Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1C.F[C:20]1C=CC([N+]([O-])=O)=CC=1F.C[C@H]1CNC[C@@H](C)N1>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][C@H:13]([CH3:20])[NH:14][C@H:15]([CH3:17])[CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)C[C@H](C)N1
Yield: 103 %

Procedure:
Crude 1-(2-fluoro-4-nitrophenyl)-cis-3,5-dimethylpiperazine (5.71 g, 103% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine by treatment of 1,2-difluoro-4-nitrobenzene (3.48 g, 21.8 mmol) with cis-2,6-dimethylpiperazine (2.50 g, 21.8 mmol). The crude product is used in the next step without chromatographic purification. LCMS-ESI (m/z): calcd for C12H16FN3O2, 253; [M+H]+ found, 254.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccccc4)cc32)cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3ccccc3)cc21
Reaction time: 15 h
Yield: 59.2 %

Procedure:
To a 5 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(7-phenyl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone (14 mg, 0.03 mmol) was dissolved in dichloromethane and then cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (0.17 ml, 0.17 mmol) was added and then stirred at 0□ for 15 hours. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain the target compound 20 as white solid (8.7 mg, 64%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][CH:29]=2)=[N:3][C:4]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ncc(Br)nc1-c1noc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c(-c3noc(-c4ccccc4)n3)n2)CC1
Yield: 88.6 %

Procedure:
5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazin-2-amine (150 mg, 0.4715 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (189.5 mg, 0.6130 mmol) and sodium carbonate (707.0 μL of 2 M, 1.414 mmol) in DMF (1.500 mL) were heated to 120° C. for 45 min in the microwave. After this time the reaction mixture was diluted with water (5 mL) and ethyl acetate (5 mL) and the layers separated. Organic layer washed with water (3×5 mL), dried (MgSO4) and concentrated in vacuo to leave the title compound as a yellow/orange solid (175.6 mg, 88% yield). 1H NMR (400 MHz, DMSO) d 1.44 (s, 9H), 2.60 (m, 2H), 3.57 (m, 2H), 4.06 (m, 2H), 6.70 (s, 1H), 7.30 (br s, 2H), 7.69 (m, 2H), 7.77 (m, 1H), 8.25 (m, 2H) and 8.51 (1H, s) ppm; MS (ES+) 421.02
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[N+]=[N-].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH:5]([OH:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(CC(O)CN=[N+]=[N-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(O)CN)cc1

Procedure:
To a stirring solution of 1-azido-3-(4-methoxy-phenyl)-propan-2-ol (1.3 g, 6.3 mmol) in 50 mL methanol under a nitrogen atmosphere was added 10 mg of 10% Pd(OH)2/C. The mixture was stirred under a balloon atmosphere of hydrogen for 18 h. The reaction mixture was filtered through a bed of celite, and the filtrate reduced to a clear oil under reduced pressure. M+1=170.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CCNCCO
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and 2-Ethylamino-ethanol were converted to yield 2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol, MS: 405 (MH+, 1Cl).
Reaction SMILES: [OH:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>>[O:17]([C:18]1[CH:19]=[CH:20][C:21]([O:1][C@H:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:22][CH:23]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Ic1ccc(Oc2ccccc2)cc1
Product: c1ccc(Oc2ccc(O[C@@H]3CN4CCC3CC4)cc2)cc1

Procedure:
3-(R)-Hydroxy-quinuclidine (the product of Reference Example 1, 152 mg, 1.2 mmol), was treated with 1-iodo-4-phenoxy-benzene (178 mg, 0.6 mmol) according to the procedure of Example 3A to provide the title compound. (80 mg, yield, 45.2%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45–1.58 (m, 1H), 1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 1H), 2.70–3.10 (m, 5H), 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.83–6.98 (m, 6H), 7.03 (tt, J=7.5, 1.0 Hz, 1H), 7.30 (t, J=7.5 Hz, 2H) ppm. MS (D m/z 296 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[CH:4][N:3]=1.O1CCCC1.[AlH4-].[Li+]>O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[N:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1ncncc1NC(=O)c1ccc(F)cc1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncncc1NCc1ccc(F)cc1
Reaction time: 6 h
Yield: 63.5 %

Procedure:
To a stirred mixture of 30 parts of N-(4-amino-5-pyrimidinyl)-4-fluorobenzamide and 360 parts of tetrahydrofuran were added portionwise 9.86 parts of lithium tetrahydroaluminate under nitrogen atmosphere. The mixture was stirred for 6 hours. Another portion of 10 parts of lithium tetrahydroaluminate was added portionwise and stirring was continued for 2 hours at room temperature. The reaction mixture was decomposed with water. The layers were separated. The aqueous phase was extracted with tetrahydrofuran. The combined organic layers were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 18 parts (63.5%) of N5 -[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine (interm. 12).
Reaction SMILES: COC1C=CC=CC=1CO.[H-].[Na+].[Cl:13]C1N=C(OC)N=C(NCCC2C=CC(OC)=CC=2)C=1.C[O:34][C:35]1[N:40]=[C:39]([NH:41][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[CH:38]=[C:37]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[O:60][CH3:61])[N:36]=1.COC1C=CC=CC=1COC1N=C(NCCC2C=CC(OC)=CC=2)C=C(OCC2C=CC=CC=2OC)N=1.Cl>CN(C=O)C.O.C(Cl)Cl.CCOC(C)=O>[ClH:13].[CH3:61][O:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[CH2:53][O:52][C:37]1[CH:38]=[C:39]([NH:41][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[N:40]=[C:35]([OH:34])[N:36]=1
Reactant: COc1ccc(CCNc2cc(OCc3ccccc3OC)nc(OC)n2)cc1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Agent: COc1ccc(CCNc2cc(OCc3ccccc3OC)nc(OCc3ccccc3OC)n2)cc1
Agent: COc1ccccc1CO
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CCNc2cc(OCc3ccccc3OC)nc(O)n2)cc1
Reaction time: 1 h
Yield: 19 %

Procedure:
To a suspension of (2-Methoxy-phenyl)-methanol (860 mg, 6.22 mmol), and sodium hydride (60%, 0.3 g) in DMF (10 mL) is add (6-Chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine [0.54 g, 1.8 mmol, Intermediate (8)] at 10° C. After 1 h at 60° C., the mixture is diluted with H2O, and extracted with ethyl acetate. The extracts are dried (MgSO4), filtered, concentrated, and chromatographed (SiO2, 40% EtOAc in Heptane) to afford a non-separable mix of the product, [2-Methoxy-6-(2-methoxy-benzyloxy)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine, and the disubstituted side product, [2,6-Bis-(2-methoxy-benzyloxy)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine. To above mixture in CH2Cl2 is added a solution of HCl in EtOAc, and the mixture is concentrated, triturated (ether), and filtered to give 141 mg (19%) of 4-(2-Methoxy-benzyloxy)-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-2-ol hydrochloride as a solid. LCMS: RT=2.07 minutes, MS: 382 (M+H). The filtrate is concentrated, and chromatographed (silica gel, 40% EtOAc in Heptane) to afford [2-Methoxy-6-(2-methoxy-benzyloxy)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine hydrochloride [39 mg, 5%, Example (48)] as an oil. LCMS: RT=3.3 minutes, MS: 396 (M+H). IC50=12 nM
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([CH3:29])[CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl.[CH3:31][C:32]1([OH:36])[CH2:35][NH:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:36][C:32]1([CH3:31])[CH2:35][N:34]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:22][C:23]=2[CH3:29])[CH2:33]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)c(C)c4)C3)o2)cc1
Reactant: CC1(O)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CC(C)(O)C5)c(C)c4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
73C (0.12 g, 0.31 mmol) and 3-methylazetidin-3-ol hydrochloride (0.041 g, 0.34 mmol) were mixed with DCM (3 ml). Triethylamine (0.085 ml, 0.61 mmol) and then sodium triacetoxyborohydride (0.129 g, 0.61 mmol) were added. The mixture was stirred at RT overnight and then diluted with DCM (10 ml). The mixture was washed with aqueous NaHCO3 (sat. 4 ml) and then the organic solution was filtered through a phase separator. The solvent was removed by evaporation and the residue was purified by silica gel chromatography eluting the product with 1-2% methanol in DCM where the methanol contained ammonia (2 M). The product was triturated from DCM/diethyl ether. There was obtained 81 mg (57%) of the title compound which was recrystallised from ethyl acetate to give a crystalline solid m. p. 121° C., 137° C. and 145° C. 1H NMR (500 MHz, CDCl3): δ 1.51 (s, 3H), 2.30 (s, 3H), 3.01 (d, 2H), 3.30 (d, 2H), 3.56 (s, 2H), 3.89 (s, 3H), 4.30 (m, 1H), 4.62 (m, 1H), 4.72 (m, 1H), 5.03 (m, 1H), 5.10 (m, 1H), 6.53 (d, 1H), 6.60 (s, 1H), 7.03 (d, 2H), 7.16 (d, 1H), 8.09 (d, 2H), MS (APCI+) m/z 465 [M+H]+, LC purity: 97%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14].[C:16]1([S:22]([N:25]2[C:29]3=[N:30][CH:31]=[C:32]([NH:41][C:42](=[O:50])[CH2:43][C:44]4[C:45]([CH3:49])=[N:46][O:47][CH:48]=4)[C:33]([NH:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:28]3[CH:27]=[CH:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:16]1([S:22]([N:25]2[C:29]3=[N:30][CH:31]=[C:32]([NH:41][C:42](=[O:50])[CH2:43][C:44]4[C:45]([CH3:49])=[N:46][O:47][CH:48]=4)[C:33]([NH:34][CH:35]4[CH2:40][CH2:39][N:38]([C:13](=[O:14])[CH2:12][O:11][CH3:10])[CH2:37][CH2:36]4)=[C:28]3[CH:27]=[CH:26]2)(=[O:23])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nocc1CC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CCC(Nc2c(NC(=O)Cc3conc3C)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.107 ml, 0.615 mmol) and methoxyacetyl chloride (0.028 ml, 0.308 mmol) were added sequentially to a solution of N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(3-methyl-isoxazol-4-yl)-acetamide (hydrochloride salt) (0.205 mmol) in CH2Cl2 (2 ml) at 25° C. The reaction mixture was stirred for 3 h at 25° C., then was partitioned between saturated NaHCO3 (6 ml) and CH2Cl2 (2 ml). The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude N-{1-benzenesulfonyl-4-[1-(2-methoxy-acetyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(3-methyl-isoxazol-4-yl)-acetamide as a brown oil/solid. LCMS (Method G, ESI): RT=0.73 min, m+H=567.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:11]2[C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])=[CH:5][CH:6]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1CCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of 1-(2-bromo-ethyl)-4-fluoro-benzene (587 mg, 3.7 mmol) and pyrrolidine-2,5-dione (succinimide, 733.3 mg, 7.4 mmol) in dimethylformamide (15 ml) was added potassium carbonate (2.0 g, 14.8 mmol) and sodium iodide (277 mg, 1.9 mmol). The reaction mixture was warmed to 60° C. and kept at 60° C. overnight with stirring. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate aqueous solution, twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (100% ethylacetate) to afford 1-[2-(4-fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309 (570 mg, 2.6 mmol, 70%) as a solid. 1H NMR (CDCl3) δ 7.14 (m, 2H), 6.94 (t, 2H), 3.68 (t, 2H), 2.84 (t, 2H), 2.63 (s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[CH:12]=[CH2:13].Cl.[CH2:15]([NH2:19])[CH2:16][CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([NH:19][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:12]=[CH2:13])[CH2:16][CH:17]=[CH2:18]
Reactant: C=CCCN
Reactant: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCNc1c([N+](=O)[O-])ccc(F)c1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To an ice-cooled solution of 1,3-difluoro-4-nitro-2-vinylbenzene (389 mg, 2.1 mmol) in DMF (8 mL) was added 3-butenylamine hydrochloride (248 mg, 2.31 mmol) and potassium carbonate (0.87 g, 6.3 mmol). The reaction mixture was stirred at RT for 2 h, and then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 2-4% EtOAc in cyclohexane) affording the title compound as an orange oil (327.6 mg, 66%). LCMS (Method B): RT 4.27 min [M+H]+ 237
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[C:7]=1Cl)(=[O:5])=[O:4])[CH3:2].Cl.[OH-:18].[Na+]>>[Cl:15][C:8]1[C:7]([OH:18])=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1O

Procedure:
A solution of the 4-ethylsulfonyl-2,3-dichlorobenzoic acid prepared in Example 3 (0.35 mole) in 500 ml of 20% sodium hydroxide was heated at reflux for 7 hours. After cooling, the aqueous solution was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate, and concentrated in vacuo to afford the crude acid. Recrystallization of the crude acid from ethyl acetate afforded the desired pure acid as white crystals. m.p. 188°-192° C.
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8](I)[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[CH3:19][C:20]1[C:24]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:12])[C:2]3([OH:1])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=C1Nc2ccc(I)cc2C1(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1)C(=O)N2
Temperature: 130 °C

Procedure:
3-Hydroxy-5-iodo-3-phenyl-1,3-dihydro-indol-2-one (130 mg, 0.370 mmol), 3,5-dimethyl-4-isoxazolylboronic acid (104 mg, 0.740 mmol), sodium carbonate (108 mg, 1.025 mmol), Pd(dppf)Cl2 (57 mg, 78 mmol) and lithium chloride (114.5 mg, 2.700 mmol) are added to a microwave vial. Dioxane/water (2:1, 3 mL) is added. The mixture is flushed with argon and the vessel heated at 130° C. for 1 h. The reaction mixture is diluted with water and dcm then extracted with dcm. The organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is dissolved in DMSO, filtered and purified with the acidic (formic acid) RP HPLC system. The product containing fractions are concentrated under reduced pressure. Dissolved in DMSO, aliquoted and freeze dried. Once more freeze dried with acetonitril: water. This afforded the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:30])[C:9]2[C:10]([CH3:29])=[C:11]([CH:25]=[C:26]([Br:28])[CH:27]=2)[C:12]([NH:14][CH2:15][C:16]2[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:60](O)(=[O:62])[CH3:61]>CN(C=O)C.O>[C:60]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]([CH3:30])[C:9]2[C:10]([CH3:29])=[C:11]([CH:25]=[C:26]([Br:28])[CH:27]=2)[C:12]([NH:14][CH2:15][C:16]2[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])[CH2:6][CH2:7]1)(=[O:62])[CH3:61]
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@@H](N)CC3)c2C)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N[C@H]1CC[C@H](N(C)c2cc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c2C)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of trans-3-((4-aminocyclohexyl)(methyl)amino)-5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.225, 0.474 mmol) in DMF (3 mL), EDCI.HCl (0.138 g, 0.718 mmol), HOBt (0.064 g, 0.47 mmol), triethyl amine (0.1 g, 0.99 mmol) and acetic acid (0.057 g, 0.949 mmol) were added at room temperature and stirred at same temperature for 18 h. On completion, water was added and extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated giving crude material; which then purified by column chromatography to afford desired compound (0.13 g, 53%).
Reaction SMILES: [NH2:1][C:2]([CH3:34])([CH3:33])[CH2:3][NH:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]([C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[CH:8][C:7]=1[C:28]([F:31])([F:30])[F:29].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[F:59][C:60]([F:65])([F:64])[C:61](O)=[O:62].CN1CCOCC1>CN(C=O)C>[CH3:33][C:2]([NH:1][C:61](=[O:62])[C:60]([F:65])([F:64])[F:59])([CH3:34])[CH2:3][NH:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]([C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=2)[C:15]([F:18])([F:16])[F:17])=[CH:8][C:7]=1[C:28]([F:31])([F:30])[F:29]
Reactant: CC(C)(N)CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (E)-N-(2-amino-2-methylpropyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (155 mg, 0.283 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (118 mg, 0.311 mmol), and 2,2,2-trifluoroacetic acid (0.026 mL, 0.340 mmol) in DMF (1 mL) was—added N-methylmorpholine (0.062 mL, 0.566 mmol). The mixture was stirred at ambient temperature for 18 h, —then partitioned between water and EtOAc. The organic phase was washed with water and—brine, —dried (sodium sulfate) and concentrated—under reduced pressure. Purification by column chromatography eluting with EtOAc in hexanes (10%-100%)—afforded the title compound as a yellow oil (26 mg, 13%).
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[CH:11][C:10]3[N:13](COCC[Si](C)(C)C)[C:14]([O:16][C@@H:17]4[CH2:21][O:20][C@@H:19]5[C@H:22]([O:25][Si](C(C)(C)C)(C)C)[CH2:23][O:24][C@H:18]45)=[N:15][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl.O>[C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[CH:11][C:10]3[NH:13][C:14]([O:16][C@H:17]4[C@H:18]5[O:24][CH2:23][C@@H:22]([OH:25])[C@H:19]5[O:20][CH2:21]4)=[N:15][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(-c3ccc(-c4ccccc4)cc3)ncc2n1COCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(-c3ccc(-c4ccccc4)cc3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 52 h

Procedure:
To 6-([1,1′-biphenyl]-4-yl)-2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine (26.0 mg, 0.039 mmol) in anhydrous DCM (1.23 mL) was added TFA (0.91 mL, 11.82 mmol). The solution stirred at RT for 52 h. The reaction solution was evaporated under reduced pressure. The residue extracted into EtOAc (35 mL) and washed with 1N NaOH (6.0 mL, 6 mmol) and water (10 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to afford the title compound. LC-MS: calculated for C24H21N3O4 415.15 observed m/e: 416.16 (M+H)+ (Rt 1.34/2.0 min).