Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[C-:2].[C-]#[C-].[Na+].[Na+].[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1>C#C>[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([OH:13])[C:1]#[CH:2])=[CH:10][CH:9]=1
Reactant: [C-]#[C-]
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: C#C
Agent: [Na+]
Product: C#CC(O)(c1ccc(N)cc1)c1ccc(F)cc1

Procedure:
Referring now to FIG. 2, wherein one non-limiting approach to the 1-(4-aminophenyl)-1-(4-fluorophenyl)-2-propyn-1-ol is presented, 4,4′-difluorobenzophenone (7) is reacted with a secondary amine HNR′″R″″ to give the 4-amino-4′-fluorobenzophenone 8, where R′″ and R″″ may be the same as R36 and R37, respectively, as set forth and claimed herein. Acetylide anion, for example, sodium acetylide in acetylene saturated dimethylformamide, is added to the carbonyl of 4-amino-4′-fluorobenzophenone 8 to give, upon aqueous workup, 1-(4-aminophenyl)-1-(4-fluorophenyl)-2-propyn-1-ol 9.
Reaction SMILES: C([NH:4][OH:5])(=O)C.CC(C)([O-])C.[K+].C1COCC1.F[C:18]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([N:35]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[N:31]=2)=[CH:22][C:19]=1[C:20]#[N:21]>CN(C=O)C.CO>[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([CH2:42][N:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:28]2[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[N:31]=[C:26]([C:23]3[CH:24]=[CH:25][C:18]4[O:5][N:4]=[C:20]([NH2:21])[C:19]=4[CH:22]=3)[CH:27]=2)=[CH:48][CH:47]=1
Reactant: CC(=O)NO
Reactant: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc(F)c(C#N)c3)nn3ccnc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc4onc(N)c4c3)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of acetohydroxamic acid (42 mg, 0.556 mmol) in DMF (1 mL) was added a solution of potassium t-butoxide in THF (0.56 mL, 0.56 mmol). The reaction solution was stirred at RT for 15 minutes and then a solution of 2-fluoro-5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile (25 mg, 0.056 mmol) from (1b) in DMF (1 mL) was added. The reaction solution was stirred at RT for 24 hours. The solution was diluted with methanol and purified by preparative HPLC to give 5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d]isoxazol-3-amine. LC/MS, m/e 463 (M+1). HPLC Rt, 3.13 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min. hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:44])=[O:4])=[CH:12][CH:11]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:39])([C:35]([F:38])([F:36])[F:37])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.131 mL, 0.131 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 47-(1); 25.9 mg, 0.044 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (19.7 mg, 77%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[CH2:24]([NH:36][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCN
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
In 120 ml of methylene chloride was dissolved 5.60 g (33.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.53 ml (39.7 mmol) of triethylamine. 3.07 ml (39.7 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. 5.34 g (28.8 mmol) of dodecylamine was added to 7.12.g of the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 2.86 g of the desired compound (yield: 29.5%, yellow oil).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH:11]([O:15][CH3:16])[CH2:12][C:13]#[N:14].C[O-].[Na+]>CO>[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]#[N:14]
Reactant: O=Cc1ccccc1
Reactant: COC(CC#N)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C#N)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
Benzaldehyde (79.5 g, 0.75 mol) and 3,3-dimethoxypropionitrile (115.1 g, 1.0 mol) were mixed together and added to a solution of sodium methoxide (54.0 g, 1.0 mol) in methanol (400 mL) over a period of 15 minutes. The mixture was stirred at room temperature overnight. Most of the methanol was evaporated in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (450 mL). The organic layer was separated, washed with brine (400 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residual oil was distilled to give 103 g (68%) of the product as a colorless oil, bp 125-130° C. (2 mm Hg).
Reaction SMILES: [OH-].[Na+].O.C[O:5][C:6](=[O:40])[CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[S:11][CH:12]=1.Cl>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[N:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2nc(CC(=O)OC)cs2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2nc(CC(=O)O)cs2)c(C)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 99.5 %

Procedure:
A mixed solution of a 6 N sodium hydroxide aqueous solution (0.02 mL) with water (0.06 mL) was added to a solution of [2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester (Example 63-(2); 15.9 mg, 0.0297 mmol) in methanol (0.4 mL) at room temperature, and the mixture was stirred at room temperature for 5.5 hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (15 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[CH:18]=[CH:17][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][C:14]=4[NH:13][C:12]=3[C:11]([C:26]([O:28][CH3:29])=[O:27])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:41]=O)=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1.CCOC(C)=O.O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:41][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:20]4[C:19]5[CH:18]=[CH:17][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][C:14]=5[NH:13][C:12]=4[C:11]([C:26]([O:28][CH3:29])=[O:27])=[N:10][N:9]=3)[C:3]=2[CH3:30])=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38]
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)OC)nnc(-c3cccc(N)c3C)c12
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(=O)OC)nnc(-c3cccc(NCc4ccc(Cl)cc4C(=O)O)c3C)c12
Reaction time: 8 h

Procedure:
To a homogeneous, burgundy solution of methyl 1-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxylate (0.1603 g, 0.394 mmol), 5-chloro-2-formylbenzoic acid (0.182 g, 0.986 mmol) and acetic acid (0.056 mL, 0.986 mmol) in dichloromethane (7.89 mL) and tetrahydrofuran (5.26 mL) under nitrogen was added sodium triacetoxyborohydride (0.251 g, 1.183 mmol), and the reaction was stirred overnight. More sodium triacetoxyborohydride (146.2 mg) was added. After 1 hr, water (6 mL) was added, and the reaction was stirred for 30 min. It was dissolved in EtOAc (100 mL) and washed with water (3×30 mL) and brine (30 mL), dried over MgSO4, and concentrated in vacuo to give a crude product, which was used in the subsequent step.
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([OH:22])=[O:21])[CH2:10][NH:9]4)=[CH:5]1)([CH3:3])[CH3:2].[CH:23]1(O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])[CH2:10][NH:9]4)=[CH:5]1)([CH3:3])[CH3:2]
Reactant: OC1CCCCC1
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)O)CN[C@@H]1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)OC3CCCCC3)CN[C@@H]1C2

Procedure:
Following the procedure of Example 1, 1.5 g of 1-isopropylergoline-8β-carboxylic acid were esterified with 15 g of cyclohexanol in the presence of 1.5 g of p-toluenesulfonic acid to yield 1-isopropyl-8β-(cyclohexyloxycarbonyl)ergoline. The product, 1.91 g of an oil, was converted to the maleate salt in a 6:1 ether/ethyl acetate solvent mixture. The salt was isolated by evaporation and then recrystallized from ether/methanol; yield=0.93 g of cyclohexyl 1-isopropyl-8β-(cyclohexyloxycarbonyl)ergoline maleate (96.77% pure by HPLC); molecular ion at 380; [α]25D =-40.64° .
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)(=[O:13])=[O:12])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]2[CH3:28])[N:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.C(O)C.O.C(OCC)(=O)C.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>[F:21][C:16]1[CH:15]=[C:14]([S:11]([C:8]([C:6]2[CH:5]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[N:3]=[C:2]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[N:7]=2)([CH3:10])[CH3:9])(=[O:13])=[O:12])[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2cc(F)cc(F)c2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A stream of nitrogen was passed through a mixture of 2-chloro-4-[2-(3,5-difluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.4 g, 3.24 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.923 g, 4.21 mmol) and 2M aqueous sodium carbonate (5.83 mL, 11.67 mmol) in DMF (6 mL), DME (5 mL), ethanol (5 mL) and water (12.5 mL) at RT. The reaction mixture was treated with dichlorobis(triphenylphosphine)palladium(II) (0.114 g, 0.16 mmol) and was stirred at 80° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25%-60% ethyl acetate in isohexane, to give the desired material as a pale yellow solid (1.496 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]1[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[N:14][C:15]([Br:19])=[CH:16][C:17]=1Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[Br:19][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][C:9](=[O:27])[N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:14]=1
Reactant: O=C(CCc1c(Br)cc(Br)nc1-c1ccccc1Cl)Nc1ccccc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(cc(Br)nc2-c2ccccc2Cl)N1c1ccccc1Cl
Yield: 50.9 %

Procedure:
N-(2-Chlorophenyl)-3-[4,6-dibromo-2-(2-chlorophenyl)-3-pyridinyl]propanamide (942 mg, 1.78 mmol) was divided into six portions and each dissolved in DMF (3 ml), and treated with potassium carbonate (50 mg, 0.362 mmol) and copper(I) iodide (15 mg, 0.079 mmol), and heated in a Smith Creator microwave at 180° for 15 min. All reactions were then combined and evaporated in vacuo. The residue was treated with water (15 ml) and extracted with dichloromethane (2×20 ml). The extracts were passed through a hydrophobic frit and evaporated in vacuo. The residue was purified by column chromatography over silica (20 g) eluting with a cyclohexane-ethyl acetate gradient (100:0-0:100). (70:30) gave the product as a white foam (406 mg, 51%).
Reaction SMILES: C[Sn](C)(C)C.[C@@H:6]1([N:14]2[CH:18]=[C:17](I)[CH:16]=[C:15]2[N+:20]([O-:22])=[O:21])[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[CH2:7]1.[C:23]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.CN(C=O)C>[C@@H:6]1([N:14]2[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]2[N+:20]([O-:22])=[O:21])[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[CH2:7]1
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Yield: 150 %

Procedure:
Tetramethyltin (287 μL, 2 mmol) was added to a DMF (2 mL) solution containing 1-(2-deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (142 mg, 0.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.02 mmol), and triphenylarsine (12 mg, 0.04 mmol), followed by reaction at 60° C. for 2 days. The reaction solution was separated between ethyl acetate (50 mL) and water (50 mL). The organic layer was concentrated and purified by HPLC to yield 1-(2-deoxy-β-D-ribofuranosyl)-4-methyl-2-nitropyrrole (15 mg, 0.06 mmol, 15%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH:11]1([N:17]2C(=O)O[C:20](=[O:21])[C:19]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:18]23)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:17][C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([OH:10])=[N:2]2)=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=c1oc(=O)n(C2CCCCC2)c2ccccc12
Reactant: Oc1n[nH]c2ccccc12
Product: O=C(c1ccccc1NC1CCCCC1)n1nc(O)c2ccccc21
Yield: 20.1 %

Procedure:
1H-Indazol-3-ol was reacted with N-cyclohexylisatoic anhydride according to the general procedure A above and afforded the desired amine as yellow solid in 20.1% yield; m.p. 150°-152° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])=O)([O-:3])=[O:2].C([O-])(=O)CC.C([O-])(=O)CCC.Cl.[NH2:30]O.C([O-])(=O)C.[Na+]>C(O)C>[N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]1[CH2:8][C:9](=[O:10])[O:11][N:30]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CCC(=O)[O-]
Agent: CCCC(=O)[O-]
Solvent: CCO
Product: O=C1CC(c2ccccc2[N+](=O)[O-])=NO1

Procedure:
The reactions of Equations 15a and 15b above can be run by procedures similar to those described in U.S. Pat. No. 3,781,438 for the preparation of 5-halo-3-phenylisoxazoles. Thus, in reaction 15a, an ethyl 2-(2-nitrobenzoyl)acetate, propionate or butyrate of Formula (XIV) is reacted with hydroxylamine hydrochloride and sodium acetate in ethanol at reflux for 0.5 to 5 hours to form a 3-(2-nitrophenyl)isoxazolin-5-one of Formula (XXVI). In reaction 15b, XXVI is reacted with an equimolar amount of triethylamine and excess phosphorus oxychloride or phosphorus oxybromide in toluene at 25° to 110° C. for 1 to 5 hours to form Xc"'.
Reaction SMILES: [CH3:1][C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O.COC1C([N+]([O-])=O)=C(O)C([N+]([O-])=O)=C(O)C=1[N+]([O-])=O.[CH3:95][O:96][C:97]1[C:105]([N+:106]([O-:108])=[O:107])=[C:104]([O:109][CH3:110])[C:103]([N+:111]([O-:113])=[O:112])=[C:102]([OH:114])[C:98]=1[N+:99]([O-:101])=[O:100]>>[CH3:95][O:96][C:97]1[C:105]([N+:106]([O-:108])=[O:107])=[C:104]([O:109][CH3:110])[C:103]([N+:111]([O-:113])=[O:112])=[C:102]([O:114][CH3:1])[C:98]=1[N+:99]([O-:101])=[O:100]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1c([N+](=O)[O-])c(O)c([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: COc1c([N+](=O)[O-])c(O)c([N+](=O)[O-])c(O)c1[N+](=O)[O-]
Product: COc1c([N+](=O)[O-])c(OC)c([N+](=O)[O-])c(OC)c1[N+](=O)[O-]

Procedure:
Alkoxylating the nitrated alkoxy derivatives forms 1,3,5-trialkoxy-2,4,6-trinitrobenzene, which remains dissolved in the organic solvent to form a 1,3,5-trialkoxy-2,4,6-trinitrobenzene/organic solvent solution. Additional organic solvent may, optionally, be added to maintain an initial volume of the organic solvent in the reaction vessel such that the 1,3,5-trialkoxy-2,4,6-trinitrobenzene remains in solution. For example, the additional organic solvent may be added to the reaction vessel to maintain a volume of from about 10 mL to about 50 mL. In one embodiment, TMOF is used as the alkoxylating agent and is reacted with the 5-methoxystyphnic acid or 3,5-dimethoxypicric acid, producing 1,3,5-trimethoxy-2,4,6-trinitrobenzene. While the example described herein utilizes TMOF as the alkoxylating agent, triethyl orthoformate or tripropyl orthoformate may be used to form 1,3,5-triethoxy-2,4,6-trinitrobenzene or 1,3,5-tripropoxy-2,4,6-trinitrobenzene, respectively.
Reaction SMILES: [NH:1]([C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:6]=1)=[O:4])[NH2:2].Cl.[N:21]([O-])=O.[Na+]>C(O)(=O)C.O>[N:1]([C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:6]=1)=[O:4])=[N+:2]=[N-:21]
Reactant: O=N[O-]
Reactant: NNC(=O)c1nc(-c2cccc3ccccc23)no1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=NC(=O)c1nc(-c2cccc3ccccc23)no1
Yield: 86.2 %

Procedure:
5-Hydrazinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole (6.47g.) was dissolved in acetic acid (125 ml.) and 2N-hydrochloric acid (75 ml.). A solution of sodium nitrite (2.0g) in water (6 ml.) as added at 0° with stirring. After 15 minutes the precipitate was filtered off and dissolved in chloroform. The chloroform solution was washed with water and dried (MgSO4). Evaporation to dryness gave title compound (5.82 g.), m.p. 114° (decomp.), λmax. (EtOH) 300 nm. (ε 8,250), νmax. (CHBr3) 1710 (C=O), 2150 and 2190 cm.-1 (N3).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:58][C:57]([O:59][C:60]3[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=3[F:67])=[CH:56][C:55]2=[O:68])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>CO>[F:66][C:65]1[CH:64]=[CH:63][CH:62]=[C:61]([F:67])[C:60]=1[O:59][C:57]1[CH2:58][N:2]([C@@H:3]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:55](=[O:68])[CH:56]=1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@@H](N)CC2CCCCO2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCO2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Yield: 29 %

Procedure:
(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride (prepared as in Example 92, 300 mg, 0.78 mmol) was dissolved in methanol (5 mL) and N,N-diisopropylethylamine (0.5 mL) was added. The mixture was evaporated to dryness. The residue was dissolved acetonitrile (8 mL). To this solution was added (E)-4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 296 mg, 0.92 mmol). The mixture was refluxed for 40 h. The mixture was evaporated and the residue was treated with ethyl acetate and water. The layers were separated and the organic layer was dried and concentrated. The crude material was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient) to afford (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamide (114 mg, 29%): HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]+ 505.2257, observed 505.2260; 1H NMR (300 MHz, CDCl3) δ ppm 1.16 (s, 6H), 1.24-1.70 (m, 5H), 1.74-1.97 (m, 2H), 2.17-2.30 (m, 1H), 3.29-3.52 (m, 2H), 3.92-4.05 (m, 1H), 3.95 (s, 3H), 4.25 (d, J=17.8 Hz, 1H), 4.43 (d, J=17.8 Hz, 1H), 4.95 (s, 1H), 5.10 (dd, J=8.6, 6.5 Hz, 1H), 6.69 (s, 1H), 6.97-7.10 (m, 2H), 7.14-7.25 (m, 1H), 7.30 (s, 1H), 8.77 (br. s., 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[O:21][C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)=[O:13])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[O:21][C:22]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)=[O:13]
Reactant: O=C(c1cccc(OCc2ccccc2)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(c1cccc(O)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 7 h
Yield: 127.6 %

Procedure:
A mixture of 1-(3-benzyloxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (95 mg) and 10% Pd-C (50% wet, 15 mg) in ethyl acetate (3 ml) -10% methanolic hydrogen chloride was stirred in the cresence of atmospheric H2 gas at room temperature for 7 hours and filtered. The filtrate was evaporated in vacuo to afford 1-(3-hydroxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (100 mg) as a crude oil.