved with DCM and washed with 5% aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude mixture was purified by column chromatography (eluent:DCM/MeOH/NH4OH 97:3:0.3) to give (E)-3-{1′-(6-fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester as a brown solid (140 mg).
Reaction SMILES: Cl[C:2]1N=[C:6]([C:8]2(N)CC(C)CC(N)C2)[C:5]([F:17])=[CH:4][N:3]=1.[Cl:18][C:19]1[N:24]=[C:23]([NH:25][CH:26]2[CH2:31][CH:30]([CH3:32])[CH2:29][CH:28]([NH2:33])[CH2:27]2)[C:22]([F:34])=[CH:21][N:20]=1.C(N1C=CN=C1)(N1C=CN=C1)=[O:36].CCN(C(C)C)C(C)C.Cl.F[C@H]1CCNC1>C1COCC1>[Cl:18][C:19]1[N:24]=[C:23]([NH:25][CH:26]2[CH2:31][CH:30]([CH3:32])[CH2:29][CH:28]([NH:33][C:2]([N:3]3[CH2:8][CH2:6][C@H:5]([F:17])[CH2:4]3)=[O:36])[CH2:27]2)[C:22]([F:34])=[CH:21][N:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1CC(N)CC(N)(c2nc(Cl)ncc2F)C1
Reactant: CC1CC(N)CC(Nc2nc(Cl)ncc2F)C1
Agent: Cl
Agent: F[C@H]1CCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(NC(=O)N2CC[C@H](F)C2)CC(Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of AP-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine, 76b, (0.14 g. 0.54 mmol) in THF (2.5 ml) was added carbonyldiimidazole (0.10 g, 0.60 mmol) and iPr2NEt (0.28 mL, 1.62 mmol). The reaction was aged 2 hours at room temp, and treated with (S)-3-fluoropyrrolidine hydrochloride (0.07 g, 0.54 mmol). The reaction was stirred at room temperature for 2 days and then concentrated to dryness to afford 202 mg of (3S)— N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5-methylcyclohexyl)-3-fluoropyrrolidine-1-carboxamide which was used without purification: LCMS RT=2.46 (M+1) 374.2, (M−1) 372.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH3:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[CH3:27])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1COC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 86 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 2-methylbenzyl bromide (18.9 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2-methylbenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (34.1 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].[Cl:13]C[CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([O-:19])=[O:18].[CH2:22](OCC)C>>[Cl-:13].[CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N+:8]([CH2:22][O:19][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: CN(C)C(=O)Oc1cccnc1
Reactant: CCOCC
Product: CN(C)C(=O)Oc1ccc[n+](COC(=O)C(C)(C)C)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Dimethylcarbamoyloxypyridine (1.66 g) and chloromethylpivalate (2.26 g) were heated to 90° C. with stirring for 2 hrs. The reaction mixture was cooled to room temperature. To this solution was added anhydrous diethylether to crystallize. The crystals were filtered off, washed three times with anhydrous diethyl ether (50 ml×3) and dried under reduced pressure. Recrystallization from acetone-ether (1:2) gave 2.76 g of 3-(dimethylcarbamoyloxy)-1-(pivalyloxymethyl)pyridinium chloride as colorless powdery crystals, m.p. 154°-155° C.
Reaction SMILES: C([O:5][C:6](=[O:39])[C:7]([CH3:38])([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:37])[NH:18][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[CH:12][CH:11]=1)[CH3:8])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:38][C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:37])[NH:18][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[CH:12][CH:11]=1)([CH3:8])[C:6]([OH:39])=[O:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CNC(=O)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CNC(=O)Cc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 50 °C
Yield: 83.2 %

Procedure:
0.23 g (0.42 mmol) of 2-methyl-2-[4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-carbamoyl}-methyl)-phenoxy]-propionic acid tert-butyl ester was dissolved in 10 ml of MeCl2. Then, 0.14 ml=0.139 g (1.28 mmol) of anisole was added followed by 0.32 ml=0.48 g (4.2 mmol) of trifluoroacetic acid. The reaction mixture was stirred at reflux (oil bath 50° C.) for 16 hours. It was then poured into crashed ice and extracted twice with MeCl2. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiO2, MeCl2/MeOH) to give 0.17 g of the title compound as colorless solid.
Reaction SMILES: [Cu]C#N.[CH:4]([Mg]Br)=[CH2:5].[C:8]([Si:12]([O:25][CH2:26][C@@H:27]1[CH2:29][O:28]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9]>>[Si:12]([O:25][CH2:26][C@@H:27]([OH:28])[CH2:29][CH:4]=[CH2:5])([C:8]([CH3:10])([CH3:11])[CH3:9])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1CO1)(c1ccccc1)c1ccccc1
Reactant: C=C[Mg]Br
Agent: N#C[Cu]
Product: C=CC[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
Copper (I) cyanide (3.60 g, 40.2 mmol) was placed in a three-necked flask under nitrogen and dried by gentle heating with a heat gun under vacuum. It was then allowed to cool to room temperature under nitrogen. This process was repeated three times, and then anhydrous tetrahydrofuran (80 mL) was added. The resulting mixture was cooled to −78° C., and then vinyl magnesium bromide (1 M solution in tetrahydrofuran, 88.5 mL, 88.5 mmol) was added dropwise while maintaining the internal temperature below −68° C. The heterogeneous mixture was warmed to −20° C. and stirred at this temperature for 30 minutes. After cooling the solution back to −78° C., tert-butyl[(2S)-oxiran-2-ylmethoxy]diphenylsilane (296 h, 8.38 g, 26.8 mmol) was added dropwise. The mixture was stirred, and allowed to gradually warm to room temperature, overnight. The reaction mixture was quenched with 100 mL ammonium hydroxide/ammonium chloride (1/10 2M NH4Cl), and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (200 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-20% ethyl acetate in heptane), to give (2S)-1-{[tert-butyl(diphenyl)silyl]oxy}pent-4-en-2-ol (296i, 5.68 g, 62% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.65-7.71 (m, 4H), 7.36-7.49 (m, 6H), 5.75-5.87 (m, 1H), 5.03-5.14 (m, 2H), 3.76-3.85 (m, 1H), 3.66-3.72 (m, 1H), 3.54-3.61 (m, 1H), 2.45 (d, J=4.03 Hz, 1H), 2.23-2.30 (m, 2H), 1.09 (s, 9H). MS: 358 [M+18].
Reaction SMILES: [Na].[CH3:2][C:3]1[C:4]([C:9](=O)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:5][CH:6]=[CH:7][N:8]=1.Cl[CH:17]([C:22](=[N:24][NH:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:23])[C:18]([O:20][CH3:21])=[O:19].Cl>CO.C1COCC1>[CH3:23][C:22]1[N:24]([NH:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=2)(=[O:27])=[O:28])[C:9]([C:4]2[C:3]([CH3:2])=[N:8][CH:7]=[CH:6][N:5]=2)=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(Cl)C(C)=NNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)CC(=O)c1nccnc1C
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(C(=O)OC)c(-c2nccnc2C)n(NS(=O)(=O)c2ccc(C)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.81 g of sodium was heated with 20 ml of methanol, then a solution of 6.8 g of 31A in 20 ml of methanol was added and the mixture was stirred at room temperature for 1 hour. Then a solution of 11.2 g of 7B in 25 ml of THF was added, and the mixture was stirred at room temperature for 2 hours. The mixture was stripped of volatiles, 100 ml of methanol was added to the residue and hydrogen chloride gas was bubbled through the mixture, which then was heated at reflux for 2 hours. The mixture was cooled, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The extract was stripped of volatiles, and the residue was triturated with 10 ml of ether. The solid product was collected and dried (Na2SO4) to give dimethyl 2-methyl-1-(tosylamino)-5-(3-methyl-2-pyrazinyl)pyrrole-3,4-dicarboxylate (31C), as a light yellow solid, m.p.: 177°-178° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.O=[C:10]1[CH:15]([C:16](OCC)=O)[CH2:14][CH2:13][S:12][CH2:11]1.C(O)(=[O:23])C>>[CH3:8][S:7][C:4]1[N:3]=[C:2]2[N:1]=[C:14]3[C:13](=[O:23])[S:12][CH2:11][CH:10]=[C:15]3[CH2:16][N:6]2[N:5]=1
Reactant: CCOC(=O)C1CCSCC1=O
Reactant: CC(=O)O
Reactant: CSc1n[nH]c(N)n1
Product: CSc1nc2n(n1)CC1=CCSC(=O)C1=N2
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
0.976 g (0.0075 mole) of 5-amino-3-methylthio-1H-1,2,4-triazole are dissolved in 6 ml of acetic acid, then 1.368 g (0.075 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-4-carboxylate are added and the reaction mixture is boiled for 30 minutes. The precipitated product is filtered off from the hot solution, washed with water and recrystallized from dimethylformamide. Thus 1.2 g (62.9%) of 2-methylthio-5,6,7,9-tetrahydrothiopyrano[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained which melt at 294°-297° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[CH2:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][NH:51]1>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][N:51]1[C:29]([C:28]1[C:24]([CH3:23])=[N:25][O:26][C:27]=1[CH2:32][C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:40])=[O:31]
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)N1CCc2ccccc2C1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1.5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and 1,2,3,4-tetrahydroisoquinoline (0.12 mL, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (ESI, POS. ION) M/Z Calcd for C22H20N2O3: 360.1474, found 360.1472.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[C:16]([CH3:25])([CH3:24])[C:15]2=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>[OH-].[Pd+2].[OH-].C(O)C>[F:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15](=[O:26])[C:16]2([CH3:25])[CH3:24]
Reactant: CC1(C)C(=O)N(C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Product: CC1(C)C(=O)N(C2CCNCC2)c2ccc(F)cc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1-benzylpiperidin-4-yl)-5-fluoro-3,3-dimethylindolin-2-one (171 mg, 0.485 mmol, EXAMPLE 44, Step 3), palladium hydroxide (20 wt % on carbon) (85 mg), formic acid (0.372 mL, 9.7 mmol) and ethanol (20 mL) was stirred at 50° C. for 1 h.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=3)[C:34]([Cl:47])=[C:33]([O:48][CH2:49][CH2:50]Cl)[C:32]=2Br)[O:11][C@@H:10]1[CH2:53][O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC>C1COCC1>[Cl:47][C:34]1[C:33]2[O:48][CH2:49][CH2:50][C:32]=2[C:31]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:53][O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[O:11]2)=[CH:36][C:35]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][CH3:46])=[CH:42][CH:43]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCCl)c2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Reaction time: 18 h
Yield: 88.3 %

Procedure:
To a solution of compound 80 (2.59 g, 2.79 mmol) in THF (28 mL) was added dropwise n-butyllithium (2.5M in hexane, 2.2 mL, 5.59 mmol) at −78° C. under an atmosphere of nitrogen. The mixture was stirred for 18 hours at −78° C. to 10° C. The mixture was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 81 (2.0 g, 88%) as brown oil.
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]>C(O)C>[OH:1][C@H:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C(=O)NCCN
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Solvent: CCO
Product: CC(C)C(=O)NCCNC[C@H](O)COc1ccccc1
Yield: 46 %

Procedure:
A mixture of (S)-1,2-epoxy-3-phenoxypropane (0.495 g.) and N-(2-aminoethyl)isobutyramide (0.429 g) in ethanol (25 ml) was heated under reflux for 48 hours. The reaction mixture was cooled and solvent removed by rotary evaporation in vacuo. The residual solid was purified by column chromatography on silica (Merck, Art. 7736) using 5% v/v methanol in dichloromethane as eluant. The solid thereby obtained was purified by recrystallisation from ethyl acetate to give (S)-N-(2-[2-hydroxy-3-phenoxypropyl]aminoethyl)isobutyramide (0.425 g), m.p. 88°-89° C., 24 [α]D -5.8° [c, 1.04; methanol], mixed m.p. with material from Example 1, 88°-89° C.