Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2C=CN=CC=2C=N1.[C:10]([C:13]1[C:21]2[C:16](=[CH:17]N=C(C)[CH:20]=2)[N:15]([CH2:23][C:24]([OH:26])=[O:25])[N:14]=1)(=[O:12])[NH2:11]>>[C:10]([C:13]1[C:21]2[CH:20]=[N:1][CH:9]=[CH:17][C:16]=2[N:15]([CH2:23][C:24]([OH:26])=[O:25])[N:14]=1)(=[O:12])[NH2:11]
Reactant: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1
Reactant: c1cc2[nH]ncc2cn1
Product: NC(=O)c1nn(CC(=O)O)c2ccncc12

Procedure:
was prepared from 1H-pyrazolo[4,3-c]pyridine [271-52-3] by using the same procedures as for the preparation of (3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid (Scheme A27). MS (LC-MS): 221 [M+H]+, tR (HPLC conditions k): 0.19 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]C(C)(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([CH:41]=[O:42])([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([CH:41]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:18]3[C:13]([CH:12]=2)=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[OH:42])([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:33]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: CCCC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC1(C(O)c2cc3cc(F)ccc3n2S(=O)(=O)c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a −78° C. solution of 1-benzenesulfonyl-5-fluoro-1H-indole (539 mg, 1.96 mmol) in 30 mL THF, t-BuLi (1.5 mL, 2.54 mmol) was slowly added. The reaction mixture was stirred for 30 minutes, then a solution of 4-formyl-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.96 mmol) in 5 mL THF was added. The reaction was allowed to stir for 2 hours at −78° C. and was then warmed to −20° C. and quenched with a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated onto silica. The material was chromatographed over a 25 g Thomson column eluting with 20% ethyl acetate 80% hexanes to afford 4-[(1-benzenesulfonyl-5-fluoro-1H-indol-2-yl)-hydroxy-methyl]-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (319 mg, 0.6 mmol) in a 53% yield as a beige foam.
Reaction SMILES: [CH3:1][C@@:2]12[C:22]([CH3:24])([CH3:23])[C@@H:5]([C:6]3[C:7](=[O:21])[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]([F:20])([F:19])[F:18])[NH:9][C:10]=31)[CH2:4][CH2:3]2.I[CH3:26].O>CN(C)C=O>[CH3:26][N:9]1[C:10]2[C@@:2]3([CH3:1])[C:22]([CH3:24])([CH3:23])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:21])[N:8]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3C(F)(F)F)c(=O)c12
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c(=O)n1-c1ccccc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 81.8 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2-trifluoromethyl-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 22; 710 mg, 2.1 mmol) and iodomethane (0.33 mL, 5.3 mmol) in N,N-dimethylformamide (5 mL) in a sealed tube was heated at 100° C. overnight. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales Aspire 90 g column, eluting with 25-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, dissolved in ethyl acetate and heated at reflux with activated charcoal for 10 min. The mixture was filtered through Celite® and evaporated to give (4S,7R)-1,7,8,8-tetramethyl-2-(2-trifluoromethyl-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (602 mg, 81%) as a light yellow solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30](=[O:33])(=[O:32])[NH2:31])=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:8]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:31][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:32])=[O:33])=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.09 ml (0.75 mmol) of pivaloyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.68 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 167 mg (1.36 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 284 mg (yield: 80.0%) of the title compound.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:25]4[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26]4)[CH2:24][CH2:23]2)[N:16]=3)=[C:9]([F:32])[CH:8]=1.Cl>C1COCC1>[F:31][C:27]1([F:30])[CH2:28][CH2:29][CH:25]([C:22]2([C:17]3[N:16]=[C:15]4[S:14][C:13]([C:10]5[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[CH:8][C:9]=5[F:32])=[N:21][C:20]4=[CH:19][CH:18]=3)[CH2:23][CH2:24]2)[CH2:26]1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CCC(F)(F)C4)CC3)nc2s1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(C4(C5CCC(F)(F)C5)CC4)nc3s2)c(F)c1
Temperature: 70 °C

Procedure:
2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluorocyclopentyl)-cyclopropyl)thiazolo[5,4-b]pyridine was treated with 5 mL THF and 5N HCl was sealed and heated to 70° C. for 1 h. The reaction mixture was cooled, quenched with ice and 10 N NaOH until basic, and diluted with water and DCM. The aq. Layer was extracted with DCM, and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The oil was adsorbed onto 5 g silica gel and dried, purified by silica gel chromatography, 0-40% EA/hexanes, to give (rac)-4-(5-(1-(3,3-difluorocyclopentyl)-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzaldehyde as a solid. MS (ESI) m/z: Calculated: 402.1; Observed: 403.0 (M++1).
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[Br:14][CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@H](CBr)NC(=O)OC(C)(C)C
Reaction time: 14 h
Yield: 50.1 %

Procedure:
(R)-tert-Butyl 1-hydroxypropan-2-ylcarbamate (1 g, 5.71 mmol) and carbon tetrabromide (2.84 g, 8.56 mmol) were stirred in CH2Cl2 (20 mL) at −20° C. under argon. A solution of triphenylphosphine (2.40 g, 9.13 mmol) in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to reach rt and stirred for 14 h. H2O (50 mL) was added to the reaction mixture and the aqueous layer was removed and the CH2Cl2 layer was dried over Na2SO4, filtered, and evaporated. The residue was applied to a silica ISCO column and eluted with 5:1 hexanes/EtOAc. Intermediate 5A (0.68 g, 2.86 mmol, 50.0% yield) was isolated as a white solid. LC-MS (ESI) 183.9 (M−tBu+H), RT=1.76 min (Method B).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:15]=[C:16]([NH2:23])[C:17](=[CH:21][CH:22]=1)[C:18](O)=[O:19]>>[Cl:13][C:14]1[CH:15]=[C:16]2[C:17]([C:18](=[O:19])[N:6]3[C:5]4[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=4[NH:3][C:2]3=[N:23]2)=[CH:21][CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: Cc1cc2nc(Cl)[nH]c2cc1C
Product: Cc1cc2[nH]c3nc4cc(Cl)ccc4c(=O)n3c2cc1C

Procedure:
3-Chloro-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 4-chloroanthranilic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:27][Si:28](N=C=O)([CH3:30])[CH3:29]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][C:17]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1cc(F)cc2cc([Si](C)(C)C)oc12)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 0.20 gm (0.68 mMol) N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane in 10 mL tetrahydrofuran was cooled to −78° C. under a nitrogen atmosphere. To this solution were then added 0.96 mL (1.53 mMoL) n-butyllithium (1.6 M in hexane) dropwise, resulting in an orange solution. After 50 minutes 0.14 mL (1.02 mMol) trimethylsilylisocyanate were added dropwise. After 15 minutes the reaction mixture was quenched by addition of 2 mL saturated aqueous ammonium chloride and was then allowed to warm to room temperature. The reaction mixture was partitioned between 150 mL ethyl acetate and 150 mL water. The phases were separated and the organic phase was washed sequentially with 150 mL water and 150 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide the desired compound.
Reaction SMILES: Br[C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]=2[CH:3]=1.[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:20]=[N:19][C:5]3[N:6]([CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]=3[CH:3]=2)=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Reactant: CCCN1CCCC(C(=O)OC)=Cc2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)OC)CCCN3CCC)cc1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A suspension of methyl 3-bromo-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (820 mg), 4-(2-butoxyethoxy)phenylboric acid (748 mg) and potassium carbonate (868 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) was stirred under an argon atmosphere for 30 minutes. Tetrakis(triphenylphosphine)palladium (140 mg) was added thereto, and the mixture was heated at 115° C. for 6 hours under an argon atmosphere, which was allowed to cool. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethyl acetate=4:1) to give methyl 3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (870 mg) as a yellow oily material.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([CH3:35])([CH3:34])[CH2:20]2)[N:11]=[C:10]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][C:45]([CH3:48])([CH3:47])[N:44]([O:49][CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[C:43]([CH3:57])([CH3:56])[CH2:42]2)[N:9]=1>>[CH:28]1([O:27][N:22]2[C:23]([CH3:25])([CH3:26])[CH2:24][CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]3[N:11]=[C:10]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]4[CH2:42][C:43]([CH3:57])([CH3:56])[N:44]([O:49][CH:50]5[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]5)[C:45]([CH3:47])([CH3:48])[CH2:46]4)[N:9]=[C:8]([N:7]=[C:2]=[O:3])[N:13]=3)[CH2:20][C:21]2([CH3:34])[CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC1(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Product: CC1(C)CC(CCCCNc2nc(N=C=O)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of oxalyl chloride with the compound prepared in Example 22.
Reaction SMILES: C1(=O)CCCCCCCCCCCCCC1.[CH2:17]1[CH2:34][CH2:33][CH2:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>>[CH:30]1([OH:31])[CH2:32][CH2:33][CH2:34][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=C1CCCCCCCC=CCCCCCCC1
Agent: O=C1CCCCCCC/C=C\CCCCCCC1
Agent: O=C1CCCCCCCCCCCCCC1
Product: OC1CCCCCCCC=CCCCCCCC1

Procedure:
Cyclopentadecanone of Synthesis Example 3 was replaced by civetone, and the ketone group was reduced under the same conditions as in Synthesis Example 3, to give 9-cycloheptadecenol.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CN(C)C=O>[ClH:3].[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH2:10][CH2:9][CH:8]=[CH2:7])=[O:12]
Reactant: NCC(=O)CCC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCCOC(=O)CCC(=O)CN
Yield: 77 %

Procedure:
To 1 ml of thionyl chloride (SOCl2) were added 3 drops of N,N-dimethylformamide (DMF) with stirring. Following the addition of 5-aminolevulinic acid hydrochloride (ALA.HCl, 200 mg, 1.19 mmol), the solution was stirred for 12 hours at room temperature. Concentration in a vacuum was conducted before the addition of 3-butenol. Then, the reaction mixture was stirred for 1.5 hours at room temperature, followed by purification by silica gel chromatography to afford 3-butenyl 5-aminolevulinate hydrochloride at a yield of 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:9]2[C:10]([C:16](O)=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:15])[C:13]=3[CH3:14])[C:16](=[O:17])[N:19]2[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(c2ccc(Cl)cc2)c2c(C(=O)O)nn(C)c2C)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)c3nn(C)c(C)c3C2c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((4-methoxybenzyl)amino)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (Step 25.4). tR: 5.07 min (HPLC 1); tR: 1.11 min (LC-MS 2); ESI-MS: 382.2 [M+H]+ (LC-MS 2); Rf=0.46 (EtOAc).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21](O)=[O:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2].[CH3:34][NH2:35]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:21]([NH:35][CH3:34])=[O:22])=[O:17])[CH2:14][CH2:15]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)O)ccc3N3CCOCC3)CC2)c(F)c1
Reactant: CN
Product: CNC(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step 2 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-morpholin-4-yl-benzoic acid and methylamine (43%, white solid, MS (m/e): 469.3 (M+H, 100%)
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[CH:9]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:30]=[N:31][C:32](F)=[CH:33][C:34]=4[CH3:35])=[O:28])[CH2:23][CH2:22]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:11][CH2:10]1.O>CN(C)C=O>[CH:9]1([C:12]2[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[C:34]([CH3:35])=[CH:33][C:32]([N:5]5[CH2:6][CH2:7][O:3][C:4]5=[O:8])=[N:31][CH:30]=4)=[O:28])[CH2:25][CH2:26]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:11]1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOC2=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of sodium hydride (168 mg, 60% in oil) in N,N-dimethylformamide (10 mL) was added oxazolidin-2-one (367 mg) under ice-cooling, and the mixture was stirred at room temperature. Thereto was added a solution of [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (400 mg) described in Preparation Example 139 in N,N-dimethylformamide (5 mL) and the mixture was stirred at 90° C. for 5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane). Then, diethyl ether was added and the mixture was stirred at room temperature. The solid was collected by filtration to give the title compound (215 mg).
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]1([CH3:36])[CH:27]=[CH:26][C:25]([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])=[CH:24][CH:23]=1.[Cl:37][CH2:38][CH2:39][CH2:40][C:41]#[CH:42]>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH3:36])=[CH:27][CH:26]=2)[CH:42]=[C:41]([CH2:40][CH2:39][CH2:38][Cl:37])[O:35]1)[CH3:33]
Reactant: CCOP(=O)(O)C#Cc1ccc(C)cc1
Reactant: C#CCCCCl
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccc(C)cc2)C=C(CCCCl)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
Method 2—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen p-tolylethynylphosphonate (67.3 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, 5-chloropent-1-yne (61.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-p-tolyl-6-chloropropyl-1,2-oxaphosphorin 2-oxide (68.5 mg, 70%) which is a title compound.
Reaction SMILES: CCOCC.[Na].Cl[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: CC(Cl)C(=O)O
Agent: [Na]
Solvent: CCOCC
Product: CC(OCc1ccccc1)C(=O)O
Temperature: 150 °C

Procedure:
An alternate method for the preparation of ether compounds corresponding to Formula I (R=alkyl, phenylalkyl) follows. Sodium metal (about 12 g) was added cautiously to a stirred cold (ice bath) portion (250 mL) of benzyl alcohol. After most of the sodium metal had dissolved, the reaction was heated to 150° C. 2-Chloropropionic acid (27.2 g, 0.25 mole) was added dropwise in 35 mL of benzyl alcohol and the resulting mixture heated on additional 3 hours. Concentration in vacuo gave crude 2-benzyloxypropionic acid which was used without further purification.
Reaction SMILES: C([C@:4]1([OH:19])[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7]C(C(=O)C)=[C:5]1[C:16](=[O:18])C)(=O)C.[Li+].[Br-].CO.O.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1>CC#N>[O:12]=[CH:11][C@@H:8]([C@H:9]([C@@H:4]([C@@H:5]([CH2:16][OH:18])[OH:32])[OH:19])[OH:10])[OH:7]
Reactant: CC(=O)C1=C(C(C)=O)[C@](O)(C(C)=O)[C@H](O)[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 3 h

Procedure:
To a solution of the crude triacetyl glucal 3 (9.54 g, 35.0 mmol) in CH3CN (150 mL) was successively added LiBr (3.65 g, 42.0 mmol), MeOH (2.25 g, 70.2 mmol), and p-toluenesulfonic acid monohydrate (p-TsOH.H20, 954 mg) at room temperature. After being stirred for 3 h, the reaction mixture was concentrated to a small volume, diluted with cold 5% NaHCO3 solution, and extracted with CHCl3. The organic extract was washed with ice-water, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed on silica gel (150 g) using 30% AcOEt-hexane to give 8 (9.01 g, 92% from D-glucose) (α-anomer:β-anomer=ca. 10:1). 8a was isolated as a single isomer, while 8b was obtained as a mixture of 8a and 8b.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:36])([CH3:35])[C:29]([NH:31][CH2:32][C:33]#[CH:34])=[O:30]>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:34]#[C:33][CH2:32][NH:31][C:29](=[O:30])[C:28]([CH3:36])([CH3:35])[CH3:27]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#CCNC(=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 57.9 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (212 mg, 0.5 mmol) and 2,2-dimethyl-N-prop-2-ynyl-propionamide (139 mg, 1 mmol) (prepared by following the procedure described in Org. Lett. 2004, 6, 3593) in DMF/triethylamine (5:1, 6 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1 to 7:3 gradient) to obtain 7-chloro-6-[3-(2,2-dimethyl-propionylamino)-prop-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 mg, 58%).