Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)N(CS(Cl)(=O)=O)C(=O)C2=CC=CC=C12.C1(=O)N(CCS(Cl)(=O)=O)C(=O)C2=CC=CC=C12.C(NS(CN1C(=O)C2=CC=CC=C2C1=O)(=O)=O)(C)(C)C.C(NS(N1C(SC)=NN=N1)(=O)=O)(C)(C)C.C([NH:73][S:74]([CH2:77][N:78]1[C:82]([SH:83])=[N:81][N:80]=[N:79]1)(=[O:76])=[O:75])(C)(C)C.FC(F)(F)C(O)=O>>[S:74]([CH2:77][N:78]1[C:82]([SH:83])=[N:81][N:80]=[N:79]1)(=[O:76])(=[O:75])[NH2:73]
Reactant: CC(C)(C)NS(=O)(=O)Cn1nnnc1S
Agent: CC(C)(C)NS(=O)(=O)CN1C(=O)c2ccccc2C1=O
Agent: CSc1nnnn1S(=O)(=O)NC(C)(C)C
Agent: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)Cn1nnnc1S

Procedure:
When phthalimidomethanesulfonyl chloride is substituted in the procedure of Example 3 for 2-phthalimidoethanesulfonyl chloride, N-t-butylphthalimidomethanesulfonamide is prepared which is converted to 1-N-t-butylsulfamoyl methyltetrazole-5-thiol as described therein. Treatment of 1-N-t-butylsulfamoylmethyltetrazole-5-thiol with trifluoroacetic acid as described in Example 3 gives 1-sulfamoylmethyltetrazole-5-thiol.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][CH2:3]1)(=[O:14])[CH3:13]
Reactant: c1ccc2c(c1)CNCCS2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (1.5 g, prepared as described in the first paragraph of Example 6 above) in acetic anhydride (15 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried and the solvent removed by evaporation to give 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine [a compound known as a Friedel Crafts catalyst from Example 46 of EP 368063 (Bayer)]. The product was recrystallised from hexane. Yield 1.55 g (m.p. 69°-70° C.).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:4].[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH2:24])=[O:23].[I-].[Na+].C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[C:22]([C:21]1[CH:20]=[C:19]([NH:18][CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[O:4])[CH:27]=[CH:26][CH:25]=1)(=[O:23])[NH2:24]
Reactant: NC(=O)c1cccc(N)c1
Reactant: COc1ccc(CCNC(=O)CCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)CNc2cccc(C(N)=O)c2)cc1OC
Temperature: 60 °C
Reaction time: 4 h

Procedure:
100 ml of dimethylformamide was added to a mixture of 25.8 g of 2-chloro-N-(3,4-dimetoxyphenethyl)acetamide, 13.6 g of m-aminobenzamide, 15.0 g of sodium iodide and 20.0 g of calcium carbonate, and the mixture was stirred at 60° C. for 4 hours. The same procedure as described in Example 1 was followed to obtain 2-(3-carbamoylphenylamino)-N-(3,4-dimethoxyphenethyl)acetamide. The product was converted to the corresponding hydrochloride salt as described in Example 5. The salt was recrystallized from a mixture of methanol and diethyl ether to obtain 21.7 g of 2-(3-carbamoylphenylamino)-N-(3,4-dimethoxyphenethyl)acetamide hydrochloride having a melting point of 142°-155° C. (dec.).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].CC1C=CC(S(O[CH2:16][C:17]2[N:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[C:28]3[O:32][N:31]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH:29]=3)[N:20]=[C:19]([NH:39][C:40]3[CH:44]=[C:43]([CH3:45])[N:42](S(C4C=CC(C)=CC=4)(=O)=O)[N:41]=3)[CH:18]=2)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C>[NH2:1][CH2:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:29]=2)[N:20]=[C:19]([NH:39][C:40]2[CH:44]=[C:43]([CH3:45])[NH:42][N:41]=2)[CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCc2cc(Nc3cc(C)n(S(=O)(=O)c4ccc(C)cc4)n3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(CN)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 110 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Sodium azide (44 mg, 0.68 mmol) was added to a solution of 6-[(4-methylphenylsulphonyloxy)methyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1-N-[4-methylphenylsulphonyl]-1H-pyrazol-3-ylamino)pyrimidine (Method 52) (159 mg, 0.22 mmol) in anhydrous DMF (2.0 ml) and the mixture heated at 110° C. for 1.5 hours. Triphenylphosphine (282.0 mg, 1.08 mmol) and water (0.10 ml) were then added and the reaction mixture heated at 100° C. for 1 hour. The mixture allowed to cool and was then passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The volatiles were removed by evaporation and the residue dissolved in methanol (5 ml) and 10M aqueous sodium hydroxide solution (0.5 ml) and stirred for 1 hour. The volatiles were removed by evaporation and the residue dissolved in water, and extracted with DCM. The extracts were combined, the solvent removed by evaporation and the residue purified by chromatography on silica gel, eluting with DCM/methanol/aqueous ammonia (100:0:0 increasing in polarity to 80:20:1) to give the title compound (48.5 mg, 53%) as a solid.
Reaction SMILES: Cl.[C:2]1([C:8]2[N:13]=[N:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=1>C(Cl)Cl>[C:2]1([C:8]2[N:13]=[N:12][C:11]([CH2:14][NH:15][S:29]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(-c2ccccc2)nn1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCc1ccc(-c2ccccc2)nn1)c1cccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
To a solution of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride (121 mg) (containing 0.458 mmol of a pure content) obtained in Reference Example 2-(c) in methylene chloride (1 ml) were added triethylamine (0.26 ml, 1.8 mmol) and 3-pyridylsulfonyl chloride (see The Journal of Organic Chemistry, 54, 389 (1989)) (83.2 mg, 0.468 mmol), followed by stirring at room temperature for 17 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; ethyl acetate:acetonitrile=1:0→0:1 (V/V), then chloroform), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (130 mg) as a slightly brown solid. (Yield: 87%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([NH2:21])[N:3]=1.CO.[OH-].[Na+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1>CN(C)C=O>[CH3:27][C:28]1[N:29]=[C:30]([CH2:34][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][C:4]([NH2:21])=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: Cc1cccc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 51.6 %

Procedure:
To 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (150 mg, 0.53 mmol) described in Manufacturing Example 18-1-1 were added methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.53 mL), which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue was added 2-chloromethyl-6-methyl-pyridine (90.2 mg, 0.64 mol.) described in manufacturing Example 10-1-1 and N,N-dimethylformamide (2 mL), which was stirred for 2 hours and 50 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (106 mg, 51.5%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=S)[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:26]>CO>[C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: S=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Solvent: CO
Product: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Temperature: 50 °C

Procedure:
65 mg of 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A1) are suspended in 4.3 ml of methanol containing ammonia (strength: 7.0 M) and heated at 50° C. for 90 hours. Subsequently, the reaction mixture is evaporated to dryness and purified by flash chromatography on LiChroprep-NH2® (eluent gradient: dichloromethane/0-100 vol. % methanol), and lyophilized from 2.0 ml of water, 5.0 ml of dioxane to afford 29.5 mg of the title compound as an amorphous, colorless solid of m.p. 117° C. (decomp.). ESI-MS: 334.3 (MH+). TLC: Rf=0.35 (LiChroprep-NH2® HPTLC, methanol/water 10:1 parts by volume).
Reaction SMILES: CC(CC(O)=O)=O.[CH3:8][CH:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:14]=1)[CH2:10][CH3:11].[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24].CCOCC>CN(C=O)C.O>[CH2:23]([NH:25][C:26](=[O:27])[O:20][CH2:19][CH2:18][O:17][C:16]1[CH:21]=[CH:22][C:13]([O:12][CH:9]([CH3:8])[CH2:10][CH3:11])=[CH:14][CH:15]=1)[CH3:24]
Reactant: CCN=C=O
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Agent: CC(=O)CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCNC(=O)OCCOc1ccc(OC(C)CC)cc1
Temperature: 25 °C

Procedure:
Dibutylin diacetate (0.004 ml) is added to a solution of the above alcohol (0.42 g, 2.0 mmol) in 1.5 ml of DMF and the mixture is chilled in an ice bath. Ethyl isocyanate (0.18 ml, 2.2 mmol) is then added and the mixture is allowed to warm slowly to RT. The mixture is then poured into ether and water containing 10% potassium dihydrogen phosphate. The aqueous phase is extracted with ether, and the combined organic phases are washed with water and with brine, dried, filtered and the solvent is removed in vacuo to give O-2-[4-(1-methylpropoxy)phenoxy]ethyl N-ethylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[BH4-].[Na+].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.[F:26][C:27]([F:32])([F:31])[C:28](O)=O>O>[F:26][C:27]([F:32])([F:31])[CH2:28][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(NCC(F)(F)F)c(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of 2-amino-5-nitrophenol (250 mg, 1.62 mmol) in 3 mL of trifluoroacetic acid stirred at 0° C., was added sodium borohydride (pellets, 375 mg, 9.91 mmol). The orange solution was allowed to slowly warm to rt and stirred for 12 h. The solution was diluted with 50 mL of water and cooled to 0° C. Solid potassium carbonate was then slowly added until the pH reached 7.The solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine (25 mL), dried with anhydrous magnesium sulfate, filtered and concentrated to give an orange solid. Flash chromatography (7:3 hexanes:EtOAc) afforded 0.32 g (83%) of 2-(2,2,2-trifluoroethyl)amino-5-nitrophenol, a yellow solid. 1H NMR (400 MHz, acetone-d6) 9.48 (broad s, 1H), 7.79 (dd, 1H, J=9.1, 2.4), 7.67 (d, 1H, J=2.4), 6.96 (d, 1H, J=8.8), 6.20 (broad s, 1H), 4.26–4.18 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:2]=1.[CH3:16]I>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH3:16])[CH:2]=1
Reactant: CI
Reactant: N#Cc1ccc(Cc2cccnc2)cc1
Product: CC(c1ccc(C#N)cc1)c1cccnc1

Procedure:
Using methodology described e.g. in example 34, 4-(3-pyridylmethyl)-benzonitrile is reacted with methyl iodide to obtain 4-[1-(3-pyridyl)-ethyl]-benzonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23](O)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:17][C:16]=2[F:31])=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O1C(CCOCCC)C1.C(O)(=O)C(CC(O)=O)O.C(OC1C=CC(C2C=CC(O)=CC=2[F:71])=NC=1)CCCCCC.CCN(S(F)(F)F)CC>C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([F:71])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:17][C:16]=2[F:31])=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-c2ccc(O)cc2F)nc1
Reactant: CCCCCCCOc1ccc(-c2ccc(OCC(O)CCOCCC)cc2F)nc1
Agent: CCCOCCC1CO1
Agent: CCN(CC)S(F)(F)F
Agent: O=C(O)CC(O)C(=O)O
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCCCCCCOc1ccc(-c2ccc(OCC(F)CCOCCC)cc2F)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 0.1 mol of 5-heptyloxy-2-(4-(2-hydroxy-5-oxaoctyloxy)-2-fluorophenyl)pyridine (prepared by heating optically active 1,2-epoxy-5-oxaoctane, obtainable from malic acid, with 5-heptyloxy-2-(4-hydroxy-2-fluorophenyl)pyridine in the presence of dry potassium carbonate and methyl ethyl ketone as solvent) in methylene chloride is cooled to -40° C. and 0.11 mol of DAST is added to it dropwise with moisture being excluded. The reaction mixture is then stirred for 12 hours while heating slowly to room temperature. Then hydrolysis is carried out with ice cooling and the reaction mixture is washed with dilute sodium hydroxide solution and several times with water. After drying over magnesium sulfate, the solvent is removed on a rotary evaporator and the crude product is purified chromatographically and - by crystallization. Optically active 5-heptyloxy-2-(4-(2-fluoro-5-oxaoctyloxy)-2-fluorophenyl)pyridine is obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][CH:14]([SH:16])[CH3:15].C(N(CC)CC)C.O>CN(C=O)C>[CH:14]([S:16][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])([CH3:15])[CH3:13]
Reactant: CC(C)S
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (2.5 g, 15.6 mmol) in DMF (50 mL) were added 2-propane thiol (1.74 mL, 18.6 mmol) and triethylamine (4.8 mL, 34.4 mmol). After stirring at ambient temperature for 1 h, the reaction mixture was poured into water (250 mL) and extracted with methylene chloride (3×50 mL). The organic layer was washed with water (2×) and brine, then dried over MgSO4 and concentrated to yield 2.98 g (86%) of 15A as a yellow oil which solidified upon standing.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:25][CH3:26])[C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:25][CH3:26])[C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1N

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-nitro-2-pyridinyl)amino]methylpiperidine (EXAMPLE 176, 9.8 g, 27.6 mmol) and 10% palladium on carbon (3 g) in ethanol (250 ml) are hydrogenated at 40 p.s.i. hydrogen for one hr. Filtration and evaporation of the solvent gives the title compound, NMR (300 MHz, CD3OD) 7.60, 7.28, 7.05, 6.86, 3.46, 3.01, 2.84, 1.90, 1.70, 1.40, 1.19 and 1.0δ.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[OH-].[Na+].ClN1C(=[O:34])C2=CC=CC=C2C1=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.C(O)(=O)C.C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:34])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: O=C1c2ccccc2C(=O)N1Cl
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A flask equipped with a stirrer is charged with acetonitrile (40 ml). Under mixing, compound VI (5 g) is added followed by 2N NaOH (17.5 ml, 4.9 eq.). The flask is cooled to −10° C. A solution of N-chlorophthalimide (2.6 g, 1.1 eq.) in dimethylformamide (DMF) (10 ml) is added dropwise over 45 min. The two-phase mixture is stirred at room temperature over 1 h. Saturated aqueous Na2S2O5 (20 ml) is then added, and the pH is adjusted to 8.5 with acetic acid. The phases are separated. The organic phase is washed with brine, and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, dried, and evaporated to dryness. The residue is taken up in a mixture of ethyl acetate (10 ml), toluene (10 ml), and hexane (30 ml). On standing, a precipitate forms in the solution which is separated by filtration to give pantoprazole (5.13 g, 98%) containing 0.3% compound VI and free of sulfone within the limit of UV detection.
Reaction SMILES: [CH3:1][O:2][C:3]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:4]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]2[CH2:24][CH2:25][CH2:26][C:18]=2[N:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:4]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]2[CH2:24][CH2:25][CH2:26][C:18]=2[N:17]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1nc(OC(C(=O)OCc2ccccc2)C(OC)(c2ccccc2)c2ccccc2)nc2c1CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)nc2c1CCC2

Procedure:
40 g (78.4 mmol) of benzyl 3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionate were dissolved in 400 ml of ethyl acetate/methanol (4:1), about 500 mg of palladium on active carbon (10%) were added, and the mixture was exposed to a hydrogen atmosphere until no further gas was taken up. The catalyst was filtered off, the solution was evaporated, and the residue was crystallized from ether.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[C:4]([CH2:16][OH:17])[N:3]=1.C([O-])(=O)C.[K+].[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:26])[CH:24]=[CH2:25]>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[CH2:9]([O:8][C:7]1[C:2]([C:24](=[CH2:25])[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[N:3][C:4]([CH2:16][OH:17])=[CH:5][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CC(=O)OCCCC
Reactant: OCc1ccc(OCc2ccccc2)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C(=O)OCCCC)c1nc(CO)ccc1OCc1ccccc1
Temperature: 120 °C

Procedure:
To a solution of 2-bromo-3-benzyloxy-6-hydroxymethylpyridine (2.94 g, 10.0 mmol) in DMF (19 ml) and water (1 ml) were added potassium acetate (2.45 g, 25.0 mmol), tetra-n-butylammonium iodide (3.69 g, 10.0 mmol), bis(triphenylphosphine)palladium dichloride (281 mg, 0.4 mmol) and n-butyl acrylate (4.31 ml, 3.84 g, 30 mmol). The mixture was placed under nitrogen and stirred and heated at 120° C. for 3 h. The mixture was cooled and poured into water (180 ml). The product was extracted into ethyl acetate (3×30 ml). The combined extracts were washed with water (3×25 ml), dried and evaporated. This residue was purified by flash column chromatography, eluting with a gradient of ethyl acetate in dichloromethane to isolate the product, an oil (2.72 g, 80%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[Cl:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C(N(CC)CC)C>O>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:24]1[C:25]([N+:26]([O-:28])=[O:27])=[C:20]([Cl:19])[N:21]=[CH:22][N:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 1 h
Yield: 105 %

Procedure:
Dibenzylamine (10.2 g) in a dichloromethane (30 mL) solution was added dropwise on an ice bath to a dichloromethane (70 mL) solution of 4,6-dichloro-5-nitropyrimidine (10 g). This was followed by the addition of triethylamine (14.4 mL) and stirring for 1 hour. Water was then added to the reaction mixture and the organic layer was subsequently washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain the title compound (19.2 g) having the physical property value indicated below.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][OH:25]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:22][CH2:23][CH2:24][OH:25])[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNCCO)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 2-amino-ethanol are processed according to the method described in Example 170 to give 6-chloro-2-{5-[(2-hydroxy-ethylamino)-methyl]-pyridin-3-yl}-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.65-2.72 (m, 2H), 3.49-3.55 (m, 2H), 3.79 (s, 3H), 3.92-3.98 (m, 2H), 4.61 (br. s., 1H), 7.37 (dd, J=8.3, 1.8 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 8.10-8.13 (m, 1H), 8.75-8.79 (m, 2H). HRMS (ESI) m/z 341.1175 [(M+H)+ Calcd for C19H18ClN4O: 341.1169].