Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][N:5]2[C:6](=[O:14])[NH:7][C:8](=[O:13])[C:9]([CH:10]3[CH2:12][CH2:11]3)=[C:4]2[C:3]=1[CH3:18].O1CCCC1.[H-].[Na+].[N+:26](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O>[NH2:26][N:7]1[C:8](=[O:13])[C:9]([CH:10]2[CH2:12][CH2:11]2)=[C:4]2[C:3]([CH3:18])=[C:2]([Cl:1])[C:16]([F:17])=[CH:15][N:5]2[C:6]1=[O:14]
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Reactant: Cc1c(Cl)c(F)cn2c(=O)[nH]c(=O)c(C3CC3)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(F)cn2c(=O)n(N)c(=O)c(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a 5° C. solution of 6-chloro-4-cyclopropyl-7-fluoro-5-methyl-pyrido[1,2-c]pyrimidine-1,3-dione (0.76 g, 2.8 mmol (Example 2)) in a mixture of dry tetrahydrofuran (20 mL) and dry dimethylformamide (10 mL) was added sodium hydride (0.12 g, 3.0 mmol, 60% mineral dispersion) portionwise. After stirring at room temperature for 30 minutes, 2,4-dinitrophenylhydroxylamine (0.65 g, 3.00 mmol) was added. The mixture was then heated at 80° C. for 45 minutes, cooled to ambient temperature, poured into ice water, and extracted with dichloromethane. The combined extracts were washed with brine, dried with sodium sulfate and concentrated. The residue was purified by column chromatography (9:1 ethyl acetate/hexanes) to afford the title compound (0.635 g). MSCI: m/z=284 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[CH:38]=[CH:37][C:18]([CH2:19][N:20]([CH3:36])[CH2:21][CH2:22][O:23]C(=O)C4C=CC(OC)=C(OC)C=4)=[CH:17][CH:16]=3)=[O:14])[S:11][C:7]=2[C:6]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:5][CH:4]=1.C(O)C>[OH-].[Na+].O>[OH:23][CH2:22][CH2:21][N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:14])=[CH:38][CH:37]=1)[CH3:36]
Reactant: COc1ccc(C(=O)OCCN(C)Cc2ccc(C(=O)Nc3nc4c(OC)ccc(N5CCOCC5)c4s3)cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)CCO)cc3)nc12
Yield: 48 %

Procedure:
3,4-Dimethoxy-benzoic acid 2-{[4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl carbamoyl)-benzyl]-methyl-amino}-ethyl ester (63 mg, 0.10 mmol) are heated in aqueous sodium hydroxide (1M, 0.5 ml) and ethanol (2 ml) to 100° C. for 30 min. The mixture is diluted with water and extracted twice with ethyl acetate. The combined organic layers are extracted with saturated aqueous sodium hydrogencarbonate, dried and evaporated to dryness. Flash chromatography (silica, eluent methylene chloride containing 5% methanol) affords the product as white crystals in 48% yield. MS: m/e=457 (M+H+).
Reaction SMILES: [CH:1]([N:4]([CH3:26])[C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:25])[N:6]=1)([CH3:3])[CH3:2].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>>[CH:1]([N:4]([CH3:26])[C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])=[C:18]([CH3:24])[CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:25])[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(N(C)C(C)C)n1
Reactant: OC[C@H](O)CCl
Product: Cc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(C)c3)no2)cc(N(C)C(C)C)n1

Procedure:
(S)-3-(4-{5-[2-(Isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propane-1,2-diol is prepared in analogy to Example 3 from 4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenol using (S)-3-chloro-1,2-propanediol; LC-MS: tR=0.78 min; [M+1]+=427.08.
Reaction SMILES: [N:1]([CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH2:5][CH2:6][CH:7]=[CH2:8])=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[NH2:1][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCC(N=[N+]=[N-])c1ccccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCCC(N)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 116.3 %

Procedure:
To a solution of 5-azido-5-(2-methoxyphenyl)-1-pentene (1.59 g. 7.33 mmol) in anhydrous ether (10 mL) at 0° C. was added to LiAlH4 in diethyl ether (1.OM, 7.33 mL) dropwise over a period of 20 minutes. The ice bath was removed and the reaction mixture was kept at room temperature for 25 minutes. The reaction solution was cooled to 0° C. to 40° C. and saturated Na2SO4 solution was added dropwise until no hydrogen gas was evolved. Anhydrous Na2SO4 was added followed by diethyl ether (70 mL), the resulting suspension was stirred at room temperature for 1 hour and the solution was then filtered through a pad of Celite™. The filtrate was evaporated to give the title compound (1.63 g) as a colorless oil, which was used for the Preparation 19 without purification. 1H NMR (CDCl3, 400 MHz)δ: 7.22 (2H), 6.93 (3H), 5.80 (1H), 4.92 (2H), 4.13 (1H), 3.82 (3H, OMe), 1.2-2.2 (6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(Cl)CCl.[CH2:22]([O:29][CH2:30][C:31](O)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: O=C(O)COCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: NC(=O)c1cc2c3ccccc3n(C(=O)COCc3ccccc3)c2nc1N
Temperature: 25 °C
Reaction time: 23 h
Yield: 21.8 %

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 150 mg, 0.663 mmol) in pyridine (7 mL) was added EDC (210 mg, 1.10 mmol), DMAP (85 mg, 0.693 mmol) and benzyloxyacetic acid (142 μL, 0.994 mmol) and the mixture was stirred at RT under an atmosphere of Ar. After 23 h, the reaction was quenched with water (20 mL), poured into a separatory funnel containing EtOAc (100 mL) and washed with water (75 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to yield 2-amino-9-[(benzyloxy)acetyl]-9H-pyrido[2,3-b]indole-3-carboxamide (28, 54 mg, 22%). NH4OAc standard conditions. DAD Retention time=7.6 min. M+H=375. 1H NMR (300 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.52-8.49 (m, 1H), 8.04 (br s, 1H), 7.83-7.77 (m, 3H), 7.47-7.29 (m, 8H), 5.30 (s, 2H), 4.72 (s, 2H).
Reaction SMILES: C(OCC)C.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[CH:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)([CH3:20])[CH3:19]>O1CCCC1>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([CH:18]([CH3:20])[CH3:19])[CH:22]=3)[N:27]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1ccc2ncccc2c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)c1ccc2nc(-c3ccc(C(C)(C)C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
To a cooled (ice bath) 2M diethyl ether solution of 4-tert-butylphenylmagnesium bromide (15 ml, 0.03 mol) was added dropwise under argon 15 ml of a tetrahydrofuran solution of 6-isopropylquinoline (5.13 g, 0.03 mol). The resulting mixture was refluxed for 5 hours, stirred at room temperature for 12 hours and quenched with water (80 ml). The yellow precipitate obtained was then filtered and washed with hexane. Crystallization in hexane:chloroform 40:1 yielded 3.7; of pure (±)-2-(4-tert-butylphenyl)-6-isopropylquinoline (40% yield). 1H NMR(CDCl3): 8.2 (m, ArH, 4H), 7.84 (m, ArH, 1H), 7.60 (m, ArH, 4H), 3.12 (s, CH(Me)2, 1H), 1.4 (s, CH(Me)2 and C(Me)3, 15H); Mass/Cl—NH3: MH31 304.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: OC1CCC(c2ccc(F)cc2)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(F)cc2)O1
Reaction time: 8 h
Yield: 93.3 %

Procedure:
2-Hydroxy-5-(4-fluorophenyl)-tetrahydrofuran (550 mg, 3.0 mmol), t-butyldimethylsilyl chloride (498 mg, 3.3 mmol) and imidazole (450 mg, 6.6 mmol) were dissolved in 2 mL of dry DMF. This solution was stirred under dry argon overnight, poured into 200 mL of water and extracted with a 2:1 mixture of ethyl acetate and hexane (3×100 mL). The combined organic extracts were washed with water (4×200 mL) and brine (100 mL), dried over sodium sulfate and evaporated to give 830 mg (93%) of 2-(t-butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (202, mixture of cis and trans isomers) as a colorless oil, which did not need any purification. 1H-NMR (CDCl3) δ 7.40-7.50(2H, m, minor isomer), 7.25-7.35 (2H, m, major isomer), 7.00-7.10(2H, m, both major and minor isomers), 5.71-5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5.20 (1H, m, major isomer), 4.90-4.98 (1H, m, minor isomer), 2.40-2.55 (1H, m, both major and minor isomers), 2.05-2.17 (1H, m, both major and minor isomers), 1.87-2.00 (1H, m, both major and minor isomers), 1.67-1.70 (1H, m, both major and minor isomers), 0.92 (s, 9H, both major and minor isomers), 0.16 (s, 6H, both major and minor isomers).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:11].Cl[C:23]1[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>>[Cl:29][C:26]1[CH:25]=[N:24][C:23]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])=[N:28][CH:27]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2nccc3ccccc23)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2nccc3ccccc23)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(isoquinolin-1-yl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 396 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1)[CH3:16].S(=O)(O)[O-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CN(C)C(=O)C>[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:25][CH:26]=1)[CH3:16]
Reactant: CCOC(=O)CCc1ccc(C=O)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1
Temperature: 155 °C
Yield: 96.9 %

Procedure:
To a round-bottomed flask were added 2-amino-4,6-dimethoxy-benzamide (0.161 g, 0.82 mmol), 3-(4-formyl-phenyl)-propionic acid ethyl ester (0.170 g, 0.82 mmol), sodium bisulfite (0.160 g, 0.902 mmol), p-toluenesulfonic acid (0.016 g, 0.082 mmol) and N,N-dimethylacetamide (10 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off and washed with water and methanol to obtain 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 97%). The compound 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 0.795 mmol) was taken up in a 1:1 mixture of THF and methanol (6 mL). A solution of potassium hydroxide (0.089 g, 1.59 mmol) in water (6 mL) was added to the reaction mixture and stirred at room temperature for 16 h. The solvent was removed and the reaction mixture was acidified with 1 N hydrochloric acid. The precipitated solid was filtered off and washed with water and methanol. The solid was further washed with methanol to obtain 3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid (0.143 g, 51%). Selected data: MS (ES) m/z: 355.0; MP 250.6-251.1° C.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.[NH3:13]>[Pd]>[NH2:13][CH:5]1[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2
Reactant: N
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: [Pd]
Product: NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 5-hydroxy-2-adamantanone (10.2 g) in 8M ammonia (in methanol, 50 ml), 10% palladium on activated carbon (1.00 g) was added and stirred under a hydrogen atmosphere at room temperature for 15 hours. After the reaction mixture was filtered, the solvent was distilled off under reduced pressure and the resulting residue was purified by NH silica gel column chromatography (eluting solvent: chloroform alone→chloroform:methanol=9:1) to give 4-aminoadamantan-1-ol (10.2 g, E-form:Z-form=4:1). 4-Aminoadamantan-1-ol thus obtained (10.2 g) was dissolved by heating in tetrahydrofuran (50 ml), and 4M hydrochloric acid (in 1,4-dioxane, 20 ml) was added thereto, followed by stirring at room temperature for 16 hours. The precipitated solid was collected by filtration to give 4-aminoadamantan-1-ol hydrochloride (12.1 g, E-form:Z-form=4:1). The resulting E/Z mixture (9.15 g) was dissolved by heating in ethanol (450 ml) and water (35.5 ml), and stirred at room temperature for 2 days. The precipitated solid was collected by filtration to give the titled compound, i.e., E-4-aminoadamantan-1-ol hydrochloride (3.59 g) as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)[C:5]([F:25])=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:11][CH:10]=3)[C:5]([F:25])=[CH:4][N:3]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(N)cc1OC
Reactant: Fc1cnc(Cl)nc1Nc1ccc(OCCCN2CCOCC2)cc1
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OCCCN4CCOCC4)cc3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine. LCMS: retn, time: 14.72 min.; purity: 94%; MS (m/e): 484 (MH+); 1H NMR (CDCl3): δ 7.89 (1H, d, J=3.3 Hz), 7.47 (2H, d, J=9 Hz), 7.22 (1H, d, J=2.2 Hz), 6.93-6.76 (5H, m), 6.64 (1H, d, J=2.2 Hz), 4.01 (2H, t, J=5.6 Hz), 3.86 (3H, s), 3.72 (3H, s), 3.71 (4H, m), 2.58-2.44 (6H, m), 1.97 (2H, m).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C1COCC1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([NH:12][C:25](=[O:26])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:10][C:9]([C:13]([F:15])([F:16])[F:14])=[N:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-n2nc(C(F)(F)F)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Yield: 104.5 %

Procedure:
According to the procedure described in Example 161C, to a solution of 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (2.237 g, 9.57 mmol) in THF (25 mL) and K2CO3 (2.48 g, 18.5 mmol) was added phenyl chloroformate (1.887 g, 12.1 mmol). The crude product was purified by silica gel chromatography with 5-20% EtOAc/hexane as eluants to afford phenyl 1-p-Tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (3.614 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 6H), 7.26 (m, 2H), 7.24 (m, 2H), 6.86 (s, 1H), 2.46 (s, 3H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:22]=[C:23]1[C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][N:24]1[CH2:41][C:42](O)=[O:43].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:42](=[O:43])[CH2:41][N:24]3[CH2:25][CH2:26][CH2:27][C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]3=[O:22])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(bis(4-fluorophenyl)methyl)piperazine (0.14 g, 0.5 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.16 g, 0.50 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.19 g, 1.00 mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.18-7.36 (m, 14H), 6.95-7.01 (m, 4H), 4.22 (s, 1H), 4.19 (s, 2H), 3.63 (t, J=4.7 Hz, 2H), 3.48 (t, J=6.4 Hz, 2H), 3.41-3.46 (m, 2H), 2.60-2.65 (m, 2H), 2.31-2.39 (m, 4H), 1.78-1.87 (m, 2H)); MS (DCI+) m/z 580 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+].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>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: Brc1ccccc1Br
Reactant: OB(O)c1ccc(F)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: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2ccccc2Br)cc1
Yield: 82.5 %

Procedure:
Under nitrogen, 1.2 g (1.0 mmol) of Pd(PPh3)4 was added to a stirred solution of 9.9 g (42 mmol) of 1,2-dibromobenzene (Aldrich) and 3.0 g (21 mmol) of 4-fluorophenylboronic acid in 42 mL of toluene, 42 mL of ethanol and 42 mL of 2M Na2CO3. After vigorous stirring at reflux for 3 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over MgSO4. Purification by silica gel chromatography (Waters Prep-500A) with hexane gave 4.35 g (81%) of 1-bromo-2-(4-fluorophenyl)benzene as a colorless oil: NMR (CDCl3) δ 7.07-7.26 (m, 3H), 7.27-7.44 (m, 4H), 7.67(d, J=8 Hz, 1H).
Reaction SMILES: Br[CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[C:11]([O:15][C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([O:15][C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4])([CH3:13])([CH3:12])[CH3:14]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: COC(=O)C(Br)C(=O)OC
Solvent: ClCCl
Product: COC(=O)C(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Dimethyl bromomalonate (6.6 ml.) was added to a stirred solution of L-alanyl-L-proline t-butyl ester (22.9 g.) in dichloromethane (40 ml.) which was cooled to 0° C., and the mixture was allowed to warm up to laboratory temperature and stirred at that temperature for 16 hours, then diluted with dichloromethane (150 ml.). The solution was washed successively twice with aqueous 0.5N-citric acid solution (150 ml. each time), water (200 ml.) and saturated aqueous sodium chloride solution (200 ml.), dried over magnesium sulphate and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of dichloromethane and ethyl acetate as eluant, and there was thus obtained as an oil N-(dimethoxycarbonylmethyl)-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][C:30]=1[Cl:29]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 3-chloro-4-(methoxycarbonyl)phenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a white solid. MS (m/e, ISP neg. ion)=582.2 [M−H+]