Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH2:23])[CH2:9][N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([C@H:8]([NH:23][C:37]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:38])[CH2:9][N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccsc1C1=CCN(C[C@@H](N)Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccsc1C1=CCN(C[C@H](Cc2ccccc2)NC(=O)C2CCCCC2)CC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A magnetically stirred solution of 0.5 g (1.52 mmol) of (1S)-1-Benzyl-2-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethylamine and 0.42 ml (3.04 mmol) of triethylamine in 30 ml of dry dichloromethane was cooled in an ice bath under a dry nitrogen atmosphere. A solution of 0.25 g (1.67 mmol) of cyclohexane carbonyl chloride in 6 ml of dry dichloromethane was added dropwise over 10 minutes. The resulting solution was stirred at 4° C. for 1 hour and then the ice bath was removed and stirring was continued overnight (app. 18 hours), during which time the reaction came up to room temperature. TLC on silica gel (4% methanol/dichloromethane) revealed the absence of starting material and a new product (Rf=0.5). The reaction was concentrated on a rotary evaporator and partitioned between 75 ml of ethyl acetate and 50 ml of 1N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The resulting oil was purified by flash chromatography on silica gel (4% methanol/dichloromethane) to give 0.34 g of the desired (S)-cyclohexanecarboxylic acid {1-benzyl-2-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-amide as oil which hardened upon exposure to vacuum. The compound was converted to its monofumerate·1.25 hydrate salt, yield=0.35 g (41%); mp=194-196° C.; [a]D25 =+5.86 (EtOH, c=0.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:23][C:24]([O:26]C)=[O:25].[OH-].[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][C:4]=1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: COC(=O)Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Methyl 2-methoxy-4-(1-Boc-4-piperidyloxy)phenylacetate (1.37 g, 3.6 mmol) was dissolved in THF (27 ml) and treated with lithium hydroxide (4.5 ml of a 1M aqueous solution, 4.5 mmol). The mixture was stirred at ambient temperature for 4.5 hours, then treated with an additional 0.9 ml of 1M lithium hydroxide and stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo, and the residue was acidified with 1M HCl, and extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was reconcentrated from ether to give 2-methoxy-4-(1-Boc-4-piperidyloxy)phenylacetic acid.
Reaction SMILES: [Li+].[Cl-].[CH2:3]([C:10]1[CH:11]=[C:12]([O:24][CH3:25])[CH:13]=[CH:14][C:15]=1OS(C(F)(F)F)(=O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH2:28]>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>[CH2:28]([C:15]1[CH:14]=[CH:13][C:12]([O:24][CH3:25])=[CH:11][C:10]=1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:27]=[CH2:26]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCc1ccc(OC)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
LiCl (3.08 g, 72.8 mmol) in a roundbottom flask was flame-dried in high vacuum, and the system was allowed to cool to RT under argon. 3-Benzyl-4-(trifluoromethanesulfonyloxy)anisole (21.0 g, 60.6 mmol), bis(triphenylphosphine)palladium(II) chloride (2.13 g, 3.0 mmol), anhydrous DMF (150 mL), and allyltributyltin (22.6 mL, 72.8 mmol) were added, and the mixture was purged with argon through three evacuation/argon flush cycles. The mixture was heated in an oil bath preset at 95° C., affording a yellow, homogeneous solution. After 1.5 h, the dark mixture was concentrated on the rotavap (high vacuum), and the residue was reconcentrated from xylenes. The resulting residue was taken up in Et2O (120 mL) and stirred briskly with 10% KF (120 mL) for 0.5 h. The layers were separated, and the aqueous layer was extracted with Et2O (2×120 mL). The combined organics were filtered through celite® to remove the insoluble solids, and the filtrate was washed sequentially with H2O (60 mL) and brine (60 mL). Drying (MgSO4) and concentration left a cloudy, yellow oil. Chromatography (silica gel, 5% EtOAc/hexanes) gave the title compound as a light yellow oil (14.21 g, 98%): TLC Rf (5% EtOAc/hexanes) 0.51; 1H NMR (250 MHz, CDCl3) δ 7.03-7.31 (m, 6H), 6.74 (dd, J=8.3, 2.7 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 5.79-5.98 (m, 1H), 4.89-5.07 (m, 2H), 3.97 (s, 2H), 3.75 (s, 3H), 3.21-3.33 (m, 2H); FTIR (CCl4) 1610, 1496, 1256, 1046, 914 cm-1 ; MS (ES) m/e 239.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[NH:41]1[CH2:48][CH2:47][CH2:46][C@@H:42]1[C:43]([NH2:45])=[O:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:37])([CH3:38])[CH2:9][C:10]([OH:36])([C:32]([F:34])([F:35])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:26]([N:41]3[CH2:48][CH2:47][CH2:46][C@@H:42]3[C:43]([NH2:45])=[O:44])=[O:27])[CH:29]=[CH:30][CH:31]=2)[CH:7]=1
Reactant: NC(=O)[C@H]1CCCN1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N2CCC[C@@H]2C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and D-prolinamide.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:25])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]>C(Cl)Cl>[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:25])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: Cc1cc(-c2c(C(C)O)oc(=O)c3ccccc23)ccn1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2c(C(C)Br)oc(=O)c3ccccc23)ccn1
Yield: 45 %

Procedure:
1 M PBr3 in DCM (846 μL, 0.846 mmol) was added to of 3-(1-hydroxyethyl)-4-(2-methylpyridin-4-yl)-1H-isochromen-1-one (intermediate B13, 140 mg, 0.498 mmol) in DCM at RT. Reaction mixture was concentrated under reduced pressure and straightforward purified via reverse phase chromatography with a Biotage C18 SNAP 60 g column (Phase A, water 95%, ACN 4.5%, formic acid 0.5%); Phase B ACN 99.5%, formic acid 0.5%) to give the title compound (80 mg, 45%).
Reaction SMILES: [CH2:1]([N:8]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][C:20]=1[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:17][CH2:16][CH:10]2[CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:21][C:20]=1[CH3:26]
Reactant: CC1CCCC(CO)CN1Cc1ccccc1
Reactant: Cc1cc(O)ccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCC2CCCC(C)N(Cc3ccccc3)C2)ccc1F
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A mixture of (1-benzyl-7-methylazepan-3-yl)methanol (2-5, 500 mg, 2.1 mmol, 1.0 equiv), 4-fluoro-3-methylphenol (300 mg, 2.4 mmol, 1.1 equiv), and PS-triphenyl phosphine resin (1.2 g, 2.4 mmol, 1.1 equiv) in dichloromethane (25 mL) was treated with DIAD (0.46 mL, 480 mg, 2.4 mmol, 1.1 equiv) and the resulting suspension was stirred for 16 hours at 23° C. The mixture was filtered and filtrate was concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes gradient) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-1-benzyl-2-methylazepane (2-6) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 6.86 (m, 1H), 6.55 (m, 2H), 3.72-1.75 (m, 20H). LRMS m/z (M+H) 342.3 found, 242.2 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=3)[CH2:8][N:7]([CH3:19])[C:6]=2[CH:20]=1.[Mn]([O-])([O-])(=O)=[O:22].[Ba+2]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=3)[C:8](=[O:22])[N:7]([CH3:19])[C:6]=2[CH:20]=1
Reactant: O=[Mn](=O)([O-])[O-]
Reactant: CC(=O)Nc1cc2c(cn1)CN(C)c1cc(Cl)ccc1-2
Agent: [Ba+2]
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cn1)c(=O)n(C)c1cc(Cl)ccc21
Temperature: 45 °C
Yield: 89.3 %

Procedure:
To a stirred solution of N-(8-chloro-6-methyl-5,6-dihydrobenzo[c][2,7]naphthyridin-2-yl)acetamide (0.6 g, 1.199 mmol) in DCM (20 mL) at rt was added barium manganate (1.536 g, 5.99 mmol) in three portions and the reaction was heated at 45° C. for 60 h. After the completion of reaction, the reaction mixture was diluted with DCM (70 mL) and passed through diatomaceous earth (Celite®). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH as an eluant) to yield N-(8-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-2-yl)acetamide (0.4 g, 1.071 mmol, 89% yield) as an off white solid. LC/MS (ESI) m/e 302.1 [(M+H)+, calcd for C15H13ClN3O2 302.1]; LC/MS retention time (method C): tR=1.88 min; HPLC retention time (method A); tR=8.82 min; HPLC retention time (method B): tR=7.99 min; 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.24 (s, 1H), 8.92 (s, 1H), 8.26 (d, J=8.80 Hz, 1H), 7.69 (d, J=2.00 Hz, 1H), 7.48 (dd, J=2.00, 8.80 Hz, 1H), 3.68 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:30])[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:30])[CH:21]([CH:2]=[O:4])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(CCCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=CC(CCc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
To a solution of potassium t-butoxide (0.673 g) in THF (20 mL) under nitrogen and cooled in an ice bath was added a solution of 1-(1-benzylpiperidin-4-yl)-4-phenylbutan-1-one from Step D (0.71 g) and methyl fornate (3.76 mL) in THF (12 mL) over 5 minute. The reaction was stirred for 15 min before being allowed to warm to rt for 2 h. The reaction was poured into water and extracted with ether (4×100 mL), methylene chloride (100 mL), and THF (100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrate under reduced pressure. The crude product was purified by FC on silica gel eluting with 5 and 20% methanol in ethyl acetate with 4% TEA to afford the title compound (0.8 g). 1H NMR (500 MHz, CDCl3) showed a 3:1 ratio of enol (δ 8.54 ppm) and aldehyde (δ 9.54 ppm) forms. Other signals from the two forms were only partially resolved. The title compound had a retention time of 9.47 min on a Zorbax SB-C18 column (4.6×75 mm) eluting with 20-100% gradient of acetonitrile in water with 0.1% TFA over 10 min at 1 mL per min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1c(Br)ccc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc(N)c1C#N
Yield: 36.3 %

Procedure:
A stirred solution of 1.7 grams (0.008 mole) of 2-amino-5-bromo-6-methylbenzonitrile, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 mL of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene was heated at 90° C. for about 20 hours. After this time, the reaction mixture was stirred with 100 mL of water, and the organic layer was separated. The organic layer was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 30/65/5 and 20/60/20 methylene chloride/petroleum ether/ethyl acetate as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 1.0 gram of 2-amino-6-methyl-5-[3,5-di(trifluoromethyl)phenyl]benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([O:15]C)=O>CO>[OH:3][NH:2][C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)=[O:15]
Reactant: COC(=O)c1ccccn1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NO)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 25.4 g. (365 mmole) of hydroxylamine hydrochloride in one liter of methyl alcohol were added 39.4 g. (730 mmole) of sodium methylate. A slight exotherm occurred and sodium chloride precipitated. The solution was allowed to cool to room temperature, 50 ml. (365 mmole) of methyl 2-pyridinecarboxylate were added, and the reaction mixture was stirred overnight. The mixture was filtered to remove the salt precipitate and the filtrate was evaporated to dryness. The residue was dissolved in 100 ml. of water, pH 10.1, the solution acidified to pH 5.0 with concentrated hydrochloric acid. The solution was diluted with 500 ml. of isopropyl alcohol added dropwise and the additional sodium chloride precipitate was filtered. The filtrate was concentrated to about 100 ml. and the insoluble product was filtered. There were obtained 37.1 g. of the product which melted at about 58° C. to about 68° C. On chilling the filtrate an additional 12.5 g. of the product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([C:18]1[CH:22]=[C:21]([NH2:23])[O:20][N:19]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:23][C:21]2[O:20][N:19]=[C:18]([C:15]([CH3:17])([CH3:16])[C:14]([F:25])([F:24])[F:13])[CH:22]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CC(C)(c1cc(N)on1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)on1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (360 mg, 1.545 mmol) in DCM (50 mL) was added 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (300 mg, 1.545 mmol), HATU (881 mg, 2.317 mmol) and triethylamine (0.645 mL, 4.63 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to yield a yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (600 mg, 1.1 mmol, 71% yield): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=6.8 Hz, 1H), 7.34-7.29 (m, 1H), 7.21 (s, 1H), 6.64 (d, J=6.8 Hz, 1H), 6.43 (s, 1H), 3.75 (s, 2H), 1.52 (s, 6H); ES-LCMS m/z 409 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(#N)C>[CH3:21][O:20][C:3]1[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 15.7 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (154 mg, 1.118 mmol) and 4-bromomethyl-benzenesulfonamide (104 mg, 0.418 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 15.7%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1.[F-].[K+].O>CS(C)=O>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([OH:29])([CH3:27])[CH3:28])[CH2:22][CH2:21]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CC(C)(O)[C@H]1CC[C@H](CN)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(O)[C@H]1CC[C@H](CNc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (100 mg, 0.38 mmol), 2-(trans-4-(aminomethyl)cyclohexyl)propan-2-ol (140 mg, 0.76 mmol) and KF (51 mg, 0.88 mmol) in DMSO (2 mL) was stirred at 130° C. overnight. LCMS showed the reaction was complete. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-76 (12 mg, 8%) as a yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]([NH2:29])([CH3:28])[C:26]#[CH:27]>C(N(CC)CC)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.[Cu]I>[NH2:29][C:25]([CH3:28])([CH3:24])[C:26]#[C:27][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)N
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
{4-[5-Bromothiophen-2-yl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (100 mg, 0.253 mmol), PdCl2(PPh3)2 (18 mg, 0.025 mmol), 1,1-dimethyl-prop-2-ynylamine (0.03 ml, 0.253 mmol) and CuI (15 mg) were dissolved in triethylamine (25 ml) and refluxed for 1 hour. The reaction mixture was filtered, evaporated to dryness and taken up in DCM, filtered and evaporated again and the residue crystallized from ether to give the title compound as red-yellow crystals. Yield: 50 mg (50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[N+:13]([O-])=O.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[NH2:13]
Reactant: CCCOc1ccc([N+](=O)[O-])c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOc1ccc(N)c(OC)c1

Procedure:
1.40 g (6.63 mmol) 2-Methoxy-1-nitro-4-propoxybenzene in 20 mL EtOAc is charged with 100 mg Pd/C (5%) and hydrogenated at rt with a hydrogen pressure of 50 psi. The mixture is filtered and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:14][S:13][CH:12](OCC)[S:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19].P(Cl)(Cl)Cl>ClCCl.[Cl-].[Zn+2].[Cl-]>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][S:13][C@@H:12]([P:21]([O:22][CH2:23][CH3:24])([O:20][CH2:18][CH3:19])=[O:25])[S:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOC1SCC(CO[Si](C)(C)C(C)(C)C)S1
Reactant: CCOP(OCC)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO[Si](C)(C)C(C)(C)C)S1
Temperature: 0 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of 4-(t-butyldimethylsilyloxymethyl)-2-ethoxy-1,3-dithiolane (example 48) (37.1 g, 126 mmol) and triethylphosphite (14.3 mL, 83.0 mmol, 0.66 eq) in dichloromethane (100 mL) were added phosphorus trichloride (3.6 mL, 42.0 mmol, 0.33 eq) and zinc chloride (catalytic) at 0° c. The solution was stirred at 0° C. for 2 hr and at room temperature for 18 hr. The solvent was evaporated and the crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (80:20 to 60:40) to give 3.64 g of the cis isomer, 8.62 g of the trans isomer and 9.95 g of the mixture (2:1 trans:cis) for a total yield of 46%.
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2)(=[O:3])[CH3:2].[C:15]([C:18]12CC3CC(CC(C3)C1)C2)(=O)[CH3:16]>>[OH:14][C:6]12[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][C:4]([C:1]([CH:15]([CH3:18])[CH3:16])([CH3:2])[OH:3])([CH2:11]3)[CH2:5]1)[CH2:7]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)C12CC3CC(CC(O)(C3)C1)C2
Product: CC(C)C(C)(O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 48 %

Procedure:
The procedure of Example 1 was repeated, except that 1.0 mol of 1-acetyl-3-adamantanol obtained according to the process of Reference Example 2 was employed instead of 1-acetyladamantane, to give 3-hydroxy-α-isopropyl-α-methyl-1-adamantanemethanol in yield of 48%.