Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:45]([CH3:47])[CH3:46])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:45]([CH3:47])[CH3:46])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(C)C)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(C)C)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 72 h
Yield: 59.1 %

Procedure:
To a solution of methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (102 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was added a solution of lithium hydroxide monohydrate (27 mg, 0.643 mmol) in water (1.8 mL). The reaction was stirred for 3 days. The crude mixture was acidified with HCl (aq, 1N, 1 mL). The crude product was purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H10 (0.1% TFA, v/v) gradient mixture. Two peaks were recorded in the prep-LC chromatogram representing the desired acid (60 A %, the faster eluting peak) and the starting ester. Corresponding fractions were pooled and evaporated in vacuo to aqueous mixtures. The resulting mixtures were extracted with EtOAc. The separated organic phases were back washed with water, separated, dried over Na2SO4, filtered and evaporated to afford 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylic acid (59.27 mg) as a glass and the recovered starting ester. LCMS calc.=686.22; found=687.44 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) 8.13 (d, J=8 Hz, 1H), 8.02-7.95 (m, 1H), 7.94-7.88 (m, 1H), 7.85 (s, 1H), 7.70-7.62 (m, 3H), 7.49 (d, J=8.5 Hz, 1H), 7.38 (s, 0.5H), 7.35-7.28 (m, 1H), 7.20-7.10 (m, 1.5H), 5.67 (d, J=7 Hz, 0.7H), 5.58 (d, J=8.0 Hz, 0.3H), 5.05 (d, J=16 Hz, 0.3H), 4.75 (d, J=16 Hz, 0.7H), 4.67 (d, J=16 Hz, 0.7H), 4.60 (d, J=16 Hz, 0.3H), 4.40-4.32 (m, 1H), 3.92 (s, 0.9H), 3.88 (s, 2.1H), 3.74-3.60 (m, 1H), 2.39 (s, 2.1H), 2.35 (s, 0.9H), 1.46 (s, 3H), 1.45 (s, 3H), 0.73 (d, J=6.5 Hz, 2.1H), 0.65 (d, J=5.5 Hz, 0.9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([SH:14])[CH:13]=1.[CH2:17]([S:19]([C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:18]>CN1C(=O)CCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([S:14][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)[CH:13]=1
Reactant: COc1ccc(Cl)cc1S
Reactant: CCS(=O)(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2OC)cc1
Temperature: 90 °C

Procedure:
Potassium carbonate (0.315 g) was added to a stirred solution of the product from step (i) (0.4 g) and ethyl-(4-bromo-phenyl)-sulfone (0.285 g) in NMP (10 ml) and the mixture heated at 90° C. for 1 h. The mixture was partitioned between water/ethylacetate, the organics separated, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 25% ethylacetate/isohexane. Yield 0.4 g
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:18]=3[CH3:19])=[CH:10][C:9]=2[CH:26]=1.[OH2:27].[C:28]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:28][O:27][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:17][C:18]=3[CH3:19])=[CH:10][C:9]=2[CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC=Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Reactant: O
Solvent: CO
Product: COC(Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)OC

Procedure:
A solution of 5-(2-methoxyethenyl)-2-(5-methyl-2-phenyl-4-oxazolyl)methylbenzofuran (0.69 g, 2.0 mmol) and p-toluenesulfonic acid monohydrate (40 mg, 0.21 mmol) in methanol (30 ml) was heated to reflux overnight. The solvent was removed, the residue was taken up in ethyl acetate, the solution was washed with 5% sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to an oil which slowly solidified on standing (0.75 g).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)/[C:5]([F:8])([F:7])[F:6].[CH3:15][I:16]>C(#N)C>[I-:16].[CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[CH:10]=[N+:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)/[C:5]([F:8])([F:6])[F:7]
Reactant: CO/N=C(\c1cccnc1)C(F)(F)F
Reactant: CI
Solvent: CC#N
Product: CO/N=C(\c1ccc[n+](C)c1)C(F)(F)F
Product: [I-]

Procedure:
E-3-(α,α,α-Trifluoroacetyl)pyridine-O-methyl oxime (D7) (6.16 g, 0.030 mol) was treated with methyl iodide (15 ml, 0.241 mol) in acetonitrile (100 ml) at reflux for 3 h. The reaction mixture was cooled and evaporated to give a gum which was triturated with ether to give the title compound (D10) as a yellow solid (10.44 g, 100%) m.p. 119°-124° C.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[CH3:8][O:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[C:18]([O:25][C@@H:26]([C@H:28]3[CH2:32][NH:31][C:30](=[O:33])[CH2:29]3)[CH3:27])[C:19]3[S:23][CH:22]=[N:21][C:20]=3[CH:24]=2)[CH:13]=[CH:12][C:11]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[C:1]([N:37]1[CH2:36][CH2:35][N:34]([C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[C:18]([O:25][C@@H:26]([C@H:28]4[CH2:32][NH:31][C:30](=[O:33])[CH2:29]4)[CH3:27])[C:19]4[S:23][CH:22]=[N:21][C:20]=4[CH:24]=3)=[N:15][C:10]=2[O:9][CH3:8])[CH2:39][CH2:38]1)(=[O:2])[CH3:3]
Reactant: COc1nc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCNCC1
Reactant: O=C(O)C(F)(F)F
Product: COc1nc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCN(C(C)=O)CC1

Procedure:
(R)-4-((R)-1-((5-(5-(4-acetylpiperazin-1-yl)-6-methoxypyridin-2-yl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one 4.39 was prepared using a procedure analogous to that described for Example 4.31 starting with the TFA salt of (R)-4-((R)-1-((5-(6-methoxy-5-(piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one 4.38.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:52][C@@H:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (26 mg, yield 57%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([S:15][CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[Br:17][CH2:18][C:19](Br)=[O:20]>C1COCC1.O>[CH3:16][S:15][C:10]1[C:9]([NH:8][C:19](=[O:20])[CH2:18][Br:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(Br)CBr
Reactant: CSc1ncccc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncccc1NC(=O)CBr
Reaction time: 17 h
Yield: 22.5 %

Procedure:
Triethylamine (197 mg, 1.95 mmol) was added to a solution of 3-amino-2-(methylthio)pyridine (248 mg, 1.77 mmol) in THF (5 ml), then a solution of bromoacetyl bromide (428 mg, 2.12 mmol) in THF (1 ml) was dropped thereinto and the mixture was stirred for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was evaporated therefrom and the residue was purified by a silica gel column chromatography (developing solvent, hexane:ethyl acetate=5:1) to provide 104 mg (yield 22%) of N-(2-methylthio-3-pyridyl)-2-bromoacetamide as colorless powdery crystals.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1C=CC=CC=1.ClC1[N:36]=[C:35]([Cl:37])[CH:34]=[CH:33][N:32]=1.IC1C=CC=CC=1>>[Cl:37][C:35]1[N:36]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[N:32]=[CH:33][CH:34]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3nccc(Cl)n3)c(=O)c2)cc1

Procedure:
4-{3-[1-(6-Chloro-pyrimidin-2-yl)-2-oxo-1,2-dihydro-pyridin-4-ylmethyl]-3H-imidazol-4ylmethyl}-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2,4-dichloropyrimidine for the iodobenzene in Step 3.
Reaction SMILES: O[Li].O.OO.C([C@H]1COC(=O)N1[C:19](=[O:40])[C@@H:20]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:21]N(C(C)C)C(=O)OC(C)(C)C)C1C=CC=CC=1.[O-:41]S([O-])=O.[Na+].[Na+]>O.C1COCC1>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:20]([CH3:21])[C:19]([OH:40])=[O:41])=[CH:38][CH:37]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
LiOH—H2O (168 mg, 4.00 mmol) was added to a stirring solution of THF (30 mL) and water (15 mL) at room temperature until it was dissolved. The mixture was treated with hydrogen peroxide (658 uL of a 35% wt. solution in water, 8.00 mmol) and allowed to stir at room temperature for 10 minutes. The reaction was cooled to 0° C. in an ice bath, and the tert-butyl (S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (1.00 g, 2.00 mmol) was added dropwise via addition funnel as a solution in THF (15 mL) over a 10 minutes. The mixture was allowed to stir overnight at room temperature to completion by LCMS analysis of the crude. The reaction was cooled to 0° C., and then treated with 1M Na2SO3 (9.00 mL) solution via addition funnel over a ten minute period. After the addition was complete, the mixture was allowed to warm to room temperature for 10 minutes. The mixture was concentrated to remove the THF, and then diluted with water. The aqueous layer was washed twice with ethyl acetate (discarded). The aqueous layer was partitioned with ethyl acetate, then treated dropwise while stirring with 1M HCl until pH 2-3 was attained. The aqueous layer was extracted twice with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The colorless oil product was dried under high vacuum for one hour to afford (S)-3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)propanoic acid as a viscous oil/foam (685 mg, 100%). LC/MS (APCI+) m/z 242.1 [M−Boc]+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][O:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]([C:23]([Cl:25])=[O:24])[CH2:15]1>C(N(CC)CC)C>[ClH:25].[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]([C:23]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:7]2[CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:24])[CH2:15]1
Reactant: C1CCN(CC2COCCN2)C1
Reactant: O=C1CC(C(=O)Cl)c2ccccc21
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)N2CCOCC2CN2CCCC2)c2ccccc21
Yield: 21 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.86 g of 3-(pyrrolidin-1-ylmethyl)morpholine, 1.96 ml of triethylamine and 0.89 g of 3-oxoindan-1-carbonyl chloride, to afford 0.35 g of the title compound, melting at 260°-265° C. (dec.).
Reaction SMILES: [C:1]([CH:5]([NH:13][NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[C:18]=1[CH2:27][CH3:28])=[O:16])[CH:6]=[C:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:41][CH3:42])[C:39]=1[CH3:40])[C:34](Cl)=[O:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([CH:5]([N:13]([C:34](=[O:35])[C:33]1[CH:37]=[C:38]([O:41][CH3:42])[C:39]([CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=1)[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[C:18]=1[CH2:27][CH3:28])=[O:16])[CH:6]=[C:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1c(C(=O)NNC(C=C(C)C(C)(C)C)C(C)(C)C)ccc2c1OCCO2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCc1c(C(=O)NN(C(=O)c2cc(OC)c(C)c(OC)c2)C(C=C(C)C(C)(C)C)C(C)(C)C)ccc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N′-(1-tert-butyl-3,4,4-trimethyl-pent-2-enyl)-hydrazide (150 mg, 0.39 mmol) and 3,5-dimethoxy-4-methylbenzoyl chloride (83 mg, 0.39 mmol) were dissolved in 5 mL CH2Cl2. 5 mL of 25% K2CO3 were added, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The phases were separated, adding additional CH2Cl2 and/or water as needed to aid manipulation. The CH2Cl2 layer was dried and solvent was removed in vacuo to provide 210 mg of crude product. This material was purified by silica gel column chromatography, eluting with a step gradient of 10-25% ethyl acetate in hexane to yield 3,5-dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-3,4,4-trimethyl-pent-2-enyl)-N′-(5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide RG115898 (83 mg, Rf=0.19 in 25% ethyl acetate in n-hexane, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.19 (s, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.69 (s, 2H), 6.61 (d, J=8.0 Hz, 1H), 5.43 (d, J=10.0 Hz, 1H), 5.41 (d, 14.4 Hz, 1H), 4.30-4.20 (m, 4H), 3.80 (s, 6H), 2.21-2.15 (m, 1H), 2.01 (s, 3H), 1.81 (m, 1H), 1.76-1.64 (m, 1H), 1.06 (s, 9H), 1.00 (s, 9H), 0.70 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]1C2C(=CC=CC=2)[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:2]1.C([Li])CCC.[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O1CCCC1.O1CCCC1.O1CCCC1.[Cl-:49].[Cl-].[Cl-].[Cr+3:52]>O1CCCC1>[Cl-:49].[Cl-:49].[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:16]([C:11]1[C:1]2[C:14](=[CH:15][CH:10]=[CH:3][CH:2]=2)[CH:13]([Cr+2:52])[CH:12]=1)[C:30]1[CH:29]=[CH:28][CH:33]=[CH:32][CH:31]=1
Reactant: [Cr+3]
Reactant: C1=C(c2ccccc2Cc2ccccn2)c2ccccc2C1
Reactant: CCCCCC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: [Cr+2]C1C=C(C(c2ccccc2)c2ccccn2)c2ccccc21
Temperature: -100 °C
Reaction time: 1 h

Procedure:
A solution of 4.63 g (0.016 mol) of [2-(1H-inden-3-yl)(phenyl)methyl]pyridine in 60 ml of tetrahydrofuran was cooled to −100° C. 11 ml of a 15% strength n-butyllithium solution in hexane (0.016 mol) were slowly added dropwise. After the addition was complete, the reaction mixture was stirred at −100° C. for a further one hour. The mixture was subsequently allowed to warm to room temperature. After stirring for a further one hour, the solution was cooled to −60° C. and 6.15 g (0.016 mol) of chromium trichloride tris(tetrahydrofuran) was added while stirring. The mixture was allowed to warm slowly to room temperature and was subsequently stirred for another 10 hours at room temperature. The reaction mixture was then refluxed for 20 minutes and subsequently cooled to room temperature. The solid which had precipitated was filtered off, washed with diethyl ether and dried under reduced pressure. This gave 4.4 g of (3-(2-pyridyl-1-phenylmethyl)indenyl)chromium dichloride (40%).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][N:5]([CH3:15])[CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1>[CH3:4][N:5]([CH3:15])[CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]#[N:1]
Reactant: N#CBr
Reactant: CN(C)CCNc1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCN(C#N)c1cnccn1
Reaction time: 72 h

Procedure:
A solution of cyanogen bromide (15.9 g, 0.150 mole) in 75 ml of tetrahydrofuran is added to a solution of 2-(2-dimethylaminoethylamino) pyrazine (16.6 g, 0.1 mole) and triethylamine (20.9 g, 0.15 mole) in 100 ml of tetrahydrofuran. After 72 hours, dilute sodium hydroxide is added and the mixture is extracted with ether. The extracts are concentrated and the residue is distilled under reduced pressure. N-(2-Dimethylaminoethyl)-N-(2-pyrazinyl) cyanamide boiling at 130°-132° C. at 0.7 mm if collected.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[NH:10][C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[N:10]([CH3:27])[C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2[nH]c3cc(-c4ccccc4)nn3c(=O)c2CN1C1CCCCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a suspension of 6-cyclohexyl-4,7-dihydro-2-phenyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8(6H)dione (2.00 g, 5.75 mmole) and potassium carbonate (795 mg, 5.75 mmole) in dry dimethylformamide (DMF, 30 mL) was added methyl idodide (0.72 mL, 12 mmole). The flask was stoppered tightly and stirred at room temperature for 24 hours. The mixture was diluted with water (150 mL), stirred for 10 minutes and suction filtered. The collected solid was washed once with water and once with 95% ethanol. Drying under vacuum left 1.91 g of white powdery solid. Crystallization from 95% ethanol (500 mL) afforded the titled product as fine white needles (1.73 g, 83%, m.p. 276°-279°). 1H NMR (CDCl3, δ) 8.05 (m, 2H, 2-phenyl H), 7.45 (m, 3H, 3,4-phenyl H), 6.45 (s, 1H, pyrazole-H), 4.33 (s, 2H, lactam CH2), 4.16 (s, 3H, CH3), 4.15 (m, 1H, cyclohexyl CH), 1.1-2.0 (m, 10H, cyclohexyl CH2); IR (mull, cm-1) 1693, 1627, 1590, 1574; UV (ethanol) λmax (ε) 206 (27,300), 226(23,920), 268(33,740), 285sh(15,570), 295(10,940), 338(6,090); MS m/e (rel. intens.) 363 (M+1, 25) 362 (M+, 100), 319(35), 280(66); Analysis calc'd for C21H22N4O2 =C, 65,59; H, 6.12 N, 15.46; Found=C, 69.64; H, 6.21; N, 15.43. TLC (silica, ethylacetate) Rf 0.80.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]([CH3:46])C(O)=O)=[CH:38][CH:37]=1)#[N:35].[C:47](OCC)(=O)C.C(OCC)C>O=P(Cl)(Cl)Cl>[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:46][C:47]2[N:8]([CH2:9][C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=3)[C:7]3[CH:6]=[CH:5][C:4]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:26])=[O:27])=[CH:3][C:2]=3[N:1]=2)=[CH:40][CH:41]=1)#[N:35]
Reactant: Nc1cc(NS(=O)(=O)c2ccccc2)ccc1NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Reactant: CC(C(=O)O)c1ccc(C#N)cc1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(CCc2nc3cc(NS(=O)(=O)c4ccccc4)ccc3n2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
N-{3-amino-4-(3,5-bis-trifluoromethyl-benzylamino)-phenyl}-benzenesulphonamide (5.5 g, 11.2 mmol) and p-cyano-phenylpropionic acid (2.35 g, 13.4 mmol) are taken up in 50 mL POCl3, and stirred for 2 h at 100-120° C. A precipitate settles out from the initially clear solution in the course of the reaction. After cooling it is diluted with 100 mL ethyl acetate/diethylether=1/1. The crystals are filtered off and washed with diethylether.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13].[CH2:14]=O.Cl>C(O)C.CS(C)=O.O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH2:14][OH:1]
Reactant: [OH-]
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Reactant: C=O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(F)c1CCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
According to the procedure of L. Florvall et al. J. Med. Chem. 29, 1406 (1986), a solution of KOH (0.75 g) in ethanol (5 mL) was added to a mixture of 2-fluoro-6-nitrotoluene (77.5 g, 0.5 mole) and paraformaldehyde (15 g, 0.5 mole) in DMSO (75 mL). The dark solution was stirred for 3 days at room temperature, diluted with water (1.2 L), neutralized with 2.5N HCl (to pH 6.5) and extracted with ether (3×). The extracts were washed with brine (1×), dried (MgSO4) and evaporated to dryness to yield a yellow solid. Trituration with light petroleum ether removed a small amount of unreacted starting material and provided 2-fluoro-6-nitrophenethyl alcohol as a pale yellow solid, 82.3 g, 89.3%, m.p. 42°-44° C. This material was used for the subsequent reaction without further purification. An analytical sample was purified by flash chromatography (silica Merck-60, hexane-ether 6:4), m.p. 45°-46° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@H:7]([OH:21])[CH2:8][NH:9][C@@H:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][C@@H:10]([N:9]1[CH2:8][C@H:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC[C@@H](O)COc1cccc(Cl)c1
Reactant: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)N1C[C@H](COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 0.82 g of 1(R)-(3-chlorophenoxymethyl)-2-[2-t-butyldimethylsilyloxy-1(S)-methylethylamino]ethanol (prepared as described in Preparation 34), 0.43 g of N,N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide were used, to give 0.85 g of the title compound having an Rf value of 0.25 (on silica gel thin layer chromatography, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =-33.4° (methanol, c=1.040).