Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].I([O-])(=O)(=O)=[O:26].[Na+].O>CO>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:26])=[CH:14][CH:15]=2)[CH:9]=1)=[O:4]
Reactant: CNC(=O)c1cc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)s1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1cc(-c2ccc(S(C)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
A mixture of N-methyl-5-(4-fluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carboxamide (1.66 g), sodium periodate (1.05 g) and water (1 ml) in methanol (100 ml) was stirred at 0° C. for 2 days. The insoluble was filtered and the filtrate was evaporated. The residue was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from ethanol to give colorless crystals of N-methyl-5-(4-fluorophenyl)-4-[4-(methylsulfinyl)phenyl]thiophene-2-carboxamide (1.1 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]2)=[C:10]([O:19][CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:9]=1.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[CH:44]=[N:45][N:46]([CH2:48][C:49]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:53]=2[F:59])=[O:50])[CH:47]=1>ClCCCl.O>[F:59][C:53]1[C:54]([F:58])=[CH:55][CH:56]=[CH:57][C:52]=1[NH:51][C:49](=[O:50])[CH2:48][N:46]1[CH:47]=[C:43]([NH:42][CH:12]2[C:11]3[C:16](=[CH:17][C:8]([O:7][CH3:6])=[CH:9][C:10]=3[O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[N:15]=[CH:14][NH:13]2)[CH:44]=[N:45]1
Reactant: Nc1cnn(CC(=O)Nc2cccc(F)c2F)c1
Reactant: COc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c2c(=O)[nH]cnc2c1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc2c(c(OC[C@H]3CCCN3C(=O)OC(C)(C)C)c1)C(Nc1cnn(CC(=O)Nc3cccc(F)c3F)c1)NC=N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
Phosphoryl chloride (0.27 ml, 2.94 mmol) was added to a solution of tert-butyl (2R)-2-{[(7-methoxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (0.550 g, 1.47 mmol) and di-iso-propylethylamine (1.02 ml, 5.88 mmol) in 1,2-dichloroethane (20 ml) and the reaction was heated at 80° C. for 1 hour. The mixture was evaporated under reduced pressure and the residue suspended in dimethylacetamide (10 ml) and then 2-(4-amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (0.370 g, 1.47 mmol) was added and the mixture was heated at 90° C. for 1 hour. The mixture was evaporated under reduced pressure and the residue stirred in a 7N solution of ammonia in methanol (100 ml) at ambient temperature for 2 hours. The mixture was evaporated under reduced pressure to leave a yellow solid which was stirred in water (50 ml) for 1 hour and then filtered and the residue purified by silica gel chromatography eluting with a 0 to 10% mixture methanol in dichloromethane to give tert-butyl (2R)-2-[({4-[(1-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]-7-methoxy-3,4-dihydroquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.400 g, 44% yield over 3 steps):
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=O)=[O:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=1[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[O:19]=[C:17]([N:59]1[CH2:58][CH2:57][CH:56]([O:55][C:54]2[CH:62]=[CH:63][CH:64]=[CH:65][C:53]=2[Cl:52])[CH2:61][CH2:60]1)[CH2:16][NH:15][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][N:11]=1)=[O:14]
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1ccc(-c2ccccc2)cn1
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid (0.07 g, 0.00027 mol) in DMF (1.5 mL) was added DIPEA (0.105 g, 0.00082 mol), HOBt (0.044 g, 0.00033 mol) and EDCI.HCl (0.062 g, 0.00033 mol) at ambient temperature. After 2 minutes 4-(2-chlorophenoxy)piperidine hydrochloride (0.081 g, 0.000327 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.0545 g (44%) of 5-phenyl-pyridine-2-carboxylic acid {2-oxo-2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethyl}-amide. LCMS: 484.18 (M+1)+, 95.40%, 1H NMR (DMSO-d6): δ 9.0 (d, 1H), 8.8 (t, 1H), 8.3 (dd, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.6-7.4 (m, 2H), 7.3-7.2 (m, 2H), 7.0-6.9 (m, 1H), 4.8-4.7 (m, 1H), 4.3 (d, 1H), 3.8-3.6 (m, 2H), 3.5 (m, 2H), 2.0-1.9 (m, 2H), 1.8-1.6 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][C:9]([O-:11])=[C:8](C(OC)=O)[C:7]=1[CH3:16])=[O:5])[CH3:2].[Na+].CC(O)=O.[I-].[Na+]>COCCOCCOC>[CH3:16][C:7]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:9](=[O:11])[CH:8]=1
Reactant: CCOC(=O)C1=C(C)C(C(=O)OC)=C([O-])C1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(=O)C=C1C
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A round-bottom flask was charged with sodium 4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate (105 g, 0.420 mol) and diglyme (1 L) to give a yellow suspension. AcOH (100 mL, 1.7 mol) was added to the resulting mixture and sodium iodide (280 g, 1.9 mol) was added portion-wise over about 5-10 min. The reaction mixture was then heated to reflux for about 3 h, cooled to room temperature, and poured over ice water (800 mL). The resulting material was extracted with Et2O (3×500 mL). The combined organic extracts were washed with brine (2×500 mL), dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure to give a brown liquid that was purified by vacuum distillation (80-85° C., 0.3 Torr) to give ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (40.6 g, 57%) as a yellow oil: 1H NMR (CDCl3) δ 6.06-5.98 (m, 1H), 4.30-4.11 (m, 2H), 3.72-3.65 (m, 1H), 2.77-2.66 (m, 1H), 2.66-2.57 (m, 1H), 2.17 (s, 3H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>CN(C=O)C>[Br:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][O:17][C:13]1[CH:12]=[C:11]([C:10]2[N:9]=[C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)[CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1Br
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4Br)c3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (100 mg, 0.36 mmol) in DMF (1.8 mL) was charged with Cs2CO3 (174 mg, 0.54 mmol) and stirred at rt for 30 min. A solution of 2-bromobenzyl bromide (89.2 mg, 0.36 mmol) in DMF was added to the reaction mixture. Reaction mixture was stirred overnight at rt under nitrogen. The crude product was left under high vacuum to remove the DMF for 2 h. The product was then purified by silica gel column chromatography (3% NH3 in MeOH):CH2Cl2 to yield the title compound as a brown/red solid; 1H NMR (CDCl3, 400 MHz) δ 2.02-2.08 (m, 1H), 2.14-2.21 (m, 1H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.85 (m, 1H), 5.21 (s, 2H), 7.00 (d, J=5.6 Hz, 1H), 7.04-7.07 (m, 1H), 7.11 (d, J=5.2 Hz, 1H), 7.18-7.23 (m, 1H), 7.25-7.30 (m, 2H), 7.33-7.37 (m, 1H), 7.42 (t, J=16 Hz, 1H), 7.55-7.61 (m, 2H); MS (ES+): m/z 450.81 (100) [MH+].
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC(S([Cl:34])(=O)=O)=CC=1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([N:8]([CH2:9][CH2:10][Cl:34])[CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCN(Cc1ccccc1)Cc1ccoc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: ClCCN(Cc1ccccc1)Cc1ccoc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 0.397 g (1.716 mmol) of 2-[benzyl-(3-furylmethyl)amino]ethanol, 0.36 ml (2.6 mmol) of triethylamine and 10 mg of 4-dimethylaminopyridine in 30 ml of dichloromethane, 0.39 g (2.1 mmol) of p-toluenesulfonyl chloride was added at room temperature, followed by stirring at room temperature for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield N-benzyl-N-(3-furylmethy)-2-chloroethylamine.
Reaction SMILES: BrC1N2N=C(F)C=CC2=NC=1.NCCC[N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].[Br:22][C:23]1[N:27]2[N:28]=[C:29]([NH:32][CH2:33][CH2:34][CH2:35]N(C)C3C=CC=CC=3)[CH:30]=[CH:31][C:26]2=[N:25][CH:24]=1>>[Br:22][C:23]1[N:27]2[N:28]=[C:29]([NH:32][CH2:33][CH2:34][CH2:35][CH:18]3[CH2:19][CH2:20][NH:16][C:17]3=[O:21])[CH:30]=[CH:31][C:26]2=[N:25][CH:24]=1
Reactant: NCCCN1CCCC1=O
Reactant: CN(CCCNc1ccc2ncc(Br)n2n1)c1ccccc1
Agent: Fc1ccc2ncc(Br)n2n1
Product: O=C1NCCC1CCCNc1ccc2ncc(Br)n2n1
Yield: 68 %

Procedure:
The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was alkylated with 1-(3-aminopropyl)pyrrolidin-2-one, under same reaction condition as used in the synthesis of N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N3-methyl-N3-phenylpropane-1,3-diamine example 5.6.29 to obtain 68% product.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[C:12]1([C:9]2[C:8]3[CH:18]=[C:4]([CH2:3][C:1]4[NH:21][N:20]=[N:19][N:2]=4)[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1ccc2occ(-c3ccccc3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2coc3ccc(Cc4nnn[nH]4)cc23)cc1

Procedure:
A mixture of 4.6 g. (0.02 mole) of 5-cyanomethyl-3-phenylbenzofuran, 1.5 g. of sodium azide and 1.2 g. of ammonium chloride in 15 ml. of N,N-dimethylformamide is heated at 110° C. for 20 hours. The reaction mixture is poured into 200 ml. of water and stirred. The mixture is extracted with 50 ml. of chloroform. The extracts are washed with water, then dried over magnesium sulfate. Evaporation provides a residue which is recrystallized from ethyl acetate to provide 3-phenyl-5-(1H-tetrazol-5yl)methylbenzofuran.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH3:9][C:3]1[C:2]2[NH:1][CH2:17][CH2:18][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(O)c1N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1NCCO2
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To a solution of 2-amino-m-cresol (5.0 g) in N,N-dimethylformamide (50 ml), potassium carbonate (28.3 g) and 1,2-dibromoethane (5.3 ml) were added and stirred at 130° C. for 4 hours and then stirred overnight at room temperature. To the reaction mixture, 1,2-dibromoethane (5.3 ml) was added and stirred at 130° C. for 6 hours. After addition of additional 1,2-dibromoethane (3.5 ml), the reaction mixture was stirred at 130° C. for 5 hours and then stirred overnight at room temperature. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 10:1) to give the titled compound, i.e., 5-methyl-3,4-dihydro-2H-1,4-benzoxazine (2.69 g) as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[OH-].[K+].CO.[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C)C=O>[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: CC(C(=O)O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
25 g (0.15 M) of 2-hydroxyphenylpropanoic acid and 16.9 g (0.12 M) of potassium hydroxide are added to a mixture of 150 ml of methanol and 20 ml of dimethylformamide in a 1000 ml reactor. After stirring for 10 minutes, 30 g (0.15 M) of 2-(4-nitrophenoxy)ethyl bromide are added and the reaction medium is then refluxed for 24 hours with stirring. The methanol is evaporated off and the residue is taken up in water. The aqueous phase obtained is first washed with ethyl acetate and then acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[C:6]([CH:8]([OH:11])[CH2:9][CH3:10])[CH:7]=1.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1
Reactant: CCC(O)c1cc(Cl)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)c1cc(Cl)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 6 %

Procedure:
1-{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml), a sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (11 mg, yield 6%).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22](Cl)[N:17]2[N:16]=1)(=[O:14])=[O:13].Cl.[CH3:27][OH:28]>>[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22]([O:28][CH3:27])[N:17]2[N:16]=1)(=[O:14])=[O:13]
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nn12
Reaction time: 0.33 h

Procedure:
Sodium (0.6 g, 26 mmol) was added to about 40 ml of methanol and allowed to react. N-(2,6-dichloro-3-methylphenyl)-7-chloro-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (2.5 g, 6.9 mmol) was added with stirring. After about 20 minutes, thin layer chromatography indicated the starting material had reacted. The solution was then acidified by adding 6N hydrochloric acid dropwise and then concentrated by evaporation under reduced pressure. The residue was triturated with water and the solid that formed was washed with water and dried to obtain 1.35 g of the title compound as a white solid, m.p. 239°-42° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=Nc1cccc2nc(C)ccc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 175 mg (0.60 mmol) of (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 103 mg (0.63 mmol) of 5-amino-2-methylquinoline and 0.3 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 230 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 5 ml (5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 135 mg of product.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:6][CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH:34]1([CH:12]([N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[CH:5][CH:6]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)c1ccc(CCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(CCc2ccc(C(=O)O)cc2)C2CCCCC2)c(OC)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of 180 mg (0.327 mmol) 4-{3-cyclohexyl-3-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-propyl}-benzoic acid methyl ester in 3 ml dioxane was added 3 ml water and 41 mg (0.98 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred for 4 h at 100° C. and then poured on 30 ml aqueous 1M hydrochloric acid and 30 ml ethyl acetate. The aqueous layer was extracted a second time with 30 ml ethyl acetate. The combined organic layers were washed with 30 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (phenomenex gemini column) eluting with a gradient of acetonitril:water (50:50 to 95:5) to give the title compound as a light yellow solid (78%). MS (Turbo Spray): m/z=536.236 [M+H].
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 37 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (37%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[C:40]5[C:35](=[CH:36][C:37]([O:41]COC)=[CH:38][CH:39]=5)[O:34][CH2:33][C:32]4([C:46]4[CH:51]=[CH:50][C:49]([O:52]COC)=[CH:48][CH:47]=4)[CH3:45])=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>CO.ClCCl>[C:11]([C:9]1[CH:8]=[C:7]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[C:40]5[C:35](=[CH:36][C:37]([OH:41])=[CH:38][CH:39]=5)[O:34][CH2:33][C:32]4([C:46]4[CH:47]=[CH:48][C:49]([OH:52])=[CH:50][CH:51]=4)[CH3:45])=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OCCN3CCN(Cc4cc(C(C)(C)C)cc(C(C)(C)C)c4)CC3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(CN2CCN(CCOc3ccc(C4c5ccc(O)cc5OCC4(C)c4ccc(O)cc4)cc3)CC2)cc(C(C)(C)C)c1
Reaction time: 2 h
Yield: 53.9 %

Procedure:
(3RS,4SR)-4-{4-{2-{4-{[3,5-Bis(t-butyl)phenyl]methyl}piperazinyl}ethoxy}phenyl}-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-3-methylchroman (150 mg, 0.21 mmol) was dissolved in methanol (1.5 ml), 6N-HCl (2 ml) was added portionwise thereto, and the mixture was stirred at 50–60° C. for 2 hours. The reaction solution was diluted with dichloromethane, which was then basified with saturated sodium bicarbonate solution. This solution was washed with water, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel column chromatography (dichloromethane:methanol=40:1) to give 75 mg (yield: 54%) of a pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:34][O:35][C:36](=[O:43])[C@H:37]([CH2:39][CH:40]([CH3:42])[CH3:41])[NH2:38].CN1CCOCC1>CN(C=O)C>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:38][C@@H:37]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:36]([O:35][CH3:34])=[O:43])=[O:12])=[O:6])[CH2:17][CH3:18]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@@H](CC(C)C)C(=O)OC)c1
Reaction time: 1 h
Yield: 88 %

Procedure:
3-[(Dipropylamino)carbonyl]benzoic acid, (1.24 g, 5 mmol) is combined with EDC (0.95 g, 5 mmol) and HOBT (0.69, 5.1 mmol) in 10 mL of DMF and stirred under nitrogen for 1 h. This solution is then added to a solution of L-leucine methyl ester hydrochloride (0.9 g, 5 mmol) and 0.55 mL (5 mmol) of 4-methylmorpholine in 5 mL of DMF. The reaction is continued for 3 days at ambient temperature. It is then quenched with 1 N KH2PO4 and diluted with ethyl acetate. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. Concentration and chromatography over silica gel, eluting with 50% ethyl acetate in heptane, affords 1.65 g (4.4 mmol, 88%) of the title compound as a colorless oil which crystallizes on standing. 1H NMR (CDCl3) δ 7.82 (m, 1H), 7.77 (s, 1H), 7.51-7.44 (m, 2H), 6.65 (d, J=8 Hz, 1H), 4.84 (m, 1H), 3.77 (s, 3H), 3.46 (br t, 2H), 3.14 (br t, 2H), 1.78-1.65 (m, 5H), 1.53 (m, 2H), 0.99 (m, 9H), 0.75 (br t, 3H).