Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]([CH3:7])[CH:5]=[CH2:6].[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([CH:26]=[N:27][OH:28])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[CH3:1][O:2][C:3](=[O:8])[CH:4]([CH:5]1[O:28][N:27]=[C:26]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]([CH3:9])[CH:19]=3)=[CH:30][CH:29]=2)[CH2:6]1)[CH3:7]
Reactant: C=CC(C)C(=O)OC
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Product: COC(=O)C(C)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 55 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using 2-methyl-but-3-enoic acid methyl ester and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude product was prepared. The crude product was purified by FCC (flash column chromatography) on silica gel to give 2-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester (0.13 g, 55%) as a solid residue. MS found: (M+H)+=405.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12][C@@H:11]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10]1.NN>C1(C)C=CC=CC=1>[F:1][C:2]([F:38])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CC[C@@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Agent: NN
Solvent: Cc1ccccc1
Product: N[C@@H]1CC[C@@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 80 °C
Yield: 92.9 %

Procedure:
To a solution of 2-((1R,3S)-3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentyl)isoindoline-1,3-dione (113 mg), available from Example 7, in toluene (0.83 mL) was added anhydrous hydrazine (66 μL), and the reaction mixture was heated at 80° C. for 12 h. The precipitate was removed by filtration, and the filtrate was evaporated in vacuo to give the title compound (80 mg). The 1H NMR data is identical to that of its (1S,3R) isomer shown in Example 6. HRMS m/z calcd for C21H22F6NO (M+H)+ 418.1607. found 546.1619.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:8]([OH:12])[CH2:9][CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]([O:12][CH2:23][CH:22]=[CH2:21])[CH2:9][CH:10]=[CH2:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CC[C@H](O)C(c1ccccc1)c1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H](CC=C)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
(2S)-1,1-diphenyl-pent-4-en-2-ol 25a (0.37 g, 1.57 mmol) was dissolved in dry DMF (2 ml) and was added to a suspension of NaH (60% in mineral oil, 0.13 g, 3.14 mmol) in dry DMF (20 ml) at 0° C. The reaction mixture was allowed to reach room temperature over a period of 1 h. The reaction mixture was cooled again to 0° C. employing an ice-bath, and neat allyl bromide (0.57 g, 4.71 mmol) was added via syringe. The reaction mixture was removed from the ice-bath and stirred overnight at room temperature. The reaction was cooled again to 0° C. and quenched by slowly adding H2O (20 ml). The resulting mixture was extracted with Et2O (3×50 ml), and the combined organic phases were washed in turn with H2O, brine, and then dried over anhydrous Na2SO4. Filtration followed by concentration gave crude product as light orange oil. Purification by chromatography (hexane/ethyl ether=10:1) gave 0.37 g (2S)-1,1-Diphenyl-2-Allyloxy-Pent-4-en (85%, [α]D=(+)19.7, c=1, MeOH).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][C:12]=1[CH2:20]C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:23]1C=C(C)C(CCO[Si](C(C)(C)C)(C)C)=C(C)C=1.COB(OC)OC>>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([CH3:20])=[CH:13][C:14]([B:17]([OH:18])[OH:19])=[CH:15][C:16]=1[CH3:23])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCc1cc(B(O)O)ccc1CCO[Si](C)(C)C(C)(C)C
Reactant: Cc1cc(Br)cc(C)c1CCO[Si](C)(C)C(C)(C)C
Agent: COB(OC)OC
Product: Cc1cc(B(O)O)cc(C)c1CCO[Si](C)(C)C(C)(C)C
Yield: 45 %

Procedure:
Using a procedure analogous to that used to prepare 46B, 50A (3.58 g, 10.5 mmol) was reacted trimethylborate to afford 50B (1.45 g, 45%) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm −0.03 (s, 6 H) 0.85 (s, 9 H) 2.33 (s, 6 H) 2.92 (t, J=7.15 Hz, 2 H) 3.75 (t, J=7.42 Hz, 2 H) 7.20 (s, 2 H).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(#N)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>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.C(N(CC)CC)C>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1)([CH3:23])[CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OCCN2CCOCC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A resealable tube was charged with 4-[2-(4-iodo-phenoxy)-ethyl]-morpholine 100b (2.00 g, 6.00 mmol), acetonitrile (40 mL), and triethylamine (5 mL). Dichlorobis(triphenylphosphine)palladium (II) (0.211 g, 0.30 mmol), copper (I) iodide (0.057 g, 0.30 mmol), and (trimethylsilyl)acetylene (0.766 g, 1.10 mL, 7.80 mmol) were added. The system was purged with argon, the tube was sealed, and the mixture stirred at 60° C. for 16 h. The reaction mixture was concentrated to afford 4-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-morpholine 101b as a dark brown solid which was used without purification. MS (MH+) 304.2; Calculated 303 for C17H25NO2Si.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:13]#[N:14])[C:9](=[NH:12])[O:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]#[C:16]N>C1C=CC=CC=1>[C:16]([N:12]=[C:9]([O:10][CH3:11])[CH:8]([C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:15]
Reactant: COC(=N)C(C#N)c1ccccc1
Reactant: N#CN
Agent: Cl
Solvent: c1ccccc1
Product: COC(=NC#N)C(C#N)c1ccccc1
Yield: 76.9 %

Procedure:
4.21 g of methyl α-phenylcyanoacetimidate hydrochloride and 1.26 g of cyanamide were mixed at room temperature and the mixture was made to react for 5 hours. Then, 50 ml of benzene was added to the reaciton mixture to extract the resulting product. The extracted solution was concentrated to dryness in vacuo and 3.06 g of methyl N-cyano-α-phenylcyanoacetimidate was obtained (yield 76.8%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([F:7])[CH:4]=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[F:7][C:5]1[CH:4]=[C:3]([C:8](=[O:9])[NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[CH:6]=1
Reactant: Nn1cc(F)cc1C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cc(F)cc1C(=O)Nc1ccccc1
Yield: 91 %

Procedure:
The title compound was prepared from 1-amino-4-fluoro-N-phenyl-1H-pyrrole-2-carboxamide (0.95 g, 3.6 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid following the experimental procedure described in Preparation 47b. 1.28 g (91% yield) of the desired compound were obtained.
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:19][C:16]([CH3:17])([CH3:18])[CH2:15][C@H:2]([OH:1])[CH2:3][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC(C)(C)C)cc1
Reactant: C1COCCN1
Product: CC(C)(C)C[C@H](O)CN1CCOCC1
Temperature: 160 °C
Yield: 67 %

Procedure:
(S)-toluene-4-sulfonic acid 2-hydroxy-4,4-dimethyl-pentyl ester obtained from Example 4, step A (700 mg, 2.4 mmol) was charged to a large microwave reactor vial and treated with morpholine (3 mL). The vial was crimped shut and heated to 160° C. for 6 minutes. The solvent was then removed. The resulting oil was dissolved in ethyl acetate and extracted 3 time with aqueous 1 M HCl. The organics were discarded and the aqueous layer was made basic with solid NaOH and extracted 3 times with ethyl acetate. The organic extracts were combined, dried over MgSO4 and the solvent was removed to afford 330 mg (67%) of material which was used without further purification: HPLC-MS calcd. for C11H23NO2 (M+H+) 202.2, found 202.5.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1.[CH2:21]([OH:23])[CH3:22].[C-]#N.[Na+]>C1COCC1.[O-2].[O-2].[Mn+4]>[CH2:21]([O:23][C:2]([C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1)=[O:1])[CH3:22]
Reactant: CCO
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CO
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cncn1C1c2ccccc2C(=O)OC1(C)C

Procedure:
To a solution of 4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.56 g, 2.0 mmol) (Example 6d) in THF (10 mL) is added ethanol (0.6 mL), sodium cyanide (0.111 g, 2.26 mmol) and manganese dioxide (2.69 g, 30.9 mmol). The mixture is stirred at reflux for 2 days, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient ethyl acetate in heptane, 20% to 90%) to give 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid ethyl ester as oil; HRMS (ESI) m/z 315.1355 [(M+H)+: Calcd for C17H18N2O4: 315.1345]; 1H NMR (400 MHz, MeOD) of the HCl salt δ ppm 1.24 (s, 3 H), 1.43 (t, J=7.1 Hz, 3 H), 1.55 (s, 3 H), 4.46 (q, J=7.1 Hz, 2 H), 6.83 (s, 1 H), 7.53 (d, J=7.6 Hz, 1 H), 7.66-7.71 (m, 2 H), 7.78 (td, 1 H), 7.91 (s, 1 H), 8.26 (dd, J=7.8, 1.3 Hz, 1 H)
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]=1[CH:10]([OH:24])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][C:31]([O:33]C)=[O:32]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]=1[CH:10]([OH:24])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:30][C:31]([OH:33])=[O:32])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)CBr
Reactant: CCCCc1oc2ccccc2c1C(O)c1ccc(-c2ccc(O)cc2)cc1
Product: CCCCc1oc2ccccc2c1C(O)c1ccc(-c2ccc(OCC(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4'-[(2-butyl-benzofuran-3-yl)-hydroxymethyl]-biphenyl-4-ol, and methyl bromoacetate in substantially the same manner, as described in Example 4, and was obtained as a yellow solid, mp 111-113° C.; MS m/e 430 (M+);
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CNC[C@@H]1O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 71.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2) and cis-pyrrolidine-3,4-diol (Stage 249.2). After purification by flash chromatography on Silica gel, the oily residue was taken-up in a toluene/MeOH mixture then evaporated to dryness under reduced pressure and dried to yield the title product as a white amorphous solid. UPLC-MS (Condition 3) tR=1.0 min, m/z=477.8-479.9 [M+H], m/z=475.8-477.9 [M−H].
Reaction SMILES: C1(S(CC2C(C(O)=O)=C(NCCNC(OC(C)(C)C)=O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[CH2:36]([N:38]([CH2:69][CH3:70])[CH2:39]/[CH:40]=[CH:41]\[C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49]([CH2:52][C:53]1[C:58]([C:59]([O:61]C)=[O:60])=[C:57]([OH:63])[C:56]([C:64]2[CH:68]=[CH:67][O:66][CH:65]=2)=[CH:55][CH:54]=1)(=[O:51])=[O:50])[CH3:37]>>[CH2:69]([N:38]([CH2:36][CH3:37])[CH2:39]/[CH:40]=[CH:41]\[C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49]([CH2:52][C:53]1[C:58]([C:59]([OH:61])=[O:60])=[C:57]([OH:63])[C:56]([C:64]2[CH:68]=[CH:67][O:66][CH:65]=2)=[CH:55][CH:54]=1)(=[O:51])=[O:50])[CH3:70]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(O)c1C(=O)OC
Agent: CC(C)(C)OC(=O)NCCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(O)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 121, starting from (Z)-methyl 6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 196).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4]O.[CH2:10](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO>>[CH2:4]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:2][OH:1])[CH3:10]
Reactant: OCC(CO)(CO)CO
Reactant: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO
Product: CCC(CO)(CO)CO

Procedure:
pentaerythritol or dulcitol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[C:5]([O:10][CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C=O)cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
5-bromo-2-hydroxy-3-trifluoromethylbenzaldehyde (63.98 g) was dissolved in N,N-dimethylformamide (130 mL), and potassium carbonate (65.79 g) and dimethylsulfuric acid (31.6 mL) were added to the solution under water cooling, and then the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (66.19 g) as a brown crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12].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.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:12][C:11]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:10]=2[CH3:9])[CH:7]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ccn1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
To 2.00 g of 2,4-dichloropyridine, 2.26 g of 2-methyl-5-nitroaniline, 121 mg of palladium (II) acetate, 336 mg of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [(±)-BINAP] and 6.16 g of cesium carbonate, 120 ml of toluene was added, and then the mixture was stirred with heating at 70° C. for 23 hours under an argon atmosphere. After insolubles were removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was washed with diethyl ether to obtain 1.22 g of the objective compound as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[I:10].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(Cl)Cl.CO>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:3]([I:10])[CH:4]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(CO)cc1I
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(=CNc1ccc(CO)cc1I)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of (4-amino-3-iodophenyl)methanol (5.97 g) and diethyl ethoxymethylenemalonate (5.34 mL) is heated at 100° C. for 30 min. The reaction is cooled to room temperature. The resulting solid is dissolved in a mixture of CH2Cl2 and MeOH, adsorbed onto silica and chromatographed (Biotage flash 40M, eluant CH2Cl2, then 0.5% MeOH/CH2Cl2). Product containing fractions are combined and condensed to afford diethyl 2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate as a white solid, m.p. 152-154° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:8]=1.[BrH:13]>>[BrH:13].[NH2:12][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][N:7]2[N:9]=1
Reactant: COc1ccc2nc(N)nn2c1
Agent: Br
Product: Nc1nc2ccc(O)cn2n1
Reaction time: 7 h
Yield: 89 %

Procedure:
A mixture of 6-methoxy[1,2,4]triazolo[1,5-a]pyridin-2-amine (780 mg, 4.75 mmol), 48% hydrobromic acid (3 mL) was stirred under refluxing conditions for 7 hr. 48% Hydrobromic acid (2 mL) was further added and the mixture was stirred under refluxing conditions for 3 hr. The mixture was concentrated under reduced pressure, and diisopropyl ether (2 mL) and ethanol (1 mL) were added to the residue. The precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound (984 mg, 89%) as a brown solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[OH:20])[CH:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:15][CH2:14]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]O>>[CH3:25][O:23][C:22](=[O:24])[CH2:21][CH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:3](=[O:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:19]([OH:20])[CH:18]=2)[CH2:14][CH2:15]1
Reactant: CO
Reactant: O=C(O)CC1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CC1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
Analogously to the description in Example 2, 7.5 g of 5-benzoyl-6-hydroxy-indane-1-acetic acid methyl ester and 50 ml of 2 N sodium hydroxide solution in 300 ml of methanol give 5-benzoyl-6-hydroxy-indane-1-acetic acid of melting point 148°-150° C (from ether-petroleum ether).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH2:51][CH3:52])[C:43]2[C:48]([CH:49]=O)=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH2:51][CH3:52])[C:43]2[C:48]([CH:49]=[C:2]([CH3:3])[CH3:1])=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCN(c1ncccc1C=O)C1CCN(Cc2ccccc2)CC1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with n-butyl lithium (1.6M, 4.3 ml, 6.8 mmol), isopropyltriphenylphosphonium iodide (2.9 g, 6.8 mmol), and 1-benzyl-4-[N-ethyl-N-(3-(formyl)-2-pyridinyl)amino]piperidine (XXI, EXAMPLE 12, 1.1 g, 3.4 mmol), the title compound is obtained, NMR (300 MHz, CDCl3) 1.08, 1.71-1.80, 1.90, 1.90-2.00, 2.01, 2.98-3.03, 3.30-3.45, 3.43, 3.57, 6.18, 6.89, 7.32-7.45, 7.46 and 8.24δ.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccnc2ccsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thieno[3,2-b]pyridin-7-ol (20 g, 0.132 mol) was suspended in phosphorous oxy chloride (80.9 g, 0.528 mol) and stirred at 100 C for 2 hours. The solution was cooled to room temperature and was poured over ice. The aqueous solution was neutralized with sodium hydroxide and the resulting precipitate was collected by filtration and washed with water. The filter cake was taken up in dichloromethane and dried over magnesium sulfate. The solution was filtered and the filtrate was concentrated to dryness to give 7-chlorothieno[3,2-b]pyridine as a brown liquid which solidified to a beige solid under high vacuum. Yield: 20.4 g (91%); MS [M+H]+ 169.9; 1HNMR (CDCl3) δ: 8.7 (d, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.3 (d, 1H) ppm.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:5]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[N:20]=C(C)C=C(C)[N:18]2[N:17]=1)(=[O:15])=[O:14].OO.S(=O)(O)[O-].[Na+]>O>[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:5]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]([NH2:20])[NH:18][N:17]=1)(=[O:15])=[O:14]
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Agent: O=S([O-])O
Agent: OO
Agent: [K+]
Solvent: O
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Temperature: 17 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (72.9 g of 85 percent pellets, 1.20 mol) was dissolved in one liter of water in a 2 liter round bottom flask and 113.3 g (0.30 mol) of wet N-(2,6-dichloro-3-methylphenyl)-5,7-dimethyl-1,2,4,-triazolo[1,5-a]pyrimidine-2-sulfonamide was added with stirring. The mixture obtained was cooled to 17° C. and 100 ml of 30 percent hydrogen peroxide solution (about 1 mole) was added with stirring over a 0.5 hour period so that the temperature did not exceed 40° C. The reaction was found to be complete after three hours by high pressure liquid chromatography. An aqueous solution of sodium bisulfite was added to quench the excess hydrogen peroxide and the solution obtained was filtered through celite and then acidified with concentrated hydrochloric acid. The precipitate that formed was collected by filtration, washed with water, and partially dried. This material, which is the N1 -acetyl derivative of the desired product, was dissolved in 800 ml of tetrahydrofuran and the resulting solution was combined with 100 ml of water and 100 ml of concentrated hydrochloric acid. This mixture was heated at reflux with stirring in a two liter round bottom flask overnight. The solvent was removed by evaporation under reduced pressure and the resulting aqueous suspension was filtered to collect the solid product. This was washed with water and dried to obtain 59.3 g (61 percent of theory) of the title compound as a white solid. This compound has an m.p. of 206°-8° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:13][C:12]=1[CH2:22][CH2:23][CH3:24])=[O:10].[N:25]1([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:9]([C:11]3[O:15][C:14]([CH:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)=[N:13][C:12]=3[CH2:22][CH2:23][CH3:24])=[O:10])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCCc1nc(C2CCCCC2)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(C2CCCCC2)oc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 50 above, 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H30N4O3 (m/e) 398, obsd 399 (M+H).