Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[I:9]([O-])(=O)(=O)=O.[Na+].II.FC(F)(F)C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[NH2:1][C:2]1[C:7]([I:9])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Nc1ccc(Br)cn1
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncc(Br)cc1I
Temperature: 80 °C
Yield: 75 %

Procedure:
To a solution of 2-amino-5-bromopyridine (2) in acetonitrile was added sodiumperiodate (0.4 equiv) and iodine (0.65 equiv). Trifluoroacetic acid (0.65 equiv) was added over 15 min and the reaction mixture was heated at 80° C. overnight. HPLC indicated 96% conversion at this point. An aqueous solution of sodium sulfite was added, followed by more water to precipitate the product which was filtered off and washed with water. The title compound (11) was isolated as a brown crystalline solid in 75% yield. MS (Turbo Spray): 298 (M+H+, 100%)
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]([C:13]1[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][OH:12].N1C=CN=C1>ClCCl>[Si:5]([O:12][CH2:11][CH:10]([C:13]1[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:9])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)n1c(C(O)CO)cc2ccccc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(C(O)CO[Si](C)(C)C(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
TBSCl (1.3 g, 8.9 mmol) in dichloromethane (20 mL) was added dropwise at 0° C. over 10 minutes to a solution of tert-butyl 2-(1,2-dihydroxyethyl)-1H-indole-1-carboxylate (2.0 g, 7.2 mmol) and imidazole (1.20 g, 17.4 mmol) in DCM (30 mL). After being stirred at room temperature for 1 hour, the mixture was washed with water (2×50 mL) and brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give an oil, which was further purified by prep-HPLC to afford tert-butyl 2-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)-1H-indole-1-carboxylate (500 mg, 18% yield) as an oil. LCMS (ESI) m/z: 318.3 [M−56−17]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:8][CH2:9][CH2:10][OH:11])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][CH2:2][C:3]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][OH:11])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCO)C(=O)CCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Chloroacetylchloride (97 g., 1 mole) in dry acetonitrile (100 ml) was added dropwise to a cold (0° C.) solution of N-ethylethanolamine (89 g., 1 mole) in acetonitrile (150 ml) and anhydrous sodium carbonate (119 g., 1.1 mole). The mixture was mechanically stirred for two hours at 0° C. and then for 14 hours at room temperature, filtered, evaporated to dryness at 40° C. and the residue was dissolved in chloroform. The resulting solution was mixed with 1N hydrochloric acid, followed by mixing with 10% aqueous sodium carbonate and aqueous saturated sodium chloride. It was then dried over anhydrous magnesium sulphate, filtered through activated charcoal and evaporated to dryness to yield N-chloroacetyl-N-ethyl-ethanolamine as a colorless oil (yield 85%) with the following indicia: MS m/e 165 (M+); 88 (M--COCH2Cl); since the IR spectrum of the liquid showed two C=O peaks, one minor at λmax 1750 cm-1 (C=O, ester) and one major at 1635 cm-1 (C=O, amide), the compound was purified on an alumina dry column using chloroform and chloroform:methanol (9:1) as eluents. The purified amide showed only one C=O group at 1635 cm-1. This pure compound (pure by TLC (thin layer chromatography), NMR (nuclear magnetic resonance), IR (infrared), MS (mass spectometry) was used for the next step. The NMR (250 MHz) of the pure amide showed peaks of the two structures which are at equilibrium in such amides: ##STR13## Therefore, δCDCl3ppm : 4.3 ##STR14## 3.9-3.2 (m, --CH2 --N--CH2CH2O--); 1.18 (--CH3, q, e.g., overlap of two triplets) s: singlet; m: multiplet; q: quartet.
Reaction SMILES: C[N:2]1[CH2:12][CH:11](C2C=CC=C(N=C=S)C=2)[C:10]2[CH:9]=[C:8]([OH:22])[C:7](Cl)=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:24]([OH:30])(C(F)(F)F)=[O:25].[C:31](#N)C>O>[CH3:31][O:30][C:24](=[O:25])[C@H:3]([N:2]1[C:5]2[C:10](=[CH:9][C:8]([OH:22])=[CH:7][CH:6]=2)[CH:11]=[CH:12]1)[CH3:4]
Reactant: CC#N
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc(N=C=S)c2)C1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)[C@@H](C)n1ccc2cc(O)ccc21
Reaction time: 0.12 h

Procedure:
Reverse Phase HPLC conditions: Column: YMC-Pack ProC18 (AS-300), 50×4.6 mm (I.D.), S-5 μm, 12 nm (No. 040506614); Mobile Phase: A: 0.1% TFA in Water; B: 0.1% TFA in acetonitrile; Gradient: 90-5% A (10-95% B) in 7 min.; Flow rate: 4.0 mL/min; Detector (UV): 220 nm. Retention time for the title compound: 3.98 min.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[CH2:4][CH2:5][C:6]([CH3:14])([CH3:13])[C:7]=1[C:8](=[O:12])[CH2:9][CH:10]=[CH2:11].C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][C:2]1[C:3](=[O:15])[CH2:4][CH2:5][C:6]([CH3:14])([CH3:13])[C:7]=1[C:8](=[O:12])[CH:9]=[CH:10][CH3:11]
Reactant: C=CCC(=O)C1=C(C)C(=O)CCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC=CC(=O)C1=C(C)C(=O)CCC1(C)C
Yield: 100.2 %

Procedure:
153 g (0.74 mole) of 2,4,4-trimethyl-3-(but-3-en-1-on-1-yl)-cyclohex-2-en-1-one (Ib) were stirred under reflux together with 135 ml of ethyl acetate and 3 g of p-toluenesulfonic acid for 2 hours. When the solution had cooled, 1,000 ml of ether were added to it, the mixture was washed with water and with saturated sodium bicarbonate solution and dried with sodium sulfate, and the solvent was distilled off under about 20 mbar. 153 g of 2,4,4-trimethyl-3-(but-2-en-1-on-1-yl)-cyclohex-2-en-1-one (Ia) were obtained, the yield being quantitative, and the product being only slightly impure according to thin-layer chromatography. Recrystallization from 500 ml of cyclohexane gave 132 g (yield: 86.8% of theory) of a product which was pure according to thin-layer chromatography; evaporating down the mother liquor gave a further 21 g (yield: 13.2% of theory) of a somewhat impure product.
Reaction SMILES: [OH:1][C@@:2]1([CH3:40])[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[N:31](COCC[Si](C)(C)C)[N:30]=[CH:29][CH:28]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O>[OH:1][C@@:2]1([CH3:40])[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[NH:31][N:30]=[CH:29][CH:28]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccnn2COCC[Si](C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: NCCN
Product: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
(S)-6-(3-Hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)nicotinamide (Stage 13.1), ethylenediamine (57.3 μL, 0.848 mmol) and 1 M TBAF in THF (848 μL, 0.848 mmol) was added to a MW vial, which was sealed and the RM was stirred at 80° C. for 24 h. The solvent was evaporated off under reduced pressure to give a residue which was dissolved in EtOAc (30 mL), washed 3 times with sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) to yield the title compound as a white solid. HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent: n-heptane/EtOH/MeOH (80:12:8), 1 mL/min, UV 210 nm) tR=13.92 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=448.2 [M+H]+, m/z=446.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 3H) 1.65-1.81 (m, 2H) 3.01 (d, J=11.54 Hz, 1H) 3.07 (d, J=10.92 Hz, 1H) 3.24-3.33 (m, 1H) 3.43-3.53 (m, 1H) 4.64-4.75 (m, 1H) 6.34-6.41 (m, 1H) 7.34 (d, J=8.66 Hz, 2H) 7.52-7.84 (m, 1H) 7.86 (d, J=9.16 Hz, 2H) 8.00-8.07 (m, 1H) 8.69-8.78 (m, 1H) 10.19 (s, 1H) 12.89-13.13 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])=[CH:40][CH:39]=1>O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([P:44]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:51])=[CH:40][CH:39]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)c1ccc(N)cc1
Reactant: O=C(O)CCc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(NC(=O)CCc2oc(-c3ccccc3)nc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-phenyl-5-oxazolepropionic acid (500 mg), triethylamine (230 mg) and tetrahydrofuran (10 ml) was added ethyl chlorocarbonate (250 mg) at −40° C., and the mixture was stirred for 1 hr. Diethyl 4-aminophenylphosphonate (420 mg) was added, and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography and 3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]-N-[4-(diethylphosphono)phenyl]propionamide (295 mg, yield 36%) was obtained as colorless prism crystals from a fraction eluted with ethyl acetate-chloroform (1:1, volume ratio). melting point: 139–140° C. (recrystallized from dichloromethane-isopropyl ether).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[C:23]([Cl:24])=[CH:22][C:20]([NH2:21])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=1>CCOCC>[C:1]([CH2:3][C:4]([NH:21][C:20]1[CH:22]=[C:23]([Cl:24])[C:17]([Cl:16])=[CH:18][C:19]=1[N+:25]([O-:27])=[O:26])=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: N#CCC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of cyanoacetic acid (1.70 g, 20 mmol) in CH2Cl2 (50 mL) oxalyl chloride (2.2 mL, 25 mmol) was added. The mixture was stirred for 2 h, more oxalyl chloride (2.2 mL, 25 mmol) was added and the mixture was refluxed while stirring for 3 h. The mixture was cooled to room temperature and evaporated twice with ethanol-free CHCl3 (20 mL) to remove excess of (COCl)2. To the residue was added 4,5-dichloro-2-nitroaniline (1.035 g, 5 mmol) and CH2Cl2 (10 mL) and the resulting mixture was stirred for 3 h, then diluted with ether (50 mL). The precipitate was filtered, washed with ether (5×10 mL) to give 0.891 g (65%) of the title compound as an orange solid: mp 156°-158° C. (from EtOH); IR (KBr) 3369, 3118, 2928, 2261, 1694, 1609, 1576, 1498, 1346 and 1280 cm-1 ; 1H NMR (DMSO-d6) δ4.00 (s, 2H), 7.94 (s, 1H), 8.31 (s, 1H), 10.70 (s, 1H, N--H). HRMS Calcd for C9H5N3O3Cl2 : 272.9708. Found: 272.9712.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CO.Cl[Pd]Cl.O>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
Methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 4-(methylsulfonyl)phenylboronic acid (7.58 g, 37.88 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (0.633 g, 0.87 mmol) were dissolved in methanol (30 mL) and divided up in two microwave vials. Each vial was heated to 100° C. in a single node microwave reactor for 35 min. DCM (250 mL) and water (250 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (250 mL). The combined organic phases were washed with brine (500 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on two Biotage® KP-SIL 340 g columns. A gradient of 20-70% EtOAc in heptane over 10 CV and then 70% EtOAc in heptane over 5 CV was used as mobile phase. The product was collected using the wavelength 253 nm. The product fractions were collected and evaporated in vacuo yielding methyl 2-(4-(methylsulfonyl)phenyl)-isonicotinate (5.66 g, 66.7%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 3.09 (s, 3H), 3.98 (s, 3H), 7.85 (dd, 1H), 8.05 (d, 2H), 8.25 (d, 2H), 8.34 (s, 1H), 8.86 (t, 1H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[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.[F:51][C:52]([F:67])([F:66])[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:13]=[C:11]([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[C:52]([F:51])([F:66])[F:67])[CH2:61][CH2:60]1)[CH2:10][NH:9][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.09128 g, 0.00036 mol) in DMF (2 mL) was added DIPEA (0.126 g, 0.00098 mol), HOBt (0.05266 g, 0.0003901 mol) and EDCI.HCl (0.07457 g, 0.00039 mol) at ambient temperature. After 2 minutes 4-(2-trifluoromethyl-phenoxy)-piperidine trifluoroactetate (0.11 g, 0.00033 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 0.072 g (46%) of biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LCMS: 483.18 (M+1)+, 95.73%, 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.64-7.54 (m, 4H), 7.46-7.3 (m, 4H), 7.02-6.9 (q, 2H), 4.75 (s, 1H), 4.4-4.2 (dd, 2H), 4.2-4.0 (m, 2H), 3.65-3.35 (m, 4H), 2.05-1.8 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:44]=[CH:43][C:18]([C:19]([NH:21][C:22]2[C:26](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:20])=[CH:17][CH:16]=1.[H-].[Na+].[CH3:47]N(C)C=O.CI>O>[CH3:47][N:21]([C:19](=[O:20])[C:18]1[CH:43]=[CH:44][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)[C:22]1[C:26](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][N:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:23]=1
Reactant: CN(C)C=O
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Yield: 83 %

Procedure:
To a mixture of diethyl (E)-2-[3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil. To remove remaining trifluoroacetic acid, water was added to the oil, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-[3-(methyl{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as a colorless oil (42.5 mg, yield 83%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C(OCC)(=O)C>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)c1ccc(OCCBr)cc1
Yield: 21.4 %

Procedure:
A suspension of 4-hydroxybenzotrifluoride (5.0 g), 1,2-dibromoethane (17.4 g) and potassium carbonate (2.6 g) in acetone (100 mL) was heated under reflux for 3 days. The reaction solution was diluted with water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated ammonium chloride (×2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.78 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.Cl.[NH2:12][C:13]([NH2:15])=[NH:14].C(N(CC)CC)C>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:12]=[C:13]([NH2:15])[N:14]=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)cnc1F
Reactant: N=C(N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Nc1ncc2cc(Br)cnc2n1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
5-bromo-2-fluoronicotinaldehyde (3.0 g, 14.78 mmol), guanidine hydrochloride (1.69 g, 17.74 mmol) and triethylamine (4.48 g, 44.35 mmol) were dissolved in 1-methyl-2-pyrrolidinone (15 mL), and the reaction mixture was stirred at 180° C. for 15 min under microwave. The mixture was cooled to RT, quenched with water (200 mL) and extracted with ethyl acetate (2×300 mL). The organic layers were combined, washed with water (3×50 mL) and brine (3×50 mL), dried over sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=3:1) to afford 6-bromopyrido[2,3-d]pyrimidin-2-amine (2.0 g, 60%) as a yellow solid. MS (ES+) C7H5BrN4 requires: 224, 226. found: 225, 227 [M+H]+.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[OH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](C(O)=O)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1.CCOCC>[C:11]([O:10][C:6]([C@H:19]1[CH2:20][CH2:21][C@H:16]([OH:15])[CH2:17][CH2:18]1)=[O:5])([CH3:12])([CH3:13])[CH3:14]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)CC1
Temperature: 80 °C
Reaction time: 25 h

Procedure:
N,N-Dimethylformamide di-tert-butyl acetal (7.4 ml, 31 mmol) was added to a solution of trans-4-hydroxy-cyclohexanecarboxylic acid (1.484 g, 10.29 mmol) in toluene (8.5 ml), and the mixture was stirred at 80° C. for 25 hours. The reaction mixture was diluted with ether, and the organic layer was sequentially washed with water, an aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give trans-4-hydroxy-cyclohexanecarboxylic acid tert-butyl ester as a colorless solid (838 m, 41%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ccc(C)cc1B(O)O
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Product: COc1ccc(C)cc1-c1cccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 57.4 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 2-methoxy-5-methyl-phenyl boronic acid (186 mg) were reacted to afford the title compound (94 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, 1H), 8.38 (d, 1H), 7.76-7.66 (m, 2H), 7.20 (m, 1H), 7.07 (m, 1H), 7.00 (m, 1H), 4.50 (m, 1H), 3.58 (s, 3H), 2.29 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=363 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH:11]=[C:10]([NH2:12])[C:9]([CH3:13])=[N:8]2)[CH:4]=[N:3]1.Cl[C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=1.[CH3:27]C(O)(C)C>>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:11]([CH3:27])=[C:10]([NH:12][C:15]3[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=3)[CH:9]=[N:8]2)[CH:4]=[N:3]1.[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH:11]=[C:10]([NH:12][C:15]3[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:24])[F:25])=[CH:17][N:16]=3)[C:9]([CH3:13])=[N:8]2)[CH:4]=[N:3]1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: Cc1nn(-c2cnn(C)c2)cc1N
Reactant: CC(C)(C)O
Product: CNc1nc(Nc2cn(-c3cnn(C)c3)nc2C)ncc1C(F)(F)F
Product: CNc1nc(Nc2cnn(-c3cnn(C)c3)c2C)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 17 %
Yield: 26 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with the mixture of 1%5-dimethyl-1′H-1,4′-bipyrazol-4-amine and 1′,3-dimethyl-1′H-1,4′-bipyrazol-4-amine (50 mg, 0.28 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (60 mg, 0.28 mmol), and t-BuOH (3 mL). The mixture was heated at 100° C. under microwave irradiation for 1 h. After removal of the volatiles, the residue was purified by prep-HPLC to afford N2-(1′,5-dimethyl-1′H-1,4′-bipyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (17 mg, 17%) as a white solid and N2-(1′,3-dimethyl-1′H-1,4′-bipyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (26 mg, 26%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:35]2[CH2:37][O:36]2)[CH:32]=[CH:33][CH:34]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:37][C@@H:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)[OH:36])=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)CC1
Yield: 16.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (0.50 g, 1.18 mmol) was reacted with (2R)-2-(3-chlorophenyl)oxirane (0.183 g, 1.18 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.063 g, 0.19 mmol).