Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[N:9]1[C:15](=[O:30])[C@@H:16]([C@@H:21]([C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[OH:22])[CH2:17][CH2:18][C:19]#[CH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])(=O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[N:9]1[C:15](=[O:30])[C@@H:16]([C@H:21]([O:22][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:17][CH2:18][C:19]#[CH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(Cl)nc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a stirred solution of 29.7 g (71.9 mmol) of (4S)-4-benzyl-3-{(2R)-2-[(S)-(6-chloropyridin-3-yl)(hydroxy)methyl]hex-5-ynoyl}-1,3-oxazinan-2-one from Step B and 15.0 mL (126 mmol) of 2,6-lutidine in 300 mL of anhydrous dichloromethane at 0° C. under an atmosphere of nitrogen was added 22 mL (94 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate at a rate slow enough to keep the internal temperature below 3° C. The reaction mixture was stirred for 16 h at 0° C. then evaporated in vacuo to remove all volatiles. The residue was diluted with 400 mL of water and extracted with diethyl ether (3×300 mL). The combined organics were washed sequentially with a 0.5 M aqueous hydrochloric acid solution (100 mL), water (100 mL) brine (100 mL) then dried over magnesium sulfate. After filtration and evaporation in vacuo the residue was purified by silica gel chromatography eluting with a 5-8% ethyl acetate in hexanes gradient to afford the title compound as a colorless foam (37 g, 97%). LC-MS: m/z (ES) 527.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][N:5]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1c[nH]nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 60 h
Yield: 62.5 %

Procedure:
A suspension of 4-bromo-3-phenyl-1H-pyrazole (6.13 g, 27.5 mmol), trityl chloride (15.3 g, 55.0 mmol), and K2CO3 (11.4 g, 82.5 mmol) in DMF (100 mL) was stirred for 60 h at 90° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, concentrated under reduced pressure. The residue was recrystallized from hexane/THF to give the title compound (8.00 g, 63% yield) as a white solid: mp 181-183° C.; 1H NMR (300 MHz, CDCl3): δ ppm 7.16-7.22 (6H, m), 7.28-7.41 (13H, m), 7.87-7.91 (2H, m). Anal. Calcd for C28H21BrN2: C, 72.26; H, 4.55; N, 6.02. Found: C, 72.43; H, 4.66; N, 5.91.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][NH:12][C:13]3[C:23]4[CH2:22][CH2:21][N:20]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:19][CH2:18][C:17]=4[CH:16]=[CH:15][C:14]=3[Cl:30])=[CH:9][CH:8]=2)OCC[O:3]1.Cl>CO>[C:2]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13]2[C:23]3[CH2:22][CH2:21][N:20]([C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])[CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][C:14]=2[Cl:30])=[CH:31][CH:32]=1)(=[O:3])[CH3:1]
Reactant: CC1(c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)OCCO1
Agent: Cl
Solvent: CO
Product: CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
Dissolve 6-{4-(2-methyl-[1,3]dioxolan-2-yl)benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.32 mmol) in methanol (5 mL) and add 1N aqueous HCl (1 mL). Stir the solution at ambient temperature for 2 h. Remove the solvent, dissolve the residue in DCM and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 17:3 and 4:1) to obtain 6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (107 mg, 79%). GC-MS m/z 424 (M+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[N:31]1([CH2:38][CH2:39][C:40]2[S:44][C:43]([C:45]([O-])=O)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[Li+]>>[N:31]1([CH2:38][CH2:39][C:40]2[S:44][C:43]([CH2:45][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C([O-])c1ccc(CCN2CCCCCC2)s1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: [Li+]
Product: CCN(Cc1ccc(CCN2CCCCCC2)s1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 75 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and lithium 5-(2-azepan-1-ylethyl)thiophene-2-carboxylate (100 mg) according to an analogous synthetic method to Example 152, the title compound (40 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[C:19]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][CH:29]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:9][CH:8]=3)=[CH:12][CH:13]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(Oc2ccc(N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COC(=O)c1ccc(Oc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 93.9 %

Procedure:
Using general procedure A, 4-(4-aminophenoxy)-benzoic acid methyl ester (Fokin; et al., Chem. Abstr., 72, 12294, 1970) (556 mg, 2.29 mmol) and 1-Boc-4-piperidone (478 mg, 2.40 mmol) gave 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (917 mg, 94%) as a crystalline solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:32][CH2:33][N:34]([C:11]3[CH:12]=[CH:13][C:14]4[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=4)[N:16]=3)[CH2:35][CH2:36]2)=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Oc1ccc(C2(O)CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
DIPEA (1.174 mL, 6.74 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (1 g, 4.49 mmol) and 4-(4-hydroxyphenyl)piperidin-4-ol (0.955 g, 4.94 mmol) in DMF (10 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature then evaporated to dryness. The residues were triturated with water and the resulting solid collected by filtration, washed with further water followed by ether, then dried under vacuum to afford 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (1.680 g, 99%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccncc1
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
36 g of N-benzyloxycarbonyl glycine was dissolved in 400 ml of dimethylformamide and the solution was cooled to -8° C., to which 56.8 g of dicylohexylcarbodiimide dissolved in 50 ml of dimethylformamide was added while maintaining the temperature at -8° to -6° C. After stirring at -6° to -3° C. for 15 minutes, 17 g of 4-aminopyridine was added at -3° to -1° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours and stirred at room temperature overnight. Then, dicyclohexylurea was filtered off and dimethylformamide was distilled off under reduced pressure. The residue was purified through the chromatography on silica gel (silica gel 1 kg; chloroform-methanol (3%→6%) as the eluent) and recrystallized from methanol-ethyl acetate to obtain 35.2 g of 4-[(N-benzyloxycarbonyl glycyl)amino]pyridine having the melting point of 154° to 156° C. This was dissolved in 1 l of methanol and 2.3 g of palladium black was added thereto followed by subjecting to the catalytic hydrogenation at room temperature and under atmospheric pressure. After 5 hours, the catalyst was filtered off and the filtrate was concentrated to about 50 ml. 200 ml of ethyl acetate was added and again the resultant solution was concentrated to about 60 ml so as to obtain the precipitate, which was allowed to stand overnight and filtered to obtain the titled compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:35]3[CH2:36][CH2:37][N:32]([C:28]4[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=4)[CH2:33][CH2:34]3)=[O:16])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccnc(N2CCNCC2)c1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: Cc1ccnc(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)c1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(4-methyl-pyridin-2-yl)piperazine to give the title compound as a colorless solid. MS: 512.3 ([M+H]+)
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]([C:7]1([CH3:12])[O:11][CH2:10][CH2:9][O:8]1)[CH3:6])C.[OH-].[K+]>O1CCOCC1.O.O>[CH3:12][C:7]1([CH:5]([CH3:6])[C:4]([OH:13])=[O:3])[O:11][CH2:10][CH2:9][O:8]1
Reactant: CCOC(=O)C(C)C1(C)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)O)C1(C)OCCO1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
2-(2-Methyl-[1,3]dioxolan-2-yl)-propionic acid ethyl ester of Example 1a (31 g, 0.1647 mol) was dissolved in the mixture of dioxane-water (1:1, 350 mL) containing potassium hydroxide (35.63 g, 0.63 mol). The reaction mixture was stirred overnight at 35° C. and concentrated under high vacuum to give a white solid which was dissolved in water (200 mL) and extracted with dichloromethane (100 mL×2). The aqueous portion was acidified to pH=2 with 2N aqueous hydrochloric acid and the product was extracted with chloroform. The organic layer was washed with brine (300 mL), dried with sodium sulfate and concentrated under vacuum. 2-(2-methyl-[1,3]dioxolan-2-yl)-propionic acid was isolated as clear oil (20.34 g, 77%) which did not require further purification.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH2:9][N:10]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:11][CH2:12]OS(C)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[Br-:24].[Li+]>CC(C)=O>[Br:24][CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)OCCN(CCOc1ccc(C#N)cc1)S(C)(=O)=O
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CS(=O)(=O)N(CCBr)CCOc1ccc(C#N)cc1

Procedure:
To a solution of methanesulfonic acid 2-{[2-(4-cyanophenoxy)ethyl]-methanesulfonylamino}ethyl ester (10 g, 0.028 mol; see step (iii) above) in dry acetone (100 mL), was added lithium bromide (4.8 g, 0.055 mol). The reaction mixture was added refluxed overnight under a nitrogen atmosphere, before being filtered and concentrated to give the title compound. Yield: 10 g (97%).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]1[S:15][C:14]([O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[CH2:1]([NH:9][CH2:10][C:11]1[S:15][C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:26])=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(Oc2ccc(CNCCc3ccccc3)s2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)s2)cc1
Temperature: 0 °C
Yield: 75 %

Procedure:
Combine 4-[5-(phenethylamino-methyl)-thiophen-2-yloxy]-benzonitrile ((139 mg, 0.415 mmol), K2CO3 (powder, 28 mg, 50 mol %) and DMSO (4 mL). Cool down to 0° C. Add hydrogen peroxide (0.124 mL) dropwise. Stir the resulting reaction mixture for 2.5 h. Partition the reaction mixture between H2O (5 mL) and CH2Cl2 (3×5 mL). Dry over sodium sulfate, filter and concentrate. Purify the residue through an SCX column with ammonia (2.0 M in methanol) to provide 105 mg (75%) of the title compound. Mass spectrum (ion spray): m/z=353.0 (M+1). 1H NMR (Cl3CD): 7.80 (d, J=8.7 Hz, 2H), 7.34-7.22 (m, 5H), 7.12 (d, J=8.7 Hz, 2H), 6.65 (d, J=3.37 Hz, 1H), 6.44 (d, J=3.7 Hz, 1H), 5.96 (bs, 2H), 3.93 (s, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.5 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH2:12]([NH2:14])[CH3:13]>O>[CH2:12]([NH:14][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])[CH3:13]
Reactant: CCN
Reactant: NS(=O)(=O)c1cnccc1Cl
Solvent: O
Product: CCNc1ccncc1S(N)(=O)=O

Procedure:
By carrying out the reaction as in Preparation 13, but starting from 2 g of 4-chloropyridine-3- sulfonamide and 20 cm3 of 70% ethylamine in water, the compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][OH:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:21][CH2:22][CH2:23][OH:24])=[O:15])=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Br)cc1
Product: COc1ccc(C(=O)NCCO)cc1/C=C/c1ccc(Br)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-43 and 2-aminoethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[C:3]=1[NH2:35].N[C:37](N)=[O:38]>O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:35]=[C:37]([OH:38])[N:8]2[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:15][CH2:16]1
Reactant: Nc1c(Cl)ncnc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: NC(N)=O
Solvent: O
Product: Oc1nc2c(Cl)ncnc2n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 220 °C
Yield: 32 %

Procedure:
A mixture of 7.5 parts of 6-chloro-N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine and 3.6 parts of urea was stirred and heated for 20 minutes at 220° C. Water was added to the reaction mixture. The precipitated product was filtered off and crystallized from methanol. The product was filtered off and recrystallized from a mixture of N,N-dimethylformamide and methanol, yielding 2.5 parts (32%) of 6-chloro-9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-9H-purin-8-ol; mp. 243.0° C. (494).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][CH2:48][CH2:49][OH:50].P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][CH2:48][CH2:49][OH:50])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCO)CCC3)cc1
Temperature: 0 °C
Yield: 85.2 %

Procedure:
A solution of 2.08 g (3.37 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)], and 1.41 g (10.14 mmol, 3.0 equiv.) of 3-bromo-1-propanol in 10 ml of toluene and 0.1 ml of N-methyl-pyrrolidone was treated with 1.44 g (10.14 mmol, 3.0 equiv.) of anhydrous disodium hydrogen phosphate. The suspension was refluxed for 24 h under an inert atmosphere. Subsequently, the reaction mixture was poured into 200 ml of an ice/water mixture and extracted three times with 150 ml of ethyl acetate. The combined organic phases were washed five times with 20 ml of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 1:1 mixture of hexane and ethyl acetate as the eluent and yielded 1.94 g (2.87 mmol, 85.2% of theory) of (3R,4R)-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 675 (M+H)+.
Reaction SMILES: C([N:8]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH2:21][OH:22])=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[N:10]1[NH:9][N:8]=[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH2:21][OH:22])[CH:11]=1
Reactant: OCc1cc(Cl)ccc1Nc1cnnn1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: OCc1cc(Cl)ccc1Nc1cn[nH]n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [2-[(3-benzyltriazol-4-yl)amino]-5-chloro-phenyl]methanol 7a (300 mg, 0.95 mmol) in MeOH (5 mL) was treated with formic acid (1.00 mL, 26.51 mmol). The mixture was degassed by vacuum/nitrogen cycles before the addition of palladium on carbon (507.1 mg, 0.48 mmol). The mixture was stirred under an argon atmosphere at room temperature for 18 h and then filtered through celite and concentrated. The material was purified by FractionLynx to afford the title compound I-9 as a solid (90.0 mg, 40%). 1H NMR (500 MHz, DMSO) δ 14.20 (1H, s), 7.85-7.80 (1H, s), 7.60 (1H, s), 7.51 (1H, s), 7.31 (1H, d), 7.19 (1H, d), 4.55 (2H, s). MS m/z: 223.1 (M−H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[F:22].Cl.[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[N:24]1([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=2[F:22])[CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Reactant: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(F)cc2c1=O
Reaction time: 1 h

Procedure:
A solution of Example 7C (13.26 g), azetidine hydrochloride (9.58 g) and triethylamine (17.2 mL) in dichloromethane (650 mL) was stirred for 2 hours, treated with triethylamine (900 mg), stirred for 1 hour, diluted with dichloromethane, washed with water and brine, dried (MgSO4), filtered, and concentrated; and the concentrate was triturated with refluxing dichloromethane, treated with diethyl ether and hexanes, and filtered.
Reaction SMILES: C([O:3][C:4](=[O:29])/[C:5](=[N:25]/[O:26][CH2:27][CH3:28])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH2:27]([O:26]/[N:25]=[C:5](\[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)/[C:4]([OH:29])=[O:3])[CH3:28]
Reactant: CCO/N=C(/C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCO/N=C(/C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 55 °C

Procedure:
As in Example 306, a solution of (Z)-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy) ethoxy]-2-thiopheneacetic acid ethyl ester (0. 141 g) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with 4N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 55° C. for 30 minutes. After the normal work up, the product was crystallized from ethyl acetate-hexane to furnish 0.07 g of (Z-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid, mp 114° C. (dec.).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[N:4][C:3]=1[CH2:2][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(C=O)cc1

Procedure:
According to the method described for Reference Example 45, 4-chloromethyl-5-methyl-2-(2-naphthyl)oxazole was allowed to react with p-hydroxybenzaldehyde to give 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzaldehyde. Recrystallization from chloroform-ether gave colorless prisms, m.p.163°-164° C.