Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[I-].[Na+].Cl[CH2:28][C:29](=[O:31])[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:28][C:29](=[O:31])[CH3:30])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Reaction time: 24 h

Procedure:
To a stirred suspension of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.50 g 0.0018 mol), sodium hydrogen carbonate (1.55 g, 0.018 mol) and sodium iodide (0.20 g) in N,N-dimethylformamide (20 ml) was added chloroacetone (0.20 g, 0.0020 mol). The reaction was stirred for 24 h, then the product was precipitated by the addition of water (50 ml). The product was collected by filtration, washed with water (3×10 ml) and dried under vacuum at 60° C. Recrystallisation from ethyl acetate/60-80 petrol gave a white crystalline solid; yield=390 mg, mp=185°-186° C.; Found: C, 66.20; H, 4.33; N, 4.20; C18H14ClNO3 requires C, 65.96; H, 4.31; N, 4.27. δ (360 MHz, DMSO-d6), 1.84 (3H, s, CH3CO), 4.26 (2H, s, CH2), 7.26 (1H, dd, J=8.7 and 2.1 Hz, 6-H), 7.30-7.46 (6H, m, aromatics), 8.02 (1H, d, J=8.7 Hz, 5-H), 11.90(1H, s, br, NH). MS (CI) m/z=328 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]>C(Cl)Cl>[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:14][CH:13]=2)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
N-(tert-Butoxycarbonyl)-p-phenylenediamine (0.209 g, 1.002 mmol), triethylamine (0.101 g, 1.002 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.279 g, 1.002 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ethanol to obtain the titled compound (0.180 g, 0.319 mmol, 48%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1c2n(c3c(-c4ccc(OC(F)(F)F)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (76 mg, 80%), MS (ISP) m/z=379.5 [(M+H)+], mp 162° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:19][C:20](=[CH2:22])[CH3:21].OS(O)(=O)=O>O1CCOCC1>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[CH2:9][C@@H:10]([C:12]([O:14][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)C
Reactant: N[C@@H](Cc1cccc(C2CCCC2)c1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc(C2CCCC2)c1
Yield: 82 %

Procedure:
According to example 54, 0.50 g of 3-cyclopentyl-L-phenylalanine.HCl was treated with 25 mL of isobutylene in 20 mL of 1,4-dioxane in the presence of 0.3 mL of conc. H2SO4. Work-up followed by acidification of the free amine with ethereal HCl afforded 0.49 g (82%) of tert-butyl 3-cyclopentyl-L-phenylalaninate.HCl as a white powder, m.p. 154-156° C.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH:32]1([C:35]2[N:40]=[C:39]([NH:41][C@@H:42]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][C@@H:43]3[OH:51])[C:38]([CH2:52][CH3:53])=[N:37][C:36]=2[C:54]2[CH:55]=[N:56][C:57]([N:61]([CH3:63])[CH3:62])=[CH:58][C:59]=2[CH3:60])[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[N:40]=[C:39]([NH:41][C@@H:42]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][C@@H:43]3[O:51][CH2:2][CH3:3])[C:38]([CH2:52][CH3:53])=[N:37][C:36]=2[C:54]2[CH:55]=[N:56][C:57]([N:61]([CH3:63])[CH3:62])=[CH:58][C:59]=2[CH3:60])[CH2:34][CH2:33]1
Reactant: CCc1nc(-c2cnc(N(C)C)cc2C)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({6-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3-ethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.81–1.19, 1.28–1.33, 2.67–2.73, 3.11–3.14, 3.42–3.51, 3.65–3.73, 4.32–4.35, 5.40–5.42, 5.72–5.75, 6.497.22–7.39, 8.19; MS (ESI+) for C28H35N5O m/z 458 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:14]([CH2:28][CH3:29])[N:13]=[N:12][N:11]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1
Reactant: CCI
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nnnn2CC)n1

Procedure:
Treat a solution of (S)-2-sec-butylamino-6-(2H-tetrazol-5-yl)-isonicotinic acid methyl ester (720 mg, 2.61 mmol) in DMF (10 mL) with potassium carbonate (541 mg, 3.92 mmol) and iodoethane (0.364 mL, 3.92 mL) at room temperature. Dilute with ethyl acetate (100 mL), wash with water (twice), saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give approximately a 1:1 mixture of the two title compounds which are used directly in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:8][CH2:9][C@@H:10]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]1)[CH3:7])[CH3:4].[I-].[K+].[CH2:19]([O:21][C:22](=[O:30])[CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28]Cl)[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22](=[O:30])[CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][N:15]1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C@@H:10]1[CH2:9][O:8][CH:6]([O:5][CH2:3][CH3:4])[CH3:7])[CH3:20]
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1
Reactant: CCOC(=O)COC/C=C\CCl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1COC(C)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 402 mg, 10.0 mmol) was added to a solution of (R)-6-(1-ethoxyethoxymethyl)-piperidin-2-one (2.02 g, 10.0 mmol) in DMF (15 mL) at 0° C. After 1 h, a solution of potassium iodide (1.66 g, 10.0 mmol) and ((Z)-4-chloro-but-2-enyloxy)-acetic acid ethyl ester (prepared according to PCT 2003/007941, 3.09 g, 16.0 mmol) in DMF (10 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched by the addition of saturated aqueous NaHCO3 (100 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (3×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10% EtOAc/CH2Cl2→60% EtOAc/CH2Cl2, gradient) afforded 1.10 g (31%) of {(Z)-4-[(R)-2-(1-ethoxyethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:4]O)(=[O:3])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19]([O:4][C:1](=[O:3])[CH3:2])[O:4][C:1](=[O:3])[CH3:2])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(-c2ccc(I)cc2)cc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)OI(OC(C)=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 6 h

Procedure:
Peracetic acid (40%, 13 ml.) is added dropwise to a stirred suspension of 4-(4-chlorophenyl)iodobenzene (12.6 g.) in acetic acid (25 ml.) at 30° C. during 1hour. The mixture is stirred at 30° C. for 6 hours, and at ambient temperature for 2 days, then evaporated to dryness in vacuo. The residue is washed with light petroleum, and is crystallised from chloroform to give 4-(4-chlorophenyl)-(diacetoxyiodo)-benzene (10.7 g.) m.p. 147°-150° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.16 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (dichloromethane/MeOH) and crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.019 g, 12%). MS (ISP) 482.1 [(M+H)+]; mp 241.5° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C)C(=O)C>[C:1]1(=[O:11])[N:5]([CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCBr
Agent: [K]
Solvent: CC(=O)N(C)C
Product: C=CCCCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A suspension of 39 g of potassium phthalimide in 150 ml of N,N-dimethylacetamide was treated at 20° C. while stirring with 27 ml of 6-bromo-1-hexene. After 4 hours, the mixture was poured into 300 ml of ice-water, extracted with ether, the organic phase was washed with 10% sodium chloride solution, dried, filtered and concentrated to dryness. There were obtained 45 g (100%) of 6-phthalimido-1-hexene, m.p. 17°-20° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccsc1
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: C1COCCO1
Product: Brc1cncc(-c2ccsc2)c1

Procedure:
A deoxygenated solution of 3,5-dibromopyridine (4.00 g, 16.9 mmol, 1 equiv), 3-thiopheneboronic acid (2.38 g, 18.6 mmol, 1.10 equiv), Pd(PPh3)4 (781 mg, 0.676 mmol, 0.0433 equiv), and 2.0 M Na2CO3 (16.9 mL, 33.8 mmol, 2.00 equiv) in dioxane (40 ml) was heated under argon at reflux for 20 h. The reaction mixture was allowed to cool, then partitioned between water (200 mL) and ethyl acetate (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (5% ethyl acetate in dichloromethane) to afford 3-bromo-5-thiophen-3-yl-pyridine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][Cl:34])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.207 mmol) produced in Example C52(v) in N,N-dimethylacetamide (1.0 mL) was added chloroacetyl chloride (36 μL, 0.455 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[4-chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide as an oily residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][N:32]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:32]5[CH2:33][CH2:34][C:35]6[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: C1=NCCc2ccccc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4ccccc4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,4-dihydro-isoquinoline following a procedure analogous to that described for Intermediate 42. Mass spectrum (ESI+): m/z=538 [M+H]+.
Reaction SMILES: I[C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)=[CH:13][CH:12]=3)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1ncc(I)c(Oc2ccc(Nc3ccc(C)cn3)cc2)n1
Reactant: OB(O)c1ccnc(F)c1
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: C1COCCO1
Solvent: O
Product: COc1ncc(-c2ccnc(F)c2)c(Oc2ccc(Nc3ccc(C)cn3)cc2)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
N-(4-(5-Iodo-2-methoxypyrimidin-4-yloxy)phenyl)-5-methylpyridin-2-amine (0.061 g, 0.14 mmol), 2-fluoropyridine-4-boronic acid (0.030 g, 0.21 mmol), and tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol) were mixed in dioxane (0.5 mL) under an argon atmosphere. Sodium carbonate (0.21 mL, 0.42 mmol, 2.0 M in water) was added via syringe, and the reaction mixture was stirred at 80° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give N-(4-(5-(2-fluoropyridin-4-yl)-2-methoxypyrimidin-4-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 404.2 (M+1). IC50 (uM) 0.016.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: CCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCC(=O)NC1=NC(=O)C2=CC=NC2=N1

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and undecanoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:25]=1.[CH:37]1([NH:40][C:41](=[O:58])[NH:42][C:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>>[CH:37]1([NH:40][C:41]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[N:25]=3)=[CH:45][CH:44]=2)=[O:58])[CH2:39][CH2:38]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nccc(Cl)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nccc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Yield: 66 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloropyrimidin-2-yl)-3-methylmorpholine (intermediate 15) and 4-(3-cyclopropylureido)phenyl boronic acid pinacol ester. Material was purified using flash chromatography (20-90% EtOAc in petroleum ether 40-60) to afford a light pink solid (130 mg, 66%).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([NH2:27])[CH3:26])=[CH:21][C:20]=1[O:28][CH3:29]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([NH:27][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=3)[CH2:3]2)[CH3:26])=[CH:21][C:20]=1[O:28][CH3:29]
Reactant: COC(=O)c1ccc([C@@H]2CCC(=O)C2)cc1
Reactant: COc1cc([C@@H](C)N)ccc1F
Agent: Cl
Product: COC(=O)c1ccc([C@@H]2CC[C@H](N[C@H](C)c3ccc(F)c(OC)c3)C2)cc1

Procedure:
General procedure B was followed using methyl 4-[(1R)-3-oxocyclopentyl]benzoate (preparation 32) as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride as the amine. The resulting isomers were separated by flash chromatography (gradient of 0-50% EtOAc in heptane containing 3% NEt3). The faster eluting peak was isolated to afford the title compound. 1H NMR (300 MHz, DMSO) 7.86 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.15 (dd, J=8.7, 1.8 Hz, 1H), 7.09 (dd, J=11.5, 8.3 Hz, 1H), 6.91-6.85 (m, 1H), 3.83 (2s, 6H), 3.80-3.70 (m, 1H), 3.05-2.86 (m, 2H), 2.22-1.52 (m, 5H), 1.41-1.27 (m, 1H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([N:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][N:17]=1)([O-])=O.C(O)(=O)C>ClCCl.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([N:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Yield: 83.2 %

Procedure:
Into a 100-mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridin-4-yl(3-(trifluoromethyl)benzyl)carbamate (760 mg, 1.37 mmol, 1.00 equiv) in dichloromethane (10 mL), and Zn (500 mg). This was followed by dropwise addition of acetic acid (0.7 mL) with stirring. The resulting solution was stirred for 3 h at room temperature. The reaction progress was monitored by LCMS. The solids were removed by filtration. The solution was adjusted to pH 8-9 with NaHCO3 (aq). The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The product was obtained as 600 mg (83%) of a black solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:39]([NH2:41])[CH3:40]>C1COCC1>[CH2:39]([NH:41][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1)[CH3:40]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCNc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 80 °C
Yield: 36 %

Procedure:
A mixture of 3-(2-fluoro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole (800 mg, 1.6 mmol) and 2M ethyl amine in THF (20 mL) was heated in a sealed tube at 80° C. for four days. Cooled to room temperature and concentrated. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexane (1:1) to give the title compound (300 mg, 36%).