Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6]1.[Cl:34][C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1(/C=C/C(=O)/C=C/C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:34][C:35]1[C:36]([NH:41][C:2]2[CH:3]=[C:4]3[C:31](=[CH:32][CH:33]=2)[O:30][CH2:29][C:25]2([CH2:28][O:27][CH2:26]2)[C:5]23[CH2:9][O:8][C:7]([NH2:10])=[N:6]2)=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: Nc1ncccc1Cl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: NC1=NC2(CO1)c1cc(Nc3ncccc3Cl)ccc1OCC21COC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 26.3 %

Procedure:
The mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (150 mg, 0.286 mmol), 3-chloropyridin-2-amine (184 mg, 1.43 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) (52 mg, 0.057 mmol), di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (97 mg, 0.23 mmol), and Cs2CO3(279 mg, 0.857 mmol) in 1,4-dioxane (7.5 ml) was stirred for 48 hours at 100° C. The reaction mixture was cooled down to ambient temperature, and partitioned with CHCl3 and water. The organic layer was dried over Na2SO4, and filtered. The residue was dissolved in toluene, and was added silica gel (neutral), and stirred at 130° C. for 3 hours. The mixture was concentrated under reduced pressure, and purified by silica gel column chromatography(CHCl3/MeOH=100:0-85:15) to give an amorphous, which was washed with CHCl3/hexane to give 6′-(3-chloropyridin-2-yl)aminodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetane]-2-amine (28 mg).
Reaction SMILES: Cl[C:2]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH3:6])=[CH2:3].[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:8]1([C:5]([OH:7])([CH3:6])[CH2:4][C:2]#[CH:3])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(Cl)CC(C)(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCC(C)(O)c1ccccc1

Procedure:
20.00 Grams of the 2-chloro-4-phenyl-1-penten-4-ol were dissolved in 50 g of toluene, and 30.5 g of a 40% sodium hydroxide aqueous solution and 65.57 g of tetra-n-butylammonium bromide were added. The mixture was allowed to react at 50° C. for 30 hours and then was subjected to separation. The organic phase was washed with water, and the toluene was distilled off under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 11.37 g of 4-phenyl-1-pentyn-4-ol; nD21 =1.537 FI-MS m/e 160(M+) (Propargyl compound/allene compound 100.0/0.0).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1CCOCC1.N1C=CC=CC=1.[CH2:20]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])C=O)[CH:21]=[CH2:22].Cl>C1(C)C=CC=CC=1.O.C(#N)C>[CH2:20]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])[CH:21]=[CH2:22]
Reactant: O=C(O)CC(=O)O
Reactant: C=CCC(C=O)CCCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCC(/C=C/C(=O)O)CCCC
Temperature: 77 °C
Reaction time: 24 h

Procedure:
Malonic acid (99.90 g, 0.96 mol), acetonitrile (360 mL), morpholine (26 mL, 0.3 mol), and pyridine (97 mL, 1.2 mol) were added in this order to the solution of 2-allylhexanal in toluene obtained by the method described above under a nitrogen atmosphere, and the mixture was slowly warmed to 72 to 82° C. over 1 hour and 20 minutes and stirred at this temperature for approximately 24 hours. The reaction mixture was cooled to room temperature. To the reaction mixture, water (480 mL) was added, and concentrated hydrochloric acid (130 mL) was added to separate an organic layer. The aqueous layer was subjected to extraction with toluene (180 mL), and the extract was combined with the organic layer, followed by extractions into aqueous layers with a 2 M aqueous NaOH solution (358 mL) and a 1.3 M aqueous NaOH solution (134 mL) in this order. The aqueous layers were combined and then adjusted to be acidic by the addition of concentrated hydrochloric acid (80 mL), followed by two extractions with toluene (240 mL and 180 mL). The organic layers were combined and then washed with water (120 mL). The organic layer was concentrated under reduced pressure to obtain the title compound (99.11 g, brown oil substance).
Reaction SMILES: [C:1]([N:8]([C:16]1[C:21](F)=CC(Br)=CC=1F)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:60][N:61]1CCNC[CH2:62]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:9]([N:8]1[CH2:16][CH2:21][N:61]([CH3:62])[CH2:60][CH2:1]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(F)cc(Br)cc1F
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of N,N-di-Boc-4-bromo-2,6-difluoro-phenylamine (5.59 g, 13.7 mmol) obtained in Step A in Example 1-D-18, palladium acetate (308 mg, 1.37 mmol), S-Phos (1.12 g, 27.4 mmol) and cesium carbonate (8.93 g, 27.4 mmol) in toluene (100 ml), 1-methyl-piperazine (6.08 ml, 54.8 mmol) was added, followed by stirring at 100° C. for 16 hours. After cooling to room temperature, 100 ml of ethyl acetate was added, which was washed with water (100 ml) and saturated aqueous ammonium chloride solution (100 ml). The organic layer was dried over sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 25/1), whereby a mixture of N-Boc-4-(4-methyl-piperazin-1-yl)-2,6-difluoro-phenylamine and 1-Boc-4-methylpiperazine was obtained. This was dissolved in ethyl acetate (60 ml), and 6M−HCl aqueous solution (30 ml) was added, followed by stirring at room temperature for 3 hours. To this, 5M-NaOH aqueous solution was added to adjust the pH to 8, followed by extraction with ethyl acetate (100 ml×2), and the organic layer was washed with brine. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 20/1), to obtain the desired compound as a brown solid (2.16 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[CH3:19])[CH:3]=1>[Pt].C(O)C>[CH3:19][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[O:9][CH2:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[NH2:16]
Reactant: Cc1ccnc(COc2ccc([N+](=O)[O-])cc2C)c1
Agent: [Pt]
Solvent: CCO
Product: Cc1ccnc(COc2ccc(N)cc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
n-Butyllithium (24 ml of a 1.6 N solution in hexanes, 38.4 mmol) was added to a stirred solution of 2,4-lutidine (4.28 g, 40 mmol) in tetrahydrofuran (70 ml) at −70° C. under an inert atmosphere. After 1 hour, air was bubbled through (for 1 hour), methanol (50 ml) was added and the reaction allowed to warm to ambient temperature. The reaction mixture was filtered and then evaporated in vacuo. Purification of the crude product by flash chromatography on silica gel, eluting with ethyl acetate, yielded 2-(hydroxymethyl)-4-picoline (700 mg, 14% yield) as a white solid. b) Sodium hydride (150 mg of an 80% dispersion in mineral oil, 5.00 mmol) was added to a stirred solution of 2-(hydroxymethyl)-4-picoline (590 mg, 5.00 mmol) in N-methylpyrrolidine (20 ml) at ambient temperature. 2-Fluoro-5-nitrotoluene (775 mg, 5.00 mmol) was added, the reaction was stirred for 18 hours at ambient temperature and the reaction was poured into water (60 ml). Collection of the yellow solid which precipitated, followed by drying in vacuo, yielded 2-((4-methyl-2-pyridyl)methoxy)-5-nitrotoluene (900 mg, 70% yield) as a yellow solid. c) 5% Platinum on carbon (50 mg) was added to a solution of 2-((4-methyl-2-pyridyl)methoxy)-5-nitrotoluene (750 mg, 2.91 mmol) in ethanol (150 ml) and the solution was stirred for 2 hours at ambient temperature under an atmosphere of hydrogen. Filtration of the reaction mixture, followed by solvent evaporation in vacuo, yielded 3-methyl-4-((4-methyl-2-pyridyl)methoxy)aniline (420 mg, 63% yield) as a yellow gum.
Reaction SMILES: O[C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[C@@H:3]1O.CS(Cl)(=O)=O.CS(O[C@@H]1C2[C@](C)(CCC(=O)C=2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)[C@@H]1OS(C)(=O)=O)(=O)=O.[N-:60]=[N+:61]=[N-:62].[Na+]>N1C=CC=CC=1.CN(C)C=O>[N:60]([C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH:3]=1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C=C1[C@@H](O)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CS(=O)(=O)Cl
Agent: C[C@]12CCC(=O)C=C1[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C=C1C(N=[N+]=[N-])=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Conversion of 6α,7α-dihydroxy-4-androstene-3,17-dione to the corresponding 6α,7α-dimethanesulfonate ester by treatment with methanesulfonyl chloride in pyridine in a manner similar to that described in Example 22B followed by treatment of the resulting 6α,7α-dimethanesulfonyloxy-4-androstene-3,17-dione with sodium azide in dimethylformamide in a manner similar to that described in above Example 22C does not yield an identifiable amount of 6-azido-4,6-androstadiene-3,17-dione. Similarly, treatment of 6α,7α-dimethanesulfonyloxy-4-androstene-3,17-dione with sodium azide in aqueous methanol in the presence of acetic acid in a manner similar to that described in Example 6, does not yield an identifiable quantity of 6-azido-4,6-androstadiene-3,17-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[F:23].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:20])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])=[CH:4][C:3]=1[F:23]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BR) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 497.0260 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[CH3:29][O:30][CH:31]1[CH2:34][NH:33][CH2:32]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:29][O:30][CH:31]1[CH2:34][N:33]([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:26])[CH2:32]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: COC1CNC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC1CN(C(=O)c2cnn(C)c2C(=O)Nc2ccn3nc(-c4ccccc4)nc3c2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-methoxyazetidine hydrochloride (37.5 mg, 304 μmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 3 hours at 70° C. under nitrogen atmosphere in a closed vessel, and then over the weekend at room temperature. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(3-Methoxyazetidine-1-carbonyl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (75 mg, 66.6%) as a very insoluble white solid. mp.: 269-270° C. MS: m/z=432.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(B)#N.[Na].Cl>C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: BC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: CCOC(=O)C1CCCC1Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
p-Chloroaniline (4 g), ethyl 2-oxocyclopentanecarboxylate (4.66 ml) and p-toluenesulfonic acid hydrate (0.66 g) were dissolved in benzene (80 ml), and the mixture was subjected to dehydrating condensation reaction under refluxing for 24 hours, and the mixture was allowed to cool. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give an oily product. This oily product was dissolved in absolute methanol (60 ml) and thereto was added sodium cyanoboron hydride (13.2 g) with stirring at room temperature in 10 portions over a period of 11 days. The reaction mixture was cooled with ice and thereto was added conc. hydrochloric acid (21 ml), and the mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the resultant to separate into layers. The organic layer was washed with water 3 tlmes, and concentrated again under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform/methanol [100:1 (v/v)] to give the oily desired product (3.76 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC.[Cl-].[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][CH2:20][OH:21])[CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1)[CH3:29]
Reactant: CNc1ccc(-c2cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3s2)cc1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN(C)c1ccc(-c2cc3ccc(OCCO)cc3s2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
2-[4-(N-Monomethylamino)phenyl]-6-[2-(t-butyldimethylsilyloxy)ethoxy]benzothiophene (115, 150 mg, 0.36 mmol) obtained in Example 56 was dissolved in dimethylformamide (5 mL) and potassium carbonate (75 mg, 0.54 mmol) and iodomethane (0.23 mL, 0.36 mmol). The reaction mixture was stirred at 80° C. for 12 hours and an aqueous solution of sodium chloride and water were added to the reaction mixture and organic compounds were extracted with dichloromethane and extracted with ethyl acetate. The recovered organic solution was washed with a brine solution and dried over sodium sulfate to remove water and the solvent was removed under reduced pressure. The resulting mixture was dissolved in tetrahydrofuran (5 mL) and tetrabutylammonium fluoride (TBAF) (143 mg, 0.54 mmol) was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture and organic compounds were extracted with ethyl acetate. The recovered organic solution was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate to remove water. Purification was performed by column chromatography to give 2-[4-(N,N-dimethylamino)phenyl]-6-(2-hydroxyethoxy)benzothiophene (118, 96 mg, 85%) as a white solid. The obtained target compound 118 had a melting point of 205-206° C., and the following physical data;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14](C([O-])=O)[CH2:13][CH2:12]2)=O)[CH:5]=[CH:6][CH:7]=1.B.Cl.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])N1CCN(C(=O)C(c2cccc(Cl)c2)C2(O)CCCCC2)CC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
A solution of 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate (200 mg, 0.46 mmol) in dry tetrahydrofuran (3 mL) under nitrogen was treated dropwise with a solution of borane (1.0 M in tetrahydrofuran, 1.60 mL, 1.60 mmol). The resulting solution was heated at 70° C. for 2 h, after which time the reaction was cooled in an ice bath and was treated dropwise with a 2N aqueous solution of hydrochloric acid (1 mL). The reaction was again heated at 70° C. for 1 h, and was then cooled and treated with methanol (1 mL). After the solvent was removed in vacuo, the resulting residue was dissolved in water (5 mL) and was washed with ethyl acetate (1×4 mL). The aqueous layer was basified with the addition of a 2 N aqueous solution of sodium hydroxide until the pH=10. The product was extracted with ethyl acetate ( 4×5 mL) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 146 mg (99%) 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol as a colorless oil. HRMS: calcd for C18H27ClN2O, 322.1812; found (ESI_FT), 323.18977. 1-[1-(3-Chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (146 mg) was dissolved in methanol (0.5 mL) and treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether. After crystallizing in the refrigerator for 16 h, the resulting solid was filtered, washed with diethyl ether and dried in vacuo to yield 110 mg (60%) 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride as a white solid. MS (ESI) m/z 323/325 ([M+H]+); HRMS: calcd for C18H27ClN2O.2.00 HCl, 394.1345; found (ESI_FT), 323.18831.
Reaction SMILES: [CH2:1]([S:4]([N:7]=[N+:8]=[N-:9])(=[O:6])=[O:5])[CH:2]=[CH2:3].C([O-])(=[O:12])C.[Na+].C(OO)(=O)C.C=CC.O1C(C)C1>O.C(Cl)Cl.C(O)(=O)C>[O:12]1[CH2:3][CH:2]1[CH2:1][S:4]([N:7]=[N+:8]=[N-:9])(=[O:6])=[O:5]
Reactant: CC(=O)[O-]
Reactant: C=CCS(=O)(=O)N=[N+]=[N-]
Agent: CC(=O)OO
Agent: CC1CO1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)CC1CO1

Procedure:
To a solution of 14.7 parts of 2-propene-1-sulfonyl azide in 105 parts of glacial acetic acid containing one part of sodium acetate was added with stirring at room temperature 40% peracetic acid in an amount in excess of that required to convert the propene radical to an epoxypropane radical. The reaction was stirred at room temperature until the peracetic acid content remained constant and then diluted with 200 parts of water and 135 parts of methylene chloride. The methylene chloride layer was removed and washed with water 5 times and then dried over magnesium sulfate. The methylene chloride solvent was removed leaving 15.1 parts of 2,3-epoxypropane-1-sulfonyl azide. The results of an infrared analysis of the product for % azido nitrogen and oxirane oxygen is tabulated below:
Reaction SMILES: [NH2:1][C:2]([C:23]#[N:24])([CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[C:8]#[N:9].C(N(C(C)C)C(C)C)C.[F:34][C:35]([F:47])([F:46])[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>ClCCl>[C:23]([C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:37]([O:36][C:35]([F:34])([F:46])[F:47])=[CH:38][CH:39]=1)([CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])#[N:24]
Reactant: CC(N)(C#N)COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)(COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
13.04 g of 3-(2-amino-2-cyano-1-propoxy)-4-(2,4-dichlorophenoxy)-benzonitrile and 6.1 g of ethyldiisopropylamine are dissolved in 120 ml of dichloromethane. After cooling the mixture to 0°, 9.9 g of 4-trifluoromethoxybenzoyl chloride is added, the reaction mixture stirred at room temperature for 6 h and then concentrated under vacuum. The residue is dissolved in ethylacetate and washed with a 1N aqueous solution of sodium hydroxide, water, a 1N aqueous solution of hydrogen chloride, again with water and finally with brine. The organic phase is dried over magnesium sulfate, filtered and evaporated. The raw residue is then recrystallized in diethylether/hexane, thus yielding the title compound with a melting point of 151-2°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[C:34]([C:36]1[CH:37]=[CH:38][C:39]([C:42](O)=[O:43])=[N:40][CH:41]=1)#[N:35].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>ClCCl.CN(C=O)C.O.C(OCC)(=O)C>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:42]([C:39]3[CH:38]=[CH:37][C:36]([C:34]#[N:35])=[CH:41][N:40]=3)=[O:43])[CH:3]=[CH:4][C:5]=2[F:33])[N:9]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)c([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
N-[(4aR,7aS)-7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.180 g, 0.39 mmol, isomer 1) is dissolved in a mixture of dichloromethane (2 mL) and DMF (0.25 mL). 5-Cyanopyridine-2-carboxylic acid (114 mg, 0.77 mmol), 1-hydroxybenzotriazole (106 mg, 0.77 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg, 0.77 mmol) are added and the reaction is stirred at room temperature overnight. The mixture is diluted with water (10 mL), ethyl acetate (10 mL) and added to a solution of 1 N NaOH (100 mL). The mixture is extracted with EtOAc (2×100 mL) and the organic layers are combined and washed with brine. The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified over silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the title compound (133 mg, 57%). ES/MS (m/e): 597 (M+H).