Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])([CH2:14][O:15]CC2C=CC=CC=2)[O:12][C@@H:11]([N:35]2[CH:42]=[CH:41][C:39](=[O:40])[NH:38][C:36]2=[O:37])[C@@H:10]1[O:43][S:44]([C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[C:50]1([CH3:53])[CH:51]=[CH:52][C:47]([S:44]([O:43][C@@H:10]2[C@H:9]([OH:8])[C@@:13]([CH2:23][O:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:26])=[O:27])([CH2:14][OH:15])[O:12][C@H:11]2[N:35]2[CH:42]=[CH:41][C:39](=[O:40])[NH:38][C:36]2=[O:37])(=[O:46])=[O:45])=[CH:48][CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@]2(CO)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2O)cc1
Reaction time: 48 h
Yield: 51.5 %

Procedure:
To a solution of compound 75 (0.80 g, 1.0 mmol) in absolute ethanol (2 cm3) was added 20% palladium hydroxide over carbon (0.80 g) and the mixture was degassed several times with hydrogen and stirring was continued under hydrogen for 48 h. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 76A (0.30 g, 49%) as a white solid material. δH (CD3OD) 7.67 (4H, m), 7.45 (1H, d, J 8.2 Hz), 7.34 (4H, m), 5.86 (1H, d, J 8.0 Hz), 5.40 (1H, d, J 8.1 Hz), 4.95 (1H, m), 4.35 (1H, d, J 5.0 Hz), 4.17 (2H, m), 3.61 (2H, s), δc (CD3OD) 165.4, 151.6, 147.5, 146.6, 141.3, 134.0, 133.8, 131,4, 130.9, 129.2, 128.9, 103.7, 88.0, 85.4, 80.7, 72.4, 71.0, 64.3, 21.7, 21.6. FAB-MS m/z 583 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH3:24]COCC>C1COCC1>[C:1]([N:8]([C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH3:11])[CH3:24])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(2R,3R)-3-(N-Boc-N-methylamino)-2-(-tert-butyldimethylsilyloxy)-pent-4-yne was synthesized according to Method Y above by the treatment of (2R,3R)-N-Boc-3-amino-2-(-tert-butyldimethylsilyloxy)-pent-4-yne (400 mg, 1.27 mmol) (Example 117B) with NaH (36 mg, 1.52 mmol) and Mel (360 mg, 2.54 mmol) in THF (30 mL). The product was obtained after silica gel column chromatography with a 0-10% Et2O in hexanes gradient. (Yield 370 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[Br:10][C:11]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)C.C(N(CC)C(C)C)(C)C>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:17]2[CH2:16][CH2:15][CH:14]([O:13][C:12]3[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:11]=3[Br:10])[CH2:19][CH2:18]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Br)c(OC2CCN(c3ncc(Br)cn3)CC2)c1
Temperature: 120 °C

Procedure:
Into a 100-mL sealable pressure flask equipped with a magnetic stirbar was added 5-bromo-2-chloropyrimidine (2.50 g, 12.9 mmol), 4-(2-bromo-5-fluorophenoxy)piperidine hydrochloride (4.00 g, 12.9 mmol), 2-propanol (30 mL) and N,N-diisopropylethylamine (4.50 mL, 25.8 mmol). The vial was sealed and heated to 120° C. for 3 h. The reaction mixture was cooled and poured into a 500 mL separatory funnel containing water (250 mL) and the mixture was extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The resulting oil was recrystallized from diethyl ether/hexanes and cooled to −40° C. to cause precipitation, then filtered through Whatman#1 filter paper to give a beige solid, which was dried overnight on the vacuum pump. MS (ESI, Q+) m/z 432, 434, 437 (M+1 for 2×35Br and 37Br).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH2:10][O:11][C:12]([CH:14](P(OCC)(OCC)=O)[F:15])=[O:13].[CH3:24][C:25]1([CH3:44])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]2[CH:30]=[C:29]([C:37](=O)[CH3:38])[C:28]([O:40][CH2:41][CH2:42][CH3:43])=[CH:27][C:26]1=2>C1COCC1>[CH2:10]([O:11][C:12](=[O:13])/[C:14](/[F:15])=[C:37](\[C:29]1[C:28]([O:40][CH2:41][CH2:42][CH3:43])=[CH:27][C:26]2[C:25]([CH3:44])([CH3:24])[CH2:34][CH2:33][C:32]([CH3:35])([CH3:36])[C:31]=2[CH:30]=1)/[CH3:38])[CH3:9]
Reactant: CCCOc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Temperature: -78 °C

Procedure:
To a solution of LDA (12.1 mL, 2.0 M in heptane/THF/ethylbenzene) in THF (10 mL) at −78° C. was added triethyl 2-fluoro-2-phosphonoacetate (5.0 g, 20.7 mmol) in THF (10 mL). The reaction flask was removed from dry ice cooling bath for 12 min and then re-cooled to −78° C. 1-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Intermediate 5, 1.98 g, 6.89 mmol) in THF (10 mL) was added and the reaction was allowed to warm up to ambient temperature over night. The reaction was quenched with aqueous NH4Cl and extracted with Et2O (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3% EtOAc-hexane) to give a ˜10:1 mixture of the title compound and its 2-Z isomer (2.2 g). The mixture was used directly in the next reaction.
Reaction SMILES: C([S:4][C:5]1[S:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])(=O)C.N1C=CN=C1>O1CCOCC1.O>[O:12]=[C:8]1[N:7]2[CH:10]([S:11][C:5](=[S:4])[CH:6]2[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[O:14])[CH2:9]1
Reactant: CC(=O)SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2S1
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1C(=S)SC2CC(=O)N21
Yield: 48.3 %

Procedure:
To a stirred solution of 100 mg of 4-nitrobenzyl 3-acetylthio-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in a mixture of 2 ml of dioxane and 0.2 ml of water was added 19.6 mg of imidazole. After 10 minutes the reaction mixture was diluted with 5 ml of 1M aqueous acid solution and extracted with dichloromethane (2×5 ml). The organic extracts were combined and backwashed with water (2×5 ml), then brine (5 ml), and finally dried and evaporated. The residue was chromatographed on slica gel, with elution by means of ethyl acetate/hexane mixtures. Fractions containing the purified product were combined and evaporated to leave an orange oil (43 mg, 48%).
Reaction SMILES: [CH3:1][N:2]([CH:21]1[CH:28]2[CH2:29][C:24]3([C:31]([O-:33])=[O:32])[CH2:25][CH:26]([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)[C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])([CH3:6])[CH3:5].C1COCC1.CO.O[Li].O>O>[CH3:1][N:2]([CH:21]1[CH:22]2[CH2:23][C:24]3([C:31]([OH:33])=[O:32])[CH2:25][CH:26]([CH2:27][CH:28]1[CH2:29]3)[CH2:30]2)[C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:9])=[O:10])([CH3:5])[CH3:6]
Reactant: CCN(C(C)(C)C(=O)N(C)C1C2CC3CC1CC(C(=O)[O-])(C3)C2)S(=O)(=O)c1ccccc1C
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCN(C(C)(C)C(=O)N(C)C1C2CC3CC1CC(C(=O)O)(C3)C2)S(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.6 %

Procedure:
N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxylate (400 mg, 0.84 mmol) was charged, and dissolved through addition of THF (5 ml), and methanol (5 ml). LiOH.H2O dissolved in H2O (4 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2˜3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxylic acid (380 mg, 0.82 mmol, 98%).
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:40]=[CH:39][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=2)=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:38][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[CH:39]=[CH:40][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])[CH:36]=[CH:35][C:34]=1[CH3:37]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1C
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1C

Procedure:
4-{4-[5-(3,4-Dimethyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(3,4-dimethyl-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C25H26N4O3 [M+H]+: 431.2078. Found: 431.2078.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[CH:11][C@H:12]([C@@H:14]([C@@H:16]([C@H:18]([CH3:20])[OH:19])[OH:17])[OH:15])[OH:13]>N1C=CC=CC=1>[CH3:20][C@@H:18]1[O:19][CH:11]([O:10][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[C@@H:12]([O:13][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:14]([O:15][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[C@H:16]1[O:17][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Solvent: c1ccncc1
Product: C[C@@H]1OC(OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl chloride (21.4 g, 152.3 mmol; 17.7 mL) was added dropwise to a cooled solution of L-fucose (5.0 g, 30.5 mmol) in pyridine (100 mL), at 0-5° C., and the mixture was stirred for three hours at room temperature. The mixture was poured onto ice water and extracted with ethyl acetate (EtOAc). The extracts were successively washed with ice cold dilute HCl, aqueous NaHCO3, and brine, dried over anhydrous MgSO4, and concentrated. The product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:29](O)=[O:30])[N:19]([CH3:28])[C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1>>[CH2:1]([NH:8][C:29]([C:18]1[N:19]([CH3:28])[C:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=2)[N:17]=1)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)NCc3ccccc3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using benzylamine (0.022 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound. HPLC/MS: 396 (M+1); Rt=4.13 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCCC.O.CC(C)CC(=O)C>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[N:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCCCCC
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A nitrogen-flushed, 3 L, Argonaut reactor system is charged with 43.9 g (0.15 mol. 1.0 eq) of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, (crude A1, from Step 1.4 above), 45.9 g (0.165 mol, 1.1 eq.) of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (A2), 0.67 g (3.0 mmol, 0.02 eq) of palladium (II) acetate, 3.73 g (6.0 mmol, 0.04 eq) of (±) 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, ±BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and 275 g (344 mL) of 4-methyl-2-pentanone. The resulting suspension is stirred and heated to 40±3° C. 73.3 g (0.225 mol, 1.5 eq) of cesium carbonate is added in 5 to 10 g portions over 15 min. The resulting suspension is stirred and heated to 100±3° C. This temperature is maintained for 3 h or until the remaining starting material, A1, is ≦2% (area normalization) as determined by HPLC analysis. The progress of the reaction is checked using the Process Steering Control. The sample is cooled to 70±3° C. and 344 g (344 mL) of water is added over 5 min. The sample is cooled to 50±3° C. and held at this temperature for 30 min. 353 g (516 mL) of heptane is added over 30 minutes and the sample is stirred for 2 h. The mixture is then cooled to 22±3° C. and held at least 4 h (hold point). The solids are filtered through a polypropylene filter pad. The filter cake is washed with a cold (4° C.) mixture of 24 g (30 mL) of 4-methyl-2-pentanone and 41 g (60 mL) of heptane. The solids are dried at 60° C. until HSGC PSC shows organic solvents to be 1%, to afford 72.6 g of A3 as a tan solid mp 215-217° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:25]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:27]=2)=[N:24][N:23]=[N:22]1>Cl.CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:33][NH:32][C:30](=[O:31])[C:29]3[CH:34]=[CH:35][C:26]([C:25]4[NH:24][N:23]=[N:22][N:21]=4)=[CH:27][CH:28]=3)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=C(C)NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Yield: 12.9 %

Procedure:
A DMF solution (1 ml) of 27.2 mg (0.10 mmol) of 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 20.4 mg (0.10 mmol) of 4-(1H-tetrazol-5-yl)-benzoic hydrazide synthesized by the method disclosed in WO03/037328 was heated at 60° C. for 6 hours with one drop of concentrated hydrochloric acid, and the precipitated solid was washed with water and collected by filtration. The solid was mixed with 1M aqueous sodium hydroxide and filtered. 1M Hydrochloric acid was added to the filtrate, and the precipitated solid was collected by filtration to obtain 5.9 mg of the desired product as a brown solid (yield 12%).
Reaction SMILES: [C:1]([O:12][CH2:13][CH3:14])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+].[Br-].C([NH3+])CCC>>[Cl:19][CH2:18][CH2:17][CH2:16][O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: CCCC[NH3+]
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: CCOC(=O)c1ccc(OCCCCl)c(OC)c1

Procedure:
WO 02/36587 describes a process for preparing a 5-alkoxy-4-halogenoalkoxy-2-nitrobenzoic acid compound from a 3-alkoxy-4-hydroxybenzoic acid compound. For example, ethyl vanillate (i.e., ethyl 4-hydroxy-3-methoxybenzoate) is reacted with 3-bromo-1-chloropropane in an aqueous potassium carbonate solution in the presence of N-butyl-ammonium bromide to produce ethyl 4-(3-chloropropoxy)-3-methoxybenzoate, and the ethyl 4-(3-chloropropoxy)-3-methoxybenzoate is reacted with 70% nitric acid in a mixture of dichloromethane and acetic acid, to give ethyl 4-chloropropoxy-3-methoxy-2-nitrobenzoate in 82% yield (based on the amount of ethyl vanillate).
Reaction SMILES: [BH4-].[Li+].[Si:3]([O:10][C@@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:13]([C:23](OC)=[O:24])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C(=O)([O-])O.[K+].O>CCOCC>[Si:3]([O:10][C@@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:13]([CH2:23][OH:24])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
Lithium borohydride (2M solution in THF, 6.19 ml) was added dropwise to a stirred solution of 1-tert-butyl 2-methyl (2R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (891 mg) in ether (100 ml) at 0° C. under an atmosphere of nitrogen. The mixture was allowed to warm to room temperature and stirred for 3 hours. A saturated solution of potassium hydrogencarbonate (5 ml) was added slowly, followed by water (20 ml). The ether layer was separated, and the aqueous layer washed with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give tert-butyl (2R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate as a clear oil (750 mg, 88%), which was used without further purification; NMR spectrum (CDCl3) 4.82 (d, 1H), 4.26-4.28 (m, 1H), 4.13-4.15 (m, 1H), 3.67-3.73 (m, 1H), 3.55 (ddd, 1H), 3.42-3.46 (m, 1H), 3.35 (dd, 1H), 1.92-2.01 (m, 1H), 1.48 (s, 9H), 0.91-0.97 (m, 1H), 0.88 (s, 9H), 0.07 (s, 6M).
Reaction SMILES: ClC1C=CC=CC=1S.C(=O)([O-])[O-].[Na+].[Na+].S([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O.C1(O)C=CC=CC=1.[BrH:46]>CN(C)C=O>[BrH:46].[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[S:31][CH:27]1[CH2:28][CH2:29][CH2:30][NH:25][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(Sc3ccccc3Cl)C2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: Clc1ccccc1SC1CCCNC1

Procedure:
A solution of 51.13 g (0.125 mole) of 3-phenylsulfonic acid ester with 1-[(4-methylbenzene)sulfonyl)-3-piperidinol, 25.2 g (0.175 mole) of o-chlorothiophenol and 58 g of sodium carbonate in dimethylformamide was heated at 100° C. for 19 hr and then was quenched in 1 liter of dilute sodium hydroxide. The mixture was extracted with several portions of methylene chloride. The combined methylene chloride extract was washed with several portions of 1M sodium hydroxide, dried over magnesium sulfate and evaporated in vacuo to give an oil which was shown by NMR and mass spectroscopy to e N-tosyl-3-(o-chlorothiophenoxy)piperidine. A mixture of the oil and excess phenol in 200 ml of 48% hydrobromic acid was refluxed for 1.5 hr. The reaction mixture was quenched in ice water, made basic with sodium hydroxide and extracted with several portions of methylene chloride. The combined methylene chloride extract was dried over magnesium sulfate and evaporated in vacuo to give an oil, the free base of the title compound. The free base was converted to the hydrobromic acid salt which was recrystallized from isopropanol-acetonitrile-isopropyl ether, m.p. 152.5°-154.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:44][C:45]1[C:53]([C:54]#[N:55])=[CH:52][CH:51]=[C:50]2[C:46]=1[CH:47]=[C:48]([CH:62]([F:64])[F:63])[N:49]2[CH2:56]/[C:57](=[N:60]/[H])/[NH:58]O>CN(C=O)C.C1COCC1.O>[Br:1][C:2]1[CH:10]=[C:6]([C:7]2[O:9][N:60]=[C:57]([CH2:56][N:49]3[C:50]4[C:46](=[C:45]([Cl:44])[C:53]([C:54]#[N:55])=[CH:52][CH:51]=4)[CH:47]=[C:48]3[CH:62]([F:64])[F:63])[N:58]=2)[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: [H]/N=C(/Cn1c(C(F)F)cc2c(Cl)c(C#N)ccc21)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cncc(Br)c3)n2)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
To a solution of 5-bromonicotinic acid (0.017 g, 0.082 mmol) in anhydrous DMF (2 mL) was added HATU (0.031 g, 0.082 mmol) and DIEA (0.011 g, 0.082 mmol) and stirred at rt. After 10 min, a solution of (1Z)-2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.023 g, 0.077 mmol) in THF (1.5 mL) was added and stirring was continued at rt. After 30 min, the mixture was heated in a microwave at 150° C. for 20 min. Upon cooling, water (˜5 mL) was added to the stirring reaction mixture and the precipitated solids were collected by filtration and washed sequentially with water and hexanes. The product was further purified by flash chromatography (0-20% EtOAc-hexanes gradient), followed by crystallization from CH2Cl2-hexanes to afford the title compound as a white solid (0.011 g, 31% yield): MS (ES) m/z 464 and 466 (M+1 Br isotopes).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (374 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as an orange oil (450 mg, 74%).