Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16]O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][O:2]1.[CH2:18]([N:20](CC)[CH2:21]C)C.CS(Cl)(=O)=O.CNC>ClCCl.O>[B:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][N:20]([CH3:21])[CH3:18])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: OCc1ccccc1B1OCc2ccccc21
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1ccccc1B1OCc2ccccc21
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of (2-(benzo[c][1,2]oxaborol-1(3H)-yl)phenyl)methanol (300 mg, 1.34 mmol) in dichloromethane (10 mL) were added sequentially triethylamine (0.373 mL, 2.7 mmol) and methanesulfonyl chloride (0.125 mL, 1.60 mmol) at 0° C. After stirring for 30 min, dimethylamine (2M in tetrahydrofuran; 3 mL) was added, and the mixture was stirred for another 30 min. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (1:2 hexane/ethyl acetate) followed by recrystallization from diisopropyl ether/hexane to give the title compound (185 mg, 55%): 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.41 (s, 3H), 4.09 (br d, J=8.5 Hz, 2H), 4.87 (d, J=13.2 Hz, 1H), 5.05 (d, J=13.2 Hz, 1H), 7.0-7.3 (m, 8H); ESI-MS m/z 252 (positive); C16H18BNO=251
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:39]=[CH:38][C:15]2[N:16]([CH:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:27]([O:29]CC)=[O:28])[C:17]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:18][C:14]=2[CH:13]=1>C(O)C.[OH-].[Na+]>[F:25][C:19]([F:24])([C:17]1[N:16]([CH:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:27]([OH:29])=[O:28])[C:15]2[CH:38]=[CH:39][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]3[N:1]=[N:2][NH:3][N:4]=3)=[CH:13][C:14]=2[N:18]=1)[C:20]([F:21])([F:23])[F:22]
Reactant: CCCCCCC(C(=O)OCC)n1c(C(F)(F)C(F)(F)F)nc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C(=O)O)n1c(C(F)(F)C(F)(F)F)nc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Yield: 91.9 %

Procedure:
Ethyl 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-2-pentafluoroethyl-1H-benzimidazol-1-yl]octanoate (0.25 mmoles, 0.14 g) was dissolved in 25 ml ethanol and 1 ml 5N NaOH. The solution heated on a steam bath for 1 hour. The solvent was removed in vacuo. The residue was dissolved in water. The pH was adjusted to 3.0 using 5 N HCl. The precipitate was collected and dried to yield 0.12 g of 2-[2-pentafluoroethyl-5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid. (MS)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C1C=CC2N(O)N=[N:17][C:15]=2C=1.C(Cl)CCl.CN>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:17][CH3:15])=[O:6]
Reactant: O=C(O)c1ccnc(I)c1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1ccnc(I)c1
Yield: 55.7 %

Procedure:
A round-bottomed flask was charged with 2-iodoisonicotinic acid (0.70 g, 2.81 mmol), HOBt (474 mg, 3.09 mmol) and EDC (593 mg, 3.09 mmol). DMF (4 mL) was added followed by methylamine (2.0M solution in THF, 8.0 mL, 16.0 mmol) and the resultant suspension was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with 70 mL diethyl ether (2×). The combined organic layers were washed twice with ˜5 mL water and once with ˜5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 24 g silica gel with EtOAc/Hexanes (gradient: 0-60% EtOAc). All fractions containing product were combined and concentrated to give 410 mg (56%) of 2-iodo-N-methyl-isonicotinamide as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH2:8].[CH:9]([CH2:11][CH:12]([CH3:19])[C:13]([O:15]C(C)C)=O)=O.[C:20](O)(=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[C:20]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:15])[CH:12]([CH3:19])[CH2:11][CH:9]=[N:8][CH2:7][CH2:6]1)(=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: NCCNCCCO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)OC(=O)C(C)CC=O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCCN1CCN=CCC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 118.2 g (1 mole) of N-hydroxypropylethylenediamine and 158.2 g (1 mole) of isopropyl 3-formyl-2-methylpropionate. From the apparatus, 18 g of water and 60 g of isopropyl alcohol were distilled off. Then, 340.5 g (1 mole) of behenic acid was charged and 18 g of water was distilled off at 180° C. and under a reduced pressure of 70 mmHg to obtain 4-behenoyloxypropyl-6-methyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([OH:17])[CH:10]=1>CCO>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10][C:11]=1[OH:17])#[N:14]
Reactant: N#Cc1ccc(N)cc1O
Reactant: Brc1ccccn1
Solvent: CCO
Product: N#Cc1ccc(Nc2ccccn2)cc1O
Temperature: 90 °C
Yield: 1 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-bromopyridine (0.21 mL, 2.2 mmol) and 4-amino-2-hydroxybenzonitrile (146 mg, 1.1 mmol) in 10% aqueous EtOH (5 mL) was heated at 90° C. for 18 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 1% yield (1.5 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][S:12][CH3:13])=[C:9]2[C:5]([C:6]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C3C(=C(CS(C)=[O:53])C(F)=CC=3)NC=2)CCC#N)=CC=1>>[F:1][C:2]1[C:10]([CH2:11][S:12]([CH3:13])=[O:53])=[C:9]2[C:5]([C:6]([CH:14]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=3)[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Reactant: CS(=O)Cc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1c(F)ccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 557 mg (1.37 mmol) of the compound from Example 51 in analogy to the synthesis of the compound from Example 88. 412 mg (71% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)=[CH:12][C:3]1=2.[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[N:14]([CH3:19])[CH:15]=[CH:16][CH:17]=3)=[CH:12][C:3]1=2
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc[nH]3)cc21
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a mixture of 4,4-dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one (1.5 g, 6.2 mmol) in dimethylformamide (20 mL) at room temperature was added sequentially potassium carbonate (4.28 g, 31 mmol) and a solution of methyl iodide (1.16 mL, 19 mmol) in dimethylformamide (5 mL). After 1 h, the reaction mixture was boiled. The reaction was cooled to room temperature, poured into water (50 mL) and extracted with ethyl ether (2×50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (40% ethyl acetate/hexane) gave the title compound as an off-white powder (0.5 g, 31%) mp 230° C. 1H NMR (CDCl3) δ 1.71 (s, 6 H), 3.42 (s, 3 H), 6.31 (dd, 1 H, J=2.9, 5.9 Hz), 6.47 (m, 1 H), 6.88 (m, 1 H), 6.94 (d, 1 H, J=8.6 Hz), 7.26 (d, 1 H, J=2.2 Hz), 7.41 (dd, 1 H, J=2.2, 8.6 Hz), 8.43 (bs, 1 H). MS ((−) ESI) m/z 255 [M−H]−. Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 68.59; H, 6.16; N, 10.49.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:23][S:24]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[C:11]3[CH:22]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)=[CH:20][CH:19]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(O)cc4)c3c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(OS(C)(=O)=O)cc4)c3c2)o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A suspension of 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenol (351 mg, 1.20 mmol), methanesulfonyl chloride (0.111 mL, 1.44 mmol) and potassium carbonate (332 mg, 2.40 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 hr and at 60° C. overnight. The reaction mixture was diluted with ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) and recrystallized from hexane/ethyl acetate to give the title compound (107 mg, yield 24%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: COc1ccc(CCl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (18.3 g), 1-(chloromethyl)-4-methoxybenzene (9.38 g) and sodium carbonate (12.7 g) in 1,2-dimethoxyethane (255 mL)-water (85.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (3.46 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent of ethyl acetate-diisopropyl ether, and the solid was collected by filtration to give the title compound (11.12 g). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.99 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[Se](=O)=[O:19]>C(Cl)Cl>[C:12]1([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([CH:1]=[O:19])=[CH:3][CH:4]=3)[N:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc2ccc(-c3ccccc3)nc2c1
Reactant: O=[Se]=O
Solvent: ClCCl
Product: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 160 °C

Procedure:
A mixture of 7-methyl-2-phenylquinoline (2.49 g, 11.4 mmol) and selenium dioxide (1.92 g, 17.3 mmol, 1.5 eq.) is heated to 160° C. (bath temp.) for 22 h. The cooled melt is suspended in CH2Cl2 with the aid of sonication and filtered through Celite and then through a plug of silica gel. This effectively removes the red color and the major lower spots. The material thus obtained is crystallized from hexanes/CHCl3, yielding a pale beige solid, mp. 108° C. The mother liquor is concentrated and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with hexanes:CH2Cl2 1:1 (1-25)→1:3 (26-53)→CH2Cl2 (54-73)→3% EtOAc in CH2Cl2 (74-85)] to obtain as pale yellow solid, mp. 109° C. 1H NMR (CDCl3, 400 MHz) δ 7.48-7.60 (m, 3H), 7.94 (d, J=8.8 Hz, 1H), 8.01-8.05 (m, 2H), 8.18-8.23 (m, 2H), 8.29 (d, J=8.8 Hz, 1H), 8.64 (s, 1H), 10.26 (s, 1H). MS (ES+): m/z 234.2 (100) [MH+]. HPLC: tR=3.0 min (MicromassZQ, nonpolar—5 min); 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 121.22 (+), 122.80 (+), 127.51 (2C, +), 128.65 (+), 128.94 (2C, +), 129.83 (+), 130.69 (Cquart), 135.84 (+), 136.68 (+), 137.21 (Cquart), 138.79 (Cquart), 147.91 (Cquart), 158.48 (Cquart), 192.14 (+); IR (film): ν=3059 cm−1, 3034, 2824, 2717, 1954, 1812, 1684, 1601, 1554, 1510, 1491, 1448, 1420, 1392, 1320, 1280, 1168, 1145, 1120, 1075, 1052, 1025, 971, 926, 897, 850, 812, 787, 757, 692, 673, 627.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.I[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: OCCNCc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCN(CCO)Cc1ccc(Cl)nc1

Procedure:
This compound was made in a manner analogous to that set forth in Step B of Example 2, using 11.3 grams (about 0.055 mole) of 2-{[(6-chloro-3-pyridyl)methyl]amino}ethan-1-ol, 25.4 grams (0.150 mole) of 1-iodopropane, and 14.5 grams (0.143 mole) of triethylamine in 50 mL of acetonitrile. The yield of the subject compound was about 2.2 grams.
Reaction SMILES: BrC[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OC)=[O:4].N[C:14]([NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]1)=S.C(N(CC)C(C)C)(C)C.CC(C)=[O:43]>>[CH2:3]([O:4][C:14](=[O:43])[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NC(N)=S)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Yield: 44 %

Procedure:
A mixture of 2-bromoacetylanisole (1.5 g, 6.5 mmol), trans-4-(aminocarbothioylamino)-1-(t-butoxycarbonyl-amino)methyl-cyclohexane (1.88 g, 6.5 mmol) and N,N-diisopropylethylamine (2.3 ml, 13.1 mmol) in acetone (20 ml) was heated at reflux temperature overnight. The solvent was evaporated, the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography over silica gel (hexanes/ethyl acetate 5:2) to give the desired product as a light brown oil (1.2 g, 44% yield): ESMS m/e=418 (MH+): 1H NMR δ 8.08 (dd, 1H, J=1.6, 7.7 Hz), 7.24 (m, 1H), 7.18 (s, 1H), 7.01 (t, 1H, J=7.6 Hz), 6.95 (d, 1H, J=8.2 Hz), 4.96 (d, 1H, J=8.1 Hz), 4.60 (m, 1H), 3.93 (s, 3H), 3.30 (m, 1H), 3.01 (t, 2H, J=6.4 Hz), 2.25 (m, 2H), 1.84 (m, 2H), 1.47 (m, 1H), 1.45 (s, 9H), 1.30-1.03 (m, 4H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][N:6]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN=Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 77.46 g (0.617 mol) of glycine methylester hydrochloride in CH2Cl2, 92 ml (0.66 mol) of triethylamine, a solution of 60 g (0.44 mol) of p-anisaldehyde in 50 ml of CH2Cl2 and 40 g of MgSO4 are successively added at 0-5° C. under N2 atmosphere. After stirring for 18 h at r.t. the reaction mixture is filtered through celite and washed with CH2Cl2. The filtrate is concentrated under reduced pressure and then the crude mixture is diluted with AcOEt. The AcOEt solution is filtered again to remove triethylamine hydrochloride and the filtrate diluted with toluene and concentrated under reduced pressure (azeotropic removal of H2O) to give 91.3 g of [(4-methoxy-benzylidene)-amino]-acetic acid methyl ester as light yellow crystals; NMR (C6D6): 3.18 (s, 3H), 3.34 (s, 3H), 4.13 (s, 3H), 6.69 (d, 2H, J=8.56 Hz), 7.70 (d, 2H, J=8.56 Hz), 7.79 (s, 1H).
Reaction SMILES: CO[C:3](=[O:28])[CH2:4][CH:5]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[C:29]([Li])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([CH2:6][CH:5]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH2:4][C:3](=[O:28])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: [Li]C(C)(C)C
Reactant: COC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(CC(=O)C(C)(C)C)c2ccncc2)CCN(C)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 108 %

Procedure:
4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacidmethylester (1.5 g, 3.9 mmol) was dissolved in THF (50 mL) and cooled to −78° C., tert-butyl lithium (16% in pentane) (6 mL, 15.13 mmol) was added dropwise under nitrogen. The reaction mixture was stirred at −78° C. for 90 min. After complete consumption of starting material, the reaction mixture was quenched with ammonium chloride solution and the reaction mixture was allowed to come to RT and extracted with EtOAc (3×100 mL), The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 1.7 g of crude 6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2,2-dimethyl-5-pyridin-4-yl-hexan-3-one. 1H NMR (CDCl3, freebase) δ (ppm): 8.41 (d, 2H), 7.31 (d, 1H), 7.19 (s, 1H), 7.1 (d, 1H), 6.93 (d, 2H), 4.25 (dd, 1H), 3.9 (t, 2H), 3.8 (m, 1H), 3.67 (dd, 1H), 2.87 (m, 3H), 2.71 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H), 2.1 (m, 1H), 1.21 s (9H). Separation by chiral HPLC provides enantiomers II-222a-b.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]1([C:12]2[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]3[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]5[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=5)[CH:27]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C4CC4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C5CC5)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-cyclopropyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M270) (349 mg, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (91 mg, 33%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCN(CC)CC.C([O-])(O)=O.[Na+].[C:38]1([CH3:63])[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH2:48][O:49][C:50](=[O:62])[C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[C:53]([S:58](Cl)(=[O:60])=[O:59])[CH:52]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl.O>[C:38]1([CH3:63])[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH2:48][O:49][C:50](=[O:62])[C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[C:53]([S:58]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:60])=[O:59])[CH:52]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)c2ccc(C)c(S(=O)(=O)Cl)c2)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCOC(=O)c2ccc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c2)cc1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole (LANSOPRAZOLE, 700 mg, 1.89 mmol), 3 mL of Et3N, and about 1 g of NaHCO3 in CH2Cl2 (15 mL) was added the sulfonyl chloride (Intermediate 49, 1.03 g, 2.47 mmol, 1.3 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 2 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried, and concentrated. The resulting residual oil was purified by column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to yield 1.1 g (78%) of 3-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 52) as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:10]2[C:5](=[CH:6][C:7]([N+:25]([O-])=O)=[C:8]([NH:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-])=O)[CH:9]=2)[N:4]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:3]1=[O:33].Cl[Sn]Cl.O>CCOC(C)=O>[NH2:25][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:1])([CH3:34])[C:3](=[O:33])[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:9][C:8]=1[NH:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)/C=C/c3ccccc3[N+](=O)[O-])c([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)/C=C/c3ccccc3N)c(N)cc21

Procedure:
(E)-N-(3,3-Dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-(2-nitrophenyl)-acrylamide is dissolved in EtOAc (70 ml). SnCl2.H2O (5.44 g; 24.1 mmol) is added and the resulting mixture is heated under reflux for 20 h. After re-cooling the mixture is filtered over basic Al2O3 (120 g) and concentrated in vacuo. The residue is taken-up in EtOAc and saturated K2CO3 solution. After an aqueous work-up the compound (0.82 g) is obtained as a yellow solid.