Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].CN(C)C=O.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>O.C(OCC)(=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([O:14][CH3:15])=[C:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1OC
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OC)c2ccccc2n1CCCCl
Temperature: 0 °C

Procedure:
20.5 g. of 2-methoxy carbonyl-3-methoxy indole are dissolved in 100 ml. of dimethyl formamide. 3 g. of 80% sodium hydride are added portion by portion thereto at 0° C., while stirring. After heating the mixture to room temperature, 20 g. of 1-bromo-3-chloro propane are added thereto. The reaction mixture is heated to 80° C. for 12 hours whereupon the solvent is drawn off. The reaction mixture is worked up in the usual manner by means of ethyl acetate and water. The resulting crude reaction product is subjected to a distillation in a tubular distillation apparatus with bulbar enlargements. 24.7 g. of 1-(γ-chloro propyl)-2-methoxy carbonyl-3-methoxy indole are obtained in the form of an oil. Said compound is dissolved in 100 ml. of dimethyl formamide. The solution is then heated with 20 g. of diethylamine to 60° C. for 5 hours. After drawing off the solvent and adding 10% hydrochloric acid to the residue, the mixture is extracted with ethyl acetate. Thereupon the aqueous phase is rendered alkaline by the addition of a sodium carbonate solution and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure. 25.8 g. of 1-(γ-diethyl amino propyl)-2-methoxy carbonyl-3-methoxy indole are obtained as an oily residue. The yield is 81% of the theoretical yield. Said compound can be converted into its crystalline maleinate with a melting point of 110°-112° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[S:29][C:11]2[S:12][CH2:13][CH2:14][C:15]3[C:16](=[N:17][N:18]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:19](=[O:21])[CH:20]=3)[C:10]=2[CH:9]=1)=O)(=[O:3])[CH3:2].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH2:6][C:8]1[S:29][C:11]2[S:12][CH2:13][CH2:14][C:15]3[C:16](=[N:17][N:18]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[C:19](=[O:21])[CH:20]=3)[C:10]=2[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)OCCc1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
To a solution of 2.8 g of 9-acetyloxyacetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one obtained in Example 51 in 40 ml of trifluoroacetic acid is added 3.0 ml of triethylsilane and the mixture is stirred for 5 hours at room temperature. After the completion of reaction, to the mixture is added water and the solution is extracted with chloroform. The extract is washed, dried and concentrated under reduced pressure. The resulting residue is subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform and methanol (99:1). The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.0 g of 9-(2-acetoxyethyl)-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 115°-117° C.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]1[CH:41]=[C:40]([C:42]([OH:44])=O)[O:39][NH:38]1.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]([Cl:64])=[C:50]([CH:63]=1)[C:51]([NH:53][C:54]1[CH:55]=[C:56]2[CH:62]=[CH:61][NH:60][C:57]2=[N:58][CH:59]=1)=[O:52]>CN(C=O)C>[Cl:64][C:49]1[CH:48]=[CH:47][C:46]([NH:45][C:42]([C:40]2[O:39][N:38]=[C:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])[CH:41]=2)=[O:44])=[CH:63][C:50]=1[C:51](=[O:52])[NH:53][C:54]1[CH:55]=[C:56]2[CH:62]=[CH:61][NH:60][C:57]2=[N:58][CH:59]=1
Reactant: Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Reactant: O=C(O)C1=CC(c2ccccc2Cl)NO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1)c1cc(-c2ccccc2Cl)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.3 %

Procedure:
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (0.084 g, 0.26 mmol) and triethylamine (50 μL, 0.35 mmol) were added to a solution of 3-(2-chloro-phenyl)-2,3-dihydro-isoxazole-5-carboxylic acid (0.058 g, 0.26 mmol) in DMF (1 ml) and the reaction stirred for 10 minutes at room temperature. 5-Amino-2-chloro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzamide (0.050 g, 0.175 mmol) was added to the reaction mixture and stirred for a further 24 hours. The solvent was removed under reduced pressure then methanol (3 ml) and ammonium hydroxide (1 ml) were added to the residue and the mixture stirred for a further 3 hours. The solvent was removed under reduced pressure and the resultant solid triturated with acetonitrile:water (1:1, 5 ml). The solid was filtered to afford 3-(2-Chloro-phenyl)-isoxazole-5-carboxylic acid [4-chloro-3-(1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl)-phenyl]-amide 0.033 g (37% yield)
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].[O:22]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]2[O:33][C:32](=[O:34])[N:31]([C:35]3[CH:40]=[CH:39][C:38](I)=[C:37]([F:42])[CH:36]=3)[CH2:30]2)=[N:23]1.[C:43]([O:47][C:48]([N:50]1[CH:55]2[CH2:56][CH2:57][CH:51]1[CH:52]=[C:53]([Sn](C)(C)C)[CH2:54]2)=[O:49])([CH3:46])([CH3:45])[CH3:44].[F-].[K+]>CN(C=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[O:22]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]2[O:33][C:32](=[O:34])[N:31]([C:35]3[CH:40]=[CH:39][C:38]([C:53]4[CH2:54][CH:55]5[N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH:51]([CH2:57][CH2:56]5)[CH:52]=4)=[C:37]([F:42])[CH:36]=3)[CH2:30]2)=[N:23]1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(I)c(F)c1
Reactant: CC(C)(C)OC(=O)N1C2C=C([Sn](C)(C)C)CC1CC2
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2C=C(c3ccc(N4C[C@H](COc5ccon5)OC4=O)cc3F)CC1CC2
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Tris(dibenzylideneacetone) dipalladium(0) (0.19 g, 0.208 mmol), triphenylarsine (0.13 g, 0.425 mmol) and lithium chloride (0.265 g, 6.31 mmol) were added to a stirred solution of 5(R)-isoxazol-3-yloxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (prepared by analogy to reference Example 28) (0.85 g, 2.1 mmol) in degassed DMF (35 ml) under nitrogen. After 5 minutes, a solution of 8-tert-butyloxycarbonyl-3-trimethylstannyl-8-azabicyclo[3.2.1]oct-2-ene (GB 2298647; 0.78 g, 2.1 mmol) in DMF (4 ml) was added and the mixture was heated at 60° C. for 18 hours. A solution of 2M potassium fluoride (30 ml) was added and the mixture stirred for 40 minutes. Solvent was evaporated and the residue partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined extracts dried (Na2SO4) and evaporated. The residue was purified by column chromatography, eluting with a gradient of dichloromethane-5% MeOH/dichloromethane to give 5(R)-isoxazol-3-yloxymethyl-3-(4-{8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene-3-yl }-3-fluorophenyl)oxazolidin-2-one as an oil of 85% purity [hplc](0.97 g, 81%). MS: 486 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10]C)=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1>[Cu](I)I>[CH2:8]([C:6]1[C:5](=[O:10])[NH:4][C:3]([CH3:12])=[C:2]([N:20]2[N:21]=[CH:22][CH:23]=[N:19]2)[CH:7]=1)[CH3:9]
Reactant: c1c[nH]nn1
Reactant: CCc1cc(Br)c(C)nc1OC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(-n2nccn2)c(C)[nH]c1=O
Temperature: 185 °C
Yield: 11.3 %

Procedure:
Into a microwave vial is added 3-bromo-5-ethyl-6-methoxy-2-methyl-pyridine (400 mg, 1.74 mmol), potassium carbonate (360 mg, 2.61 mmol), copper iodide (50 mg, 0.263 mmol) and 1,2,3-triazole (201 μL, 3.47 mmol). The vial is flushed with nitrogen before anhydrous dimethylformamide (4 mL) is added then sealed. The reaction is heated in the CEM Discover microwave at 185° C. for 20 min (4 bar pressure attained). LC/MS shows the reaction is incomplete. The reaction is re-microwaved to 180° C. for 20 min. Further copper iodide (50 mg) is added, the reaction flushed with nitrogen and is re-microwaved to 180° C. for 20 min. LC/MS shows the reaction is complete with the formation of 2 materials. The reaction is diluted with water and extracted with six portions of dichloromethane. The combined extracts are then dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1, increasing to 2:1 then 1:1). Fractions containing the higher Rf product are combined, the solvent evaporated and the residue is triturated twice with heptane and twice with ether to give 3-ethyl-6-methyl-5-(1,2,3-triazol-2-yl)-1H-pyridin-2-one (40 mg, 11% yield) as a white powder. LC/MS: RT: 2.19 min, MS: m/e=205 (M+H); 1H NMR (δ, ppm): 11.93 (1H, s), 8.04 (2H, s), 7.40 (1H, s), 2.41 (2H, q), 2.06 (3H, s), 1.09 (3H, t).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[N:15]([C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:17])[C:14]([O:28]C)=[N:13][C:12]([CH3:30])=[C:11]2[C:31]([O:33][CH3:34])=[O:32])[CH:6]=[CH:7][C:8]=1[F:9]>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[N:15]([C:16]([O:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[O:17])[C:14](=[O:28])[NH:13][C:12]([CH3:30])=[C:11]2[C:31]([O:33][CH3:34])=[O:32])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A solution of 10% aqueous HCl (5 mL) was added to a stirring solution of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)-carbonyl]pyrim-idine (4.10 g, 9.10 mmol) in THF (20 mL) at room temperature and the resulting solution was stirred overnight. The THF was removed in vacuo and the resulting residue was extracted with EtOAc (3×20 mL), washed with brine (10 mL) and then dried over Na2SO4. The solvent was removed in vacuo, giving (+)-6-(3,4-di-fluorophenyl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a viscous oil (3.8 g, 8.5 mmol). The oil was dissolved in THF (20 mL) and 3-bromo-propylamine hydrobromide (2.33 g, 10.8 mmol) and NaHCO3 (1.81 g, 21.5 mmol) were added. The resulting suspension was stirred at room temperature overnight. The THF was removed in vacuo and the resulting residue was dissolved in water (10 mL) and then extracted with EtOAc (3×20 mL). The EtOAc extracts were combined, dried over Na2SO4, filtered and the solvent was removed, giving (+)-1-(3-bromopropylcarbamoyl)-6-(3,4-difluorophenyl)-4-methyl-2-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (3.28 g, 83%): 1H NMR δ 2.05-2.15 (m, 2 H), 2.43 (s, 3 H), 3.40-3.56 (m, 4 H), 3.72 (s, 3 H), 6.69 (s, 1 H), 7.08-7.27 (m, 3 H), 7.57 (br s, 1 H), 8.84 (br t, 1 H). Anal. Calcd for C17H18N3O4 F2Br: C, 45.76; H, 4.07; N, 9.42. Found: C, 45.70; H, 3.99; N, 9.16.
Reaction SMILES: COC1C=CC2C(=CC=CC=2)C=1.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22]C)([OH:15])=[O:14]>>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]([OH:15])=[O:14]
Reactant: COc1ccccc1C(=O)O
Agent: COc1ccc2ccccc2c1
Product: O=C(O)c1ccccc1O
Yield: 89.9 %

Procedure:
The method described in Example 4 is applied with the alteration that instead of 2-methoxynaphthalene 3.04 g (20 mmol) of 1-carboxy-2-methoxybenzene is used yielding 2.48 g (89.9%) of 2-hydroxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[Cl-].[NH4+].O1CC[CH2:26][CH2:25]1>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:25]#[CH:26]
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC1CCCCO1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(C)(O)CCC=C(C)CCC=C(C)COC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of 6,10-dimethyl-11-(2-tetrahydropyranyl) oxy-5,9-undecadien-2-one (90 mg, 0.31 mmol) in tetrahydrofuran (5 ml) was stirred on an ice bath under argon atmosphere. To the solution was added lithium acetylide ethylenediamine complex (180 mg, 1.95 mmol), and the mixture was warmed to room temperature and stirred for 3 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(2-tetrahydropyranyl)oxy-6,10-dodecadien-1-in-3-ol (75 mg, 75%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[O:17][CH2:16][CH2:15][N:14](CC4C=CC=CC=4)[CH2:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25]>[Pd].CO>[ClH:25].[C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[O:17][CH2:16][CH2:15][NH:14][CH2:13]3)[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
Palladium on carbon (10 wt %, 300 mg, 0.282 mmol) was added to a solution of 2-(4-phenyl-1H-imidazol-2-yl)-4-(phenylmethyl)morpholine (900 mg, 2.82 mmol) and 36% aqueous HCl (0.713 mL, 8.45 mmol) in CH3OH (50 mL) under nitrogen, and the reaction mixture was stirred under hydrogen at 25° C. for 1.5 hours. The mixture was filtered, washed by methanol (150 mL), and concentrated to afford an HCl salt of the title compound (600 mg) as a brown solid. LC-MS (ES) m/z=230 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Oc1ccccc1NC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Oc1ccccc1NC2
Temperature: 55 °C

Procedure:
A solution of 1-3 (1.16 g, 4.80 mmol) in THF (50 mL) was treated with a solution of 1M LiAlH4 in THF (10.0 mL, 10.0 mmol) and heated to 55° C. for 2 hours. The reaction was quenched with aqueous ammonium chloride and extracted with diethyl ether. The solvents were removed in vacuo to afford 1-4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35]CC4C=CC=CC=4)=[C:31]([C@@H:43]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH2:44][CH2:45][N:46]([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH:30]=3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[CH2:67][OH:68])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[Si:60]([O:59][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:67][OH:68])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([C@@H:43]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:44][CH2:45][N:46]([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH:30]=2)=[CH:24][CH:25]=1)([C:63]([CH3:66])([CH3:64])[CH3:65])([CH3:62])[CH3:61]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(CO)c3)cc2)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)cc2)ccc1O)C(C)C
Temperature: 25 °C

Procedure:
{2-(benzyloxy)-5-[(1R)-2-({2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethoxy)phenyl]ethyl}amino)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}methanol (Preparation 48, 280 mg, 0.30 mmol) was dissolved in ethanol (6 ml) and palladium hydroxide (20% by weight on carbon, 14 mg, 0.02 mmol) was added. The reaction was the hydrogenated under 40 psi at room temperature for 18 hours, cooled to room temperature and the reaction filtered through Celite™ and the filtrate solvent removed in vacuo to furnish the title compound as a gum, 235 mg.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([NH2:17])[C:14]([Br:18])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].[Li+].[OH-].O>C1COCC1.O>[C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([NH:17][S:27]([CH3:26])(=[O:29])=[O:28])[C:14]([Br:18])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(N)c(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(C(C)=O)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a mixture of 2-acetyl-6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (500 mg, 1.61 mmol) and triethylamine (650 mg, 6.43 mmol) in THF (20 mL) was added MsCl (406 mg, 3.54 mmol) dropwise at 0° C. under N2. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with H2O and extracted with EtOAc, and then the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was dissolved in THF (20 mL) and then a solution of LiOH/H2O (200 mg/6 mL) was added. The mixture was stirred at room temperature for 1 hour, then water was added to the mixture and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography to give compound 2-acetyl-5-bromo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (280 mg, yield: 44.8%). 1H-NMR (CDCl3, 400 MHz) δ 9.83 (s, 1H), 8.97 (s, 1H).7.91 (s, 1H), 7.07 (s, 1H), 3.06 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 389/391.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].S(OC)(O[CH3:17])(=O)=O>C1COCC1.[H-].[Na+]>[CH3:17][O:12][CH:9]1[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]1
Reactant: CCCCCC1CCC(O)CC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC1CCC(OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, to a solution of 4-pentylcyclohexanol (2.0 g, 11.75 mmol) in anhydrous THF (60 mL), NaH was added (60%, 0.94 g, 23.5 mmol) at 0° C. and stirred for 30 minutes, followed by the addition of dimethyl sulfate (1.68 mL, 17.62 mmol). The mixture was refluxed for 12 hrs and cooled to 0° C. The reaction was quenched with saturated ammonium chloride solution (20 mL). THF was removed under vacuum and the residue was extracted with CH2Cl2 (3×25 mL). The collected organic portion was dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexanes/ethyl acetate: 15/1) to provide probe 1 (2.0 g, quant.) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ=0.79-0.85 (m, 10 H), 1.28-1.38 (m, 7 H), 1.46 (br, 2 H), 2.02 (br, 2 H), 3.32 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ=8.1, 20.9 (2 carbons), 24.1 (2 carbons), 30.2 (2 carbons), 32.6, 34.8, 45.2, 55.5, 74.8; MS (ESI) calcd for C12H25O [M+H]+/z: 185.19. found: 185.31.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH2:26][OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH2:26][O:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.16 ml of methanesulphonyl chloride followed by 3.86 ml of triethylamine are added to a solution of 5 g of (R)-3-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester in 80 ml of DCM cooled to 0° C. The medium is stirred at 0° C. for 1 h 30 min and 0.7 ml of triethylamine and 0.54 ml of methanesulphonyl chloride are again added. After 30 min at 0° C., the medium is hydrolysed, and the organic phase is washed twice in water and then with a saturated NaCl solution, and then dried over MgSO4. The medium is evaporated, to give 6.8 g of a pale yellow oil.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].N1CCOCC1.Cl>CN(C=O)C.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.CCOC(C)=O>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: CCOC(=O)CCCCBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Temperature: 55 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
To 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 5.31 mmol) in dry DMF (25 ml) was added Cs2CO3 (1.905 g, 5.84 mmol), followed by ethyl 5-bromovalerate (1.46 g, 6.99 mmol). The mixture was heated at 55° C. for 18 h then allowed to cool. It was degassed by repeatedly evacuating and readmitting nitrogen, then morpholine (3.70 ml, 42.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.865 mmol) were added and the mixture stirred for 5 h. EtOAc (75 ml), 2M HCl (40 ml) and water (20 ml) were added and the organic phase was separated, washed with brine (3×25 ml), filtered to remove some insoluble yellow solid, dried (Na2SO4) and evaporated. The residue (2.5 g) was purified by aminopropyl SPE (20 g), loading in THF-MeOH (1:1), washing with MeOH and eluting the product with DCM-MeOH (1:1) containing 5% added AcOH to afford the title compound (1.53 g).
Reaction SMILES: [O:1]=[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][S:22]([C:25]3[S:26][C:27]([N+:30]([O-])=O)=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[O:20])=[CH:14][CH:13]=2)[C:10](=[O:33])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C>CO.[Pd]>[NH2:30][C:27]1[S:26][C:25]([S:22]([NH:21][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([N:11]3[C:10](=[O:33])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])=[CH:13][CH:14]=2)=[O:20])(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: O=C(Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1)NS(=O)(=O)c1ccc([N+](=O)[O-])s1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NC(=O)Nc2ccc(-n3c(=O)[nH]c4ccccc4c3=O)cc2)s1
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl]{[(5-nitro (2-thienyl))sulfonyl]amino}carboxamide (from Example 1148) (20 mg, 0.041 mmol) in methanol (1.5 mL) and triethylamine (11 μL, 0.08 mmol) was added 10% Pd/C (5 mg, 0.005 mmol) under argon. The reaction mixture was hydrogenated under 1 atm H2 for 3 hr. filtered, concentrated and HPLC purified to give the aniline (6 mg, 33%). ES-MS (M+H)+=458.