Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:13]=[C:14]1[C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([NH:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=1)=[O:33]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A solution of (4-(trifluoromethyl)phenyl)methanamine (0.033 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.50-7.54 (m, 2H), 7.17-7.33 (m, 12H), 6.39 (t, J=6.1 Hz, 1H), 4.34 (d, J=6.1 Hz, 2H), 4.07 (s, 2H), 3.51 (t, J=6.5 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H); MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[C:37]([C:39]1([C:42](O)=[O:43])[CH2:41][CH2:40]1)#[N:38]>>[C:37]([C:39]1([C:42]([N:6]2[CH2:5][C:4]([N:8]3[CH:12]=[C:11]([C:13]4[CH:18]=[N:17][N:16]5[C:19]([C:22]6[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=6)=[CH:20][N:21]=[C:15]5[CH:14]=4)[CH:10]=[N:9]3)([CH2:3][C:1]#[N:2])[CH2:7]2)=[O:43])[CH2:41][CH2:40]1)#[N:38]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)C2(C#N)CC2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and 1-cyanocyclopropanecarboxylic acid. LCMS (M+H)+: m/z=589.2.
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:19]C(=O)C)[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:7]([CH3:28])[NH:6][C:5]1=[O:29])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(O)C>[C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[OH:19])[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:7]([CH3:28])[NH:6][C:5]1=[O:29])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(=O)N(C(C)=O)C1c1cc([N+](=O)[O-])ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(=O)N(C(C)=O)C1c1cc([N+](=O)[O-])ccc1O
Reaction time: 18 h

Procedure:
To a suspension of the Compound 1a (1.03 g) in ethanol (60 mL) at ambient temperature was added potassium carbonate (2.0 g). After stirring for 18 hours, to the reaction mixture was added saturated aqueous ammonium chloride. The reaction mixture was then extracted with methylene chloride and the combined organic extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by flash chromatography on silica gel eluted with methanol:methylene chloride (3:97) to yield the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH:16]([OH:18])[CH3:17])=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[CH:7][C:8]([CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[N:9][CH:10]=1
Reactant: COCOc1cnc(CC(C)(C)C)cc1C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COCOc1cnc(CC(C)(C)C)cc1C(C)=O
Reaction time: 5 h

Procedure:
To a solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol (24.4 g, 96.3 mmol) and sodium bicarbonate (32.4 g, 385 mmol) in CHCl3 (500 mL) at 0° C. was added Dess-Martin Periodinane (53.1 g, 125 mmol). The reaction was stirred 5 h, quenched with saturated aqueous Na2SO3 (300 mL), extracted with CH2Cl2 (3×250 mL), the combined organic layers washed with saturated NaCl (300 mL), dried (Na2SO4), and concentrated to give a yellow oil. Purification by ISCO (330 g SiO2, 20% EtOAc/Hexane) gives 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone as a clear, colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][C:12]1[C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([C:14]1[CH:13]=[C:12]([CH3:11])[C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1)=[O:6]
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cccc(Br)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.08 g (9.48 mmol) 3-bromo-benzoic acid chloride, 1.41 g (9.48 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium trichloride were heated to 125° C. with stirring for 1.5 h. Then the mixture was mixed with ice water and the grease precipitated was separated from the solvent by decanting. The residue was dissolved in EtOAc, evaporated down and a little MeOH was triturated. The precipitate formed was suction filtered, washed with diethyl ether and dried i. vac.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Product: c1cc(N2CCC(N3CCCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 19 and pyrrolidine.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.Br[CH:19]1[CH2:22][CH2:21][CH2:20]1>>[CH:19]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH2:22][CH2:21][CH2:20]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: BrC1CCC1
Product: Oc1ccc2ncn(C3CCC3)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and bromocyclobutane, prepared in a similar manner as the one described in Example 1.2, the title compound was obtained. LCMS m/z=190.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 2.07 (m, 2H), 2.67 (m, 2H), 2.78 (m, 2H), 5.24 (m, 1H), 6.95 (d, J=8.9 Hz, 1H), 8.08 (d, J=8.9 Hz, 1H), 9.33 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH2:12][S:13][C:14]#[N:15]>>[S:13]([CH2:12][O:8][C:6](=[S:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:14]#[N:15]
Reactant: Cc1ccc(C(O)=S)cc1
Reactant: N#CSCCl
Product: Cc1ccc(C(=S)OCSC#N)cc1
Yield: 80 %

Procedure:
20.5 g (0.11 mol) of the K salt of 4-methyl-thiobenzoic acid and 11.7 g (0.11 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 22.5 g of a light powder resulted and, after recrystallisation from ligroin, 18 g of white crystals resulted; melting point 55° (this corresponds to a yield of 80% of the theoretical conversion).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:24])[C:19]([O:21]CC)=[O:20])[CH2:14][C@H:13]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:24])[C:19]([OH:21])=[O:20])[CH2:14][C@H:13]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)C(=O)N1CC[C@H](NC(=O)c2nc(Cl)c(CC)[nH]2)[C@H](OCC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCO[C@@H]1CN(C(=O)C(=O)O)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.7 %

Procedure:
Ethyl cis(±)-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)(oxo)acetate obtained in Example (132a) (122 mg, 0.316 mmol) was dissolved in THF (3 mL). A 1 N aqueous sodium hydroxide solution (0.95 ml, 0.95 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with 1 N hydrochloric acid and concentrated under reduced pressure. Then, the residue was purified by preparative HPLC (TSK-gel, Toso, elution solvent: water/acetonitrile=17/3→1/1) to obtain 79.8 mg of the title compound as a colorless amorphous solid (68%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:5]3[CH:14]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.C1COCC1.CO.[Li+].[OH-].CC(O)=O>[Cl-].[Na+].O>[Br:1][C:2]1[C:3]2[C:4]([S:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of the ester of Step 9 (80 mg) in a 3:1 mixture of THF/MeOH (3 mL) at r.t. was added 1N LiOH (1 mL, aqueous solution). The reaction mixture was stirred at r.t. for 2 h and AcOH (0.5 mL) and brine (5 mL) were added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 40% EtOAc/hexane containing 1% AcOH to provide 70 mg of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: O=C1CCCCCC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Yield: 78.2 %

Procedure:
The general McMurry coupling protocol, described for 14 was followed. Reaction of (4-bromophenyl)(4-hydroxyphenyl)methanone (2.77 g, 10 mmol), and cycloheptanone (3.6 mL, 30 mmol) afforded 2.795 g (78%) of the title compound 200 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=8.1 Hz, 2H), 7.04 (d, J=6.3 Hz, 2H), 7.01 (d, J=6.3 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.74 (s, 1H), 2.32 (m, 4H), 1.59 (s, 8H).
Reaction SMILES: [F:1][C@@:2]12[C@:15]3([CH3:16])[C:10](=[CH:11][C:12](=[O:17])[CH:13]=[CH:14]3)[C@@H:9]([F:18])[CH2:8][C@H:7]1[C@@H:6]1[CH2:19][C@@H:20]3[C@:24]([C:25](=[O:31])[CH2:26][O:27]C(=O)C)([C@@:5]1([CH3:43])[CH2:4][C@@H:3]2[OH:44])[CH2:23][N:22]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)[CH2:21]3.F[C@@]12[C@]3(C)C(=CC(=O)C=C3)[C@@H](F)C[C@H]1[C@@H]1C[C@@H]3[C@](C(=O)CO)([C@@]1(C)C[C@@H]2O)CN(CC1C=CC=C(C)C=1)C3>>[F:1][C:2]12[C:15]3([CH3:16])[C:10](=[CH:11][C:12](=[O:17])[CH:13]=[CH:14]3)[CH:9]([F:18])[CH2:8][CH:7]1[CH:6]1[CH2:19][CH:20]3[C:24]([C:25](=[O:31])[CH2:26][OH:27])([C:5]1([CH3:43])[CH2:4][CH:3]2[OH:44])[CH2:23][N:22]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)[CH2:21]3
Reactant: CC(=O)OCC(=O)[C@@]12CN(Cc3ccc4ccccc4n3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cc1cccc(CN2C[C@@H]3C[C@H]4[C@@H]5C[C@H](F)C6=CC(=O)C=C[C@]6(C)[C@@]5(F)[C@@H](O)C[C@]4(C)[C@]3(C(=O)CO)C2)c1
Product: CC12C=CC(=O)C=C1C(F)CC1C3CC4CN(Cc5ccc6ccccc6n5)CC4(C(=O)CO)C3(C)CC(O)C12F

Procedure:
The title compound was prepared from compound 11 (130 mg, 0.215 mmol) following the procedure described in Example 5 for the synthesis of compound 9. Compound 12 (68 mg, 56% yield) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12](I)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1([CH3:34])[C:31]([CH3:33])([CH3:32])[O:30][BH:29][O:28]1>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([B:29]2[O:30][C:31]([CH3:33])([CH3:32])[C:27]([CH3:34])([CH3:26])[O:28]2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(COCC(=O)OC(C)(C)C)cc1I
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(COCC(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1

Procedure:
The procedure used in Example 3: step b was followed using (3-iodo-4-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 300: step a) 600 mg, 1.65 mmol), PdCl2(PPh3)2 (58 mg, 0.08 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography yielded the title compound contaminated with the product resulting from halide reduction (569 mg, 95%). The material was used without further purification. 1H-NMR (CDCl3): δ 7.73 (d, 1H, J=1.9 Hz), 7.38 (dd, 1H, J=2.1, 7.9 Hz), 7.18 (d, 1H, J=7.9 Hz), 4.61 (s, 2H), 3.97 (s, 2H), 2.55 (s, 3H), 1.50 (s, 9H), 1.37 (s, 9H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:40]=[CH:39][CH:38]=[CH:37][C:14]=2[C:15]([NH:17][C:18]2[CH:36]=[CH:35][C:21]([C:22]([N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)=[O:16])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:40]=[CH:39][CH:38]=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:36]=[CH:35][C:21]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1)=[O:16]
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Yield: 85.2 %

Procedure:
A mixture of 1-{4-[2-[6-phthalimidohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (3.75 g), hydrazine hydrate (0.44 ml) and ethanol (30 ml) is refluxed for 3.5 hours. The precipitated crystal is collected by filtration, dried and purified by silica gel column chromatography (eluent; chloroform:methanol:aqueous ammonia=100:10:1), and recrystallized from methanol/diethyl ether to give 1-{4-[2-(6-aminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.52 g) as white powder, m.p. 135.5°-137.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[H-].[Na+].I[CH:26]([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.ClCCl.CN(C=O)C>[CH:26]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:16]=2)[CH:12]=[CH:13]1)([CH3:28])[CH3:27]
Reactant: CN1CCN(c2ccc3cc[nH]c3c2)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)n1ccc2ccc(N3CCN(C)CC3)cc21
Temperature: 95 °C
Yield: 20.7 %

Procedure:
A mixture of 6-(4-methylpiperazinyl)-indole (8.3 mg, 0.386 mmol), K2CO3 (21 mg, 0.154 mmol), NaH (3 mg, 0.125 mmol), DMF (0.1 ml) and 2-iodopropane (26.3 μl, 0.154 mmol) in 0.5 ml of toluene was heated to 90-100° C. for 1 hr. After cooling, dichloromethane was added and the mixture passed a silica gel column, eluting with 1% 2M ammonia/methanol in dichloromethane, to give the title compound (8.2 mg, 83% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:17])[F:18])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
72 g of 5-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 16a were dissolved in 500 ml of tetrahydrofuran, and hydrogenated on 5 g of palladium on carbon (5%) at room temperature for 5 hours with 15 to 20 bar of hydrogen. The mixture was then filtered and the solvent stripped off in vacuo. The yield was 60 g (93% of theory) and the boiling point was 80° to 82° C. at 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.5 and -79.4 ppm; 1H-NMR: 4.68 ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[N:8]=[N+:9]([O-:20])[C:10]2[CH:19]=[C:18]3[C:14]([CH2:15][CH2:16][CH2:17]3)=[CH:13][C:11]=2[N:12]=1>COCCOC>[O-:20][N+:9]1[C:10]2[CH:19]=[C:18]3[C:14](=[CH:13][C:11]=2[N:12]=[C:7]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[N:8]=1)[CH2:15][CH2:16][CH2:17]3
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: NCCCO
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCO)nc2cc3c(cc21)CCC3
Yield: 97.4 %

Procedure:
3-Aminopropanol (0.99 mL, 12.9 mmol) was added to a stirred solution of chloride 21 (956 mg, 4.3 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 50 (1.09 g, 98%) as a yellow solid: mp (MeOH/DCM) 190-190.5° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.40 (s, 1H, H-5), 5.61 (br s, 1H, NH), 3.78 (br s, 1H, OH), 3.67-3.73 (m, 4H, CH2O, CH2N), 2.97-3.03 (m, 4H, H-6, H-8), 2.15 (p, J=7.5 Hz, 2H, H-7), 1.82-1.88 (m, 2H, CH2); 13C NMR δ 159.2, 155.0, 147.9, 143.6, 130.0, 120.3, 114.8, 59.0, 37.7, 33.1, 33.0, 32.3, 25.7. Anal. calcd for C13H16N4O2: C, 60.0; H, 6.2; N, 21.5. Found: C, 59.8; H, 6.2; N, 21.6%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[CH:2]1.[O:11]1[CH2:15][CH2:14][CH:13](O)[CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N1C2C(=CC=CC=2)C=C1>ClCCl>[O:11]1[CH2:15][CH2:14][CH:13]([O:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)[CH2:12]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: OC1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: c1cc2ccc(OC3CCOC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 1H-indol-6-ol (2.00 g, 15.02 mmol), tetrahydrofuran-3-ol (1.46 mL, 18.0 mmol), and triphenylphosphine (4.33 g, 16.52 mmol) in dichloromethane (80 mL) at 0° C. was added diisopropyl diazene-1,2-dicarboxylate (3.49 mL, 18.03 mmol) over 10 min. The mixture was stirred at room temperature for 16 hr. The starting indole and desired product were detected in a ratio of 3:2. The dark mixture was diluted with CH2Cl2 (80 mL), washed with 1N NaOH (50 mL), water (50 mL), and brine (50 mL). The organic solution was dried over anhydrous MgSO4. The desired product (0.642 g, 3.16 mmol, 21.03% yield) was isolated as viscous oil by ISCO (300 g silica gel, solid loading, 10-50% ethyl acetate/hexane).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:16][CH:15]2[O:17][CH:11]([CH2:12][N:13]([CH2:18][CH2:19][N:20]([CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:14]2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:20]([CH2:19][CH2:18][N:13]2[CH2:14][CH:15]3[O:17][CH:11]([CH2:10][NH:9][CH2:16]3)[CH2:12]2)[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:33][CH:32]=1)#[N:35]
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCN(CCOc3ccc(C#N)cc3)S(C)(=O)=O)CC(C1)O2
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CNCC(C1)O2
Reaction time: 1 h

Procedure:
To a saturated solution of HCl(g) in dioxane (100 mL) was added 7-(2-{[2-(4-cyanophenoxy)ethyl]methanesulfonylamino}ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (3.5 g, 0.0070 mol; see step (i) above), after which the reaction was stirred for 1 h. On completion of the reaction (as determined by TLC), dioxane was decanted and product (semi-solid) dissolved in methanol (25 mL). After concentrating the methanol, dry ether (50 mL) was added and the solvent was again concentrated. This was repeated twice and finally the product was dried under high vacuum. Yield: 3.0 g (99%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:33])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Solvent: ClC(Cl)Cl
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
2.23 g of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-1H-benzimidazole(6 mmol) prepared in Example 1 was dissolved in 20 ml of chloroform, 1.24 g of m-chloroperbenzoic acid(1.2 equivalent) dissolved in 20 ml of chloroformwas added thereto dropwise at below 5° C., and stirred at the same temperature for about 10 minutes. The reaction mixture was washed with aqueous NaHCO3 and dried over MgSO4. The residue obtained after removing the solvent under a reduced pressure was purified by silica gel column chromatography and recrystallization, to obtain 1.33 g of lansoprazole as a white-light brown solid (yield: 60%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[CH2:8]([Si:11]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:12](Cl)[CH3:13])[CH:9]=[CH2:10].C([Si](C1C=CC(F)=CC=1)(C1C=CC(F)=CC=1)CCCl)C=C>CN(C)C=O.O.ClCCl.CC(C)=O>[CH2:8]([Si:11]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH:12]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[CH3:13])[CH:9]=[CH2:10]
Reactant: c1nc[nH]n1
Reactant: C=CC[Si](c1ccc(F)cc1)(c1ccc(F)cc1)C(C)Cl
Agent: C=CC[Si](CCCl)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C=CC[Si](c1ccc(F)cc1)(c1ccc(F)cc1)C(C)n1cncn1
Reaction time: 1 h

Procedure:
A mixture of 1.78 g (37 mmol) of 50% sodium hydride, 30 ml of dimethylformamide, and 2.56 g (37 mmol) of 1H-1,2,4-triazole is stirred at 50° for one hour, and a solution of 10 g (33.7 mmol) of a 1:1 mixture of allyl[bis(4-fluorophenyl)]-1-chloroethylsilane and allyl[bis(4-fluorophenyl)]-2-chloroethylsilane in 10 ml of dimethylformamide is added. The mixture is stirred at 50° for 64 hours, cooled, diluted with water, and extracted with ether. The ether extracts are washed with water and brine, dried over sodium sulfate, and evaporated to leave a viscous oil. Chromatography over silica gel eluting with 4:1 dichloromethane-acetone provides the title compound.