Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([CH3:26])[CH:16]=[CH:15][C:14]([C:17]([NH:19][C@H:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:11]1([CH3:26])[CH:12]=[CH:13][C:14]([C:17]([NH:19][C@H:20]([CH:24]=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)N[C@H](CO)C(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)N[C@H](C=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.6 %

Procedure:
Dimethylsulfoxide (2.2 ml, 31 mmol) was slowly added via syringe to a stirred −78° C. solution of oxalyl chloride (15 ml, 171 mmol) in methylene chloride (35 ml) under inert atmosphere. After 10 min., a solution of N-p-toluoyl valinol (6.0 g, 29 mmol) in methylene chloride (50 ml) was added and the stirring was continued for additional 15 min. Triethylamine was added (6 ml, 389 mmol) and the reaction was allowed to warm to ambient temperature. After 1.5 h, the reaction was diluted with 50% ethyl acetate in hexanes and washed with water and brine. Filtration through a pad of silica gel and subsequent solvent removal left a solid residue. Chromatography eluting with 20% ethyl acetate in hexanes, then 33% ethyl acetate in hexanes gave N-p-toluoyl valinaldehyde (3.6 g) as a solid, which was utilized in Step 6.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[ClH:5]>O1CCOCC1>[ClH:5].[NH2:3][C:2]([NH2:4])=[NH2+:1].[NH2:3][C:2]([NH2:4])=[NH2+:1].[NH2:3][C:2]([NH2:4])=[NH2+:1].[NH2:3][C:2]([NH2:4])=[NH2+:1].[NH2:3][C:2]([NH2:4])=[NH2+:1].[NH2:3][C:2]([NH2:4])=[NH2+:1].[NH2:3][C:2]([NH2:4])=[NH2+:1].[NH2:3][C:2]([NH2:4])=[NH2+:1].[NH2:3][C:2]([NH2:4])=[NH2+:1]
Reactant: N=C(N)N
Agent: Cl
Solvent: C1COCCO1
Product: NC(N)=[NH2+]

Procedure:
The compound 46 was prepared using General Procedure F, using the Boc-protected dendrimer guanidine 45 (0.31 g, 78.6 mmol) in 2N HCl in dioxane (10 mL). The nona-guanidinium HCl salt (46) was obtained in 91% (0.18 g) yield as a colorless hygroscopic solid. 1H NMR (CD3OD): δ 8.62 (s, 1H, ArH), 8.54 (s, 2H, ArH), 3.65 (m, 42H, CH2O and CH2NHCO), 3.33 (m, 36H, CH2NHCO and CH2NH), 2.60 (m, 6H, CH2CO), 2.44 (m, 26H, CH2CO); 13C NMR (CD3OD): δ 174.62, 173.65, 168.00, 158.55, 136.12, 131.74, 130.20, 70.00, 68.45, 61.56, 41.94, 39.57, 38.11, 37.39, 34.79: ESI-MS m/z 2138 [M+H]+, 2172 [M−Cl]+.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([OH:22])[C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:11][C@@H:10]([O:23][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4]>C(#N)C>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([OH:22])[C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:11][C@@H:10]([OH:23])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1csc2cncn12
Agent: Cl
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(O)c1csc2cncn12
Temperature: 15 °C
Reaction time: 0.08 h
Yield: 117.8 %

Procedure:
Concentrated hydrochloric acid (2.0 ml) is added dropwise to a solution of 525 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (stereoisomer A) in 50 ml of dry acetonitrile under ice cooling (internal temperature 7° C.). The mixture is stirred in this state for 5 min, and the temperature is then raised to 15° C. over a period of 20 min. The reaction solution is concentrated to about 20 ml under reduced pressure, and the concentrate is adjusted to pH 8.5 by addition of 40 ml of a 5% aqueous sodium hydrogencarbonate solution. The mixture is then extracted three times with 100 ml of ethyl acetate. The combined organic layers are dried over magnesium sulfate, and the solvent is removed by evaporation under reduced pressure to give 457 mg of crude (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (stereoisomer A) as a milky white amorphous material.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:9])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OCC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(C(=O)NC2(C(=O)O)CC2)cc1
Yield: 73.3 %

Procedure:
Dissolve ethyl 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylate (4.25 g, 15.33 mmol) in 1,4-dioxane (60 mL) and add lithium hydroxide (LiOH) (3.22 g, 76.63 mmol) dissolved in water (30 mL). Stir the reaction for approximately 16 hours at ambient temperature. Concentrate the mixture under reduced pressure, add water, acidify with 5N HCl, and collect the precipitate by filtration to give the title compound (2.8 g, 73%) as a white solid: MS (m/z): 248 (M+1).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>C1(C)C=CC=CC=1>[N+:22]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:6](=[O:8])[C:5]([O:12][CH2:13][CH3:14])=[O:11])([O-:24])=[O:23]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccncc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of freshly prepared sodium ethoxide was added diethyl oxalate (1.5 eq.) followed by 4-methyl-3-nitro pyridine (1 eq.) in toluene and reaction mixture was stirred overnight. It was then concentrated under reduced pressure and acidified with acetic acid to obtained red solid, which on further purification, by column chromatography provided the ethyl 3-(3-nitropyridin-4-yl)-2-oxopropanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>COC(C)(C)C>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: O
Product: OC1(c2cccnc2)CCN(Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
(α) A solution of 16.7 g (106 mmol) of 3-bromo-pyridine in 200 ml of tert-butyl methyl ether was cooled to -75° C. Thereto there was added dropwise within 45 minutes a solution of 66 ml (106 mmol) of n-butyllithium (1.6M in hexane) and the mixture was stirred at -75° C. for one hour. Subsequently, a solution of 10.0 g (52.8 mmol) of 1-benzyl-4-piperidone in 50 ml of tert-butyl methyl ether was added dropwise at -70° C. to -75° C. and thereafter the mixture was stirred for 2 hours. Subsequently, the mixture was left to warm to room temperature. Thereafter, it was hydrolyzed with 50 ml of water and extracted with 100 ml of ethyl acetate. The organic phase was dried over magnesium sulphate and finally the solvent was evaporated under reduced pressure, with the product beginning to separate. From the evaporated mother liquor there were isolated by crystallization from a mixture of ethyl acetate and hexane a further 1.9 g, so that a total of 8.4 g (60% of theory) of 1'-benzyl-2',3',5',6'-tetrahydro-1'H-[3,4']bipyridinyl-4'-ol were obtained as a colourless solid; MS: 268 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>>[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][NH:15][C:16]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][N:2]=1)=[S:17]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1ccsn1
Product: CN(C)CCNC(=S)NCCNCc1ccsn1

Procedure:
By the procedure of Example 40(a)(ii), N-(3-isothiazolylmethyl)ethylenediamine is reacted with 2-dimethylaminoethyl isothiocyanate to give N-(2-dimethylaminoethyl)-N' -[2-(3-isothiazolylmethylamino)ethyl]thiourea. Reacting with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>CCN(CC)CC>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C[C@H](O)COCc1ccccc1
Yield: 89.2 %

Procedure:
In a 100 ml autoclave were charged 20.0 g (84.7 mmol) of ethyl 4-benzyloxy-3-oxobutyrate, 16 ml of ethanol, and 31 mg (0.034 mmol) of Ru2Cl4((R)-Tol-BINAP)2.NEt3, and asymmetric hydrogenation was performed at 100° C. under a hydrogen pressure of 10 torr for 3 hours (conversion: 100%). The solvent was evaporated under reduced pressure to give 18.0 g of the title compound as liquid.
Reaction SMILES: I[C:2]1[C:10]([N+]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[OH:23][CH2:24][CH2:25][CH:26]=[CH:27]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[OH:23][CH2:24][CH2:25][CH:26]=[CH:27][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:15][C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5](=[O:14])[NH:6]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: OCCC=CB(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc[nH]c1C=C1C(=O)Nc2cccc(C=CCCO)c21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 2) in dimethoxyethane (5 mL) was added 4-hydroxy-1-butenyl-boronic acid (48 mg, 0.418 mmol) (from Example 68 above), tetrakis(triphenylphosphine)palladium(O) (39 mg, 0.034 mmol) (Aldrich) and 2M Na2CO3 solution in H2O (0.34 mL). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 1,3-dihydro-4-(4-hydroxy-but-1-enyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one as a yellow solid. (Yield 21 mg, 50%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:30][CH2:31][CH2:32][CH2:33][S:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)s1
Yield: 64.5 %

Procedure:
To a solution of 1.27 g (8.91 mmol) of 5-methyl-2-thiophenecarboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.68 g of the desired compound (yield: 64.5%, colorless powder). mp: 86.0°-87.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:15]([C:14]2[CH:20]=[CH:21][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CCOC(=O)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2cc(Cl)ccn2)cc1
Temperature: 45 °C

Procedure:
To a cold (0° C.) solution of 4-chloro-2-picoline (10 g, 78.4 mmol) and ethyl 4-methoxybenzoate (14.1 g, 78.4 mmol) in tetrahydrofuran (100 mL) was added lithium bis(trimethylsilyl)amide (157 mL, 1.0 M in tetrahydrofuran, 157 mmol) dropwise via a pressure equalizing funnel over half an hour. Upon complete addition, the ice bath was removed and the resulting solution was heated at 45° C. for 15 hours. The mixture was cooled to room temperature, and the solution was concentrated. Methanol was added to quench the reaction, resulting in the formation of a yellow precipitate. The precipitate was collected by filtration and dried to give the product as a mixture of enol and ketone tautomers. MS m/z 262 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](I)[CH3:8].[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH3:20])[C:12]=1[OH:21]>C(#N)C>[CH3:20][C:13]1[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]([CH3:10])[C:12]=1[O:21][CH2:7][CH3:8]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOc1c(C)cc([N+](=O)[O-])cc1C

Procedure:
300 mmol (326 g) of caesium carbonate and 374 mmol (58.5 g) of ethyl iodide are added in succession to a solution of 149.5 mmol (25 g) of 2,6-dimethyl-4-nitrophenol in 1300 ml of acetonitrile. The whole is heated at reflux under an inert atmosphere for 15 hours. The reaction mixture is subsequently cooled and then filtered, and the filtrate is evaporated. The residue is dissolved in ethyl acetate and washed with water and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C[N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.N1CCOCC1>C1COCC1>[OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][C:7]([CH3:10])([CH3:11])[O:8]2)[O:4][C@H:3]1[C:12]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:14]
Reactant: CN1CCOCC1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
Step-IV: To a stirred solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxole-5-carboxylic acid (20 g, 98 mmol) in THF (400 ml) was added TBTU (47.2 g, 147 mmol), N-methylmorpholine (NMM, 16.16 ml, 147 mmol) at room temperature and stirred for 30 min. To it was added morpholine (12.99 ml, 147 mmol) and stirred for 6 h. The solid was filtered off by filtration and it was washed with THF. The filtrate was concentrated and resulting residue was purified by silica gel column chromatography to give 17.8 g of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-morpholin-4-yl-methanone as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.33 (s, 3H), 1.49 (s, 3H), 3.42-3.53 (m, 2H), 3.62-3.83 (m, 6H), 4.47 (d, J=2.0 Hz, 1H), 4.57 (d, J=3.6 Hz, 1H), 4.59 (d, J=2.0 Hz, 1H), 6.00 (d, J=3.2 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (10 g, 62.9 mmol) and 2,2,2-trifluoroethanol (6.29 g, 62.9 mmol) in THF (100 mL) at 25° C. was treated with Cs2CO3 (20.5 g, 62.9 mmol) and stirred for 8 hours before being diluted with the addition of water and extracted with EtOAc. The organic extract was dried (Na2SO4), concentrated, and subjected to flash chromatography (3% EtOAc-petroleum ether) to give 4-fluoro-1-nitro-2-[(2,2,2-trifluoroethyl)oxy]benzene (10 g, 67%) as a yellow solid. MS (m/z) 240.0 (M+H+).
Reaction SMILES: [CH2:1]([P:17](=[O:20])([OH:19])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+:22]>CCCCCC>[Na+:22].[Na+:22].[CH2:1]([P:17](=[O:18])([O-:20])[O-:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCP(=O)([O-])[O-]
Yield: 97 %

Procedure:
306 g (1 mol) of hexadecylphosphonic acid (produced as in example 13) are suspended in 1.5 l of hexane and 200 ml of a 10 molar solution of sodium hydroxide are added; the suspension is refluxed for 2 hours and water removed by azeotropic distillation. The reaction solution is filtered and the residue is washed with water and hexane and dried under reduced pressure to obtain 340 g (97% of theory) of hexadecylphosphonic acid disodium salt as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(I)n[nH]c2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a solution of 6-fluoro-3-iodo-1H-indazole (8.6 g, 32.8 mmol) in THF (200 mL) at 0° C. was slowly added portionwise sodium hydride (60% in mineral oil, 1.58 g, 39.4 mmol). The reaction mixture was stirred at room temperature for 10 min then cooled to −10° C. and isopropylmagnesium chloride (2.0 M in THF, 19.7 mL, 39.4 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min then additional isopropylmagnesium chloride (2.0 M in THF, 8.2 mL, 16.4 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min then tributylchlorostannane (11.6 mL, 42.7 mmol) was slowly added. Stirring was continued at −10° C. for 20 min then at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl then diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane (0.5% Et3N) to afford 6.53 g (47%) of 6-fluoro-3-tributylstannanyl-1H-indazole as a light brown viscous oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.65 (dd, J=8.7, 5.3 Hz, 1H), 7.20 (dd, J=9.3, 2.1 Hz, 1H), 6.92 (td, J=9.0, 2.1 Hz, 1H), 1.53-1.67 (m, 6H), 1.28-1.43 (m, 6H), 1.20-1.28 (m, 6H), 0.89 (t, J=7.4 Hz, 9H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.C(OC)(OC)OC.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[OH-].[Na+]>CO>[CH3:38][C:34]1[S:33][CH:37]=[C:36]([N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[NH:12][N:11]=[C:10]([C:13]4[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[C:9]=3[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:6][CH2:7]2)[N:35]=1
Reactant: O=Cc1nccs1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COC(OC)OC
Product: Cc1nc(N2CCC(c3[nH]nc(-c4ccc(Cl)cc4)c3-c3ccncc3)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) in 12 mL of MeOH was added trimethyl orthoformate (2.6 g, 24.4 mmol) and 2-thiazolecarboxaldehyde (1.4 g, 12.2 mmol). The suspension was stirred at room temperature for 2 h. To this mixture was added NaCNBH (1.5 g, 24.4 mmol) and the resulting suspension was stirred at room temperature for 7 days. The mixture was poured onto 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine (1×100 mL), dried over Na2SO4, filtered and concentrated to leave a solid. This solid was triturated with ether and filtered to afford the title compound: MS (M+H): 436 (base peak).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:31]=3)[CH2:14][CH:13]=[CH:12][N:11]2[CH3:16])[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: Cn1c(I)ccc1CC[C@]1(C)COC(=O)N1
Reactant: CC1(C)OB(c2cccc(OCCC3CCCCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1C=CCC1(CC[C@]1(C)COC(=O)N1)c1cccc(OCCC2CCCCC2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.8 %

Procedure:
(4R)-4-Methyl-4-[2-(5-iodo-1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (0.3101 g, 0.92 mmol) obtained in Example (40a), 2-[3-(2-cyclohexylethyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4646 g, 1.41 mmol), dichlorobis(triphenylphosphine)palladium(II) (63.1 mg, 0.09 mmol) and cesium carbonate (0.6006 g, 1.81 mmol) were suspended in a mixed solvent of dimethoxyethane (8 ml) and water (2 ml) and stirred at 80° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:2) as the eluent to afford the crude product. Furthermore, the crude product thus obtained was purified using a preparative reversed phase HPLC column [Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (41.1 mg, yield: 11%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.B(F)(F)[F:11].[F:14][B-:15]([F:18])([F:17])[F:16].[H+].FF>C(#N)C>[F:14][B-:15]([F:18])([F:17])[F:16].[F:14][B-:15]([F:18])([F:17])[F:16].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: [O-][N+]12CCN(CC1)CC2
Reactant: FB(F)F
Agent: FF
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 130.5 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (12.8 g, 0.1 mole), boron trifluoride gas (6.8 g, 0.1 mole), and tetrafluoroboric acid (50% solution, 12 g, 0.1 mole) in acetonitrile (200 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 0.15 mole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 21 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (65% yield).