Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]([C:12]1([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3([C:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:11])[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)=[N:32][CH:33]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: N#Cc1ccc(Cl)nc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NNC(=O)C1(c2ccc(-c3ccc(C#N)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.6 %

Procedure:
A mixed solution of the compound (100 g, 249 mmol) obtained in Example 60-1), 2-chloro-5-cyanopyridine (44.8 g, 323 mmol), potassium carbonate (68.7 g, 497 mmol), and tetrakis(triphenylphosphine)palladium (14.4 g, 12.4 mmol) in 1,2-dimethoxyethane (800 mL) and water (200 mL) was stirred at 100° C. for 8 h, then at 80° C. for 14 h, and further at 100° C. for 5 h. The reaction mixture was cooled to room temperature, insoluble substances were filtered off, dichloromethane was added to the filtrate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution in this order. The solvent was distilled off under reduced pressure, and the residue was washed with dichloromethane and hexane and then purified by silica gel column chromatography (ethyl acetate:methanol=1:1) to obtain the title compound (24.1 g, 26%) as a white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[CH:20]1([CH:26]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH:20]1([CH2:26][N:3]2[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]3/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/3)[CH2:5][CH2:4]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and cyclohexanecarbaldehyde (0.11 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature for 3 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (94 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:13][N:14]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[C:13]([C:2]1[C:3]([CH3:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)#[N:14]
Reactant: CN1CCCC1=O
Reactant: Cc1ccc2cccnc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccc2cccnc2c1C#N

Procedure:
Prepared by reacting 8-bromo-7-methyl-quinoline with zinc cyanide in the presence of tetrakis(triphenylphosphine)palladium in N-methylpyrrolidinone under a protective gas atmosphere at 100-105° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]2)[N:3]=1.FC(F)(F)C(O)=O.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([NH:37][C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[N:29]1.C(N(CC)CC)C.O>CN(C)C=O>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([NH:37][C:38]([N:40]2[CH2:45][CH2:44][N:43]([C:2]3[S:6][N:5]=[C:4]([N:7]4[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]4)[N:3]=3)[CH2:42][CH2:41]2)=[O:39])=[N:29]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nsc(Cl)n2)CC1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of tert-butyl [1-(5-chloro-1,2,4-thiadiazol-3-yl)piperidin-4-yl]carbamate (442 mg, 1.39 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (500 mg, 1.39 mmol) in dimethylformamide (5 ml) was added triethylamine (0.969 ml, 6.95 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured to water, and a solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 335 mg (45.6%) of the desired product as a solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.C(O)(C)C>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[O:21][N:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of 129b (280 mg, 0.49 mmol) in THF (4 mL), i-propanol (4 mL), and water (2 mL) was added lithium hydroxide (24 mg, 0.98 mmol). The reaction mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 129 as a white solid (85 mg, 33%). MS-ESI: [M+H]+ 531.3. 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.54 (d, J=3.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.91 (d, J=1.0 Hz, 1H), 7.78 (dd, J=1.0, 13.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 6.26 (s, 1H), 4.92 (s, 1H), 4.43 (d, J=6.0 Hz, 2H), 3.61 (s, 3H), 2.32 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:27]=[CH:26][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]([CH3:25])[CH2:23][OH:24])[CH:20]=3)[C:15]([OH:17])=[O:16])=[C:9]([F:28])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].N1C=CN=C1.C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)C.O>[N:1]1([C:5]([C:7]2[CH:27]=[CH:26][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]([CH3:25])[CH2:23][O:24][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:20]=3)[C:15]([OH:17])=[O:16])=[C:9]([F:28])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzoic acid (9.8 g, 0.025 mol), t-butyldimethylsilylchloride (11.3 g, 0.075 mol) and imidazole (17.08 g, 0.25 mol) in DMF (100 mL) was stirred at RT for 24 hours. Water (100 mL) was added and the mixture extracted into diethyl ether (3×100 mL). The extracts were combined and washed with water (3×100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo to give a golden oil. Saturated aqueous sodium bicarbonate (100 mL) and diethyl ether (100 mL) were added and stirred for 30 mins. The aqueous layer was acidified with 1M citric acid solution and extracted into diethyl ether (3×100 mL). The extracts were combined, dried (MgSO4), filtered, and evaporated in vacuo and the crude product chromatographed on silica, eluting with ethyl acetate, to give the desired compound. (6.32 g).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.Cl[C:13]1([CH3:33])[CH2:17][CH2:16][N:15](S(C2C=CC(C)=CC=2)(=O)=O)[C@@H:14]1[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(OCC)C>C1COCC1>[CH3:33][C:13]1[CH:17]=[CH:16][NH:15][C:14]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)[C@H]1N(S(=O)(=O)c2ccc(C)cc2)CCC1(C)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1[nH]ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
DBU (15.0 mL, 100 mmol) was added dropwise to a solution of ethyl 3-chloro-3-methyl-1-[(4-methylphenyl)sulfonyl]prolinate (15 g, 43 mmol) in THF (100 mL). The mixture was stirred overnight at RT. Diethyl ether (100 mL) and ice cold 5% HCl (100 mL) were added, the layers separated. The organic layer was washed again with washed with ice cold 5% HCl (100 mL) and water (50 mL) followed by saturated sodium bicarbonate (100 mL) and saturated NaCl (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford ethyl 3-methyl-1H-pyrrole-2-carboxylate (5.6 g, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (br. s., 1H) 6.84 (t, 1H) 6.00 (t, 1H) 4.21 (q, 2H) 2.25 (s, 3H) 1.28 (t, 3 H). MS: m/z 153.9 (M+1).
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C>FC(F)(F)C(O)=O>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:3][C:4](=[O:5])[OH:10]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Yield: 86.4 %

Procedure:
The t-butyl ester (10, 100 mg, 0.22 mmol) in trifluoroacetic acid (5 mL) was stirred in an ice bath for 30 minutes. Trifluoroacetic acid was removed under reduced pressure, the crude product was recrystallized from EtOAc/hexane to give 76.8 mg (0.19 mmol, 87% yield) of a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]=[CH:7][C:8](O)=[O:9])([O-])=O>C(O)C.[Ni]>[NH:1]1[C:4]2[C:5](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:7][C:8]1=[O:9]
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: O=C1CCc2ccccc2N1
Reaction time: 5 h
Yield: 57 %

Procedure:
A slurry of 50.0 g (0.259 mol) of o-nitrocinnamic acid in 500 mL of ethanol was treated with 5 teaspoons of Raney Ni and hydrogenated on a Parr shaker overnight at an initial pressure of 50 psi. In the morning, the pressure was increased again to 50 psi and the reaction was continued for an additional 5 h. The reaction mixture was filtered to remove the catalyst and then washed through a bed of silica gel with a mixture of ethyl acetate and ethanol to remove traces of nickel salts. Evaporation of the filtrate gave the desired product in 57% yield. NMR (DMSO-d6) δ 2.45 (2H, t, J=7), 2.87 (2H, t, J=7), 6.87 (2H, d of d, J=7, 7), 7.12 (2H, d of d, J=7, 10), 10.08 (1H, s). m.p. 165-166° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C[Si](C)(C)N[Si](C)(C)C.[Li].C([O:27][C:28](=O)[C:29]([F:32])([F:31])[F:30])C>C(COC)OC>[O:1]=[C:2]1[CH:7]([C:28](=[O:27])[C:29]([F:32])([F:31])[F:30])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C(F)(F)F)C(=O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
5.0 g (25 mmol) of t-butyl 3-oxopiperidin-1-carboxylate was dissolved in dimethoxyethane, and the resulting solution was cooled to −78° C., then 30 mL (30 mmol) of lithium hexamethyldisilazane (LHMDS, 1M in THF) was dropwise added and stirred for about 1 hour, followed by dropwise addition of 3.9 mL (33 mmol) of ethyltrifluoroacetate. After stirring for 1 hour, a dryice/acetone bath was removed and then further stirred for about 2 hours and 30 minutes with the reaction solution being heated to room temperature. After the reaction solution was washed with a saturated aqueous ammonium chloride, extraction was conduced three times with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, then the residue was purified by column chromatography (20:1 dichloromethane:methanol) to give 6.0 g of the title compound in a yield of 81%.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH2:3][CH3:4].[CH3:14][S:15]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[NH2:34])(=[O:17])=[O:16].Cl.N1C=CC=CC=1>C(#N)C>[CH3:14][S:15]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]1[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=[C:1]1[CH2:2][CH2:3][CH3:4])(=[O:17])=[O:16]
Reactant: CCCC(OCC)(OCC)OCC
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reaction time: 0.67 h
Yield: 85.3 %

Procedure:
Triethyl orthobutyrate (2.2 mL, 14 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.6 g, 12 mmol) in acetonitrile (60 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 40 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide 3.7 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]([O:29][CH3:30])=[C:9]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:14]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]([O:29][CH3:30])=[C:9]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:37][CH3:36])[N:22]=3)[CH:14]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(Cl)n3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nccc(Oc2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)ccc2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-(2-chloro-pyrimidin-4-yloxy)-4-methyl-benzamide and 2 ml of a 2 M methylamine solution in tetrahydrofuran is stirred overnight at ambient temperature in a closed microwave glass container. For working up the reaction mixture is diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is chromatographed on a silica gel column with ethyl acetate/cyclohexane (50:50→100:0) as eluant.
Reaction SMILES: B(F)(F)F.CCOCC.C(O[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][C@H:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:43]([CH2:44][CH2:45][C@:28]12[CH3:29])[C@:41]1([CH3:42])[C@H:36]([CH2:37][C:38](=[O:46])[CH2:39][CH2:40]1)[CH2:35][CH2:34]3.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:18]([O:17][CH:13]([O:14][CH2:15][CH3:16])[C@@H:39]1[CH2:40][C@@:41]2([CH3:42])[C@@H:36]([CH2:35][CH2:34][C@@H:33]3[C@@H:43]2[CH2:44][CH2:45][C@@:28]2([CH3:29])[C@H:30]3[CH2:31][CH2:32][C@@H:27]2[O:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[CH2:37][C:38]1=[O:46])[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(OCC)[C@@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC4CCCCO4)CC[C@@H]32)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Under an argon atmosphere at less than -30° C. boron trifluoride etherate (100 ml., 115.4 g., 0.704 mole) was added to a solution of triethylorthoformate (109.5 ml., 97.56 g., 0.658 mole) in dichloromethane (300 ml.). The temperature was raised to 0° C., kept there for 15 min., then lowered to -70° C. A solution of (5α,17β)-17-[(tetrahydro-2H-pyran-2-yl)oxy]androstan-3-one (0.3 mole) in dichloromethane (250 ml.+50 ml. for rinsing) was then added, followed by diisopropylethylamine (166.5 ml., 123.5 g., 0.955 mole), the latter while maintaining the temperature at less then -55° C. The temperature was lowered to -70° C. for 1 hr. The mixture was then quenched in aqueous sodium bicarbonate solution (3 1., made by dissolving 300 g. of sodium bicarbonate in 3.5 1. of water). The layers were separated. The aqueous layer was extracted with dichloromethane (250 ml.). The combined dichloromethane layers were washed twice with cold hydrochloric acid (2N, 1200 ml., 600 ml.), then with half-saturated aqueous sodium bicarbonate solution (800 ml.), dried and stripped of dichloromethane. The residue was triturated with hexane, affording (2α,5α,17β)-2-(diethoxymethyl)-17-[(tetrahydro-2H-pyran-2-yl)oxy]androstan-3-one (70.57 g., 49% yield, m.r. 165°-168° C.).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=1[CH:16]=[CH2:17])[CH2:2]C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[F:15][C:8]1[C:7]2[CH:16]=[CH:17][CH2:2][CH2:1][NH:5][C:6]=2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: C=CCCNc1c([N+](=O)[O-])ccc(F)c1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c2c1NCCC=C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a solution of but-3-enyl-(3-fluoro-6-nitro-2-vinylphenyl)amine (327.6 mg, 1.386 mmol) in DCM (30 mL) was added Grubbs catalyst (2nd generation, benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium) (47 mg, 0.055 mmol). The reaction mixture was stirred at RT for 16 h, and then a further portion of the Grubbs catalyst (47 mg, 0.055 mmol) was added and stirring continued for a further 64 h. The reaction mixture was concentrated in vacuo and then purified by column chromatography (Si—PCC, eluant 2-6% EtOAc in cyclohexane). The recovered starting material (145 mg) was dissolved in DCM (20 mL) and Grubbs 2nd generation catalyst (30 mg, 0.035 mmol) was added. The reaction mixture was heated under reflux for 6 h, then left at RT for 16 h. The reaction mixture was concentrated in vacuo, combined with the product from the initial purification and purified by column chromatography (Si—PCC, eluant 2-8% EtOAc in cyclohexane) affording the title compound as a red solid (225.4 mg, 78%). 1H NMR (CDCl3, 300 MHz): 8.90 (1H, bs), 8.09 (1H, dd, J=9.4, 6.0 Hz), 6.67 (1H, dt, J=12.3, 1.8 Hz), 6.47 (1H, t, J=9.6 Hz), 6.16 (1H, dt, J=12.3, 4.7 Hz), 3.52 (2H, q, J=4.9 Hz), 2.65 (2H, dq, J=4.8, 1.8 Hz)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:31])[CH2:11][N:12]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:30])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C([O-])([O-])=O.[K+].[K+]>ClCCCl.CN(C1C=CN=CC=1)C.O>[CH3:39][S:40]([O:31][CH:10]([CH2:11][N:12]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:30])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[CH:13]1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])(=[O:42])=[O:41]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: Cn1c(=O)c2c(-c3ccccc3)n(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(3-(tert-butyldimethylsilyloxy)-2-hydroxypropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 2) (1 g, 2.25 mmol) in DCE (20 ml) was added triethylamine (1.57 ml, 11.27 mmol), DMAP (28 mg, 0.025 mmol) and methanesulfonyl chloride (0.89 ml, 11.3 mmol) at 0° C. and reaction stirred for 2 hours at RT. Solid K2CO3 was added to the reaction mixture and then it was diluted with water and extracted with DCM (3×20 ml). The organics were passed through a hydrophobic frit and concentrated in vacuo to yield the title compound as a brown oil which was used without further purification;
Reaction SMILES: [CH3:1][N:2]([C:6]1[C:7]([I:20])=[C:8]([C:17]([Cl:19])=[O:18])[C:9]([I:16])=[C:10]([C:14]=1[I:15])[C:11]([Cl:13])=[O:12])C(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:6]1[C:14]([I:15])=[C:10]([C:11]([Cl:13])=[O:12])[C:9]([I:16])=[C:8]([C:7]=1[I:20])[C:17]([Cl:19])=[O:18]
Reactant: CC(=O)N(C)c1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: ClC(Cl)(Cl)Cl
Product: CNc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I

Procedure:
The reaction mixture (now a heterogeneous paste) was poured into a mechanically-stirred slurry of ice water (1:1, 1L), the precipitate filtered and bashed with water (2×100 ml), saturated aqueous sodium bicarbonate (4×200 ml) and finally water to neutral pH (4×300 ml). The product was dried overnight at 40° C. and 0.3 mm Hg over KOH pellet, then redried over P2O5 to yield 5-(N-methyl acetamido)-2,4,6-triiodoisophthaloyl dichloride (XIV) as a slightly off-white, granular solid (60.0 g, 92% yield). TLC (85% CCl4 /15% acetone): Rf (XII):0.79; Rf (XIV):0.59.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NCC[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[CH3:23])[CH2:19][CH2:18][CH2:17]2>>[C:1]1([CH2:7][C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[CH3:23])[CH2:19][CH2:18][CH2:17]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1cc2c(cc1CCN)CCC2
Product: Cc1cc2c(cc1C(=O)Cc1ccccc1)CCC2

Procedure:
Phenylacetyl chloride was reacted with 5-aminoethyl-6-methylindan to produce the desired product. After recrystallization from benzene it melted at 125.5°-127° C.