Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20]>N1C=CC=CC=1>[CH3:20][CH:19]([CH3:21])[CH2:18][C:17]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:22]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 58.1 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (1.1 g, 5.0 mmol) and isovaleryl chloride (0.68 mL, 5.5 mmol) in pyridine (10 mL) provided 3-methyl-N-[6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]-furan-2-yl]butyramide (0.87 g). Mp 154-155° C.;MS (FAB) m/z 300 ([M+H]+); Anal. Calcd. for C19H25NO2: C, 76.22; H, 8.42; N, 4.68; Found: C, 76.07; H, 8.52; N, 4.89.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[Cl:11][C:12]([Cl:16])=[C:13]([F:15])[F:14].C(N(CC)CC)C>O>[Cl:11][C:12]1([Cl:16])[CH:7]([C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:8][C:13]1([F:15])[F:14]
Reactant: FC(F)=C(Cl)Cl
Reactant: C=Cc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2CC(F)(F)C2(Cl)Cl)cc1

Procedure:
p-Methoxystyrene (40.8 g., 0.30 mole), 1,1-dichloro-2,2-difluoroethylene (55.8 g., 0.42 mole), and triethylamine (3.0 ml., 0.02 mole) are heated in a sealed tube (25 × 615 mm) at 125°-130° C. for 16 hrs. The cooled mixture is then poured into water, the reaction product extracted with ether, and the extracts washed with water, dried (MgSO4), and evaporated to an oil. Distillation of the oil yields 69.0 g. (86%), b.p. 80°-85° C. (0.1 mm), of the desired intermediate sutiable for use in the next step. Part of the oil was chromatographed (alumina, cyclohexane), and redistilled, b.p. 81° C. (0.02 mm), nD27 1.5207.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Cl[CH2:30][C:31](=O)[CH3:32]>C(#N)C>[CH3:32][C:31]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[CH:30]=1
Reactant: Nc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)ccn1
Reactant: CC(=O)CCl
Solvent: CC#N
Product: Cc1cn2ccc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cc2n1
Yield: 37.5 %

Procedure:
Compound 19 was prepared according to a process similar to that described in step 10.2, by reacting 0.12 g (0.32 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.059 g (0.63 mmol) of 1-chloropropan-2-one in 4 mL of acetonitrile. 50 mg of the expected product are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C(COC)OC>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH3:9])[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1ccc2ccccc21
Reactant: Clc1ccnc(Cl)n1
Solvent: COCCOC
Product: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 122.7 %

Procedure:
To a stirred solution 2,4-dichloropyrimidine (70.5 g, 463.76 mmol) in dimethoxyethane (900 mL) was added FeCl3 (77.16 g, 459.12 mmol) and 1-methyl indole (68.28 g) at 60° C. The resulting mixture was stirred overnight at 60° C. After cooling, a solid was precipitated by adding methanol (345 mL) and water (900 mL). The resulting slurry was stirred for 3 h. The solid was collected by filtration, washed with CH3OH (1.38 L) and dried at 50° C. overnight to give the title compound (138.7 g, 81.5%) as a purple solid; 1H NMR (CDCl3) 3.89 (3H, s), 7.36-7.41 (3H, m), 7.49 (1H, s), 7.96 (1H, s), 8.34 (1H, s), 8.45 (1H, s); m/z: ES+ MH+ 244.05.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].[F:36][C:37]([F:49])([C:45]([F:48])([F:47])[F:46])[CH2:38][CH2:39][CH2:40]S(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:40][CH2:39][CH2:38][C:37]([F:49])([F:36])[C:45]([F:48])([F:47])[F:46])[C:12]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)([CH3:25])[CH2:13][O:14]2)=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)CCCC(F)(F)C(F)(F)F
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCNCCCC(F)(F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4-(9-aminononyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (82.3 mg, 0.17 mmol) was dissolved in 5 ml of methylenechloride under argon atmosphere, which was then cooled down to 0° C. 4,4,5,5,5-pentafluoropentylsulfonyl chloride (110.4 mg, 0.42 mmol) in 1 ml of methylene chloride and triethylamine (0.07 ml, 0.5 mmol) was added thereto, and the mixture was stirred at the same temperature for 30 minutes. The reaction was quenched with water, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subject to flash chromatography in silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (81 mg, yield: 67%) as a colorless oil.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[N:14]=[C:13]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[N:19]=3)=[CH:17][C:12]2=[C:11]2[N:28]([CH3:31])[CH:29]=[N:30][C:10]=12)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:31][N:28]1[C:11]2=[C:12]3[CH:17]=[C:16]([C:18]4[N:19]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=4)[NH:15][C:13]3=[N:14][C:9]([NH:7][CH3:6])=[C:10]2[N:30]=[CH:29]1
Reactant: CC(=O)Nc1cccc(-c2cc3c(nc(N(C)C(=O)OC(C)(C)C)c4ncn(C)c43)[nH]2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nc2[nH]c(-c3cccc(NC(C)=O)n3)cc2c2c1ncn2C
Reaction time: 0.25 h

Procedure:
A436.2 (55 mg, 0.13 mmol), was dissolved in DMA (5 mL) and the solution heated to 70° C. One equivalent of 1.0M potassium t-butoxide in THF (0.14 ml, 0.14 mmol) was quickly added and the reaction heated at 70° C. for thirty minutes. A second equivalent of 1.0M potassium t-butoxide in THF (0.14 ml, 0.14 mmol) was quickly added and the reaction mixture stirred an additional thirty minutes. The reaction mixture was concentrated in vacuo. The crude product residue was chromatographed on Silica Gel (230-400 Mesh) eluting with 2-5% MeOH/CH2Cl2 to give the Boc-protected intermediate, tert-butyl-7-(6-acetamidopyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamate as an off-white solid. (26 mg, 60% yield). The solid was dissolved in methylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL) was added and the reaction mixture stirred for 0.25 h. The solvent was evaporated under reduced pressure to provide A436 (20 mg, 60%). M+H+=336.34 1H NMR (400 MHz) MEOD δ 9.20 (s, 1H), 8.02 (m, 1H), 7.78 (m, 1H), 7.71 (d, 1H), 7.56 (s, 1H), 4.33 (s, 3H), 3.45 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:37][C:38]([NH:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:15]([N:17]([CH2:27][C:28]1[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[S:31][CH:32]=1)[C@@H:18]([CH3:26])[CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:16]>>[S:31]1[CH:32]=[C:28]([CH2:27][N:17]([C@@H:18]([CH3:26])[CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:37][C:38](=[O:39])[NH:40][C:41]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 40 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxy-propan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@@H:10]2[O:19][C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]2[CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[CH3:40].C(=O)([O-])[O-].[K+].[K+]>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>[F:33][C:34]1[CH:35]=[C:36]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@@H:10]3[O:19][C@@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@@H:12]4[C@@H:11]3[CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[CH:6][CH:7]=2)[CH:37]=[CH:38][C:39]=1[CH3:40]
Reactant: CC1(C)O[C@H]2O[C@@H](/C=C/c3ccc(Br)cc3)[C@@H](CCN3C(=O)c4ccccc4C3=O)[C@H]2O1
Reactant: Cc1ccc(B(O)O)cc1F
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+]
Product: Cc1ccc(-c2ccc(/C=C/[C@@H]3O[C@@H]4OC(C)(C)O[C@@H]4[C@@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cc1F
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step k above (0.5 g), 3-fluoro-4-methylphenylboronic acid (0.314 g), tetrakistriphenylphosphinepalladium (0) (0.057 g), and potassium carbonate (0.414 g) was dried under high vacuum for 10 minutes. The vacuum was released under nitrogen atmosphere and dry dimethylformamide (5 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 30% ethyl acetate in hexane as eluant to afford the title compound (0.37 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7]S[N:9]=2)[C:5]([Br:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[NH2:9][C:10]1[C:2]([Br:1])=[CH:3][CH:4]=[C:5]([Br:11])[C:6]=1[NH2:7]
Reactant: Brc1ccc(Br)c2nsnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1c(Br)ccc(Br)c1N
Temperature: 25 °C
Reaction time: 30 h
Yield: 79.5 %

Procedure:
A mixture of 4,7-dibromo-2,1,3-benzothiadiazole (synthesized according to as described in K. Pilgram, J. Heterocycl. Chem., 7 (1970), 629) (16.0 g, 54.4 mmol) and NaBH4 (38.1 g, 1.0 mol) in 500 ml ethanol was stirred at room temperature for 30 hours. The solvent was evaporated and the residue mixed with 500 ml water. The obtained mixture was extracted into diethyl ether (5×150 ml). The combined extracts were washed with brine (2×100 ml) and dried over anhydrous Na2SO4. Evaporation of the solvent and drying under reduced pressure afforded 11.5 g (79.5%) of the product.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].S(OC)(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)=O)[CH2:27]2>CCCCCC>[CH3:2][O:4][C:20]12[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[C:21]1=[CH:30][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)[CH2:29]2
Reactant: COc1cccc(C(=O)C2C3CC4CC(C3)CC2C4)c1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: COc1cccc(C=C2C3CC4CC(C3)CC2(OC)C4)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A quantity (11.3 g, 0.042 mol) of 3-methoxyphenyl adamant-2-yl ketone obtained according to Example 1 was suspended in 90 ml of molecular sieve-dried (3 Å) dimethylsulfoxide (DMSO). Heat was applied to dissolve the suspended solid. Upon cooling to room temperature with stirring, a fine suspension was formed. Potassium tertbutoxide (8.5 g, 0.070 mol) was added under an argon atmosphere. After 5 minutes, a nearly homogenous orange solution resulted, which was placed in a water bath at 50° C. Dimethyl sulfate (4 ml, 0.042 mol) was added dropwise by syringe over a period of 10 minutes. After 15 minutes of further stirring, an additional 3.3 ml of dimethyl sulfate (0.034 mol) was added in the same fashion. Subsequently, the colorless solution was stirred overnight at room temperature. After cooling in an ice bath, 0.5 g of K2CO3 and 125 ml of ice water added and the mixture extracted with three 50 ml portions of ethyl acetate. The combined organic fractions were washed with three portions of water, once with 50 ml of saturated aqueous NaCl solution, and dried over K2CO3. The solvent was removed in vacuo to yield an oil. The oil was dissolved in hexane, and the resulting solution filtered through Celite and concentrated in vacuo to provide 11.5 g (96% yield) of a viscous, straw-colored oily substance. TLC indicated a clean conversion to an enol ether (Rf 0.68; E. Merck Al2O3 --CH2Cl2 hexanes - 50:50) with a trace of the ketone starting material. The oil was distilled from K2CO3 (b.p. 148°-150° C., 0.25 mm Hg). Under these conditions, slight yellowing occurred in the still head. I.R. analysis of this distillate revealed a small ketone absorption band at 1670 cm-1. I.R. (CH2Cl2) 2900 cm-1, 1670 cm-1 (weak),1600 cm-1, 1590 cm-, 1580 cm-1, 1570 cm-1, 1095 cm-1, 1080 cm-1 ; 1H-NMR 60 MHz (CDCl3): δ 1.5-2.0 (m, 12H), δ 2.55 (s, 1H), δ 3.2 (s, 1H), δ 3.25 (s, 3H), δ 3.75 (s, 3H), and δ 6.7-7.3 (m, 4H). These data confirmed that the structure of the product was: ##STR28##
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[OH-].[K+]>CC(O)C>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)N1CCC(CNc2ccc(C3=NCCO3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1cc(C2=NCCO2)ccc1NCC1CCNCC1
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A mixture of 13.3 parts of ethyl 4-[[[4-(4,5-dihydro-2-oxazolyl)phenyl]amino]-methyl]-1-piperidinecarboxylate, 22.4 parts of potassium hydroxide and 240 parts of 2-propanol was stirred for 6 hours at reflux temperature. The reaction mixture was evaporated. The residue was taken up in water and the whole was evaporated again till all traces of 2-propanol were removed. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 5.1 parts (49.1%) of N-[4-(4,5-dihydro-2-oxazolyl)phenyl]-4-piperidinemethanamine as a residue (int. 77).
Reaction SMILES: O1CCCCC1O[CH:8]([CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH3:9].CO.Cl.C(OCC)(=[O:26])C>O>[C:18]([O:17][CH:11]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:8][CH2:9][OH:26])(=[O:20])[CH3:19]
Reactant: CCOC(C)=O
Reactant: CCCOCC(CC(C)OC1CCCCO1)OC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCOCC(CCCO)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2-tetrahydropyranyloxy-4-acetoxy-5-propoxypentane (11.5 g., 0.42 mole), methanol (700 ml.), concentrated hydrochloric acid (3 ml.) and ethyl acetate (70 ml.) is stirred at room temperature for 1 hour. The reaction mixture is poured into cold H2O (1500 ml.) and the organic layer is extracted with ether. The combined extracts are washed with saturated sodium bicarbonate solution, then brine, and dried over anhydrous magnesium sulfate. The solvent is removed under vacuum and the residual oil is distilled to give the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].C([Mg]Cl)(C)C.[C:31]([CH:39]1[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:38][C:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:13])([F:15])[F:14])[C:6]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:5]2[C:22]([F:23])([F:24])[F:25])[CH:39]1[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]1
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Reactant: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(O)(c2ccccc2)c2ccc3nc(C(F)(F)F)c(-c4ccccc4)c(C(F)(F)F)c3c2)CC1
Reaction time: 0.15 h

Procedure:
A ˜−70° C. solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (754 mg, 1.61 mmol, Intermediate 8, step d) in THF (1.4 mL) was treated with iPrMgCl (0.784 mL, 2.06 M in THF, 1.61 mmol) dropwise via syringe under argon over the course of 3 min to provide a light amber solution. After 9 min, the opaque yellow slurry was removed from the cold bath and stirred under ambient conditions for 4 min. A solution of 1-(4-benzoylpiperidin-1-yl)ethanone (442 mg, 1.91 mmol, Intermediate 27) in THF (0.3 mL) was added to the olive drab slurry rapidly dropwise over ˜15 sec, and the homogeneous brown solution was stirred at room temperature overnight. The light amber solution was then quenched with 5 M NH4Cl (1 mL) and extracted with 2-methoxy-2-methylpropane (1×10 mL, 1×2 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was flash chromatographed using 50% acetone/heptane (isocratic elution), and impure fractions were additionally flash chromatographed using 90% EtOAc/heptanes (isocratic elution) to afford the title compound as an off-white foam. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=10.11 Hz, 1H), 8.24 (dd, J=5.56, 9.09 Hz, 1H), 7.94 (t, J=8.84 Hz, 1H), 7.54 (t, J=7.33 Hz, 2H), 7.41-7.51 (m, 3H), 7.33-7.41 (m, 2H), 7.28 (br. s., 3H), 4.71 (d, J=7.58 Hz, 1H), 3.86 (br. s., 1H), 3.00-3.21 (m, 1H), 2.74-2.89 (m, 1H), 2.52-2.69 (m, 1H), 2.44-2.52 (m, 1H; D2O-exch), 2.05 (d, J=2.02 Hz, 3H), 1.69-1.84 (m, 1H), 1.31-1.55 (m, 3H); MS m/e 573.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]2[C:34]([O:36][C:37](=O)[C:27]=2[CH:26]=1)=[O:35]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:34](=[O:35])[C:28]3[C:27](=[CH:26][CH:25]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=3)[C:37]2=[O:36])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-phenylbenzoxazole (420 mg, 1.42 mmol) and 1,2,4-benzenetricarboxylic anhydride (273 mg, 1.42 mmol) the title compound was obtained, (460 mg, 66%). 1H NMR (DMSO) δ 13.85(s, 1H), 8.51(dd, 1H), 8.41(s, 1H), 8.29(d, 1H), 8.16(m, 2H), 7.95(d, 1H), 7.81(m, 4H), 7.58(m, 2H), 7.54(d, 1H), 7.48(d, 1H), 4.12(s, 3H). MS 491 m/z (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:14][C:13]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][N:11]1[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:7])=[O:6].[I-].[Na+].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:14][C:13]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][N:11]1[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCCl)(c2ccccc2)S1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN=[N+]=[N-])(c2ccccc2)S1
Temperature: 90 °C
Reaction time: 4 h
Yield: 119.8 %

Procedure:
The optically active N-[5-(3-chloropropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.50 g, 2.90 mmol) obtained in Step 1 mentioned above, sodium iodide (8.69 g, 58.0 mmol) and sodium azide (1.89 g, 29.0 mmol) were suspended in DMF (20 mL), and the suspension was stirred at 90° C. for 4 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether to give optically active N-[5-(3-azidopropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.82 g).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCSc1ccccc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCSc1ccccc1

Procedure:
3-(Phenylthio)-1-propanol (3.00 g), 1,6-dibromohexane (5.5 ml), aqueous 12.5M sodium hydroxide (27 ml) and TAB (802 mg) were vigorously stirred at room temperature overnight. The mixture was diluted with water (60 ml), extracted with diethyl ether (3×90 ml), and the combined, dried organic extracts were evaporated. The residual oil was purified by FCC eluting with System B (1:99→1:24) to give the title compound (4.01 g) as a colourless oil. T.l.c. (System B 1:3) Rf 0.35.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH3:20]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13][N:25]3[CH2:26][CH2:27][CH:22]([O:21][CH2:18][CH2:19][CH3:20])[CH2:23][CH2:24]3)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Reactant: CCCOC1CCNCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3cc(F)ccc32)CC1
Yield: 72 %

Procedure:
The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.501 g, 1.43 mmol) and 4-propyloxypiperidine (0.205 g, 1.43 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF28) (0.375 g, 71%). 1H NMR (CDCl3) d 7.12-7.08 (m, 1H), 6.74-6.69 (m, 2H), 4.59 (q, J=15.0 Hz, J=31.0 Hz, 2H), 4.01-3.88 (m, 2H), 3.39 (t, J=6.8 Hz, 2H), 3.29-3.22 (m, 1H), 2.77 (t, J=6.3 Hz, 1H), 2.63 (t, J=5.6 Hz, 1H), 2-26-2.12 (m, 3H), 2.04-1.96 (m, 2H), 1.88-1.84 (m, 2H), 1.62-1.50 (m, 4H), 0.93-0.87 (m, 6H); 13C NMR (CDCl3) d 164.2, 158.9 (d, J=241.9 Hz), 146.5 (d, J=12.1 Hz), 125.2 (d, J=3.0 Hz), 116.1 (d, J=9.6 Hz), 109.0 (d, J=22.3 Hz), 105.2 (d, J=25.8 Hz), 75.2, 69.8, 67.8, 63.5, 52.8, 51.8, 45.5, 31.9, 31.8, 29.4, 23.5, 17.0, 10.8.