Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:21]4[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=4)=[O:26])=[CH:7][CH:6]=3)=[CH:9][O:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1ccc(-c2coc3ncnc(N)c23)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccc(-c3coc4ncnc(N)c34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A 0° C. suspension of Example 13E (50 mg, 0.22 mmol) in dichloromethane (3 mL) was treated with p-tolylisocyanate (0.031 mL, 0.24 mmol), warmed to room temperature, and stirred overnight. The resulting precipitate was collected by vacuum filtration, washed with dichloromethane, and dried to provide 55 mg (70%) of the desired product. MS (ESI(+)) m/e 360 (M+H)+; 1H NMR (DMSO-d6) δ 8.80 (s, 1H), 8.60 (s, 1H), 8.25 (s, 1H), 7.92 (s, 1H), 7.6 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 6.52 (br s, 2H), 2.25 (s, 3H); Anal. Calcd. for C20H17N5O2: C, 66.84; H, 4.77; N, 19.49. Found: C, 66.58; H, 4.65; N, 19.42.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Clc1nc2ccccc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1nc2ccccc2s1
Temperature: 100 °C
Reaction time: 22 h
Yield: 82.4 %

Procedure:
Commercially available 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (417 mg, 1.98 mmol) was dissolved in 1,2-dimethoxyethane (20 mL), and 2-chloro-1,3-benzothiazole (0.25 mL, 2.02 mmol), palladium (II) acetate (23.0 mg, 0.102 mmol), triphenylphosphine (105 mg, 0.400 mmol) and an aqueous potassium carbonate solution (3M, 1.3 mL, 0.433 mmol) were added, followed by stirring at 100° C. for 22 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-20%) to afford the desired compound (490 mg, yield 82%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[C:3]#N.[H-].C([Al+]CC(C)C)C(C)C.[OH2:22].Cl>CCCCCC>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:22]
Reactant: CC(C)(C#N)c1ccccc1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To a solution of 2-methyl-2-phenylpropanenitrile (290 g, 2.00 mol) in hexane (2000 mL) at 0° C. under N2 is added diisobutylaluminum hydride (DIBAL-H) (2600 mL, 1M in hexane) over a period of 80 minutes. The reaction mixture is stirred at 6–14° C. for 15 minutes, then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture is cooled to 0° C. and H2O (50 mL) is added slowly during 1 hour. Aqueous HCl (900 mL, 15%) is then added slowly to maintain a gentle reflux. The reaction mixture is stirred for 17 hours and the organic phase is separated. The aqueous layer is extracted with ethyl acetate (400 mL) and the combined organic layers are washed with water (300 mL), brine (300 mL) and dried over Na2SO4. The organic extracts are filtered and concentrated to give 2-methyl-2-phenylpropanal as an oil (275 g, 92.8% yield, 98.2% by HPLC area).
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(#N)C.[CH2:15]([O:17][C:18]([C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:35]Br)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:15]([O:17][C:18]([C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:35][N:7]1[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]1)=[O:19])[CH3:16]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Temperature: 40 °C
Yield: 80 %

Procedure:
To a solution of 107.7 g of 4-trifluoromethyl piperidine hydrochloride in 450 mL of water were added 2.7 L of acetonitrile, 224 g of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and 157 g of potassium carbonate. The resulting mixture was heated to 40° C. for 2 h, allowed to cool to room temperature then concentrated under reduced pressure. The residue was taken into 2 L of dichloromethane then washed twice with 500 mL of water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/ethanol from 100/0 to 90/10) followed by washing of the collected solid with diisopropyl ether to give 212 g of 2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazole-5-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[N-:12]=[N+:13]=[N-:14].[Na+]>C(#N)C>[N:12]([CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7])=[N+:13]=[N-:14]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: CO[Si](CCCN=[N+]=[N-])(OC)OC

Procedure:
1.0 mole of 3-chloropropyltrimethoxysilane and 1.1 moles of sodium azide were heated in the presence of 3 mole percent of the catalyst described in Example 1 (a) in 500 ml of acetonitrile for eight hours with stirring and under reflux. After separation of the salt the subsequent distillation under reduced pressure gave the 3-azidopropyltrimethoxysilane now in a yield of 95 weight percent.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.CCOCC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][C:17]=1[O:22][CH3:23].[ClH:24]
Reactant: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1cc(C2(O)CCNCC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-Chloro-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (502 mg) in MeOH (5 mL) was added a solution of HCl in ether (2 M, 9.5 mL). The resultant mixture was stirred at room temperature for 1 h followed by the addition of ether (50 mL). The reaction mixture was stirred at 0° C. for an additional 30 min, then filtered and concentrated to provide 4-(4-Chloro-3-methoxy-phenyl)-piperidin-4-ol (69) in the form of HCl salt as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:28])=[C:8]([C@H:14]2[CH2:16][C@H:15]2[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[C:9]=1[O:10]COC)(=[O:3])[CH3:2].Cl.O>O1CCOCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:28])=[C:8]([C@H:14]2[CH2:16][C@H:15]2[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: COCOc1c(C(C)=O)ccc(F)c1[C@H]1C[C@H]1NC(=O)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(F)c([C@H]2C[C@H]2NC(=O)Nc2ccc(Cl)cn2)c1O
Reaction time: 0.25 h

Procedure:
(+,-)-N-(cis-2-(5-Acetyl-2-fluoro-6-methoxymethoxy)-cyclopropyl)-N'-(5-chloropyrid-2-yl)-urea (Example 56) was dissolved in dioxane and concentrated hydrochloric acid was added. The solution was stirred for 15 minutes, was diluted water and evaporated. The residue was co-evaporated with water to yield the title product as a solid. 1H-NMR DMSO-d6 δ 1.2 (m, 1H) 1.3-1.5 (m, 1H) 2.0 (q, 1H) 2.6 (s, 3H) 3.4 (m, 1H) 6.8 (t, 1H) 7.4 (d, 1H) 7.7 (m, 1H) 7.8-8.0 (m, 2H) 9.2 (s, 1H) 11.1 (bs, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:40])[NH:41][CH2:42][CH2:43][C:44]([N:29]1[CH2:28][CH2:27][CH:26]([C:24](=[O:25])[NH:23][C:10]2[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH:13]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)[CH2:31][CH2:30]1)=[O:45])([CH3:37])([CH3:35])[CH3:36]
Reactant: N#Cc1ccc(Oc2cc(NC(=O)C3CCNCC3)cc(Oc3ccc(C#N)cc3)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 68.3 %

Procedure:
Following the procedure of Example 9(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine 1.0 g (2.28 mmol) and 3-tert-butoxycarbonylamino-propionic acid (0.431 g, 2.28 mmol) were used to afford 0.95 g of the required product. 114 NMR (DMSO-d6): δ 1.4 (9H, s), 1.42 (4H, m), 2.31 (3H, m), 1.8 (2H, t), 2.81 (2H, m), 3.15 (1H, m), 3.7 (1H, m), 6.76 (1H, s), 7.26 (6H, m), 7.86 (4H, d), 10.01 (1H, s).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[N+]([C:20]1[O:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=1)([O-])=O>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([S:1][C:20]3[O:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=3)[NH:6][C:5]=2[CH:7]=1
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ccc(C(F)(F)F)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Aldehyde intermediate preparation: 2-mercapto-6-trifluoromethyl-1H-benzimidazole (0.65 g, 2.98 mmol) dissolved in 5 ml of anhydrous tetrahydrofuran is added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.095 g, 3.16 mmol) in anhydrous tetrahydrofuran (2 ml) over a 20 minutes period. The reaction mixture is stirred for 2 hours at room temperature. Then 5-nitro-2-furaldehyde (0.42 g, 2.98 mmol) dissolved in 5 ml of anhydrous tetrahydrofuran is added dropwise over a 15 minutes period and the reaction mixture is stirred at room temperature for an additional 16 hours period. Sodium hydride (67 mg, 2.23 mmol) is then added and the reaction mixture is stirred for an additional 2 hours period at room temperature. The reaction mixture is then concentrated under reduced pressure, dissolved in ethyl acetate (50 ml) and washed with water (2×10 ml). The organic phase is dried over MgSO4, concentrated under reduced pressure and the residue is triturated in diisopropylether, collected by filtration and dried under vacuum to yield 720 mg of 5-(6-trifluoromethyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde as a beige powder. Yield=77%, Analytical LC/MS (method B): retention time=3.73 min., m/z=313.01 (positive ion mode).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[N:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:11]=1Br.O>C1COCC1>[Br:6][C:7]1[N:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]([CH2:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:20][CH2:21]2)=[O:15])[CH:11]=1
Reactant: O=C(Cn1c(-c2ccccc2)nc(Br)c1Br)N1CCN(c2ncccn2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1cc(Br)nc1-c1ccccc1)N1CCN(c2ncccn2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
9.4 mL 2.5 mol/L butyllithium solution in THF was added dropwise to 11.8 g 2-(4,5-dibromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone in 150 mL THF at −78° C. under argon. The reaction mixture was stirred 2 h at −78° C. followed by careful and dropwise addition of water to the mixture. The resulting mixture was stirred 30 min at −78° C. and then again water was added at 0° C. The mixture was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified chromatoraphie on silica (petrolether 1/ethylacetate 1). Diisopropylether was added to the residue and the precipitate was filtered and dried to give 1.7 g desired product. Rt: 0.94 (method B), ESI+: 427
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CCOC1=NS(=O)(=O)c2cc(N)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC1=NS(=O)(=O)c2cc(NC(C)=O)ccc21

Procedure:
A solution of 6-amino-3-ethoxy-benzoisothiazole-1,1-dioxide (0.23 g) and acetic anhydride (0.1 ml) in pyridine (1 ml) was stirred at room temperature for 15 hrs. Concentration and trituration under ether/petrol (1:1) gave the title compound (0.24 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH:20]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cl)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 10.1 %

Procedure:
N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.595 mmol), 5-chloro-2-methoxyphenylboronic acid (132 mg, 0.714 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg, 0.03 mmol) and cesium carbonate (232 mg, 0.714 mmol) were mixed in acetonitrile and water (10:1, 20 mL). The reaction mixture was stirred at 120° C. under nitrogen for 6 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate, concentrated and purified by prep-HPLC to give the desired product (21.3 mg, 10.2%). LCMS (ESI): RT (min)=1.216, M+H+=352.9, Method=I; 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.14 (s, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 7.84-7.42 (m, 4H), 7.18 (d, J=8.4 Hz, 1H), 3.78 (s, 3H), 2.09-2.05 (m, 1H), 0.88-0.83 (m, 4H).
Reaction SMILES: C([C:3]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7](O)=O)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:14][C:12]1[CH:13]=[CH:3][C:4]2[O:5][CH:6]=[CH:7][C:10]=2[CH:11]=1
Reactant: O=Cc1cc(Br)ccc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Brc1ccc2occc2c1
Yield: 39.7 %

Procedure:
To a mixture of 2-formyl-4-bromophenoxy acetic acid (50 g, 0.192 mol), sodium acetate (100 g, 1.21 mol) in acetic acid (250 mL) at 100° C. was added acetic anhydride (100 mL) portions during a period of 3 h. The reaction mixture was then refluxed for 20 h. The solvent was removed by distillation and residue diluted with 3N HCl (500 mL) and refluxed for 2 h. The reaction mixture was then concentrated under vacuum and product extracted with pet. ether (3×200 mL). The organic layer was washed with 10% NaHCO3 solution and evaporated to give 5-bromo-1-benzofuran (15 g, 40%) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.S(=O)(=O)(O)O.C(Cl)(Cl)Cl>O>[Cl:1][C:2]1[C:17]2[C:10](=[O:12])[C:9]3[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2oc2c([N+](=O)[O-])ccc(Cl)c12
Reaction time: 4.5 h

Procedure:
The 1-chloro-4-nitro-9H-xanthen-9-one was prepared as follows: Crude 2-(5'-chloro-2-nitrophenoxy)-benzoic acid (50 g) was added to 200 g of concentrated sulfuric acid. The mixture was held at 75° C. for 4.5 hours, and added to a stirred mixture of 1.5 1 of chloroform and water containing ice as needed to maintain the temperature below 35° C. The chloroform layer was separated, washed with 5% sodium bicarbonate, evaporated to dryness and the residue was crystallized from 200 ml of toluene and 30 ml of cyclohexane to provide the product mp 175°-186° C.
Reaction SMILES: [Na][Na].[C:3]([C:5]([SH:10])=[C:6]([C:8]#[N:9])[SH:7])#[N:4].Br[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13]Br>>[C:8]([C:6]1[S:7][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:10][C:5]=1[C:3]#[N:4])#[N:9]
Reactant: N#CC(S)=C(S)C#N
Reactant: BrCC(Br)c1ccccc1
Agent: [Na][Na]
Product: N#CC1=C(C#N)SC(c2ccccc2)CS1
Temperature: 40 °C

Procedure:
To a stirred suspension of 18.6 g of the disodium salt of 1,2-dicyano-1,2-dimercaptoethylene under nitrogen is added 26.4 g of 1,2-dibromo-1-phenylethane. After stirring at 40° C. for one-half hour, the mixture is heated under reflux for 1.5 hours, cooled, filtered, and the solvent removed under reduced pressure. The residue is crystallized by filtration with carbon tetrachloride to give the product, 2,3-dicyano-5,6-dihydro-5-phenyl-p-dithiin, as golden brown crystals, melting point 121.5° C. to 124° C. A purified sample had melting point 125° C. to 126.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:21])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N+:6]([O-:21])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc[n+]([O-])c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 25 mL of a chloroform solution containing 1.72 g of 4-methoxyquinoline, 3.16 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with 20 mL of an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a light brown oily substance, 4-methoxyquinoline N-oxide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-])=O)=[CH:5][C:4]([C:10]2[N:14]=[CH:13][O:12][N:11]=2)=[N:3]1.[Cl-].[NH4+].C1COCC1.[OH-].[Na+]>[Zn].CO>[CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:10]2[N:14]=[CH:13][O:12][N:11]=2)=[N:3]1
Reactant: Cn1nc(-c2ncon2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2ncon2)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a mixture of 3-(1-methyl-5-nitro-1H-pyrazol-3-yl)-1,2,4-oxadiazole (2.0 g, 10.3 mmol) and ammonium chloride (7.68 g, 143 mmol) in a 1:1 mixture of THF (32 mL)/MeOH (32 mL) at 0° C. was added zinc dust (9.38 g, 143 mmol) portionwise. The ice bath was removed after about 10 min and the reaction was stirred at ambient temperature for about 1 h. The reaction mixture was filtered through a pad of Celite® rinsing with MeOH (30 mL) and then concentrated under reduced pressure. The crude material was partitioned between DCM (20 mL) and water (10 mL). The organic layer was separated and the aqueous layer was back extracted with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The aqueous layer was acidified using 1 N HCl to about pH 3 and DCM (50 mL) was added. The organic layer was separated dried over MgSO4, filtered and concentrated under reduced pressure to provide additional crude material. The aqueous layer was basified using 1 N NaOH to about pH 9. The precipitate was collected by vacuum filtration, combined with the batches collected from the organic layers and dried in a vacuum oven at about 50° C. for about 16 h to afford 1-methyl-3-(1,2,4-oxadiazol-3-yl)-1H-pyrazol-5-amine (1.2 g, 7.27 mmol, 71%, which was used without further purification). LC-MS (Table 1, Method g) Rt=0.71 min, m/z 166 (M+H)+. 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 9.55 (s, 1H), 5.80 (s, 1H), 5.47 (s, 2H), 3.61 (s, 3H).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19](C)[CH2:20]CCC(C)C)[CH2:10]1.S(CCCCCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(=O)C)C1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1[OH:39]>>[I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:39])[CH3:20])[CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl 6-iodohexyl ether, an equivalent amount of pregn-5-en-20-one-3β-yl 6-iodohexyl ether, there was prepared 6-(pregn-5-en-20-one-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (Step D). TLC data and Rf values are given in the above Table.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:28][CH3:29])=[C:14]([C:16]2(O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]2=[O:26])[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[OH:37][C@H:38]1[CH2:42][NH:41][C@H:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:39]1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:28][CH3:29])=[C:14]([C:16]2([N:41]3[CH2:42][C@H:38]([OH:37])[CH2:39][C@H:40]3[C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]2=[O:26])[CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 50.0 g of the compound obtained in Step 204-3 and (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (138 mmol) as starting materials, respectively 5.25 g (Isomer A: colorless amorphous) and 14.9 g (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound and a mixture of isomers A and B (11.0 g) were obtained by a similar method to Step 28-2.