Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][CH:21]1[CH2:26][CH:25]2[CH2:27][CH:23]([C:24]2([CH3:29])[CH3:28])[CH:22]1[CH2:30]O.[CH2:32]([N:34](S(F)(F)F)[CH2:35]C)C.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][CH:21]1[CH2:26][CH:25]2[CH2:27][CH:23]([C:24]2([CH3:29])[CH3:28])[CH:22]1[CH2:30][N:34]([CH3:35])[CH3:32]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1(C)C2CC(Nc3cnn(CC(=O)NCc4ccncc4)c(=O)c3Br)C(CO)C1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC1C(Nc2cnn(CC(=O)NCc3ccncc3)c(=O)c2Br)CC2CC1C2(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
rac-2-[5-Bromo-4-{[2-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]amino}-6-oxopyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (43 mg, 0.0877 mmol) in dichloromethane (3 mL) was mixed with (diethylamino)sulfur trifluoride (17 μL, 0.128 mmol) at ˜78° C. and stirred at −78° C. for 10 minutes and then stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform/methanol=10/1) to give the desired product (16% yield).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=[O:33])[C:10](=[CH:29]OCC)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([O:23][CH2:24][CH2:25][O:26][CH3:27])[C:14]=2[Br:28])=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:35]O>C(O)C>[Br:28][C:14]1[C:15]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=1[C:11]([C:10]1[CH:29]=[N:35][O:33][C:9]=1[CH:6]1[CH2:8][CH2:7]1)=[O:12]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)c(OCCOC)c1Br)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)c2cnoc2C2CC2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Sodium acetate (1.65 g) was added to a stirred mixture of 3-cyclopropyl-2-ethoxymethylene-1-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]propan-1,3-dione (8.5 g) and hydroxylamine hydrochloride (1.77 g) in ethanol. The mixture was stirred at room temperature overnight and then evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was chromatographed on silica eluted with a mixture of ethyl acetate and cyclohexane (1:5) to give 4-[2-bromo-3-(2-methoxyethoxy) 4-methylsulphonylbenzoyl]-5-cyclopropylisoxazole (compound 181) as a yellow oil (3.3 g), NMR (CDCl3), 1.3(2H, m), 1.4(2H,m), 2.6(1H, m), 3.3(3H, s), 3.5(3H, s), 3.9(2H, m), 4.5(2H, m), 7.3(1H, d), 8.0(1H, s), 8.1(1H, d).
Reaction SMILES: NC(N)=O.[C:5]1([C:11]2[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][N:20]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][C:24]1([CH3:25])[C:13]2[S:12][C:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:15][C:14]=2[CH2:16][CH2:17][O:18]1
Reactant: OCCc1csc(-c2ccccc2)n1
Reactant: CC(=O)CCN(C)C
Agent: NC(N)=O
Product: CN(C)CCC1(C)OCCc2nc(-c3ccccc3)sc21

Procedure:
By following the procedure of Example 2(a) but using as starting material in Example 2(a) an appropriate starting material of formula II, for example, those described in Examples 2 to 14 and an appropriate aminoketone of formula III in which R2 and n are as described above and A is CH2NR4R5 wherein R4 and R5 are as described above, the amino compounds of formula I listed in Examples 31 to 46 are obtained. For example, according to the present procedure 2-phenyl-4-(β-hydroxyethyl)thiazole condenses with 1-(N,N-dimethylamino)-3-butanone to give the title compound, identical to the amine described in Example 31.
Reaction SMILES: C([Mg]Br)C.Br[C:6]1[N:10]2[N:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[N:16]1[CH:17]=[CH:18][N:19]2[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][C:20]=12>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[N:10]([C:6]([CH:25]([C:23]3[CH:22]=[CH:21][C:20]4[N:19]([CH:18]=[CH:17][N:16]=4)[CH:24]=3)[OH:26])=[CH:7][N:8]=2)[N:11]=1
Reactant: O=Cc1ccc2nccn2c1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: OC(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Reaction time: 0.5 h

Procedure:
Ethyl magnesium bromide (3 M in Et2O, 333 μL, 1 mmol) was added to a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (116 mg, 0.5 mmol) in THF (5 mL) at rt . The RM was stirred for 30 min and imidazo[1,2-a]pyridine-6-carbaldehyde (154 mg, 2 mmol) in THF (3 mL) was added dropwise. After 1 h the RM was extracted with a solution of NH4Cl and EtOAc. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, Hexane/EtOAc=95:5->0:100) to afford the title compound as a yellowish crystalline compound (tR 2.72 min (conditions 3), MH+=300.2).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20]([CH3:24])([OH:23])[CH2:19][CH2:18]1>>[O:12]1[CH2:13][CH2:14][C@@H:10]([O:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([NH:16][CH:17]3[CH2:22][CH2:21][C:20]([CH3:24])([OH:23])[CH2:19][CH2:18]3)[N:4]=2)[CH2:11]1
Reactant: CC1(O)CCC(N)CC1
Reactant: Clc1ncc(Br)c(O[C@@H]2CCOC2)n1
Agent: Cl
Product: CC1(O)CCC(Nc2ncc(Br)c(O[C@@H]3CCOC3)n2)CC1

Procedure:
Using the procedure of Example 78, Step 2, (R)-5-bromo-2-chloro-4-(tetrahydrofuran-3-yloxy)pyrimidine was reacted with 4-amino-1-methylcyclohexanol HCl salt to provide the title compound. MS (ESI) m/z: Found: 372 (M++1), Calc. 371 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(Cl)cc1
Yield: 74.3 %

Procedure:
The title compound was synthesized from methyl 4-(4-chlorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (85 mg, 0.293 mmol) and lithium hydroxide monohydrate (67 mg, 1.58 mmol) according to General Procedure 7. The crude product was purified by flash chromatography (0-80% EtOAc/Heptane) to give 4-(4-chlorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (14) as a light red solid (60 mg, 69%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.04-2.14 (m, 1H), 2.42-2.59 (m, 1H), 2.59-2.65 (m, 2H), 2.72 (dd, J=13.37, 7.91, 1H), 2.78 (dd, J=13.37, 6.83, 1H), 3.21-3.29 (m, 1H), 6.29 (s, 1H), 7.14-7.19 (m, 2H), 7.24-7.28 (m, 2H); LCMS-MS (ESI+) 274.2 (M−H); HPLC (UV=100%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[S:23](=[O:27])(=[O:26])([OH:25])[OH:24]>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[S:23]([O-:27])([OH:26])(=[O:25])=[O:24]
Reactant: O=S(=O)(O)O
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CC(C)=O
Product: O=S(=O)([O-])O
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a solution of 5.0 g olanzapine base in 150 ml acetone was added at room temperature 0.435 ml of 95% sulfuric acid. The mixture was stirred overnight at 4° C. The formed crystals were isolated by filtration, washed with 20 ml of acetone and 20 ml of ether and dried overnight at 40° C. in vacuo. Yield: 5.87 g (approx. 0.25 eq. acetone present).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][S:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[NH:17][CH2:16][CH2:15]2>>[C:1]1([NH:7][C:8]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([S:11][CH3:10])=[C:20]([C:21]([F:22])([F:24])[F:23])[CH:19]=3)[CH2:15][CH2:16]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CSc1cc2c(cc1C(F)(F)F)NCC2
Product: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccccc1)CC2
Yield: 34 %

Procedure:
This was prepared from phenyl isocyanate and 5-methylthio-6-trifluoromethyl indoline in 34% yield m.p. 163-165° C.
Reaction SMILES: O.O.Cl[Sn]Cl.[N:6]1([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[NH:13][N:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[N:6]1([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[NH:13][N:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(-n3ccnc3)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]nc(-n3ccnc3)c2c1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
SnCl2.2H2O (1.03 g, 4.56 mmol) was added to 3-(1H-imidazol-1-yl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (210 mg, 0.912 mmol) in ethyl acetate (100 mL). The mixture was heated to reflux for 1 hour. The cooled reaction mixture was diluted with ethyl acetate and treated dropwise with saturated aqueous sodium bicarbonate. The slurry was stirred for 30 minutes and then filtered through celite. The filtrate was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to yield 3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine (90 mg, 49% yield) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][CH:10]([C:14]#[N:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2].O1CCCC1.B#B.[BH4-].[Na+]>COCCOCCOC>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][CH:10]([CH2:14][NH2:15])[CH2:11][CH:12]([OH:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Agent: B#B
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: C1CCOC1
Product: NCC1CCc2ccc([N+](=O)[O-])cc2C(O)C1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
20 g of 3-nitro-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile were added under nitrogen to 200 ml of anhydrous tetrahydrofuran and diborane [prepared by introducing a solution of 23 g of sodium borohydride in 640 ml of diglyme at 20° C. over 4 hours into a solution of 118 g of a ether-boron trifluoride complex in 250 ml of diglyme (J.A.C.S., Vol. 82 (1960), p. 685] was bubbled into the mixture for 30 minutes at room temperature. The mixture was then heated for 31/2 hours on a bath at 50° C. and was then cooled to 20° C. 100 ml of water were added thereto dropwise over 10 minutes followed by 50 ml of fuming hydrochloric acid. The mixture was refluxed for an hour and was cooled to 20° C. after which 100 ml of water were added. The mixture was extracted with ethyl acetate and the organic phase was washed with water. The combined aqueous phases were made alkaline at 10° C. with concentrated sodium hydroxide and was iced. The mixture was vacuum filtered and the white product was washed with water. The wash waters were washed with methylene chloride containing 20% of methanol and the organic phase was washed with water. The while precipitate from the aqueous phase was dissolved in 100 ml of water and the solution was added to the organic extracts. The mixture was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 14 g of a yellow oil which was crystallized from ethyl acetate to finally obtain 13 g of a mixture of cis and trans isomers of 3-nitro-7-aminomethyl-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-ol melting at ≃150° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C(O)(=O)C>O>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:18]([CH2:17][C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13])[C:5]2=[O:7]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C1OC(=O)c2c(O)cccc21
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)c(OC)c1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
A mixture of 3-hydroxyphthalic anhydride (1.24 g, 7.6 mmol), 2,4-dimethoxybenzylamine (1.14 mL, 7.6 mmol) and acetic acid (5 mL) was heated at 80° C. for 24 hours. The mixture was allowed to cool and diluted with water (20 mL). The white solid was collected by filtration, washed well with water and dried to give the title compound (1.73 g, 73%). 1H NMR (DMSO-d6) 11.00 (1H, s), 7.62 (1H, dd), 7.29 (1H, d), 7.21 (1H, d), 6.90 (1H, d), 6.56 (1H, d), 6.43 (1H, dd), 4.59 (2H, s), 3.79 (3H, s), 3.72 (3H, s). MS: [M−H+] 314.
Reaction SMILES: Cl.C[O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.Cl>[OH-].[K+].O>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:23])=[O:3])=[CH:10][CH:9]=3)=[CH:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
4-[(7-Chloro-4-quinolinyl)amino]benzoic acid methyl ester hydrochloride (15.0 g, 43.0 mmol) is stirred in 150 mL of 1N KOH (aq) and refluxed for 1.5 hours, over which time the material dissolves. The hot solution is then poured into a 1 L Erlenmeyer flask containing a stirring solution of 107 mL of 1N HCl (aq) in 500 mL of water. A yellow solid forms immediately and the mixture is allowed to cool to room temperature. The solid is filtered and washed with cold methanol and ether, and allowed to air dry in the funnel, to afford 9.31 g (31.2 mmol, 73% yield) of product as a pale yellow solid: 1H NMR (Me2SO-d6, 300 MHz) δ12.6 (br s, 1H) 9.4 (br s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 7.94 (m, 3H), 7.6 (d of d, J=2.1, 9.3 Hz, 1H), 7.4 (d, J=8.7 Hz, 2H) 7.2 (d, J=5.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]([CH:21]([CH:27]([CH3:29])[CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]=[O:20]>>[CH2:25]([O:24][C:22]([CH:21]([NH:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH:27]([CH3:28])[CH3:29])=[O:23])[CH3:26]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCOC(=O)C(N=C=O)C(C)C
Product: CCOC(=O)C(NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1)C(C)C
Yield: 95.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 14.56 mg (0.0852 mMol) ethyl 2-isocyanato-3-methylbutyrate, 25.0 mg (95%) of the title compound were recovered.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1.[CH2:17](Br)[C:18]#[CH:19].Cl>CO.CN(C=O)C.O>[CH2:19]([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)[C:18]#[CH:17]
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: C#CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: C#CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Reaction time: 2.5 h
Yield: 28.3 %

Procedure:
To a stirring solution of NaOH in MeOH (2.5 M, 18.8 mL) and DMF (60 mL) was added 1 (4.33 g, 18.8 mmol). The mixture was allowed to stir for 45 min at 23° C. before propargyl bromide (80% in PhMe, 3.36 mL, 22.56 mmol) was added slowly over 10 min. After 2.5 h, an aqueous solution of 1 M HCl was added to achieve pH=6, where upon a white precipitate forms. Water was then added and the organic layer was extracted 3×EtOAc and the combined organic extracts washed 1×H2O, 1× brine, and then dried over MgSO4. The solvents were removed in vacuo and the crude residue purified by flash chromatography using Hexanes:EtOAc on a Biotage purification system to yield 3 as a pale yellow solid (1.43 g, 29%).
Reaction SMILES: [Cl:1][CH:2]([CH2:10][CH2:11][Cl:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:13]O>Cl>[Cl:1][CH:2]([CH2:10][CH2:11][Cl:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:13])=[O:8]
Reactant: CO
Reactant: O=C(O)CCCCC(Cl)CCCl
Agent: Cl
Product: COC(=O)CCCCC(Cl)CCCl
Yield: 98.6 %

Procedure:
9 g (0.042 moles) of (+)-6,8-dichlorooctanoic acid are dissolved in 120 ml of methanol containing 0.45 ml of aqueous hydrochloric acid at 37% by weight. The solution is refluxed for two hours, the solvent is evaporated at reduced pressure, 17 ml of toluene are added and the obtained solution is washed twice with 10 ml of water. The toluene phase is concentrated under vacuum, thus obtaining 9.4 g of methyl (+)-6,8-dichlorooctanoate (yield=98.6%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12]3)=[CH:8][CH:9]=2)[C:4]([S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[N:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]3)=[CH:8][CH:9]=2)[C:4]([S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[N:3]1
Reactant: Cn1nc(S(=O)(=O)c2cccc3ccccc23)c2cc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(S(=O)(=O)c2cccc3ccccc23)c2cc(N3CC[C@@H](N)C3)ccc21
Temperature: 25 °C
Yield: 91.6 %

Procedure:
tert-Butyl {(3R)-1-[1-methyl-3-(naphthalen-1-ylsulfonyl)-1H-indazol-5-yl]pyrrolidin-3-yl}carbamate (0.200 g, 0.395 mmol) was dissolved in dichloromethane and to this was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature over night. The solvent and excess trifluoroacetic acid was evaporated and the residue was dissolved in ethyl acetate. The organic mixture was washed with saturated aqueous potassium carbonate. The solvent was evaporated to afford a pure (3R)-1-[1-methyl-3-(naphthalen-1-ylsulfonyl)-1H-indazol-5-yl]pyrrolidin-3-amine (15, 0.147 g, 92%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=O.[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (24 mg, 0.050 mmol), β-alanine (2.39 g, 26.8 mmol) and NaOMe solution (40 mL, 20 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was further purified by silica gel chromatography (0-80% EtOAc/hexanes+2% AcOH) to give 20 mg of the title compound. MS: (+) m/z 535.21 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:29])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1

Procedure:
125 g of crude omeprazole, obtained by oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole with 3-chloroperoxybenzoic acid, were dissolved while stirring in a mixture of 100 ml of 40% of aqueous methylamine and 125 ml of acetone at room temperature. To this clear solution was added 2000 ml of acetone, the combined solution was stirred for 1 hour at room temperature, and thereafter cooled to a temperature in the range of −10 to −15° C. The product formed was filtered off and then washed with acetone. The crystals formed still wet were suspended in 400 ml of water at room temperature and thereafter stirred vigorously for 1 hour while cooling to a temperature not exceeding 20° C. with an ULTRA-TURRAX® mixer (type 18/10, Janke&Kunkel). The product obtained—omeprazole form C was filtered off, washed with water, and dried in vacuo at room temperature to constant weight.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH:18](O)[CH3:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH:18]=[CH2:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)c1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Solvent: Cc1ccccc1
Product: C=Cc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Yield: 96 %

Procedure:
To a solution of 1-(2-(3,5-diphenylpyridazin-4-yl)oxazol-4-yl)ethanol (30 mg, 0.08 mmol) in toluene (4 mL), p-tolenesulfonic acid (10 mg) was added and the reaction mixture was refluxed for 2 h. After complete consumption of starting materials, reaction was quenched by solid K2CO3. Solvents were evaporated under reduced pressure to obtain the crude product that was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-Hexane) to furnish 2-(3,5-diphenylpyridazin-4-yl)-4-vinyloxazole (25 mg, 89%) as a gummy liquid.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][C:27]([C:42]#[N:43])=[N:28][C:29]=3[NH:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:12][C@@H:11]1[CH2:44][O:45][CH3:46])(=O)C1C=CC=CC=1>N>[OH:15][C@@H:14]1[C@H:10]([OH:9])[C@@H:11]([CH2:44][O:45][CH3:46])[O:12][C@H:13]1[N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][C:27]([C:42]#[N:43])=[N:28][C:29]=2[NH:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](O)[C@@H]1O
Reaction time: 24 h

Procedure:
(2R,3R,4R,5R)-4-(Benzoyloxy)-5-[2-cyano-6-(phenethylamino)-9H-purin-9-yl]-2-(methoxymethyl)tetrahydro-3-furanyl benzoate (8.0 g, 19.5 mmol) (preparation 46) was dissolved in a saturated ethanolic solution of ammonia (300 ml). The solution was allowed to stand at room temperature for 24 hr, then re-saturated with ammonia gas and allowed to stand for a further 48 hr. The solvent was then removed under reduced pressure and dichloromethane added to the residue. The dichloromethane was then removed under reduced pressure and more dichloromethane (50 ml) added. The insoluble material was filtered off and dried. This was found to be the title compound (3.1 g) which was a solid.