Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][N:15]([CH3:38])[C:16](=[O:37])[CH2:17][CH2:18][C:19]2[CH:36]=[CH:35][C:22]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=3[C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>O.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][N:15]([CH3:38])[C:16](=[O:37])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=3[C:27]([OH:29])=[O:28])=[CH:35][CH:36]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccccc1COc1ccc(CCC(=O)N(C)CCc2ccc(OC)c(OC)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCN(C)C(=O)CCc2ccc(OCc3ccccc3C(=O)O)cc2)cc1OC
Yield: 87.5 %

Procedure:
Lithium hydroxide (12 mg, 0.488 mmol) in water (1 ml) was added to methyl 2-[(4-{3-[[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (120 mg, 0.244 mmol) dissolved in THF (2 ml). The mixture was then irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and washed with brine and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, then MeOH/DCM (1:99) as eluant gave 102 mg the desired product, yield 87.5%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:34][CH3:35]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:34][CH3:35])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=S(=O)(c1ccccc1)c1ccc2[nH]c3c(c2c1)CCN(Cc1ccccc1)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(Cc1ccccc1)CC2

Procedure:
A 0° mixture of 3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (EXAMPLE 1, Step II, 301 mg, 0.723 mmol) in dry DMF (5 mL) is treated with sodium hydride (60% in oil, 32 mg, 0.795 mmol), and allowed to warm to 20-25° over 1.5 hr. The mixture is then cooled (0°), treated with iodoethane (64 μL, 0.795 mmol) and allowed to slowly warm to 20-25° under nitrogen over 72 hr. The resultant mixture is diluted with ethyl acetate (50 mL) and washed with H2O (3×25 mL) and saline (25 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid. The solid is purified via chromatography (20 g SG; ethyl acetate/heptane, 65/35) to give the indole as a solid, mp=188-191°; IR (drift) 1477, 1373, 1300, 1289, 1157, 1148, 1094, 766, 756, 738, 728, 701, 694, 645 and 621 cm−1; NMR (300 MHz, CDCl3) 8.10-8.20, 7.90-8.05, 7.65-7.75, 7.20-7.50, 4.11, 3.82, 2.85-3.05 and 1.27 δ; MS (EI) m/z 444 (M+), 326, 324, 312, 167, 154, 132, 118, 96, 91 and 64.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(C)C)(C)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(c2ccc(CO)cc2)CC1
Yield: 61.9 %

Procedure:
To a solution of tert-butyl-[4-(1,4-dioxa-spiro[4.5]dec-8-yl)benzyloxy]dimethylsilane (12.1 g, 33.3 mmol) in acetone (12 ml) and water (1.2 ml) was added pyridinium p-toluenesulfonate (2.51 g, 9.99 mmol) at room temperature. The mixture was refluxed for 3 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=60/40) to afford 4-(4-hydroxymethylphenyl)cyclohexanone as a colorless solid (4.21 g, 20.6 mmol, 62%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:29])([F:28])[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1.[H-].[Na+].O>CN(C=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:27][C:25]3[S:26][C:22]([C:21]([F:29])([F:28])[F:20])=[N:23][N:24]=3)[C:3]=2[N:10]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc(Nc2ncnc3sc(Cc4c(Cl)cccc4Cl)nc23)s1
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a solution of 7-chloro-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidine (83 mg, 0.3 mmol) and 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamine (63 mg, 0.4 mmol) in DMF (1 mL) was added NaH (60% dispersion in oil; 20 mg, 0.5 mmol) at rt. After 12 h, the reaction mixture was poured into H2O (5 mL) and the resulting solid was collected by vacuum filtration and washed with 1:1 (IPA-H2O) to afford the title compound as a yellow solid (48 mg, 41%). MS (ESI): mass calcd. for C15H7Cl2F3N6S2, 462.0; m/z found, 462.9 [M+H]+. 1H NMR ((CD3)2SO): 8.45 (s, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.46-7.41 (m, 1H), 4.72 (s, 2H).
Reaction SMILES: CC1C([N+]([O-])=O)=CC=C(C)C=1OC.[CH3:14][O:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([N+:23]([O-])=O)[C:17]=1[CH2:26][C:27](=O)[C:28]([OH:30])=[O:29]>>[CH3:14][O:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[C:17]=1[CH:26]=[C:27]([C:28]([OH:30])=[O:29])[NH:23]2
Reactant: COc1c(C)ccc([N+](=O)[O-])c1CC(=O)C(=O)O
Agent: COc1c(C)ccc([N+](=O)[O-])c1C
Product: COc1c(C)ccc2[nH]c(C(=O)O)cc12

Procedure:
The compound was prepared via 2,6-dimethyl-3-nitroanisole (b.p. 94°-98° C/0.4 mm Hg) and 3-(2-methoxy-3-methyl-6-nitrophenyl)-pyruvic acid (m.p. 140°-142° C).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-1-carboxylate (0.36 g, 1.0 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.43 g, 1.5 mmol, from Example 108, Step 1) and DIPEA (0.53 mL, 3.0 mmol) in ethanol (6 mL) was heated at 100° C. overnight. The mixture was concentrated and purified on silica gel column (eluting with 0 to 100% EtOAc in hexanes) to give tert-butyl 3-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate. LCMS calculated for C28H38 ClN6O4 (M+H)+: m/z=557.3. found: 557.3. The Boc intermediate isolated was treated with trifluoroacetic acid (0.8 mL, 10 mmol) in methylene chloride (5 mL) at room temperature for 1 hour. The mixture was stripped to dryness to give the desired product as TFA salt. 4 mg of the salt was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C18H22ClN6O (M+H)+: m/z=373.2. found: 373.1
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH3:14])[C@@H:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:7]1[CH2:36][NH:37]CC1C=CC=CC=1)(=[O:3])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:16]=2)[CH3:14])[C@@H:8]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C@@H:7]1[CH2:36][NH2:37])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1CNCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1CN
Reaction time: 16 h

Procedure:
To a solution of the crude oil from Step M in 50 mL ethanol was added 0.2 g (20% by weight) of 10% Pd(OH)2—C. The mixture was hydrogenated at 50 PSi for 16 hr at room temperature. The catalyst was filtered through a filter aid pad. The solvent of the filtrate was removed under vacuum to give the title compound (0.35 g). 1H-NMR (CDCl3) δ: 7.70 (1H, s), 7.23 (2H, m), 7.21 (2H, s), 6.98 (2H, m), 4.48 (1H, q, J=6.5 Hz), 4.15 (2H, m), 3.27 (1H, m), 2.86 (2H, m), 2.53 (1H, d, J=11.0 Hz), 2.36 (1H, m), 2.07 (3H, s), 1.98 (2H, m), 1.75 (1H, m), 1.55-1.27 (2H, m), 1.37 (3H, d, J=6.4 Hz). MS: (MH)+ 536.5.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:39]=[CH:38][C:25]([O:26][C@H:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[CH2:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:23]=[CH:24][C:25]([O:26][C@H:27]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:28]([O-:30])=[O:29])=[CH:38][CH:39]=2)=[CH:11][CH:12]=1)[CH2:4][CH2:5][CH3:6].[Na+:2]
Reactant: CCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 67 %

Procedure:
Ethanol (30 ml) and a solution of 1N sodium hydroxide in ethanol (2.74 ml) were added to (2R)-2-(4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoic acid (1.51 g, 3.05 mmol) and the mixture was concentrated. To the residue was added diisopropylether to give the object compound as a solid. 1.06 g (yield 67.0%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Reactant: COc1ccc(CO)cn1
Product: COc1ccc(COc2nccnc2NS(=O)(=O)c2cccc(Cl)c2Cl)cn1

Procedure:
Prepared by the method of Example 28b using 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28a) (0.338 g) and (6-methoxy-3-pyridinyl)methanol (0.21 g). Yield 0.23 g.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.O.O.[C:28]([O-])(=[O:30])C.[Na+]>CC(C)=O>[C:19]1([N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH:28]=[O:30])=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)[O-]
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 73 %

Procedure:
30 mL of dimethylformaldehyde (DMF) was put into a 250 mL flask, cooled to 0° C. and 3.8 mL of POCl3 was slowly added thereto. Then, 10 g of triphenylamine was added to the resultant mixture and heated to 70° C. for 5 hours. The reaction container was cooled to room temperature and then a reactant solution was poured into ice water. Subsequently, 40 g of sodium acetate trihydrate was put for neutralization and then an organic layer was separated with methylenechloride. The obtained organic layer was dried using magnesium sulfate and methylenechloride was removed under reduced pressure, yielding a product. The product was recrystallized using methanol and a light yellow solid was finally obtained, yielding 73% of a desired product. Data of NMR spectra confirmed that the product had the same structure as 4-(diphenylamino)benzaldehyde, that is, the compound (1) in the reaction scheme 2.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6](O)[CH2:7][CH2:8][CH3:9]>>[Cl:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: O=C(O)CCl
Reactant: CCCCO
Product: CCCCOC(=O)CCl

Procedure:
Following the procedure described in Examples 1 and 2, but heating while stirring for 4 hours to 105° a mixture comprising of 181 parts of butanol and 189 parts of chloroacetic acid, there is obtained butyl chloroacetate; nD20 =1,428.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8](O)=[O:9])(=O)C.C(Cl)(=O)C(Cl)=O.C[O-].[Na+].CO.Cl.[CH3:34][N:35](C)[CH:36]=O>ClCCl.O1CCCC1>[CH2:15]([O:14][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([OH:4])[CH:13]=1)[C:8]([N:35]([CH3:36])[CH3:34])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: CC(=O)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: C[O-]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Acetoxy-5-benzyloxybenzoic acid (1.0 g) was suspended in dichloromethane (12 mL), oxalyl chloride (0.49 g), N,N-dimethylformamide (0.01 mL), tetrahydrofuran was added sequentially, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and then dichloromethane was added to the residue. Dimethylamine hydrochloride (0.28 g) and pyridine (0.1 mL) were added to the reaction mixture and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in tetrahydrofuran (15 mL). Sodium methoxide-methanol solution (5.2 mol/L, 1.02 mL) was added to the reaction mixture and stirred at room temperature for 30 minutes. One mol/L hydrochloric acid was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: ethylacetate/hexane=1/1) to give the title compound (0.67 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:4][CH:3]=1.[CH3:25][C:26]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([CH2:35][S:36]([C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[O:37])=[N:28][CH:27]=1.O.O.O.[Mg+2:52]>ClCCl.CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:13])[C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:27]=[N:28][C:29]([CH2:35][S+:36]([O-:37])[C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].[Mg+2:52]
Reactant: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 64.5 %

Procedure:
Esomeprazole magnesium trihydrate (200 g) was dissolved in a mixture of dichloromethane (1200 ml) and methanol (1200 ml) at 25-30° C., Any undissolved material was filtered off and triethylamine (2 ml) was added to the filtrate. The clear solution thus obtained was spray dried in a mini spray dryer (Model Buchi—190) with an inlet temperature of 65-68° C. and an outlet temperature of 22-42° C. in 2 to 3 hours. The solid was further dried under vacuum at 60-65° C. for 14 to 15 hours to yield 120 g of esomeprazole magnesium of amorphous form. X-ray powder diffraction pattern showed a plain halo, which demonstrates the amorphous nature of the product. The following physical characteristics were obtained: Purity 99.77% by HPLC, Chiral purity 99.90% by HPLC, SOR 145.9°, Mg content 3.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].S(F)([O-])(=O)=O.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=C[OH2+])[CH3:17].O.[OH-].[K+]>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[N:10][NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH3:17]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CN1CCCCC1=C[OH2+]
Agent: O=S(=O)([O-])F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN1CCCCC1=NNc1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 17.7 parts of 2,4-dichlorophenylhydrazine in methylene chloride was added dropwise to the above reaction mixture containing [1-(2-ethoxy-2-oxoethyl)piperidin-2-ylidene]methyloxonium fluorosulfate while keeping the temperature of the reaction less than 30° C. After the addition was completed the reaction was stirred for an additional 30 minutes. The reaction mass was then poured into 1000 parts of water. The pH was raised to 12.0 with 20% potassium hydroxide solution. The crude product was extracted with three successive portions of 1000 parts of methylene chloride. The organic extracts of the product were dried over anhydrous sodium sulfate. The solution of the product was filtered to remove the drying agent. The solvent was removed at a reduced pressure of 50-300 mm with a rotary evaporator leaving the crude product which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27](Cl)=[O:28]>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][C:2]([NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([F:33])=[C:24]([F:23])[CH:25]=3)([CH3:21])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccc(F)c(F)c1
Yield: 79.1 %

Procedure:
Using the method of Example 601, 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 770 mg, 2.59 mmol) was reacted with 3,4-difluorobenzoyl chloride (1.14 g, 6.48 mmol). The crude product was purified as described in Example 601 to provide 896 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-3,4-difluorobenzamide as a white solid, mp 165-166° C. MS (APCI) m/z 438 (M+H)+; Anal. Calcd for C24H25F2N5O: C, 65.89; H, 5.76; N, 16.01. Found: C, 65.84; H, 5.58; N, 15.92.
Reaction SMILES: CO[C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=1[CH3:19]>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:3]([OH:4])[C:17]2[C:12](=[C:13]([CH3:19])[C:14]3[N:18]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:3]([OH:4])[C:15]=3[CH:16]=2)[N:11]=1)=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1c(N)cccc1N
Solvent: CO
Product: COC(=O)c1cc(O)c2cc3c(O)cc(C(=O)OC)nc3c(C)c2n1
Reaction time: 0.17 h

Procedure:
A solution of acetylene dicarboxylic acid dimethyl ester (2.8g.) in dry methanol (20ml.) was added to a solution of 2,6-diamino-1-methylbenzene (1.2g.) in dry methanol (20ml.), and the mixture heated under reflux for 3 hours. The mixture was then cooled and filtered, and the solid residue of bis anil (1.9g., m.p. 194°-196°C., crystallised from dimethylformamide) was added in portions to boiling diphenyl ether (50ml.), and the mixture was kept at 240°-145°C. for 10 minutes. The mixture was then cooled, and filtered, and the solid residue was washed with petroleum ether (b.p. 40°-60°C.; 750ml.), and crystallised from dimethylsulphoxide to give 2,8-dimethoxycarbonyl-4,6-dihydroxy-10-methylpyrido[3,2-g]quinoline, m.p. 296°C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[OH:37]/[N:36]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 151, step 3, 4′-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=467.3 [M+H]+.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28](/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:42]=2[CH3:51])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[OH:31][C:30]1[C:25](=[O:24])[NH:26][N:27]=[C:28]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:43][C:42]=2[CH3:51])[CH:29]=1
Reactant: Cc1cc(C(F)(F)F)ccc1/C=C/c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1CCc1cc(O)c(=O)[nH]n1
Yield: 36 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[2-methyl-4-(trifluoromethyl)phenyl]-ethenyl]pyridazine (Intermediate 76) except that THF was used as the solvent. The crude product was purified by reverse phase chromatography, eluting with 5-100% acetonitrile with acid modifier) and then recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 4-hydroxy-6-{2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl}-2,3-dihydropyridazin-3-one as a white powder (0.23 g, 36%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)CC)C.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>C(#N)C>[C:1]([O:5][C:6](=[O:10])[CH2:7][N:8]([CH3:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(CC(=O)OC(C)(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In acetonitrile (80 mL) was stirred sarcosine t-butyl ester•hydrochloride (10.1 g, 55.5 mmol) and triethylamine (6.57 g, 65 mmol). To this was added 2-fluoronitrobenzene (5.66 g, 40 mmol) and the mixture was stirred overnight at 50° C. The solution was evaporated at a reduced pressure until free of acetonitrile. The residue was partitioned between ether (100 m]L) and water (100 mL). The ether layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated at reduced pressure to give an oil which was dried at 60° C. in vacuo to remove all traces of fluoronitrobenzene. MS: M++1=267.1 Da.