Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].C(Cl)(Cl)Cl.[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:50]3[CH2:49][CH2:48][CH:47]([N:44]4[CH2:43][CH2:42][N:41]([CH3:40])[CH2:46][CH2:45]4)[CH2:52][CH2:51]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCN(C)CC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 85.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (36 mg, 0.072 mmol) in THF (2 mL)/CHCl3 (2 mL) were added 1-methyl-4-(4-piperidinyl)piperazine (40 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (38 mg, 85%). LC-MS m/z 619 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.33 (m, 2H), 1.83 (d, 2H), 2.28 (s, 3H), 2.30 (s, 3H), 2.65 (m, 11H), 4.11 (m, 2H), 4.23 (m, 1H), 4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([N:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]2[C:37](OC)=[O:38])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH:7]([N:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:26][CH:25]2[CH2:37][OH:38])[CH2:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C(CO)C1
Temperature: -20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a mixture of LiAlH4 (500 mg, 13.5 mmol) in THF (40 mL) at −40° C. under argon, a solution of 1-tert-butyl 3-methyl 4-(1-benzhydrylazetidin-3-yl)piperazine-1,3-dicarboxylate (1.8 g, 3.87 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at −5° C. to 5° C. for 1 h and cooled to −20° C. Then water (2 mL) and NaOH (15%) aqueous were added. The resulting mixture was stirred for 15 min. The solid was filtered, and the cake rinsed with ethyl acetate. The combined filtrate was dried over Na2SO4 and concentrated in vacuo to afford the product (1.6 g, 94% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].[C:12]([O:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:23](O)[CH:22]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:26]2[CH:27]=[C:21]([O:20][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:22]=[CH:23][CH:25]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C(Oc1cccc(O)c1)c1ccccc1
Reactant: CCc1ccc(CCO)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(CCOc2cccc(OC(=O)c3ccccc3)c2)nc1
Reaction time: 1 h

Procedure:
To a solution of 2-(5-ethyl-pyridin-2-yl)-ethanol (480 mg, 3.17 mmol, example 69) in THF (10 mL) is added resorcinol monobenzoate (630 mg, 2.94 mmol), triphenylphosphine (850 mg, 3.24 mmol) and diethyl azodicarboxylate (510 μL, 3.24 mmol). The resulting mixture is stirred for 1 h then concentrated. The residue is purified by flash chromatography (silica, 35% ethyl acetate in hexane) to give the title compound as a yellow oil. MS (ESI) 348 (M+H)+.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.Cl.[CH3:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][C:20]=1[CH2:28][NH:29][CH3:30].C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:29]([CH3:30])[CH2:28][C:20]2[CH2:21][C:22]3[C:27]([C:19]=2[CH3:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:16])=[CH:8][CH:7]=1
Reactant: CNCC1=C(C)c2ccccc2C1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(CN(C)C(=O)/C=C/c2ccc(N)nc2)Cc2ccccc21
Reaction time: 8 h
Yield: 51.7 %

Procedure:
EDC (0.383 g, 2.0 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.328 g, 2.0 mmole), 3-methyl-2-(methylaminomethyl)indene hydrochloride (0.420 g, 2.0 mmole), HOBT H2O (0.306 g, 2.0 mmole), and triethylamine (0.57 mL, 4.0 mmole) in anhydrous DMF (18 mL) at RT. The reaction was stirred overnight and concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (3% MeOHI CH2Cl2) gave the title compound (0.33 g, 52%) as a colorless solid: MS (ES) mnle 320.2 (M+H)+. Anal. Calcd for C20H21N30.0.4H2O: C, 73.57; H, 6.72; N, 12.86. Found: C, 73.94; H, 6.92; N, 12.50.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.ClCCl.[CH3:24][O:25][C:26]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][C:27]=1[CH2:28][N:29]1[CH2:34][CH:33]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)[N:32]2[CH:48]=[C:49](I)[CH:50]=[C:31]2[C:30]1=[O:52]>O1CCOCC1.O>[CH3:24][O:25][C:26]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][C:27]=1[CH2:28][N:29]1[CH2:34][CH:33]([CH:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]2)[N:32]2[CH:48]=[C:49]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][C:8]([F:20])([F:19])[F:7])[CH:11]=3)[CH:50]=[C:31]2[C:30]1=[O:52]
Reactant: COc1ccc(CN2CC(C3CCN(C(=O)OC(C)(C)C)CC3)n3cc(I)cc3C2=O)c(OC)c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN2CC(C3CCN(C(=O)OC(C)(C)C)CC3)n3cc(-c4cccc(OC(F)(F)F)c4)cc3C2=O)c(OC)c1
Yield: 31.8 %

Procedure:
Cesium carbonate (32.6 mg, 0.1 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (20 mg, 0.1 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepaladium (4 mg, 0.005 mmol) complex with dichloromethane, were subsequently added to a solution of tert-butyl 4-[2-(2,4-dimethoxybenzyl)-7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]piperidine-1 carboxylate (30 mg, 0.05 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere. The mixture was heated at 90° for 4 hours in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. Purification by flash chromatography on silica gel column (Hex/EtOAc 8/2) afforded the compound tert-butyl 4-{2-(2,4-dimethoxybenzyl)-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}piperidine-1-carboxylate as oil (10 mg, 32%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>CCOC(C)=O.O>[CH2:25]([O:24][C:22]([N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH2:12]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCc2ccc([N+](=O)[O-])cc2C1
Yield: 91.8 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (11.0 g, 51.25 mmol) in EtOAc (150 mL) at 0° C. in an ice bath add a solution of K2CO3 (15.65 g, 113.25 mmol) in water (150 mL) followed by benzyl chloroformate (8.37 mL, 56.37 mmol) and vigorously stir the reaction at room temperature for 24 h. Separate the layers and extract the aqeuous with more EtOAc (150 mL). Wash the organics with sat. NaHCO3 (200 mL), sat. NH4Cl (200 mL) and water (200 mL), then dry (Na2SO4). Concentrate in vacuo to give 14.70 g of 7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as an oil which partially crystallizes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].CO.[H][H]>[Pt]=O.O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)ccc1OC

Procedure:
A 2 liter Parr Bottle was charged with 11.6 grams (55 mmol) methyl-2-methoxy-5-nitrobenzoate, 450 mL of methanol and 150 mL of tetrahydrofuran (THF). Platinum oxide was added (460 mg) and the mixture was hydrogenated under 45 psi hydrogen for 1 hour. The reaction mixture was filtered through Celite® (diatomaceous earth) and evaporated. The reaction mixture was diluted with 500 mL of methylene chloride, and then washed with water and brine. The organic phase was dried and evaporated (9.9 grams). This material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:12])[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCO
Product: Cc1nc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To a pressure vessel, a mixture of 6-chloro-2-methyl-3-nitro-pyridin-4-ylamine (0.75 g, 4.00 mmol) and morpholine (1.40 mL, 16.0 mmol) in absolute ethanol (16 mL) was stirred at 120° C. for 3 days. Absolute ethanol was evaporated in vacuo and the crude product was dissolved in a mixture of THF:EtOAc and this then subjected on top of a silica gel pad. Elution with EtOAc gave, after evaporation, the title compound as a yellow solid (0.89 g, 93%): IR (KBr, cm−1) 3460, 3330, 1627, 1597, 1553, 1233, 1113; 1H NMR (400 MHz, DMSO) δ 7.13 (s, 2H), 5.89 (s, 1H), 3.66-3.63 (m, 4H), 3.46-3.44 (m, 4H), 2.50 (s, 3H); LCMS (+ESI, M+H+) m/z 239; HPLC: 99% (220 nm).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19]>>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(F)cc1F
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)cc1

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-227 using 4-fluoro-nitrobenzene and 2,4-difluorophenol (heat 2 hours at 50° C.). Purify the material by silica gel chromatography (Prep.2000) eluting with methylene chloride/hexane 1:1 to provide the title compound as a slowly crystallizing oil. Mass spectrum (m/e): 251.1 (M*). (Bruker 300) 1H NMR (CDCl3) δ 8.17-8.22 (2H, d), 7.14-7.21 (1H, m), 6.90-703 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:27]2[CH2:29][CH2:28]2)=[C:9]([F:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Mg]>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:27]2[CH2:29][CH2:28]2)[C:9]([F:26])=[CH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: FC(=CCc1ccc(F)c(Oc2ccccc2)c1)C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A solution of 1-(p-chlorophenyl)-1-cyclopropyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-1,3-butadiene (26 g, 0.064 mol) in a methanol/tetrahydrofuran solution (15:1) is treated with magnesium turnings (7.72 g, 0.317 mol), stirred at room temperature for 4 hours, quenched with hydrochloric acid, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water, 2 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (5:95) gives the title product as an oil (21.4 g, 82%) which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in 100 mL of ethanol was added powdered sodium carbonate (2.1 g, 20.1 mmol) and piperazine-1-carboxylic acid tert-butyl ester (3.75 g, 20.1 mmol). The reaction was heated to reflux for 5 hours, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 400 mL of ethyl acetate and extracted with water (100 mL) and brine (100 mL). The organic phase was then dried over sodium sulfate, filtered, and concentrated in vacuo to a clear oil. Flash column chromatography (silica gel, gradient elution from 10% ethyl acetate-hexanes to 50% ethyl acetate-hexanes) yielded 4.63 g of the title compound (I-1a).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)[CH:13]=1.C(N(CC)CC)C>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)[CH:19]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: Nc1cccc(-c2cccnc2)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(-c2cccnc2)c1
Yield: 47.4 %

Procedure:
A solution of 5-bromo-2-chloro-3-nitropyridine (7.0 g, 29 mmol) and 3-(pyridin-3-yl)phenylamine (5.0 g, 29 mmol) in 1-methyl-2-pyrrolidinone (10 ml) and triethylamine (4 ml, 29 mmol) was heated at 100° C. for 90 minutes. The reaction was cooled, suspended in ethyl acetate (400 ml) and insoluble material removed by filtration. The filtrate was then washed with water, brine and dried over anhydrous sodium sulphate. This solution was filtered and pre-adsorbed on to silica gel. Purification by silica gel chromatography eluting with hexane containing triethyline (1%) on a gradient of ethyl acetate from 20% to 35% gave N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(pyridin-3-yl)phenyl]amine as a red solid (5.1 g, 47%); δH (400 MHz, CDCl3) 7.35-7.45 (2H, m, ArH), 7.51 (1H, t, J 8, ArH), 7.62 (1H, d, J 8, ArH), 7.88-7.91 (2H, m, pyridyl-H and NH), 8.53 (1H, s, pyridyl-H), 8.62 (1H, d, J 5, pyridyl-H), 8.68 (1H, s, pyridyl-H), 9.88 (1H, s, pyridyl-H), 10.14 (1H, s, pyridyl-H); m/z (ES+) 371 and 373 (M++H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.O.[CH3:14][N:15]=[C:16]=[O:17]>C1C=CC=CC=1>[CH3:14][NH:15][C:16]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:17]
Reactant: ON=C1CCOc2ccccc21
Reactant: CN=C=O
Solvent: O
Solvent: c1ccccc1
Product: CNC(=O)ON=C1CCOc2ccccc21
Reaction time: 8 h

Procedure:
A 60 g (0.37 mole) portion of 4-chromanone oxime in 770 ml of benzene was refluxed until all water was removed via a Dean-Stark trap, 0.5 hrs. The solution was cooled to 25-30°, treated with 0.5 ml of triethylamine followed by the dropwise addition of 20 ml (0.33 mole) of methyl isocyanate at less than 70°. The reaction mixture was refluxed for 3 hrs., stored at room temperature overnight, filtered, and stripped of benzene under reduced pressure. The residue was treated with 200 ml of ether, cooled 20 min. and filtered. The white crystalline product was washed with 100 ml of ether and dried, m.p. 123°-126°. Yield: 64 g (88%).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:27][S+](C)C.[OH-].[K+].C(#N)C>O>[C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:27][O:21]3)=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[N:9]=1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(C=O)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Reactant: C[S+](C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cc(C2CO2)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 60 °C

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 2.99 g (8.79 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-formylphenyl)-pyridin-2-ylamine, 1.79 g (8.79 mmol) trimethylsulfonium iodide, 0.98 9 (17.59 mmol) powdered potassium hydroxide, 44 mL acetonitrile, and 0.5 mL water. The reaction was heated to 60° C. for 2.5 hours, then cooled, filtered, and evaporated. The yellow oil was used directly, 3.3 g (˜100%).
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:26]2[CH:25]=[N:24][C:23]([NH:22][CH3:21])=[CH:28][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: CNc1ccc(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)O)n2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (9) (0.65 g, 1.68 mmol) in toluene (20 mL) and EtOH (7 mL) were added N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 12 (1.44 g, 3.36 mmol in theory) and 2 N Na2CO3 aq. (2.5 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.2 g, 0.168 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(6-(methylamino)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-2) (0.020 g, 3.2%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:17])=[C:14]([OH:16])[CH:15]=1>CCO>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[C:14]([OH:16])[CH:15]=2)[N:3]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: CCO
Product: Nc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Temperature: 90 °C
Yield: 47 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 4-amino-2-chloropyrimidine (70 mg, 0.5 mmol) and 5-amino-2-chlorophenol (78 mg, 0.5 mmol) in 10% aqueous EtOH (2 mL) was heated at 90° C. for 18 h. The title compound was obtained in 47% yield a (60 mg) and used for the next step without additional purification.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl[C:17]1[CH:18]=[C:19]([N:26]([C:31]2[C:50]([CH:51]3[CH2:53][CH2:52]3)=[CH:49][C:34]3[C:35]([C:45]([NH:47][CH3:48])=[O:46])=[C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[O:37][C:33]=3[CH:32]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C.O>[CH:51]1([C:50]2[C:31]([N:26]([C:19]3[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:18]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:32][C:33]3[O:37][C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[C:35]([C:45](=[O:46])[NH:47][CH3:48])[C:34]=3[CH:49]=2)[CH2:53][CH2:52]1
Reactant: COC(=O)CC(=O)OC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(C(=O)OC)C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
To a stirred suspension of Cs2CO3 (17.5 g, 53.8 mmol) in DMF (20 ml) under a nitrogen atmosphere was added dimethyl malonate (2.57 mL, 22.4 mmol) at room temperature. This was followed by the addition of a sonicated solution of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (10.0 g, 17.9 mmol) in DMF (50 mL) at room temperature by dropwise addition. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with EtOAc (3×40 mL). The organic layer was washed with water (3×50 mL), dried over sodium sulfate and evaporated to dryness. The crude product triturated with ether and the solid collected by filtration to afford the title compound in 68% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (d, J=4.7 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 8.04 (s, 1H), 7.90-8.00 (m, 2H), 7.36-7.51 (m, 3H), 7.26-7.31 (m, 1H), 7.14-7.20 (m, 1H), 5.45-5.56 (m, 1H), 3.52-3.64 (m, 9H), 2.84 (d, J=4.5 Hz, 3H), 1.88-2.03 (m, 1H), 0.82-1.00 (m, 2H), 0.69 (d, J=3.1 Hz, 1H), 0.29-0.50 (m, 1H). LCMS (m/z, ES+)=654 (M+H+).