Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([Br:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:17]1(=O)[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([Br:16])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=1)=[O:5]
Reactant: NC(=O)COc1c(Br)ccc(C(=O)O)c1Br
Reactant: O=C1CCCC(=O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)COc1c(Br)ccc(C(=O)OC2=CC(=O)CCC2)c1Br

Procedure:
0.400 g (1.10 mmol) of 2,4-dibromo-3-(aminocarbonylmethoxy)benzoic acid, 0.140 g (1.20 mmol) of cyclohexane-1,3-dione, 0.222 g (1.10 mmol) of N′-(3-dimethyl-aminopropyl) -N-ethylcarbodiimide hydrochloride and 0.001 g of DMAP was stirred for 14 hours at RT in 15 ml of CH2Cl2. The mixture was subsequently diluted with CH2Cl2 and with 0.5 N HCl, and washed with water, with saturated NaHCO3 solution and again with water. After the combined organic phases have been dried over Na2SO4 and concentrated completely, 3-oxo-1-cyclohexenyl 2,4-dibromo-3-(aminocarbonylmethoxy)benzoate was obtained as a yellow resin, which had sufficient purity for the subsequent reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]2[C:33](=[O:42])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]2=[O:41])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCNCCOc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Reaction time: 120 h
Yield: 85 %

Procedure:
[2-(4-Nitrophenyl)ethyl]{2-[(4-nitrophenyl)oxy]ethyl}amine (253 mg) and 2-(6-bromohexyl)-1H-isoindole-1,3(2H)-dione (1186 mg) were dissolved in DMF (4 ml) and basified by the addition of DIPEA (0.665 ml). The reaction was stirred for 120 h. The reaction mixture was evaporated to dryness and the residue dissolved in DCM, the solution was absorbed onto a pad of silica and purified on a silica cartridge (12 g) eluting with the following gradient: (A=DCM, B=methanol) t=0 min: B=10%; t=7.5 min: B=0%; t=22.5 min: B=5%. The desired product eluted at ˜15% B (isocratically) and evaporation of the solution to dryness gave the title compound (0.364 g).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:14])([CH3:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4].Cl[CH2:17][C:18]([N:20]1[CH2:24][C@@H:23]([F:25])[CH2:22][C@H:21]1[C:26]#[N:27])=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[C:26]([C@@H:21]1[CH2:22][C@H:23]([F:25])[CH2:24][N:20]1[C:18](=[O:19])[CH2:17][NH:14][C:11]1([CH3:13])[CH2:12][CH:7]2[CH2:6][N:5]([C:3]([N:2]([CH3:1])[CH3:15])=[O:4])[CH2:9][CH:8]2[CH2:10]1)#[N:27]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Reactant: CN(C)C(=O)N1CC2CC(C)(N)CC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)N1CC2CC(C)(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)CC2C1
Yield: 57.7 %

Procedure:
5-Amino-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12f (130 mg, 0.616 mmol), (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (117.4 mg, 0.616 mmol) and potassium carbonate (85 mg, 0.616 mmol) were dissolved in the solvent mixture of 2 mL of dichloromethane and 2 mL of N,N-dimethylformamide with stirring under nitrogen atmosphere. The reaction mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure to remove N,N-dimethylformamide and dichloromethane. The resulting residue was purified by silica gel column chromatography to obtain 5-[2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-hexahydro-cyclopenta[c]pyrrole-2(1H)-carboxamide 13h (0.13 g, yield 58%) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](C)=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].C([O-])=O.[NH4+:15]>C(O)C.[Pd]>[NH2:15][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([OH:11])[CH:6]=1
Reactant: Cc1ccc(C(C)C)c(O)c1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CCO
Product: CC(C)c1ccc(N)cc1O

Procedure:
To a refluxing solution of 2-isopropyl-5-methyl-phenol (1.3 g, 8.65 mmol) and ammonium formate (1.3 g, 20.62 mmol) in ethanol (50 mL) was added 10% Pd/C (887 mg, 8.33 mmol). The mixture was refluxed for an additional 5 minutes, cooled and filtered through a pad of celite. The solvent was removed by evaporation to give 5-amino-2-isopropylphenol which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 6.71 (d, J=8.1 Hz, 1H), 6.04 (d, J=2.2 Hz, 1H), 5.97 (dd, J=8.1, 2.2 Hz, 1H), 4.65 (s, 2H), 3.08-2.94 (m, 1H), 1.07 (d, J=6.9 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=O)=[O:9])[CH:5]=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:13])(=[O:11])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cncc(Br)c1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A mixture of 5-bromo-pyridine-3-sulfonic acid (Example B.2 step 1) (7.14 g, 30 mmol), phosphorus pentachloride (9.68 g, 47 mmol) and phosphorus oxychloride (20 mL) was heated to reflux for 4 h (according to J. Org. Chem. 1989, 54(2), 389). The reaction mixture was concentrated to dryness to give a yellow semisolid, dissolved in ice water and tert-butyl-methyl-ether, and cautiously added sat. NaHCO3-sol. until neutralized, saturated with solid NaCl, separated phases, dried organic layer over Na2SO4. Removal of the solvent in vacuum gave the title compound as a yellow solid (7.57 g, 98%). MS (EI) 254.9 [(M)+], 256.9 [(M+2)+] and 258.9 [(M+4)+]; mp 64° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[S:13][C:14]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.O.O.[Sn](Cl)Cl>CCO>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3OC)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(-c3ccc(N)cc3OC)sc2c1
Yield: 88.1 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-(2-methoxy-4-nitrophenyl)-6-methoxybenzothiazole (1.0 g, 3.13 mmol) and tin (II) dichloride dihydrate (5.66 g, 25.08 mmol) in EtOH (50 ml) to give the title compound (0.79 g, 89%) as a pale yellow solid after work-up and recrystallisation from EtOH.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([C:23]([CH3:31])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39](N1C=CN=C1)=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:32])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([C:23]([CH3:24])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:31])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14]1)=[O:40]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccccc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccccc1)C1CCN(C(=O)Nc2ncc[nH]2)CC1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
The amine from above (230 mg, 0.50 mmol), and imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (300 mg, 1.0 mmol) were combined in DMF (2.5 mL) and treated with DIPEA (0.52 mL, 3.0 mmol). The solution was stirred at 75° C. for 3 hours and then concentrated under reduced pressure. This afforded, after column chromatography with silica gel (50:1:0.2 CH2Cl2:MeOH:NH4OH), COMPOUND 309 (180 mg, 65%). 1H NMR (CDCl3): δ 1.17 (q, 2H, J=12.3 Hz), 1.55 (d, 2H, J=12.3 Hz), 1.61 (s, 6H), 2.29 (s, 3H), 2.53 (m, 3H), 3.36 (s, 2H), 3.64 (s, 2H), 4.08 (d, 2H, J=12.9 Hz), 6.68 (s, 2H), 7.00 (d, 2H, J=7.5 Hz), 7.08 (m, 1H), 7.19 (m, 3H), 7.36 (s, 1H), 7.85 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 8.48 (br d, 1H, J=3.3 Hz). 13C NMR (CDCl3) δ 18.87, 28.30 (2C), 31.29 (2C), 42.88, 44.58 (2C), 54.13, 55.33, 58.30, 121.67, 126.02 (2C), 126.32, 128.88 (2C), 130.40, 134.13, 135.41, 137.73, 143.49, 144.91 (2C), 145.48, 146.91 (2C), 149.84, 155.60, 156.53, 158.59. ES-MS m/z 559 (M+H). Anal. Calcd. for C31H36N7OCl.0.3CH2Cl2: C, 64.42; H, 6.32; N, 16.80; Cl, 9.72. Found: C, 64.26; H, 6.35; N, 16.64; Cl, 9.47.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][CH:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)CC(=O)O
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (84 mg, 81%), MS (ISP) m/z=415.4 [(M+H)+], mp 202.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3-methyl-butyric acid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[NH2:19].[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:25]1([NH:19][C:18]2[CH:17]=[C:16]([F:15])[C:22]([F:23])=[C:21]([F:24])[CH:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCCC1
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1cc(NC2CCCC2)cc(F)c1F
Reaction time: 3.5 h

Procedure:
Under ice-cooling, 11.5 g of sodium triacetoxyborohydride was added in small portions to a solution of 4.0 g of 3,4,5-trifluoroaniline and 3.6 ml cyclopentanone in 150 ml dichloroethane and 3.1 ml acetic acid, and, after rising to room temperature, stirred for 3.5 hours. Aqueous saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform and subsequent drying over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 5.4 g of N-cyclopentyl-3,4,5-trifluoroaniline.
Reaction SMILES: [Na+].[Br:2][C:3]1[C:4]([F:17])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([NH:9][CH2:10][C:11]([O-])=[O:12])[CH:8]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[F:17])[NH:14][C:11](=[O:12])[CH2:10][NH:9]2
Reactant: O=C([O-])CNc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CNc2cc(Br)c(F)cc2N1
Temperature: 25 °C

Procedure:
A solution of N-(5′-bromo-4′-fluoro-2′-nitrophenyl)glycine sodium salt (0.450 g, 1.54 mmol, as prepared above) and tin (II) chloride dihydrate (1.039 g, 4.605 mmol, Aldrich, used as received) in ethanol (7.0 mL) was refluxed for 30 min. It was then cooled to room temperature and solvent was removed under vacuum. The residue was diluted with water (15.0 mL) and basified with 10% Na2CO3 to pH ˜8. The resulting suspension was extracted with ethyl acetate (100 mL). The ethyl acetate was dried over anhydrous NaSO4 and removed under vacuum to yield 0.241 g (64%;)of the title compound as a yellow powder, m.p. 214-216° C.; 1H NMR (DMSO-d6): δ 3.684 (s, 2H), 6.062 (s, 1H), 6.631 (d, 1H, J=9.3 Hz), 6.825 (d, 1H, J=6.6 Hz), 10.303 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.CN(C=O)C.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:27][C:28]1[CH:29]=[C:30]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:9]3[C:10]4[CH2:11][CH:2]([OH:1])[CH2:3][CH2:4][C:5]=4[CH:6]=[CH:7][CH:8]=3)=[O:21])=[CH:15][CH:16]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
Next, to a solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-4-iodobenzamide (100 mg, 0.25 mmol) in a 3 to 1 mixture of DMF and H2O was added 3,4-difluorophenylboronic acid (80.3 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium(0) (8.82 mg, 0.01 mmol), and sodium carbonate (80.9 mg, 0.76 mmol). The mixture was stirred at 80° C. for 2.5 hours, and after cooled to room temperature, the product was extracted with diethyl ether. The organic layer was washed with water then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. After triturated with ethylacetate and hexane, the solid was filtered to afford 3′,4′-difluoro-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)biphenyl-4-carboxamide (51.9 mg, 54%).
Reaction SMILES: [C:1]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])(=[O:3])[NH2:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>O1CCCC1>[CH3:14][N:15]([CH3:17])[CH:16]=[N:2][C:1]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])=[O:3]
Reactant: CCOP(=O)(OCC)C(N)=O
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(=O)N=CN(C)C

Procedure:
a solution of 54 parts of diethyl carbamoylphosphonate and 36 parts of dimethyl formamide dimethyl acetal was refluxed in 1000 parts of anhydrous tetrahydrofuran for eight hours. The solvent was removed under reduced pressure to give 70 parts of diethyl 1-dimethylaminomethyleneaminocarbonylphosphonate, nD24 = 1.4970.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[S:13][CH:12]=[C:11]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=1.CS(O[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][N:42]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:43][C@H:44]([OH:56])[C:45]2[C:53]3[S:52][C:51](=[O:54])[NH:50][C:49]=3[C:48]([OH:55])=[CH:47][CH:46]=2)=[CH:37][CH:36]=1)(=O)=O>C(#N)C>[OH:56][C@H:44]([C:45]1[C:53]2[S:52][C:51](=[O:54])[NH:50][C:49]=2[C:48]([OH:55])=[CH:47][CH:46]=1)[CH2:43][N:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:10]=[C:9]([CH3:8])[S:13][CH:12]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:40][CH:39]=1)[C:57](=[O:58])[O:59][C:60]([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: Cc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Temperature: 80 °C

Procedure:
Triethylamine (0.25 mL) was added to a solution of (5-methylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 104, step b) (0.195 g) in acetonitrile (2.5 mL). This solution was added to a solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.5 g) in acetonitrile (2.5 mL). The resulting mixture was heated at 80° C. for 48 hours. The reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a cream solid. Yield 0.33 g.
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([C:24]3[N:25]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[N:26]=[C:27]4[C:32]=3[CH:31]=[CH:30][CH:29]=[CH:28]4)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:25]2[C:24]([CH:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]4([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]4)=[CH:14][CH:13]=3)=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)=[N:26]2)=[CH:34][CH:35]=1
Reactant: COC(=O)C1(Oc2ccc(OCC(c3c4ccccc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(Oc2ccc(OCC(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-1-(4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-phenoxy)-cyclopropanecarboxylic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as yellow oil. MS: m/e=533.2 [M−H−].
Reaction SMILES: [C:1]([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][N:27](C(OCC3C=CC=CC=3)=O)[CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCNCC1
Yield: 36 %

Procedure:
To a Parshaker flask were added benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-5-fluoropyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate (850 mg, 1.56 mmole) and 20% Pd(OH)2 in actived carbon (880 mg, 1.25 mmole), then was added MeOH (100 mL) under nitrogen gas. The reaction mixture was shaken under 50 psi hydrogen overnight. The reaction mixture was filtered through a celite. The celite cake was washed with MeOH and the filtrate was concentrate in vacuo. The resulting crude product was purified by flash column chromatography (basic alumina, 40 g) eluting w/0-20% MeOH/DCM to afford the title product as a white solid (230 mg). 1H NMR (400 MHz, CD2Cl2) 8.18 (d, J=2.87 Hz, 1H), 5.15 (br s, 1H), 4.71-4.63 (m, 1H), 4.56-4.47 (m, 1H), 4.47-4.34 (m, 2H), 4.25-4.14 (m, 1H), 3.96-3.82 (m, 1H), 3.16 (d, J=12.34 Hz, 2H), 2.67-2.54 (m, 2H), 1.85-1.66 (m, 2H), 1.64-1.52 (m, 1H), 1.40-1.26 (m, 2H), 1.20 (d, J=6.60 Hz, 3H), 1.18 (s, 9H), 1.10 (d, J=6.46 Hz, 3H). HRMS(C) tR=2.36 min; MS m/z 410.2571 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[C:30]([Br:32])[C:29]([OH:33])=[C:28]([Br:34])[CH:27]=1>C(OCCO)C>[Br:32][C:30]1[CH:31]=[C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:27]=[C:28]([Br:34])[C:29]=1[OH:33]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cc(Br)c(O)c(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cc(Br)c(O)c(Br)c3)c2cc1OC
Yield: 89.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 320.3 mg (1.2 mmol) of 4-amino-2,6-dibromophenol to give 427.1 mg (89.2%) of the product as a gray solid, m.p.>250° C., mass (electrospray, m/e): M+H 479.7, 481.6.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18](Br)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)CCC>C1(C)C=CC=CC=1.[Pd]>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Br)cc2o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(-c3cccnc3)cc2o1
Yield: 55.6 %

Procedure:
The 2-(1-BOC-2-(S)-pyrrolidinyl)-6-bromofuro[3,2-b]pyridine (0.24g, 0.64 mmol) obtained from Example 46a above was dissolved in toluene (6 mL). Tributyl-3-pyridyltin (0.36 g, 1.3 mmol), palladium (O) tetrakis(triphenyl phosphine) (40 mg) was then added to the toluene solution and the resultant mixture was heated under reflux for 16 h. The desired product was extracted with CH2Cl2, dried over MgSO4 and filtered. Solvent was then removed under reduced pressure and the residue was chromatographed (silica gel: Hexane/EtOAc, 5:1 to EtOAc) to afford an oil (0.13 g, 56%). MS (CI/NH3) m/z: 366 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 1.33, 1.55 (2s, 9H), 1.92-2.38 (m, 3H), 3.43-3.70 (m, 2H), 5.08 (m, 1H), 5.15 (m, 1H), 6.75 (brs, 1H), 7.43 (m, 1H), 7.86 (s, 1H), 7.93 (m, 1H), 8.66 (m, 1H), 8.72 (brs, 1H), 8.89 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=1[CH:11]=[N:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26][N:27](C=O)[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=1[C:11]1[N:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:28]=[N:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(OCc2ccccc2)c(C=Nc2cccnc2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(OCc2ccccc2)c(-c2cncn2-c2cccnc2)c1
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of N-(2-(benzyloxy)-5-chlorobenzylidene)pyridin-3-amine (0.929 mmol) in DMF (3 mL) at room temperature, was added NaH (1.12 mmol) and the solution was stirred for 1 h, followed by the addition of imine (0.929 mmol). After stirring for 4 d, the reaction mixture was diluted with satd. NH4Cl solution and the product was extracted with EtOAc. The combined organic extract was dried (Na2SO4) and concentrated to afford the crude. Chromatographic purification afforded the final product. Yield 21%. 1H NMR: 4.64 (s, 2H), 6.70 (d, 1H), 6.96 (m, 2H), 7.16-7.30 (m, 8H), 7.71 (s, 1H), 8.31 (d, 1H, J=2.4 Hz), 8.53 (dd, 1H, J=1.8 Hz, 3.0 Hz)