Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:27][C@@H:28]1[CH2:30][O:29]1.C(N(CC)CC)C>CCO>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][C@H:28]([OH:29])[CH3:30])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: C[C@@H]1CO1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCS(=O)(=O)c1cccc(-c2ccc(OC[C@@H](C)O)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 140 °C
Yield: 19.9 %

Procedure:
A 5 mL microwave vial was charged with Compound 157 (200 mg, 0.545 mmol), (R)-2-methyloxirane (191 μL, 2.72 mmol), triethyl amine (8 μL, 0.054 mmol) and 2 mL of EtOH. The reaction mixture was heated at 140° C. for 30 min. in microwave. Solvents were removed in vacuum and the residue was purified by preparative HPLC to yield the title compound (46 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3H) 1.25 (d, J=6.06 Hz, 3H) 2.27 (s, 3H) 3.41 (q, J=7.33 Hz, 2H) 3.94 (m, 1H) 4.09-4.16 (m, 2H) 4.97 (d, J=4.04 Hz, 1H) 7.07-7.14 (m, 2H) 7.57 (s, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.96-8.00 (m, 2H) 8.09 (s, 1H) 8.28 (d, J=1.52 Hz, 1H) 11.94 (s, 1H); [M+H] calc'd for C23H25N2O4S, 425.2; found, 425.3.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[CH:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH2:33]([O:35][NH2:36])[CH3:34].C([O-])(=O)C.[Na+].O>O.CCO>[C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:16]3[CH2:17][CH2:18][C:19](=[N:36][O:35][CH2:33][CH3:34])[CH2:20][CH2:21]3)[C:23]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]3)=[O:24])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCC(=O)CC2)CC1
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCON=C1CCC(N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-Cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid (0.055 g, 0.12 mmol) in 1 ml of H2O/EtOH (2:1) was added ethoxyamine hydrochloride (0.024 g, 0.24 mmol) and sodium acetate (0.032 g, 0.24 mmol). The reaction mixture was stirred at room temperature for 24 h and treated with water. The aqueous layer was extracted with CH2Cl2 (3×) and the organic layer was dried with sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by HPLC to obtain 5-cyclohex-1-enyl-3-[(4-ethyoxyimino-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (0.015 g, 26%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(Nc2ccccc2)n1
Temperature: 100 °C
Yield: 11.8 %

Procedure:
In a sealed tube was 2-chloro-4-methoxypyrimidine (1.00 g, 6.92 mmol) in 2-propanol (5 mL). Aniline (0.757 mL, 8.30 mmol) and DIEA (1.45 mL, 8.30 mmol) were added and the reaction mixture was stirred at 100° C. until the reaction was complete by HPLC. The reaction mixture was cooled to room temperature. The resulting thick suspension was filtered, washed with ethanol, collected and dried under vacuum to yield the desired product (0.164 g) as a white solid. The filtrate was concentrated and then partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a yellow solid. The crude product was purified by flash column chromatography, eluting with 25:1 dichloromethane/EtOAc. The desired product (0.548 g) was obtained as a white solid, which was combined with the filtered product to yield 0.712 g (51%) total desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.20 (d, J=5.5 Hz, 1H), 7.77 (d, J=7.8 Hz, 2H), 7.27 (t, J=8.0 Hz, 2H), 6.94 (t, J=7.4 Hz, 1H), 6.28 (d, J=5.5 Hz, 1H), 3.91 (s, 3H). LRMS (ESI pos) m/e 202 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:16][NH:17][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:14]1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CC1
Solvent: CCO
Product: N#Cc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Following the general procedure 2B, 733 mg (4.42 mmol) of 4-fluro-3-nitrobenzonitrile in 80% aqueous ethanol (20 mL) was added cyclopropylmethylamine (377 mg, 5.3 mmol) at room temperature. The mixture was stirred at 60° C. for 3 h before work-up. The crude product (920 mg, 96%) was used for the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.51–8.47 (br, 1H), 7.59 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 3.22–3.20 (m, 2H), 1.25–1.15 (m, 1H), 0.73–0.59 (m, 2H), 0.42–0.35 (m, 2H). MS (ESI) [2×(M+H)+]: 436.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[N:8]=[C:9](O)[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH3:24])=[C:18]([CH3:25])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:9]1[C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=3)[O:13][C:11]=2[N:12]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=2)[N:8]=1
Reactant: COc1c(C)cc(-c2nc3c(O)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1c(C)cc(-c2nc3c(Cl)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C

Procedure:
10 g of 5-(4-chlorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidin-7-ol and 50 ml of phosphorus oxychloride were heated at 90° C. for 5 h. The mixture was then allowed to cool. The solid formed was filtered off with suction, washed with diethyl ether and dried. This gave 10.4 g (99%) of the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1>CC(O)=O.O>[Br:1][C:11]1[S:10][C:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C:6]=2[CH:12]=1
Reactant: CN1CCc2sccc2C1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2sc(Br)cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Bromine (0.3 mL) in HOAc (10 mL) was slowly added over 5 min to a mixture of 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.0 g, 6.5 mmol) in acetic acid (10 mL) and water (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. Work-up: the reaction mixture was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (300 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was recrystallized from 1:4 EtOAc/petroleum ether (150 mL) to afford the title compound as white solid (660 mg, 43%). 1H NMR (DMSO-d6, 400 MHz): δ 6.91 (s, 1H), 3.33 (s, 2H), 2.73-2.71 (m, 2H), 2.52-2.51 (m, 2H), 2.33 (s, 3H). LCMS: 233 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:25][C:24]([O:26][C@H:27]3[CH2:32][O:31][C@H:30]([CH2:33][OH:34])[C@@H:29]([OH:35])[CH2:28]3)=[N:23][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:37]1[CH:42]=[CH:41][C:40]([CH:43]([NH2:48])[C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[NH2:48][CH:43]([C:40]1[CH:41]=[CH:42][C:37]([C:11]2[CH:10]=[CH:9][C:8]([C:7]3[N:6]=[C:5]4[N:23]=[C:24]([O:26][C@H:27]5[CH2:32][O:31][C@H:30]([CH2:33][OH:34])[C@@H:29]([OH:35])[CH2:28]5)[NH:25][C:4]4=[CH:3][C:2]=3[Cl:1])=[CH:13][CH:12]=2)=[CH:38][CH:39]=1)[C:44]([F:45])([F:46])[F:47]
Reactant: NC(c1ccc(Br)cc1)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC(c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)cc1)C(F)(F)F
Temperature: 80 °C

Procedure:
A 10 mL reaction vial was charged with (2R,3S,5R)-5-((6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)-tetrahydro-2H-pyran-3-ol (61.2 mg, 0.122 mmol), 1-(4-bromophenyl)-2,2,2-trifluoroethanamine (35 mg, 0.102 mmol), potassium phosphate tribasic (108 mg, 0.509 mmol), and [1,1′-[1,1′-Bis(Diphenyl-phosphino)-Ferrocene]Dichloropalladium (II) (14.89 mg, 0.020 mmol). The reaction vessel was evacuated and backfilled with N2 (×3), and degassed dioxane (339 μl) and water (339 μl) were added. The reaction was heated to 80° C. for 4 h, then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by mass directed reverse phase HPLC eluted with acetonitrile in water containing 0.1% formic acid. The desired fractions were combined and lyophilized to give the title compound as a white solid. LC-MS: calculated for C26H24ClF3N4O4 548.14 observed m/e: 549.14 (M+H)+ (Rt 1.55/4 min); 1H NMR δ (ppm) (CD3OD): 7.90 (d, 1H), 7.84 (s, 1H), 7.78 (s, 4H), 7.67 (d, 2H), 5.42 (q, 1H), 5.12 (septet, 1H), 4.35 (dd, 1H), 3.88 (d, 1H), 3.66-3.59 (m, 2H), 3.37 (t, 1H), 3.18-3.15 (m, 1H), 2.76-2.74 (m, 1H), 1.69 (q, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:33]1([CH2:36][N:37]([CH2:45]OC)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34]1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:45][N:37]([CH2:36][CH:33]1[CH2:34][CH2:35]1)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(CC1CC1)C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
(R)-4-Benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (2.0 g, 6.06 mmol) was added to a flask in DCM (75 ml) followed by TiCl4 (1.38 g, 7.28 mmol) and DIEA (0.823 g, 6.37 mmol). The reaction was allowed to stir for about 15 to about 20 minutes at −78° C. at which point tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (1.57 g, 7.28 mmol) was added. The reaction allowed to stir for 5 minutes, and the −78° C. bath was replaced with a 0° C. bath. The reaction was then allowed to stir for 3 hours at room temperature. After the reaction was determined to be complete by HPLC, the reaction was cooled to 0° C. and quenched by the slow addition of aqueous NaHCO3 while stirring for 10 minutes. The organic layer was separated, and the aqueous layer was re-extracted (3×EtOAc). The combined organics were dried with MgSO4, filtered and concentrated. The crude residue was purified by column chromatography, eluting 6:1 to 2:1 hexane/EtOAc to give tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate (2.70 g, 87%) as light brown oil. (LCMS (APCI+) [M−Boc+H]+ 412.9; Rt: 4.42 min)
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]([C:11]1[CH:15]=[C:14]([S:16][CH3:17])[NH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:13]1[C:14]([S:16][CH3:17])=[CH:15][C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:12]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CSc1cc(C(C)(C)C)n[nH]1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CSc1cc(C(C)(C)C)nn1C(=O)N(C)C
Yield: 62 %

Procedure:
Dimethylcarbamoyl chloride (10.7 g, 9.1 ml) was added to a solution of 3-t-butyl-5-(methylthio)pyrazole (17.0 g) and pyridine (8 ml) in benzene (100 ml). The reaction mixture was refluxed (at 80°) for 24 hours, allowed to cool, and washed with water (50 ml), 2 N HCl, (25 ml) and water again (50 ml). The organic layer was dried, and evaporated to give an oil which soon crystallised. Recrystallisation from petrol afforded 1-(dimethylcarbamoyl)-3-t-butyl-5-(methylthio)pyrazole, 15.1 g, 62% yield, of melting point 58°-60°.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:15]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (12 g, 0.3 mol 60% in mineral oil) in 600 ml toluene and 400 ml dimethyl formamide was added 2,6-dihydroxynaphthalene (80 g, 0.5 mol) and the mixture was heated to reflux over a thirty minute period. Benzyl chloride (65 ml, 71.5 g, 0.56 mol) was added dropwise and the mixture was refluxed for 10 hours. After cooling to room temperature, the mixture was washed 6 times with water to remove the dimethyl formamide. The resulting toluene solution was washed twice with 150 ml 0.5N sodium hydroxide to remove unreacted starting material and then with water and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated to 150 ml. The solid which had crystallized was collected by vacuum filtration and washed with a small amount of toluene to yield 2-benzyloxy-6-hydroxynaphthalene.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.OS(O)(=O)=O>CO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH2:18][C:2]([CH2:6][CH3:7])([OH:1])[C:3]([OH:5])=[O:4])[CH:14]=[CH:15][CH:16]=1
Reactant: CCC(=O)C(=O)O
Reactant: CC(=O)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(O)(CC(=O)c1cccc(Cl)c1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A RBF was charged with 2-oxobutanoic acid (2.50 g, 24.5 mmol) and 3.2 mL of water and the mixture was cooled to 0° C. The acid was neutralized by slow addition of 20% aqueous KOH. 3′-chloroacetophenone (3.79 g, 24.5 mmol) was added, followed by a 1.3 M solution of KOH (2.20 g, 39.2 mmol) in MeOH. The reaction mixture was stirred at 0° C. for 48 h. The mixture was brought to pH 2 by dropwise addition of conc. H2SO4. The MeOH was removed in vacuo, and 25 mL of water was added. The heterogeneous mixture was filtered through Celite, and the filter cake was washed with water and CH2Cl2. The layers of the filtrate were separated, and the aqueous portion was extracted with additional CH2Cl2. The combined organics were dried with MgSO4, filtered and concentrated to a volume of ˜25 mL. Hexane was added until the mixture became cloudy, and upon standing a white crystalline solid formed. The mother liquor was decanted and the solids were washed with hexane and dried to provide 4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid as a white crystalline solid. MS m/z=279 [M+Na]+. Calc'd for C12H13ClO4: 256.69.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].[BH4-].[Na+]>C(O)(C)C.O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:26])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:25])[CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCC(C)(C)CCCC(=O)CCCCCC(C)(C)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)CCC(C)(C)CCCC(O)CCCCCC(C)(C)C(=O)OCC
Temperature: 45 °C
Yield: 97.7 %

Procedure:
To a solution of 2,2,12,12-tetramethyl-8-oxopentadecanedioic acid diethyl ester (33.6 g, 84.3 mmol) in 60% aqueous isopropanol (337 mL) was added sodium borohydride (1.6 g, 41 mmol). The reaction mixture was heated to 45° C. for 2 h, diluted with water (400 mL), and extracted with MTBE (2×200 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product (33.0 g, 98%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, J=7.2 Hz, 4H), 3.55-3.45 (m, 1H), 1.60-1.18 (m, 26H), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.1, 72.0, 60.3, 42.4, 40.9, 37.7, 30.4, 25.8, 25.4, 25.1, 14.5. HPLC: 87.5% pure.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.Cl.C([N:41]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([NH2:41])=[O:26])=[CH:22][N:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.4 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxylic acid (0.17 g), 1-hydroxybenzotriazole ammonia complex (0.08 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxamide as colorless crystals (0.15 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: Cl.[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.[C:11](Cl)(=[O:18])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15].C(N(CC)CC)C>ClCCl>[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH:9][C:11](=[O:18])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[CH2:5][CH2:4]1
Reactant: NC1CCC(F)(F)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCC(F)(F)CC1)OCC(Cl)(Cl)Cl

Procedure:
4,4-difluorocyclohexylamine hydrochloride (8) is acylated with 2,2,2-trichloroethyl carbonochloridate (9) using an organic base such as triethylamine in an inert solvent such as dichloromethane to give 2,2,2-trichloroethyl 4,4-difluorocyclohexylcarbamate, (7), Step 1.
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][C:7]1[C:8]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCI>CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2([C:8]3[C:7](=[CH:16][C:11]4[O:12][CH2:13][CH2:14][O:15][C:10]=4[CH:9]=3)[O:6][CH2:2]2)[C:18]1=[O:26]
Reactant: O=C1Nc2ccccc2C1c1cc2c(cc1O)OCCO2
Reactant: C1CCOC1
Agent: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A 2000 L stainless steel crystallizer was charged with N,N-dimethylformamide (113.7 kg) and tetrahydrofuran (1070.9 kg). The contents were cooled to 0-5° C. and 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (12.0 kg, 42.4 mol) was added, followed by cesium carbonate (30.4 kg, 93.3 mol). A solution of chloroiodomethane (9.4 kg, 53.7 mol) in N,N-dimethylformamide (16.9 kg) was added at a rate of 39.5 kg/h such that the temperature of the reaction mixture was maintained between 0 and 5° C. The reaction mixture was stirred at 0-5° C. for 2 h and heated at 20-25° C. for 18.5 h. The mixture was filtered and the filter cake was suspended in tetrahydrofuran (26.4 kg) and filtered again. The combined filtrates were combined and concentrated to a volume of 110 L under reduced pressure at a temperature <60° C. The mixture was cooled to 20-25° C. and purified water (1200.8 kg) was added at a rate of 343.1 kg/h. The mixture was cooled to 0-5° C. and filtered. The filter cake was suspended in water (310.5 kg), filtered and dried at a temperature <60° C. until the water content was 10.6% by weight by Karl-Fisher titration. A 200 L reactor was charged with tetrahydrofuran (98.0 kg). The partially-dried filter cake (˜11.0 kg) was added to the 200 L reactor by means of a solid addition funnel. The mixture was heated at reflux for 4.5 h, cooled to 10-15° C. and stirred for 3.5 h at 10-15° C. The mixture was filtered and the filter cake was washed with cold (0-5° C.) tetrahydrofuran (2×10.7 kg) and dried in a tray dryer at a temperature <55° C. to afford 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (6.88 kg, 63%) as a pale yellow solid: purity (HPLC-UV at 210 nm) 98.3%; mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.58 (br s, 1H), 7.26-7.19 (m, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.99-6.90 (m, 2H), 6.47 (s, 1H), 6.16 (s, 1H), 4.74, 4.60 (ABq, JAB=9.2 Hz, 2H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ178.4, 154.7, 144.0, 141.8, 137.8, 132.6, 128.7, 123.8, 122.3, 121.5, 111.1, 109.8, 98.7, 79.5, 64.2, 63.6, 57.7; MS (ES+) m/z 295.9 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:15]([O:24][CH3:25])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:11]([O:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH3:25])=[O:23])[CH:9]=[CH:8][CH:7]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)Oc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1SCCc1cccc(OC(C)(C)C)c1
Yield: 98.2 %

Procedure:
1-(2-Bromoethyl)-3-tert-butoxybenzene (320 mg, 1.244 mmol) was dissolved in acetonitrile (15 ml). Methyl thiosalicylate (209 mg, 1.244 mmol) was added and then potassium carbonate, anhydrous (258 mg, 1.866 mmol) was added. The mixture was heated to reflux for 3 hours and then evaporated under vacuum to dryness. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using ethyl acetate/heptane (5:95) as eluant gave 421 mg desired product, yield 98%.