Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14])=[O:4].C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[N:41]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[C@@H:43](O)[CH2:42]2>C1COCC1.CC#N>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]([C:13]([O:15][C@@H:43]1[CH:44]2[CH2:47][CH2:48][N:41]([CH2:46][CH2:45]2)[CH2:42]1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1ccccc1NC(C(=O)O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine 2-(2-(methoxycarbonyl)phenylamino)-2-phenylacetate (I34) (611 mg, 1.47 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (559 mg, 1.47 mmol), and HOBT (226 mg, 1.47 mmol) are dissolved in THF (7 mL) and MeCN (3 mL). (R)-Quinuclidin-3-ol (375 mg, 2.95 mmol) is added and the mixture is stirred at RT for 1 hour. Solvents are evaporated, the residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated. The crude is purified by preparative HPLC and the collected fractions are evaporated, the residue is dissolved in EtOAc and washed with NaHCO3 and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated to afford compound the title compound as a colorless compound (95 mg, 16% yield, mixture of diastereoisomers).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1.O>[C:10]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1ccsc1N
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1sccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-Amino-thiophene-3-carboxylic acid amide (20.3 g, 143 mmol) in dry pyridine (150 mL) is cooled to 0° C. Acetylchloride (11 mL, 156 mmol) is added dropwise to the solution. The resulting mixture was stirred at room temperature overnight. The mixture is then diluted with water and the resulting suspension is filtered. The cake is dried overnight in a vacuum-oven at 50° C. to yield the desired product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH:33]([OH:37])[C:34](O)=[O:35])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH:33]([OH:37])[C:34]([NH:16][CH2:15][CH2:14][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:35])=[CH:38][CH:39]=1
Reactant: C#CCOc1ccc(CCN)cc1OC
Reactant: O=C(O)C(O)COc1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(O)COc2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (5.0 g, 20 mmol) and N,N-diisopropylethylamine (10 g, 78 mmol) are dissolved in 70 ml of N,N-dimethylformamide. To this solution 3-(4-chloro-phenoxy)-2-hydroxy-propionic acid (4.3 g, 20 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (9.5 g, 22 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 6:4) to give 3-(4-chloro-phenoxy)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-propionamide (Compound E1.24).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Reactant: O=C(Cl)C1CCCCC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)C2CCCCC2)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (0.98g) as starting compound was reacted and treated in the same manner as in Example 1 using cyclohexanecarbonyl chloride (0.54 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.77 g) to give 4-amino-5-chloro-N-(1-(3-cyclohexanecarbonylaminopropyl)pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:13]([O:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=O)[NH:20][CH:19]=1)=[O:17])[CH3:14]>N1CCCCC1.CC(O)C>[CH2:13]([O:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21](/[CH:24]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[C:3]([I:12])[C:2]([F:1])=[CH:10][CH:9]=3)[NH:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(ccc(F)c2I)N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1C
Temperature: 80 °C

Procedure:
A suspension of 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.5 g, 1.8 mmol) (Example 2A) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (0.39 g, 2.17 mmol) (Example 116A above) in 1% piperidine in 2-propanol (6 mL) was heated at 80° C. for 3 h. The precipitate was collected and washed with water to give (Z)-5-(5-Fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. (Yield 0.67 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:23])=[CH:17][CH:18]=1
Reactant: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 63.7 %

Procedure:
3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.08 mmol), isopropylamine (0.010 ml, 0.12 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28 mg, 0.12 mmol) in dry methylene chloride (1 ml) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and was purified by a silica gel column chromatography (methylene chloride:ethyl acetate=4:1) to obtain the title compound (18 mg, 0.051 mmol, yield 64%).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[OH:38][C:39]12[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][C:41]([C:49](O)=[O:50])([CH2:42]3)[CH2:40]1)[CH2:46]2>O1CCCC1.C(OCC)(=O)C>[Cl:8][C:5]1[S:4]/[C:3](=[N:2]\[C:49]([C:41]23[CH2:42][CH:43]4[CH2:44][CH:45]([CH2:46][C:39]([OH:38])([CH2:48]4)[CH2:40]2)[CH2:47]3)=[O:50])/[NH:7][CH:6]=1
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: Nc1ncc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(/N=c1/[nH]cc(Cl)s1)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-5-chlorothiazole hydrochloride (Aldrich) (1.00 g, 5.84 mmol) in tetrahydrofuran (50 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.12 g, 5.84 mmol), 1-hydroxybenzotriazole (0.79 g, 5.84 mmol), triethylamine (2.04 mL, 14.6 mmol), and 3-hydroxyadamantane-1-carboxylic acid (Acros) (1.15 g, 5.84 mmol). The mixture was stirred overnight at room temperature and was diluted with ethyl acetate, washed with 1 M aqueous sodium carbonate, dried (Na2SO4), filtered and concentrated. Purification by column chromatography (SiO2) using a gradient of 0% to 100% ethyl acetate:hexane provided the title compound. MS (ESI+) m/z 313 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (640 mg, 1.54 mmol) in tetrahydrofuran (8 mL) was added trimethyl(trifluoromethyl)silane (0.683 mL, 4.62 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.308 mL, 0.308 mmol) at 0° C. After the mixture was stirred at 0° C. for 30 min and at room temperature for 1 h, to the mixture was added 1N hydrochloric acid (2 mL) at 0° C., and the reaction mixture was stirred at room temperature for 30 min. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (329 mg, 0.678 mmol, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: OC1CCN(Cc2ccc(Br)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OC1CCN(Cc2ccc(Br)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
0.428 g (0.00184 mol) of 1-(4-bromo-benzyl)-piperidin-4-ol was dissolved in 8 ml of dimethylformamide and treated with 0.097 g (0.00079 mol) of dimethylaminopyridine and 0.222 g (0.00158 mol) of 4-fluoro-benzoic acid. The mixture was cooled to 0° and 0.334 g (0.00174 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added. The mixture was warmed to room temperature and stirred for 18 hrs. The solvent was distilled off and the residue was taken up in ethyl acetate and treated with silica gel. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.47 g (76%) of 1-(4-bromo-benzyl)-piperidin-4-yl 4-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[P:27]([O-:39])([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28]>>[P:27]([O:39][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:28]
Reactant: CN1CCC(=NO)CC1
Reactant: CCCCOP(=O)([O-])OCCCC
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CCCCOP(=O)(OCCCC)OC1(N=O)CCN(C)CC1

Procedure:
Dibutyl 1-methyl-4-nitrosopiperidin-4-yl phosphate was prepared from 1-methyl-piperidin-4-one oxime, lead tetraacetate and dibutyl phosphate using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 4.03-4.17 (4H, m), 2.77-2.88 (2H, m), 2.27-2.40 (6H, m), 2.12-2.24 (4H, m), 1.59-1.83 (6H, m), 1.38 (4H, q, 7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:33]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOCC>[ClH:33].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[O:13])[C:4]=23)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (65 mg, 0.13 mmol) in neat TFA (5 mL) was stirred at room temperature for 20 minutes. TFA was then removed in vacuo, and the residue was evaporated from CH2Cl2 (10 mL). The oily residue obtained was dissolved in CH2Cl2 (0.5 mL) and treated with 2M HCl in Et2O. After 30 minutes at room temperature, the solid formed was filtered, washed with additional Et2O and dried to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide hydrochloride (38 mg, 62% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.79 (s, 1H), 9.31 (s, 1H), 8.27 (br s, 1H), 8.23 (s, 1H), 7.59 (br s, 1H), 3.46-3.41 (m, 2H), 3.34-3.27 (m, 2H), 3.11-3.04 (m, 1H), 2.88-2.80 (m, 1H), 2.17-2.11 (m, 1H), 1.94-1.85 (m, 3H), 1.79-1.74 (m, 2H), 1.72-1.65 (m, 3H), 1.60-1.55 (m, 2H), 1.52-1.45 (m, 1H); LCMS (APCI+) m/z 406.0, 408.1 (M+H)+, Retention time=2.42 minutes (Method 2).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:28]([O:29]C(=O)C)[C@H:27]([O:33]C(=O)C)[C@@H:26]([CH2:37][O:38]C(=O)C)[O:25][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[CH2:24])=[CH:17][CH:16]=1)(=O)C.C[O-].[Na+]>CO.O1CCCC1>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]=[CH2:24])=[CH:19][CH:20]=1)[C@@H:6]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:33])[C@H:28]([OH:29])[C@H:5]1[OH:4]
Reactant: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
To a solution of 2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.44 g) in methanol (2.5 mL) and tetrahydrofuran (1.5 mL) was added sodium methoxide (28% methanol solution, 0.30 mL), and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction mixture was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloro-methane/methanol=10/1) to give 2-(4-allyloxybenzyl)phenyl β-D-glucopyranoside (0.23 g).
Reaction SMILES: CS(OC(C)C(OC)(OC)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)(=O)=O.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].[C:31](O)(=O)C>>[O:14]([C:15]1[CH:20]=[C:19]([CH:27]([CH3:31])[C:26]([OH:29])=[O:28])[CH:18]=[CH:17][CH:16]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:8][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: CC(=O)O
Reactant: COC(OC)(c1cccc(Oc2ccccc2)c1)C(C)OS(C)(=O)=O
Agent: [Na+]
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1

Procedure:
The oil from Example 27, 1,1-dimethoxy-1-(3-phenoxyphenyl)prop-2-yl methanesulfonate, and 14.9 g of sodium acetate are dissolved in 200 ml of acetic acid and the resulting mixture is heated to reflux. After refluxing for four hours, the mixture is cooled to 25° C. and most of the acetic acid is removed by distillation. The residue is dissolved in 150 ml of ethyl ether and extracted several times with water. The ether is evaporated and replaced by 10 ml of methanol, 50 ml of water, and 7.5 g of sodium hydroxide. The resulting mixture is heated to reflux and refluxed for one hour. The methanol is removed by distillation and the resulting aqueous solution is extracted with 200 ml methylene chloride and acidified with hydrochloric acid. The suspension formed is extracted with 150 ml of methylene chloride and the organic layer is dried over magnesium sulfate. The solvent is removed to yield 4.04 g of 2-(3-phenoxyphenyl)-propionic acid [which is characterized by an NMR spectra in deuterochloroform of τ =8.54 (doublet, J=2.5), 5.23 (quartet, J=2.5), 2.45-3.15 (multiplet), 1.5.]
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=C(OC)C=C[C:9]=1[C:10]([NH:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Li])[CH2:21]CC.C(Cl)(=O)C.O.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:32][O:33][C:34]1[CH:17]=[C:8]2[C:9](=[CH:31][CH:30]=1)[C:10](=[O:11])[N:12]([CH3:13])[C:20]([CH3:21])=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CNC(=O)c1ccc(OC)cc1Cc1ccccc1
Reactant: [Li]CCCC
Solvent: O
Solvent: CC(=O)Cl
Product: COc1ccc2c(=O)n(C)c(C)c(-c3ccccc3)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of 11 (5.00 g, 19.6 mmol) in THF under Argon at −70° C. was added n-butyllithium (18.8 mL, 2.5M). After 0.5 h acetyl chloride (2.10 mL, 29.4 mmol) was added. Stirred 0.5 h then added water and warmed to room temperature. Removed the solvent in vacuo and added 1N hydrochloric acid. Extracted with ethyl acetate (4×) and dried the combined organic portions with magnesium sulfate (anh.). Removal of the solvent in vacuo followed by trituration with ether gave 12 as a light solid (2.54 g, 9.10 mmol, 46.4%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:41][N:42]1[C:46]([CH2:47][CH2:48]O)=[CH:45][CH:44]=[N:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH3:41][N:42]1[C:46]([CH2:47][CH2:48][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:27][CH2:28]3)=[CH:33][CH:34]=2)=[CH:45][CH:44]=[N:43]1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: Cn1nccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (3.70 mL, 18.77 mmol) was added to 4-(1-(3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenol (6.2 g, 17.06 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (2.368 g, 18.77 mmol) and triphenylphosphine (4.92 g, 18.77 mmol) in THF (150 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 1 day. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford crude product. Product was dissolved in DCM (100 mL) and washed with 2M NaOH (100 mL) twice. Organic layer was evaporated to afford 6-(4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine anhydrous Form A (4.95 g, 61.5%) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9](Cl)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CS(C)=O>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([N:17]3[C:16](=[O:18])[C:15]4=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]4[C:13]3=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC1CCN(C2CCCCC2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1C1CCN(C2CCCCC2)C1

Procedure:
A rapidly stirred suspension of 160 g. of N-cyclohexyl-3-chloropyrrolidine, 148 g. of potassium phthalimide and 700 ml. of dimethyl sulfoxide is heated at 110°-113° C. for 16 hours and filtered while hot. Water is added and the precipitate is filtered off, washed with water, air-dried and recrystallized from iso-octane-benzene to give 1-cyclohexyl-3-phthalimidopyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=C(Cc1ccc(Cl)nc1)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
2-chloropyridine-5-acetic acid (6.0 gm, 34 mmole), 3-fluorobenzylamine (4.5 ml, 34 mmole), PyBOP (18 gm, 36 mmole), and DIEA (12.5 ml, 75 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol (6.3 gm, 70%); H1-NMR INOVA-500 (CDCl3) δ 3.562 (s, 2H), 4.429 (d, J=6.5 Hz, 2H), 5.868 (s, 1H), 6.929-7.015 (m, 3H), 7.300-7.333 (m, 2H), 7.668 (dd, J=8, 2.5 Hz, 1H), 8.280 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].O.[OH-].[Li+].CO.O>O1CCCC1>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([OH:11])=[O:10])[CH2:4][CH2:5]1)#[N:2]
Reactant: COC(=O)c1cccc(C2(C#N)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.9 %

Procedure:
To a solution of methyl 3-(1-cyanocyclopropyl)benzoate (1.3 g, 6.4 mmol) in tetrahydrofuran (12 mL) were added lithium hydroxide-monohydrate (0.44 g, 11 mmol), methanol (4.0 mL) and water (6.0 mL), and the mixture was stirred at room temperature for 14 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (5.0 mL). The mixture was adjusted to pH 5 by slowly adding 1N hydrochloric acid. The precipitated white precipitate was collected by filtration, washed with water, and air-dried to give the title compound (0.73 g, 61%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:1][C:2]1[C:7]2[N:8]3[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2c(n1)sc1cccc(C)c12
Yield: 47.3 %

Procedure:
Ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 4-methly-2-amino benzothiazole (8.0 g, 48.7 m.mol) and ethyl bromopyruvate (14.0 g, 71.7 mmol), 6.0 g (45% Yield) of ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as a brown solid. (M+H) 261.