Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:76]([O:78][CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)=[O:77])[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:33][C@H:34]([C:47]([NH:49][C@H:50]([C:58]([NH:60][C@H:61]([C:69]([O:71]C(C)(C)C)=[O:70])[CH2:62][CH2:63][CH2:64][NH:65][C:66](=[NH:68])[NH2:67])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42]C(C)(C)C)=[CH:38][CH:37]=1)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[NH:1]([C:76]([O:78][CH2:79][C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1)=[O:77])[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:33][C@H:34]([C:47]([NH:49][C@H:50]([C:58]([NH:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][CH2:63][CH2:64][NH:65][C:66](=[NH:67])[NH2:68])=[O:59])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:48])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:61][C:69]([OH:71])=[O:70].[CH3:61][C:69]([OH:71])=[O:70]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
1.6 g of Z-Lys(Boc)-Lys(Boc)-Tyr(But)-Phe-Arg-OBut are dissolved in 15 ml of 90% strength trifluoroacetic acid. The solution is left to stand at room temperature for 1 hour and is concentrated. The residue is triturated with ether and is suction-drained. The residue is then dissolved in water and chromatographed over a weakly basic ion exchanger (acetate form). The eluate is concentrated and chromatographed in 90% strength methanol over a crosslinked, hydroxypropylated dextran gel. Yield 920 mg, [α]D24 =-29.7° (c=1, methanol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=O)[C:11]([O:13]CC)=O.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([OH:13])=[N:23][C:18]2[C:17]([N:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(=O)c1nc2ccccc2s1
Solvent: CCO
Product: Oc1nc2ccccc2nc1-c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a solution of ethyl 2-(benzo[d]thiazol-2-yl)-2-oxoacetate (Example 13a, 655 mg, 2.78 mmol) in EtOH (5.6 mL) was added o-phenylenediamine (300 mg, 2.78 mmol). The reaction mixture was heated with stiffing at 90° C. for 1 hr (a yellow/green solid appeared quickly), cooled to 0° C., and the solid filtered and rinsed with cold EtOH. The solid was dried under vacuum overnight to provide the title compound (3-(benzo[d]thiazol-2-yl)quinoxalin-2-ol, 313 mg, 40% yield) as a yellow green solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Br:11])[C:3]=1[Br:12].C1([O-])C=CC=CC=1.[Br:20][C:21]1[C:26]([O:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35]Cl)=[C:25]([Br:38])[C:24]([Br:39])=[C:23]([Br:40])[C:22]=1[Br:41]>[OH-].[K+].COCCO>[Br:20][C:21]1[C:26]([O:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][O:8][C:7]2[C:6]([Br:9])=[C:5]([Br:10])[C:4]([Br:11])=[C:3]([Br:12])[C:2]=2[Br:1])=[C:25]([Br:38])[C:24]([Br:39])=[C:23]([Br:40])[C:22]=1[Br:41]
Reactant: O=C(Oc1c(Br)c(Br)c(Br)c(Br)c1Br)c1ccccc1CCl
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Agent: [K+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: COCCO
Product: O=C(Oc1c(Br)c(Br)c(Br)c(Br)c1Br)c1ccccc1COc1c(Br)c(Br)c(Br)c(Br)c1Br

Procedure:
In a two-liter flask, 5.6 of potassium hydroxide was dissolved at 75° C in 800 ml of methyl glycol; then 48.9 g (= 0.1 mole) of pentabromphenol was stirred in. To this phenolate solution, at 75° C, 64.15 g was added of the o-chloromethylbenzoic acid pentabromophenyl ester, prepared as in Example 9a, and the mixture was heated with stirring to ebullition. It was refluxed for an hour, then cooled, and the solids were isolated and worked up as described in the preceding examples.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].O.[O:21]=[C:22]1[O:26][C@H:25]2[CH2:27][C@@H:28]([O:32][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:34])[C@H:29]([CH:30]=O)[C@H:24]2[CH2:23]1>COC(C)(C)C>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:30]/[C@@H:29]1[C@@H:24]2[C@@H:25]([O:26][C:22](=[O:21])[CH2:23]2)[CH2:27][C@H:28]1[O:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.378 g, 1.50 mmol) in t-butyl methyl ether (5 ml), lithium hydroxide monohydrate (60.8 mg, 1.45 mmol) was added and the mixture was stirred for one hour at room temperature. Water (0.15 ml) and (3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydro cyclopenta[b]furan-4-carbaldehyde (10) (0.274 g, 1.00 mmol) were added thereto and the mixed solution was stirred for approximately 3 hours at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane=1:2), to give (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan (11) (0.201 g; 0.495 mmol; yield: 49.5%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH:20]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:23]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.O1CCCC1>[Pt]=O.CO>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:23]=3)[CH2:20][CH2:21]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CC=C(c3cn(-c4ccccc4)c4ccccc34)CC1)O2
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(c3cn(-c4ccccc4)c4ccccc34)CC1)O2
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2,3-Dihydro-2,4,6,7-tetramethyl-2-[[1,2,3,6-tetrahydro-4-(1-phenyl-3-indolyl)-1-pyridyl]methyl]-5-benzofuranamine (0.36 g), platinum oxide (72 mg), tetrahydrofuran (2 mL) and methanol (4 mL) was stirred for 3.5 hours at 60° C. under hydrogen atmosphere. The mixture was cooled, the catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=5:1) to afford 2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(1-phenyl-3-indolyl)-1-piperidinyl]methyl]-5-benzofuranamine. This was dissolved in methanol and to the resulting solution 1 equivalent of oxalic acid solution in methanol was added. The mixture was concentrated and to the residue was added ethanol and diethyl ether. The resulting powdery product was collected to afford the 0.10 g of the title compound. Yield 24%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].N1([C:22]([C:24]2[CH:33]=[CH:32][C:27]3[NH:28][C:29](=[O:31])[NH:30][C:26]=3[CH:25]=2)=O)C=CN=C1.P(Cl)(Cl)(Cl)=O.O>ClC1C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:22]([C:24]2[CH:33]=[CH:32][C:27]3[NH:28][C:29](=[O:31])[NH:30][C:26]=3[CH:25]=2)=[N:16][N:15]=1
Reactant: O=C(c1ccc2[nH]c(=O)[nH]c2c1)n1ccnc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]c(=O)[nH]c3c2)o1
Temperature: 100 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a suspension of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) in chlorobenzene (2 mL) was added 5-(imidazole-1-carbonyl)-1,3-dihydro-benzoimidazol-2-one (315 mg, 1.38 mmol) and stirred for 18 h at 100° C. After cooling to ambient temperature phosphorus oxychloride (126 μL, 1.38 mmol) was added and the suspension was stirred for 4 h at 100° C. It was then cooled to ambient temperature and water (2 mL) was added, stirred for 15 min, and the resulting precipitate filtered off and washed with water (5 mL) and tert-butylmethylether (5 mL). Recrystallisation from ethanol afforded the title compound (257 mg, 78%) which was obtained as a light-grey solid. MS: m/e=360.1 [M+H]+.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[C@@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:4]3[CH2:7][C@@H:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1N[C@H]2CC[C@@H]1C2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1[C@@H]2CC[C@@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 59.6 %

Procedure:
To a solution of ethyl (1S, 3R, 4R)-2-azabicyclo[2.2.1]heptane-3-carboxylate (807 mg, 4.77 mmol) in chloroform (8 ml) were added triethylamine (0.67 ml, 4.77 mmol) and 4-methoxybenzenesulfonyl chloride (1.08 g, 5.25 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl (1S, 3R, 4R)-2-[(4-methoxyphenyl) sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.965 g, 60%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].N1C=CC=CC=1.[C:17]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>O1CCCC1.O.Cl>[C:17]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)Sc2ccccc2C(=O)O)cc1
Yield: 52.7 %

Procedure:
Thiosalicylic acid (1.28 g, 8.3 mmol) was suspended in tetrahydrofuran (10 ml). While stirring, pyridine (1.64 g, 21 mmol) and then a tetrahydrofuran solution (5 ml) of 4-(acetylamino)benzoyl chloride (1.67 g, 9.1 mmol) were dropwise added to the suspension under ice cooling. After the reaction mixture was stirred for 15 hours, the mixture was diluted with water and 6N hydrochloric acid was added thereto to make its liquid property acidic. The mixture was extracted (50 ml×2) with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation and the residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (1.38 g, 53%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[C:7]([C:20]#[N:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)[Cl:25]>Cl.C(O)C>[ClH:25].[C:1]([C:5]1[S:9][C:8]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:20]([NH2:21])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc2c(s1)Nc1ccccc1N=C2N
Yield: 90 %

Procedure:
Add 5-tert-butyl-2-(2-nitro-phenylamino)-thiophene-3-carbonitrile (21.2 g, 70 mmol) to a solution of tin(II)chloride dihydrate (46.1 g, 209 mmol) in conc. HCl (200 mL) and ethanol (600 mL). Reflux the mixture for 2 hours. Concentrate the solution to 200 mL and add to water (1 L). Filter and wash with water then hexanes to obtain the title compound as an orange powder (19.4 g): 1H NMR (DMSO-d6) δ 1.27 (s, 9H), 6.86 (d, 1H), 6.89 (s, 1H), 6.95 (d, 1H), 7.03 (t, 1H), 7.11 (t, 1H), 8.69 (s, 1H) 9.11 (s, 1), 9.52 (s, 1H), 10.88 (s, 1H); MS (APCI) m/z (rel intensity) 272 (100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C([O-])O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3,5-dimethyl-4-hydroxybenzoic acid (2 g, 0.012 mol) in anhydrous methanol (60 mL) was cooled in an ice-bath and thionyl chloride (5 mL) was added drop wise to this solution. The reaction was stirred in the ice-bath for one hour and was then warmed to room temperature and stirred for 16 hours. Solid sodium bicarbonate was then added to neutralize the acid and then the mixture was evaporated to dryness by rotary evaporation. The residue was partitioned between ethyl acetate and water (100 mL each). The ethyl acetate layer was separated and washed once with brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Yield=2.146 g, white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1CCNC1
Reactant: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example101) (226 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (163 mg, 64%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[C:13]([F:26])[C:12]=1[F:27])[CH2:2][CH2:3][CH3:4].C(O[C:36]1[CH:55]=[CH:54][C:39]([C:40]([O:42][C@@H:43]([C:50]([F:53])([F:52])[F:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:41])=[CH:38][CH:37]=1)C1C=CC=CC=1.[CH3:56]N(C1C=CC=CN=1)C>C1COCC1.C(N=C=NC(C)C)(C)C>[F:51][C:50]([F:52])([F:53])[C@H:43]([O:42][C:40]([C:39]1[CH:38]=[CH:37][C:36]([O:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH2:4][CH3:56])=[C:12]([F:27])[C:13]=3[F:26])=[CH:22][CH:21]=2)=[O:25])=[CH:55][CH:54]=1)=[O:41])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: CN(C)c1ccccn1
Reactant: CCCCOCCCCOc1ccc(-c2ccc(C(=O)O)cc2)c(F)c1F
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCCC[C@@H](OC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(OCCCCOCCCCC)c(F)c3F)cc2)cc1)C(F)(F)F
Reaction time: 24 h
Yield: 65 %

Procedure:
To a solution of 4′-(4-butoxybutoxy)-2′,3′-difluorobiphenyl-4-carboxylic acid (27) (1 equi.), (4-hydroxybenzoic acid (R)-1-trifluoromethyl-heptyl ester (13, Scheme 7) (1 equi.), and DMAP (dimethylaminopyridine) (0.1 equi.) in THF (25 mL/mmole), DIC (diisopropyl carbodiimide) (1.2 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) gave 2′,3′-difluoro-4′-(4-pentyloxybutoxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethylheptyloxycarbonyl]-phenyl ester (28) as a white solid (65%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:5][CH2:6][OH:7].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH3:3][N:4]([C:8]1[N:9]=[CH:10][CH:11]=[CH:12][N:13]=1)[CH2:5][CH2:6][O:7][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Sodium hydride (60% in oil, 4.40 g) was added to a solution of 2-(methyl-2-pyrimidylamino)ethanol (15.3 g) in N,N-dimethylformamide (400 ml) at room temperature under nitrogen atmosphere and stirred for 1 hour. A solution of 4-fluorobenzaldehyde (13.6 g) in N,N-dimethylformamide (100 ml) was added dropwise and stirred at room temperature for 15 hours. The reaction mixture was poured onto ice (200 g) and concentrated. The residue was dissolved in ethyl acetate, washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzaldehyde (18.4 g, yield 72%) as crystals from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Recrystallization from ethyl acetate-hexane gave colorless crystals. m.p. 74-75° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]3[C:23]([CH2:26][OH:27])=[CH:24][CH:25]=[C:14]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C)C1C=CN=CC=1.C1COCC1>[C:35]([O:27][CH2:26][C:23]1[N:15]2[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18][C:11]3([CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[C:14]2=[CH:25][CH:24]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A solution of (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methanol (1.66 g, 4.60 mmol) and 4-(dimethylamino)pyridine (561 mg, 4.60 mmol) in dry THF (40 mL) was cooled to 0° C. Triethylamine (2.56 mL, 18.4 mmol) was then added to the reaction mixture followed by dropwise addition of acetic anhydride (1.27 mL, 13.5 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. It was then concentrated and purified by column chromatography (silica gel: 10-40% EtOAc in hexanes) to give (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl acetate (1.32 g, 61% yield over two steps). ESI-MS m/z calc. 402.5, found 403.7 (M+1)+; Retention time: 1.31 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].Br([O-])(=O)=[O:42].[Na+]>CCOC(C)=O.O.O.[Ru]=O>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8](=[O:42])[CH2:9][CH2:10][CH2:11][C@H:12]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:13][O:14][Si:15]([C:28]([CH3:30])([CH3:31])[CH3:29])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=[Ru]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(=O)CCC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a stirred solution of the material from Step 2 (339.5 g, 595 mmol) in EtOAc (1000 mL) and H2O (1400 mL) at room temperature were added sodium bromate (250 g, 1657 mmol) and ruthenium oxide hydrate (3 g, 19.86 mmol). The reaction mixture was stirred at room temperature overnight, 50% of conversion. The mixture was then heated at 55° C. overnight. Additional sodium bromate (100 g) was added and the resulting mixture was heated at 40° C. for 12 hours. Upon cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was extracted with EtOAc (2×). The combined organics were then washed with aqueous sodium bisulfite and brine, and dried over MgSO4. The filtrate was treated with charcoal (Darco® G-60, Norit Americas Inc., Marshall, Tex.) and filtered through a pad of silica gel. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to yield 128 g of the title compound as a colorless viscous oil. 1H NMR (CHCl3-d): δ 7.67-7.62 (m, 4H), 7.58-7.52 (b, 1H), 7.42-7.35 (m, 6H), 4.72-4.65 (b, 1H), 3.70-3.62 (m, 2H), 3.58-3.52 (m, 1H), 2.76-2.62 (m, 2H), 1.75-1.55 (m, 2H), 1.48 (s, 9H), 1.42 (s, 9H), 1.32-1.23 (m, 2H), 1.05 (s, 9H).
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.Cl.[CH3:10][O:11][C:12](=[O:21])[CH:13]([N:18]=[N+]=[N-])[CH2:14][CH2:15][CH2:16][CH3:17]>C(OCC)(=O)C.[Re]([O-])(=O)(=O)=O.[Na+]>[CH3:10][O:11][C:12](=[O:21])[C:13]([N:18]=[C:2]=[O:1])=[CH:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(N=[N+]=[N-])C(=O)OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=[Re](=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCC=C(N=C=O)C(=O)OC
Reaction time: 1 h

Procedure:
27.3 mg (0.1 mmole) of sodium perrhenate and 1.04 grams (5.25 mmoles) of diphosgene were present at 80° C. in 1 ml of ethyl acetate saturated with hydrogen chloride. Then there were added within 20 minutes with vigorous stirring 1.71 grams (10 mmoles) of 2-azidohexanoic acid methyl ester dissolved in 5 ml of ethyl acetate. The reaction was ended after 1 hour uniform development of gas. The reaction mixture was then filtered with suction over a vacuum frit and the ethyl acetate distilled off under reduced pressure. The crude product thus obtained was distilled in a high vacuum (0.0013 mbar) at 50° to 55° C. apparatus temperature in a bulbed tube. There resulted 1.35 grams (79.8% of theory) of analytically pure 2-isocyanato-2-hexenoic acid methyl ester as a colorless, readily mobile liquid: