Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@:10]([C:26]#[C:27][CH2:28]O)([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([SnH:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C@H:13]2[CH2:12][CH2:11][C@@:10]3([CH:26]=[C:27]([Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:28][O:25]3)[C@:9]1([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:15][C@H:14]2[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(O)C#CCO
Reactant: CCCC[SnH](CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=C[C@@]2(CC[C@H]3[C@H](S(=O)(=O)c4ccccc4)C[C@]2(c2ccccc2)N3Cc2ccccc2)OC1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol) was added to a degassed solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-(3-hydroxypropynyl)-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 13; 1.8 g, 3.7 mmol) in tetrahydrofuran (50 ml). The mixture was cooled to +5° C. before tri-n-butyltin hydride (1.3 g, 4.4 mmol) was added. The mixture was allowed to warm to room temperature and stirred for a further 18 hours before triphenylphosphine (1 g, 3.7 mmol) and diethyl azodicarboxylate (0.65 g, 3.7 mmol) were added. After 3 hours the mixture was concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5 and 10% ethyl acetate/iso-hexanes to give the title compound (154 mg, 5.5%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([O:19]CC2C=CC=CC=2)[CH:18]=1)[C:8]([NH:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:9])[CH3:3].C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:19][C:17]1[CH:16]=[C:7]([CH:6]=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:18]=1)[C:8]([NH:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:9]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2nccs2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Yield: 84.9 %

Procedure:
3-[(1-Methylethyl)oxy]-5-[(phenylmethyl)oxy]-N-1,3-thiazol-2-ylbenzamide (11.2 g) was dissolved in trifluoroacetic acid (60 mL) and treated with thioanisole (17.8 mL). The mixture was left to stir at ambient temperature for 18 hours before the trifluoroacetic acid was removed in vacuo. The residues were treated with isohexane (100 mL) and the solid filtered off, before being washed with further isohexane (2×20 mL). The solid was dissolved in ethyl acetate (200 mL) and washed with aqueous saturated sodium hydrogen carbonate solution (100 mL). The organics were washed with water (100 mL) and brine (100 mL), and dried (MgSO4) before evaporation in vacuo to afford a solid which was washed with isohexane (200 mL) and dried in vacuo to give the desired compound (7.18 g). 1H NMR δ (d6-DMSO): 1.27 (d, 6H), 4.55 (m, 1H), 6.49 (m, 1H), 7.02 (s, 1H), 7.14 (s, 1H), 7.25 (d, 1H), 7.54 (d, 1H), 9.73 (s, 1H), 12.44 (s, 1H). m/z 279 (M+H)+, 277 (M−H)−
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl.C(O)(=O)C.CCOCC>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][C:15](=[O:16])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:7][CH2:6]3)[C:11]=2[N:20]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2n1
Yield: 28.8 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (Intermediate 202, 0.125 g) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (50 mg) and sodium acetoxyborohydride (110 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane and trituration of the product from ether gave 37.6 mg of the title compound as acetic acid salt.
Reaction SMILES: [CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=3[CH3:27])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:33]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>C1COCC1>[CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:41][CH2:40][CH2:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])(=[O:25])=[O:24])=[CH:19][C:18]=3[CH3:27])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reaction time: 4 h

Procedure:
A solution of 4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]-3-methylbenzenesulfonyl chloride (Intermediate 20, 100 mg; 0.22 mmol) in anhydrous THF (10 ml) was treated with beta-alanine tert-butyl ester hydrochloride (Bachem, 43 mg; 0.24 mmol) and triethylamine (60 μl; 0.43 mmol). After stirring for 4 hours, the precipitate was filtered and purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc, to give the title compound as a yellow solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH2:39][CH:40]=O)[CH2:34][CH2:33]2)[CH2:28][CH2:27]1)#[N:25]>COC(C)(C)C.O>[CH3:2][O:3][CH:4]=[CH:40][CH2:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C@H:29]2[CH2:28][CH2:27][C@H:26]([C:24]#[N:25])[CH2:31][CH2:30]2)[CH2:37][CH2:36]1
Reactant: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.11 g of methoxymethyl-triphenylphosphonium chloride were suspended in 60 ml of tert.butyl methyl ether while gassing with argon and treated at room temperature within 2 minutes with 1.26 g of potassium tert.butylate. The suspension was stirred at room temperature for a further 1 hour, then cooled to 0° C. and treated dropwise within 5 minutes with a solution of 1.98 g of 3-[trans-4-(trans-4-cyanocyclohexyl)cyclohexyl]propionaldehyde in 25 ml of tert.butyl methyl ether. The reaction mixture was stirred at 0° C. for a further 45 minutes, then diluted with 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the crude product (5.1 g) on silica gel at 0.5 bar with ethyl acetate/petroleum ether (vol. 5:95) gave 2.0 g of trans-4-[trans-4-(4-methoxy-3-butenyl)cyclohexyl]cyclohexanecarbonitrile as a colorless milky oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:6]1[C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=[CH:8][C:7]=1[NH2:10]
Reactant: Nc1ccc2ncsc2c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1ccc2ncsc2c1Br
Yield: 129.3 %

Procedure:
To a solution of benzo[d]thiazol-6-amine (100 mg, 0.67 mmol) in 6 ml CHCl3 was added Br2 (42 mg, 0.27 mmol) in CHCl3 (10 ml) dropwise about 15 min. The mixture was concentrated under reduced pressure, and the residue was crystallized from DCM:MeOH (5:1) to give 7-bromobenzo[d]thiazol-6-amine (80 mg, 80%).
Reaction SMILES: C(OC([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)=O)C.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:12]([N:7]1[CH2:6][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CNCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-ethoxycarbonylpiperazine (4.6 g, 29.1 mmol) in dry methylene chloride (200 mL), was added benzoyl chloride (3.55 ml, 29.1 mmol) and triethylamine (2 ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO3 solution was added and the aqueous phase was extracted with ethyl acetate (3×200 ml). The organic layers were combined, dried over MgSO4 and concentrated to give a crude mixture, which included the desired product XXXIX. The crude was then used for the further reaction without purification.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[S:4]1[C:5]([C:22]2([OH:25])[CH2:23][CH2:24][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:20][CH2:21]2)=[CH:6][N:7]=[CH:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)c1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cncs2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-trimethylsilanyl-thiazole (Fluka, 5.0 g, 31.8 mmol) in THF (20 mL) at −78° C. was treated with n-BuLi (2.5 M in hexanes, 15.3 mL, 38.2 mmol) dropped slowly over 10 min. The reaction was stirred for an additional 20 min. at −78° C. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 6.0 g, 38 mmol) in THF (15 mL) was slowly dropped into the reaction. After addition, the reaction was stirred for an additional 2 hours at −78° C. The reaction was then quenched with water and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid. To this solid in THF (20 mL) was added TBAF (1.0 N in THF, 30 mL) at room temperature. The reaction was stirred for 1 hour. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([O:11][S:12](=[O:33])(=[O:32])[NH:13][C:14](=[O:31])[CH2:15][C:16]2[C:21]([CH:22]([CH3:24])[CH3:23])=[CH:20][C:19]([CH:25]([CH3:27])[CH3:26])=[CH:18][C:17]=2[CH:28]([CH3:30])[CH3:29])=[C:4]([CH:34]([CH3:36])[CH3:35])[CH:3]=1.[C:37](O)(=[O:39])[CH3:38].O>>[OH:39][CH2:37][CH2:38][NH:1][C:2]1[CH:3]=[C:4]([CH:34]([CH3:36])[CH3:35])[C:5]([O:11][S:12](=[O:33])(=[O:32])[NH:13][C:14](=[O:31])[CH2:15][C:16]2[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:18][C:19]([CH:25]([CH3:26])[CH3:27])=[CH:20][C:21]=2[CH:22]([CH3:23])[CH3:24])=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:7]=1
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(N)cc2C(C)C)c(C(C)C)c1
Reactant: CC(=O)O
Solvent: O
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(NCCO)cc2C(C)C)c(C(C)C)c1
Reaction time: 8 h

Procedure:
[(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 4-amino-2,6-diisopropyl-phenyl ester (1.0 g, 1.9 mmol) was suspended in 50 mL of 1:1 glacial acetic acid/water and a stream of ethylene oxide was bubbled in for 15 minutes. The reaction mixture was sealed and allowed to stir overnight. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. Dried the organic layer over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.07 g of the title compound as a tan solid; mp 149-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[I:26]Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][C:3]=1[I:26]
Reactant: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: ClI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (50 mg, 0.15 mmol) [See Ex. 28 above] in glacial acetic acid (5 mL) was added a solution of ICl (24 mg, 0.15 mmol) in glacial acetic acid (1.5 mL). The resulting mixture was stirred at rt for 1 h, then poured into saturated aqueous Na2S2O5. The pH was adjusted to neutral by the addition of 2.5 N NaOH and extracted with EtOAc. The organic extract was concentrated under reduced pressure, and the residue was purified by flash chroma-tography, eluting with a solvent gradient of 2-10% MeOH/CHCl3. The material that was isolated was recrystallized from Et2O/Hex to afford the title compound: 1H NMR (CDCl3): d 8.42 (d, 2H); 8.18 (d, 1H); 7.68 (dd, 2H); 7.42 (m, 4H); 7.09 (t, 2H); 6.77 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7](O)[N:6]=1)=[O:4].P(Cl)(Cl)([Cl:16])=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([Cl:16])[N:6]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(C#N)c(O)n1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(Cl)n1

Procedure:
5-Cyano-6-hydroxy-pyridine-2-carboxylic acid methyl ester is treated with phosphorus oxychloride in dimethylformamide in accordance with known methods to give 6-chloro-5-cyano-pyridine-2-carboxylic acid methyl ester.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])C.Cl>O1CCCC1.O>[Cl:29][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
Lithium hydroxide (51 mg) was added at ambient temperature to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (0.27 g) (Example I4) in tetrahydrofuran (3 ml) and water (0.75 ml). The reaction mixture was stirred at 50° C. for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with water, acidified by addition of aqueous hydrochloric acid (2M) and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.25 g), which was used without further purification. 1H-NMR (DMSO-d6, 400 MHz): 13.1 (s, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.65 (m, 4H), 4.40 (m, 2H), 2.55 (s, 3H).
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][N:23]=1)=[O:20].C(N(CC)C(C)C)(C)C>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:28]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:17]=4[CH3:16])=[N:23][CH:24]=3)=[O:29])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)cn1

Procedure:
As described for Example 46, the reaction of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine (1 mmol) with 2-[(2-methyl-5-fluorobenzoyl)amino]-5-pyridinylcarbonyl chloride (1.0 mmol) in dichloromethane in the presence of N,N-diisopropylethylamine (3 mmol) gives the product as a glass.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][N:9]2[CH:12]=[CH:13][N:14]=[C:8]2[CH:7]=1)=[O:5].[C:16]([Mg]Br)#[C:17][CH3:18]>C1COCC1>[N:14]1[CH:13]=[CH:12][N:9]2[CH:10]=[CH:11][C:6]([C:4](=[O:5])[C:16]#[C:17][CH3:18])=[CH:7][C:8]=12
Reactant: CC#C[Mg]Br
Reactant: CON(C)C(=O)c1ccn2ccnc2c1
Solvent: C1CCOC1
Product: CC#CC(=O)c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Imidazo[1,2-a]pyridine-7-carboxylic acid methoxy-methyl-amide (187 mg, 0.91 mmol) in THF (10 ml) at −78° C. was added 1-propynylmagnesium bromide (0.5M in THF, 2.74 ml). The reaction was allowed to warm to room temperature and stirred for 1.5 h before being quenched with 2M HCl (2 ml) and washed with CH2Cl2. The aqueous fraction was basified using Na2CO3 and extracted with CH2Cl2. The organic fraction was dried (MgSO4), filtered and the solvent removed in vacuo to afford the product (168 mg). MS: [M+H]+=185.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][C@@H:30](O)[C@@H:31]([OH:33])[CH3:32]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]3([CH3:2])[O:33][C@H:31]([CH3:32])[C@H:30]([CH3:29])[O:3]3)=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[C:15]([C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[O:28])[CH:16]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1
Reactant: C[C@H](O)[C@@H](C)O
Product: C[C@@H]1OC(C)(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)O[C@@H]1C

Procedure:
The title compound was prepared using 4-Acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide and (2R,3S)-Butane-2,3-diol following the procedure described in the preceding two examples. MS: m/z 487 M++1).
Reaction SMILES: C([O:5][C:6](=[O:49])[C@H:7]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:8][C:9]([O:11][CH2:12][CH:13]1[C:25]2[C:20](=[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]3=[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]3=2)[C:19]2[C:14]1=[C:15]1[CH:41]=[CH:40][CH:39]=[CH:38][C:16]1=[C:17]1[CH:37]=[CH:36][CH:35]=[CH:34][C:18]1=2)=[O:10])(C)(C)C.C(OCC)C>FC(F)(F)C(O)=O.O>[CH:41]1[C:15]2[C:16](=[C:17]3[CH:37]=[CH:36][CH:35]=[CH:34][C:18]3=[C:19]3[C:14]=2[CH:13]([CH2:12][O:11][C:9]([NH:8][C@H:7]([C:6]([OH:49])=[O:5])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:10])[C:25]2[C:20]3=[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]3=[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]3=2)[CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Yield: 92.5 %

Procedure:
A solution of Nα-17-tetrabenzo(a,c,g,i)fluorenylmethoxycarbonyl-L-phenylalanine tert-butyl ester (68.2 mg, 0.106 mmol) in trifluoroacetic acid (950 μl) and water (50 μl) was sonicated for 2.5 h. The solvent was removed in vacuo to give a purple residue. A mixture of diethyl ether and petrol b.p. 40-60° C. (1:1) was added. The precipitate obtained was chilled overnight, filtered, washed with petrol and finally dried in a vacuum desiccator over P2O5 to give compound (55) (57.6 mg, 93);
Reaction SMILES: [Cl:1][C:2]1[C:18]([O:19][CH2:20][C:21]#[N:22])=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:10](=[O:11])[C:4]=2[C:3]=1[Cl:23].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C>[Cl:1][C:2]1[C:18]([O:19][CH2:20][C:21]2[NH:26][N:25]=[N:24][N:22]=2)=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:10](=[O:11])[C:4]=2[C:3]=1[Cl:23]
Reactant: N#CCOc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CCC2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1c2c(cc(OCc3nnn[nH]3)c(Cl)c2Cl)CCCC1C1CCCC1
Temperature: 0 °C

Procedure:
To a solution of (3,4-dichloro-5-oxo-6-cyclopentyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetonitrile (5.7 g., 0.0165 mole) in DMF (25 ml.) is added sodium azide (1.26 g., 0.0194 mole) and ammonium chloride (1.05 g., 0.0194 mole). The mixture is heated at 85°-90° C. for one hour, cooled and poured into ice water. The mixture is acidified with 6 N HCl. The gummy solid that forms is triturated with butyl chloride and then crystallized from butyl chloride-methanol to obtain 5-(3,4-dichloro-5-oxo-6-cyclopentyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxymethyl)tetrazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[CH3:13][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([CH3:13])[C:3]([O:2][CH3:1])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of the compound of Example 14A (23.2 g, 0.138 mol) in dry tetrahydrofuran (30 mL) was added dropwise over 30 min to a −78° C. solution of lithium hexamethyldisilazide (prepared from hexamethyldisilazane (35 mL, 0.165 mol) and n-butyllithium in hexane (2.5 M, 58 mL, 0.145 mol)) in dry tetrahydrofuran (100 mL). The solution was stirred at −78° C. for 1 h, and then a large excess of methyl iodide was added. The solution was stirred at −78° C. for 30 min and was then warmed to ambient temperature for 18 h. The solution was quenched by addition of saturated ammonium chloride solution and diluted with water. The mixture was concentrated in vacuo to remove tetrahydrofuran and then extracted with ethyl acetate. The organic layer was extracted with water (2×) and saturated NaCl solution, followed by drying (Na2SO4) and concentration in vacuo. The residue was distilled under reduced pressure (70-75° C./0.5 mm Hg) to afford the title compound (21.9 g, 87%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.49 (d, J=7.35 Hz, 3 H) 3.70 (m, 4 H) 7.01 (m, 2 H) 7.27 (m, 2 H).