Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[S:9])[NH2:8])=[CH:3][CH:2]=1.Br[CH:11]([C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[C:18]1([C:17]2[N:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[S:9][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=S)c1ccncc1
Reactant: CCOC(=O)C(Br)C(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccncc2)nc1-c1ccccc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a suspension of pyridine-4-carbothioamide (2.9 g, 21 mmol) in ethanol (150 mL) was added ethyl 2-bromo-3-oxo-3-phenylpropanoate (5.9 g, 22 mmol), and the mixture was heated under reflux for 8 hr. The reaction solution was allowed to cool to room temperature, and the solid was collected by filtration, washed with diethyl ether, dried, suspended in ethyl acetate (250 mL), and washed with saturated aqueous sodium bicarbonate solution (150 mL×2). The combined aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether, and collected by filtration to give the title compound (3.7 g, 57%) as a colorless solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]2[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:26][CH3:27])=[N:12][C:11]=1[C:28]([F:31])([F:30])[F:29]>C1COCC1>[CH2:24]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:26][CH3:27])[C:18]=1[C:13]1[N:12]=[C:11]([C:28]([F:31])([F:29])[F:30])[C:10]([CH2:9][OH:8])=[C:15]([O:16][CH3:17])[CH:14]=1)[CH3:25]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(C(F)(F)F)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1cc(OC)c(CO)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of LiAlH4 (1 M in THF, 2 mL, 2 mmol) is added to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-2-trifluoromethyl-nicotinic acid methyl ester (200 mg, 0.54 mmol) in THF (5 mL) at 0° C. The mixture is warmed to room temperature and stirred for 2 hours. The mixture is cooled to 0° C. and Na2SO4.10H2O is added to quench the reaction. The mixture is filtered through Celite and the filtrate is concentrated in vacuo. The crude product is purified by PTLC (hexanes/ethyl acetate 3:1) to give [6-(2,6-diethyl-phenyl)-4-methoxy-2-trifluoromethyl-pyridin-3-yl]-methanol as a white solid. 1H NMR: (CDCl3) 7.28 (t, 1H), 7.14 (d, 2H), 6.99 (S, 1H), 4.92 (d, 2H), 3.97 (s, 3H), 2.28 (m, 4H), 1.05 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[O:26])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[H-].[Na+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][N:20]([CH2:29][CH:31]5[CH2:32][O:33]5)[CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[O:26])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)c1c-2c(N2CCN(CC3CO3)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of compound 5x (0.35 g, 1 mmol, obtained from the above Synthesis Example 12) in dry DMF (20 mL) was added NaH (60% in oil, 2.64 g, 66.0 mmol) at 0° C. for 1 hr. After stirring at room temperature for 8 hrs, epichlorohydrin (0.92 g, 10 mmol) was added and stirred for a further 1 hr. The reaction mixture was partitioned between H2O and CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The resultant residue was purified by column chromatography (MeOH/CH2Cl2=1:10) to give the title compound 5kkk (0.33 g, 84% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2Cl)[CH:6]=1)=[O:4].[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[NH:33][C:29]2[CH:30]=[C:31]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH3:23])=[CH:32]3)[CH:6]=1)=[O:4]
Reactant: CN(CCN1CCOCC1)C(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N(C)CCN5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid methyl-(2-morpholin-4-yl-ethyl)-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 450 (MH+), HPLC Rf: 3.58 min.; HPLC purity: 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:28]3[CH2:27][CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NCCN1CCCCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCN1CCCCC1
Reaction time: 10 h
Yield: 88.8 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 250 ml of toluene, 4.05 ml (0.0305 mol) of 2-piperidinoethylamine and 0.13 g of p-toluenesulphonic acid monohydrate were added thereto and the mixture was boiled for 4 hours on a water separator. After concentration the residue was hydrogenated with 1.3 g of Raney-nickel in 500 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with CH2Cl2 /MeOH 49:1. There were obtained 4.45 g (89%) of oily rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(2-piperidinoethyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([O-:9])=[O:8].[Na+].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: CCI
Reactant: O=C([O-])C1CCC=CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCC=CO1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of sodium 3,4-dihydro-2H-pyran-2-carboxylate (150.0 g, 10 mol), ethyl iodide (192.3 g, 1.2 mol), sodium carbonate (10 g), and dimethylformamide (500 ml) was heated at 105°-110° C. for 5 hours. The reaction mixture was cooled to room temperature and water (450 ml) was added to dissolve inorganic sales. The mixture was extracted with four 200 ml portions of benzene. The combined organic layers were washed with four 200 ml portions of water and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed by rotary evaporation. The oily residue was distilled under reduced pressure giving a yield of 87% of product having a bp of 75°-80° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:31]=[C:30]([NH2:32])[NH:29][N:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:32][C:30]3[NH:29][N:28]=[C:27]([CH3:26])[CH:31]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cc(N)[nH]n1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)[nH]n1
Temperature: 140 °C
Yield: 17.4 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 3-methyl-1H-pyrazol-5-amine (51.1 mg, 526 μmol), BINAP (10.9 mg, 17.5 μmol), palladium (II) acetate (19.7 mg, 87.7 μmol) and sodium tert-butoxide (84.3 mg, 877 μmol) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 50-100% ethyl acetate in hexanes) gave N-tert-butyl-2-(3-methyl-1H-pyrazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (27 mg, 60.9 μmol, 17.3%) as a brown solid. MS (EI/CI) m/z: 444.3 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([CH3:24])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[NH:36][C:37]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([CH3:24])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:38]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c4ccccc34)c2[nH]c1=O

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-3-methylpyrido[2,3-b]pyrazin-2(1H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a slightly yellow solid (28 mg, 42%).
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC#N>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CN(Cc2ccc(CNCc3ccccn3)cc2)C2CCCc3cccnc32)cc1
Reaction time: 18 h
Yield: 60.6 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.220 g, 0.390 mmol) in CH3CN (8 mL), at room temperature, was added powdered K2CO3 (0.153 g, 1.11 mmol) followed by excess benzyl bromide (0.20 mL, 1.68 mmol). After 18 hours, the reaction mixture was concentrated and the residue was partitioned between CH2Cl2 (10 mL) and water (5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography (2 mm plate, 20:1 CH2Cl2—CH3OH) provided the desired product (0.106 g, 44%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[CH2:19][CH2:20][C:21]([CH3:23])=[CH2:22])=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:20][C:21]([CH3:23])=[CH2:22])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: C=C(C)CCOP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CCOc1ccc(Br)cc1Cl
Temperature: 85 °C

Procedure:
To a mixture of 4-bromo-2-chlorophenol (0.98 g, 4.71 mmol), and Cs2CO3 (2.05 g, 6.28 mmol) in DMF (4.49 mL) at room temperature was added 3-methylbut-3-en-1-yl diphenyl phosphate (1.00 g, 3.14 mmol, synthesized according to a procedure in U.S. Pat. No. 5,006,550, 9 Apr. 1991) dropwise via a syringe. The reaction mixture was heated to 85° C. for 1 hour. It was then allowed to cool to room temperature and was diluted with water (20.0 mL). The resulting mixture was extracted with hexane (75.0 mL, 2×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to give the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH3:13])=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([Cl:24])=[N:10][C:9]=2[CH3:13])=[N:6][CH:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
A solution of Example 57A (7.32 g, 30.6 mmol) in THF (150 mL) was cooled to −78° C., and treated carefully with LiHMDS (1 M in THF, 37 mL, 37 mmol). The mixture was stirred at −78° C. for 20 minutes, then was treated all at once with hexachloroethane (14.5 g, 61.2 mmol). The flask was removed from the cold bath, and the reaction mixture was stirred overnight at room temperature. After this time, the mixture was diluted with Et2O and washed with saturated NH4Cl solution and water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (100% hexane, then 0% to 20% EtOAc/hexane) to afford 7.44 g (89%) of the title compound as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J=2.4, 1H), 7.87 (dd, J=8.4, 2.4, 1H), 7.48 (dd, J=8.7, 0.7, 1H), 2.57 (s, 3H). MS (DCI+) m/z 273/275 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][NH:6][S:7]([C:10]1[S:11][C:12]([CH2:15][CH2:16][CH:17]2[CH2:34][NH:33][C:20]3[N:21]=[C:22]([NH:26]C(=O)C(C)(C)C)[N:23]=[C:24]([OH:25])[C:19]=3[CH2:18]2)=[CH:13][CH:14]=1)(=[O:9])=[O:8])C.Cl>[OH-].[Na+]>[NH2:26][C:22]1[N:23]=[C:24]([OH:25])[C:19]2[CH2:18][CH:17]([CH2:16][CH2:15][C:12]3[S:11][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:35])=[O:3])(=[O:8])=[O:9])=[CH:14][CH:13]=3)[CH2:34][NH:33][C:20]=2[N:21]=1
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CCc1ccc(S(=O)(=O)NCC(=O)O)s1)C2
Yield: 109.2 %

Procedure:
A solution of 33 mg (0.062 mmol) of N-{5-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]thien-2-ylsulfonyl}glycine ethyl ester in 3.0 mL of 1.0N sodium hydroxide was stirred at room temperature for 24 hours. The reaction mixture was then acidified with 1.0N hydrochloric acid and the white precipitate was collected by filtration to give 28 mg of N-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]thien-2-ylsulfonyl}glycine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
A solution of 5-bromo-2-nitropyridine (15 g, 73.9 mmol) in DMF (300 mL) was sparged with Ar, treated with Cs2CO3 (48.2 g, 148 mmol) and 2-chloro-4-hydroxypyridine (10.53 g, 81 mmol), sparged again with Ar and heated at 85° C. overnight. The mixture was cooled to RT, filtered through a bed of silica gel, washed thoroughly with EtOAc, and the filtrate treated with 5% LiCl and stirred overnight. The layers were separated, the aqueous layer extracted with additional EtOAc (4×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The residue was dissolved in EtOAc, treated with 5% LiCl, stirred for 1 h, the layers separated and the aqueous layer extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex). The material was suspended in MTBE, sonicated and the resulting solid collected via filtration to afford 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (6.06 g, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, J=2.4, 1H), 8.43-8.39 (m, 2H), 8.06 (dd, J=8.8, 2.8 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.23 (dd, J=5.6, 2.0 Hz, 1H); MS (ESI) m/z: 252.0 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[N:10]=2)[CH2:3]1)(=[O:23])=[O:22]
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 3-hydroxy-1-[4-(thiophene-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (571 mg, 1.93 mmol) (obtained as described in Reference Example 66(2)) in methylene chloride (28 ml) were added methanesulfonyl chloride (0.18 ml, 2.32 mmol) and triethylamine (0.33 ml, 2.32 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (1:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(thiophene-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (490 mg, yield 91%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:11][CH:10]=2)[CH2:4]1.[C:23](O)(=[O:26])[CH:24]=[CH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:12]=[CH:11][CH:10]=2)[CH2:4]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N2CCC[C@H](N)C2)n1
Reactant: C=CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(NC(=O)OC(C)(C)C)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of 114c (1.39 g, 4.22 mmol), acrylic acid (0.3 mL, 4.5 mmol), HATU (1.7 g, 4.5 mmol) and DIPEA (3.8 mL, 9 mmol) in DCM (30 mL) was stirred at rt overnight. The mixture was washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 6-(3-acrylamidopiperidin-1-yl)pyridin-2-ylcarbamate 114d (880 mg, 60%) as brown oil. The material was used for the next step directly.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30]>[Ni]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[NH:11][C:8]3=[CH:9][C:10]4[C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[N:4]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]=4[CH:6]=[C:7]3[N:22]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(CCC(C)C)C(=O)C3(C)C)cc1
Agent: [Ni]
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4CCC(C)C)cc1
Yield: 81 %

Procedure:
2-(4-Methoxy-phenyl)-7,7-dimethyl-5-(3-methyl-butyl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one is prepared from N-[3,3-dimethyl-1-(3-methyl-butyl)-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-methoxy-benzamide (167 mg) as described in Example 1b using Raney-nickel (25 mg). After aqueous work-up 2-(4-methoxy-phenyl)-7,7-dimethyl-5-(3-methyl-butyl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (120 mg) is obtained by flash chromatography on silica gel eluting with light petroleum/EtOAc (1:1).
Reaction SMILES: [CH2:1]([CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1)[CH2:2][CH3:3].C([Li])CCC.[CH:15](=[O:17])[CH3:16]>CCCCCC>[OH:17][CH:15]([C:4]1([CH2:1][CH2:2][CH3:3])[S:9][CH2:8][CH2:7][CH2:6][S:5]1)[CH3:16]
Reactant: CC=O
Reactant: CCCC1SCCCS1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCC1(C(C)O)SCCCS1
Yield: 86.9 %

Procedure:
The synthesis was carried out in a similar manner to Example 4/(a), but using 8 g (49.3 mmol) of 2-n-propyl-1,3-dithian, 52 mmol of n-butyllithium (32.5 ml of a 1.6 M solution in n-hexane) and 2.5 g (56.8 mmol) of acetaldehyde. 8.84 g of 2-(1-hydroxyethyl)-2-n-propyl-1,3-dithian were obtained as a colorless oil.
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[F:48][C:49]1[CH:58]=[C:57]2[C:52]([CH2:53][N:54]([CH:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)[C:55](=[O:59])[NH:56]2)=[CH:51][CH:50]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:48][C:49]1[CH:58]=[C:57]2[C:52]([CH2:53][N:54]([CH:60]3[CH2:65][CH2:64][N:63]([C:1]([O:2][C@H:3]([CH2:18][C:19]4[CH:27]=[C:26]([CH3:28])[C:25]5[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:24]=5)[CH:20]=4)[C:4](=[O:17])[N:5]4[CH2:10][CH2:9][CH:8]([N:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)[CH2:7][CH2:6]4)=[O:37])[CH2:62][CH2:61]3)[C:55](=[O:59])[NH:56]2)=[CH:51][CH:50]=1
Reactant: O=C1Nc2cc(F)ccc2CN1C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3Cc4ccc(F)cc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 7-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (56.2 mg, 1.0 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (79 μL, 0.45 mmol) and the reaction stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (3:97:1 methanol/dichloromethane/triethylamine) to give 93 mg (53%) as a tan foam solid. Mass spec.: 776.48 (MH)+.