Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=CC(C(C2CCN(CC(O)=O)CC2)=O)=CC=1)C.FC1C=CC(C(C2CCN(CC(O)=O)CC2)=O)=CC=1.C1(CCO)CC1.[CH:47]1([CH2:50][CH2:51][O:52][C:53]2[CH:70]=[CH:69][C:56]([C:57]([CH:59]3[CH2:64][CH2:63][N:62]([CH2:65][C:66]([OH:68])=[O:67])[CH2:61][CH2:60]3)=[O:58])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.[NH2:71][CH2:72][C:73]1[NH:74][C:75](=[O:83])[C:76]2[CH2:82][O:81][CH2:80][CH2:79][C:77]=2[N:78]=1.C(O)(C(F)(F)F)=O>C(#N)C.O>[CH:47]1([CH2:50][CH2:51][O:52][C:53]2[CH:70]=[CH:69][C:56]([C:57]([CH:59]3[CH2:60][CH2:61][N:62]([CH2:65][C:66]([OH:68])=[O:67])[CH2:63][CH2:64]3)=[O:58])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.[CH:47]1([CH2:50][CH2:51][O:52][C:53]2[CH:70]=[CH:69][C:56]([C:57]([CH:59]3[CH2:60][CH2:61][N:62]([CH2:65][C:66]([NH:71][CH2:72][C:73]4[NH:74][C:75](=[O:83])[C:76]5[CH2:82][O:81][CH2:80][CH2:79][C:77]=5[N:78]=4)=[O:68])[CH2:63][CH2:64]3)=[O:58])=[CH:55][CH:54]=2)[CH2:48][CH2:49]1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: O=C(O)CN1CCC(C(=O)c2ccc(OCCC3CC3)cc2)CC1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCC(C(=O)c2ccc(OCCC3CC3)cc2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2

Procedure:
{4-[4-(2-Cyclopropyl-ethoxy)-benzoyl]-piperidin-1-yl}-acetic acid was prepared following the general procedures for the synthesis of 2-(4-(4-ethoxybenzoyl)piperidin-1-yl)acetic acid from 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid and 2-cyclopropyl-ethanol. The title compound (74.3 mg, 0.143 mmol) was prepared following the general procedure of Example 1 from {4-[4-(2-cyclopropyl-ethoxy)-benzoyl]-piperidin-1-yl}-acetic acid and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one. MS (ESI) m/z 495.5 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.) t=1.51 min. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.07-0.05 (m, 2H), 0.23-0.36 (m, 2H), 0.58-0.75 (m, 1H), 1.47-1.65 (m, 6H), 2.01-2.18 (m, 2H), 2.37 (br. s., 2H), 2.78-2.89 (m, 3H), 3.20 (dd, J=15.41, 6.32 Hz, 2H), 3.69 (t, J=5.56 Hz, 2H), 3.98 (t, J=6.57 Hz, 2H), 4.05 (d, J=5.56 Hz, 2H), 4.20 (s, 2H), 6.90 (d, J=9.09 Hz, 2H), 7.81 (d, J=8.59 Hz, 2H), 8.08 (t, J=5.81 Hz, 1H), 12.24 (br. s., 1H). HRMS calculated for C27H35N4O5: 495.2607 (M+H). found (ESI, [M+H]+): 495.2622.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].[O:17]1[C:19]2([CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[CH2:18]1>CN(C)C=O.O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:19]2([OH:17])[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)=[CH:4][C:3]=1[CH3:10]
Reactant: C1CC2(CCS1)CO2
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1Br
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (700 mg) in N,N-dimethylformamide (7 mL) is added Cs2CO3 (1.7 g) and 1-oxa-6-thiaspiro[2.5]octane (586 mg). The mixture is stirred for 12 hour at 100° C. The mixture is diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with water and brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→60:40) to give the title compound. Yield: 986 mg; LC (method 7): tR=1.14 min; Mass spectrum (ESI+): m/z=348 [M+NH4]+.
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH2:11][C:12]2([CH2:24][O:25][C:26](=[O:34])[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH3:23])[S:14][CH2:13]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[C:28]1([NH:27][C:26]([O:25][CH2:24][C:12]2([CH2:11][O:10][C:8](=[O:9])[NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH3:23])[S:14](=[O:36])[CH2:13]2)=[O:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cccc2c1C(=O)C(COC(=O)Nc1ccccc1)(COC(=O)Nc1ccccc1)CS2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc2c1C(=O)C(COC(=O)Nc1ccccc1)(COC(=O)Nc1ccccc1)CS2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3,3-bis(phenylcarbamoyloxymethyl)-5-methylthiochroman-4-one (190 mg, 0.4 mmol) in MeOH (5 ml) was admixed with a solution of sodium metaperiodate (92 mg, 0.43 mmol) in water (1 ml), and stirred at RT for 72 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3×30 ml), the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. After column chromatography purification of the residue (silica gel, 1:1 cyclohexane/EtOAc), the desired product was obtained as a white solid (190 mg, 89% of theory, m.p. 76-82° C.).
Reaction SMILES: N.C([O:9][CH2:10][CH:11]([CH2:16][S:17]CC1C=CC=CC=1)[C:12]([CH3:15])([CH3:14])[CH3:13])C1C=CC=CC=1.[Na].[Cl-].[NH4+]>C(OCC)C.O.CO>[CH3:13][C:12]([CH3:15])([CH3:14])[CH:11]([CH2:16][SH:17])[CH2:10][OH:9]
Reactant: CC(C)(C)C(COCc1ccccc1)CSCc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)C(CO)CS
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Anhydrous liquid ammonia (400 ml) was stirred at -70°, under a current of nitrogen. 2-Benzylthiomethyl-3,3-dimethylbutyl benzyl ether (7.0 g) in dry diethyl ether (100 ml) was added and this was followed by sodium (4.0 g) in small pieces. The resulting mixture was stirred at -70° for 3 hours and then allowed to warm up to 20° C. Ammonium chloride (20 g) was added followed by dry methanol (70 ml). When all the sodium had dissolved, water was added and the mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 3,3-Dimethyl-2-mercaptomethyl-butan-1-ol was obtained as a pale yellow oil (2.8 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 98.2 %

Procedure:
In a manner similar to Example 4, Step (b), 4-(3′,4′-dichloro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (1.360 g, 0.004033 mol) was refluxed in 6 M aqueous hydrochloric acid (25 mL) to give 1.280 g of 4-(3′,4′-dichloro-biphenyl-4-yl)-4-oxo-butyric acid as a white solid; mp 154-156° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH3:14].[BH4-].[Na+]>C(O)(C)(C)C>[CH3:14][O:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1c(CO)cccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 68.4 %

Procedure:
A solution of 14.0 g of 2-methoxy-3-nitro-benzoic acid methyl ester in 245 ml of tert-butanol was treated with 6.75 g of sodium borohydride, and the heterogeneous mixture to 80° C. Methonol (62 ml) was slowly added at a dropwise rate over 2 hr. After 3 hr at 80° C., the solvent was evaporated at 40° C. under reduced pressure and the residue was treated with water, acidified with hydrochloric acid, extracted with ethyl acetate, the extracts washed with brine, dried, and evaporated to dryness. Purification of the residue by flash column chromatography on silica gel afforded 8.3 g of (2-methoxy-3-nitro-phenyl)-methanol as a brown solid. ##STR157##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][C:15]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:31])=[N:14][C:15]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:27])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1nc2cc(OCc3ccccc3)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(OCc3ccccc3)cc2n1
Temperature: 56 °C
Reaction time: 0.03 h
Yield: 72 %

Procedure:
To phosphorous oxychloride (10 mL) cooled to 5° C. was added portionwise 7-(benzyloxy)-2-(4-fluorobenzoyl)quinazolin-4(3H)-one (500 mg, 1.34 mmol) followed by the addition of DMF (4 drops). The mixture was warmed to 56° C. over 10 min and held at this temperature for 2 min, then the heating bath was removed. The mixture was concentrated, and the residue was diluted with EtOAc, then the solution was and washed with cold water, saturated sodium bicarbonate (aq), brine, and dried over sodium sulfate. The solution was concentrated to afford (7-(benzyloxy)-4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone as an off-white solid (380 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.40 (s, 2 H) 7.37-7.45 (m, 5 H) 7.52-7.55 (m, 2 H) 7.66-7.71 (m, 2 H) 8.09-8.14 (m, 2 H) 8.31 (d, J=9.04 Hz, 1 H). LC-MS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:37]=[C:36]([CH3:38])[O:35][N:34]=1.[Cl-].[Na+]>O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:32][C:33]3[CH:37]=[C:36]([CH3:38])[O:35][N:34]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: Cc1cc(CBr)no1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Product: COCCc1nc2c(N)nc3cc(OCc4cc(C)on4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol was alkylated as described in the general procedure for Examples 7-20, using 2 equivalents of cesium carbonate and 1.1 eq of 3-(bromomethyl)-5-methylisoxazole. After stirring overnight at room temperature, the reaction mixture was poured into 200 mL of water containing 20 g of sodium chloride. The resulting precipitate was filtered, dissolved in dichloromethane, and purified by flash column chromatography on silica gel, eluting with a gradient of 0-8% methanol in dichloromethane. The clean fractions were combined and concentrated. The resulting solid was slurried in cold acetonitrile, filtered, and dried under reduced pressure to yield 315 mg of 1-[4-amino-2-(2-methoxyethyl)-7-(5-methylisoxazol-3-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 169.0-170.0.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:2].[CH3:20][C:21]1([CH3:32])[O:26][C:25](=[O:27])[C:24](=[CH:28]OC)[C:23](=[O:31])[O:22]1>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:28]=[C:24]2[C:23](=[O:31])[O:22][C:21]([CH3:20])([CH3:32])[O:26][C:25]2=[O:27])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:2]
Reactant: N#Cc1ccc(N)cc1OCCCN1CCOCC1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CC1(C)OC(=O)C(=CNc2ccc(C#N)c(OCCCN3CCOCC3)c2)C(=O)O1
Yield: 74.2 %

Procedure:
4-Cyano-3-(3-morpholinopropoxy)aniline (2.5 g, 9.6 mmol) and 2,2-dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (2.4 g, 13 mmol), (Montatsh. Chem. 1967, 98, 564), in ethanol (40 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the solid was collected by filtration to give 5-((4-cyano-3-(3-morpholinopropoxy)anilino)methylene)-2,2-dimethyl-1,3-dioxane-4.6-dione (2.96 g, 74%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7]([C:14]([O:16]CC)=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 79.8 %

Procedure:
A solution of 400 mg of ethyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 86(b)] in 3.5 ml of a 1N aqueous solution of sodium hydroxide was stirred at room temperature for 1 hour. Insoluble matter was then filtered off, and 3.5 ml of 1N aqueous hydrochloric acid were added to the filtrate. The amorphous powder which precipitated was collected, to give 301 mg of the title compound, melting at 150° C. (with softening).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[N:23]([CH2:24][C:25]3[O:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:9][CH2:8]1.N>CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH:2]1([N:7]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]3[N:23]([CH2:24][C:25]4[O:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:9][CH2:8]2)[CH2:1][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccc(Cn2c(NC3CCCNCC3)nc3cccnc32)o1
Agent: N
Agent: O=C(O)C(=O)O
Solvent: CO
Product: Cc1ccc(Cn2c(NC3CCCN(C4CCCCC4)CC3)nc3cccnc32)o1
Yield: 23.9 %

Procedure:
A mixture of 6 parts of N-(hexahydro-1H-azepin-4-yl)-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]-pyridin-2-amine ethanedioate(1:2) and 64 parts of methanol, saturated with ammonia was stirred for 5 minutes at reflux temperature. After cooling, the precipitate was filtered off and the filtrate was evaporated. A mixture of the residue, 5 parts of cyclohexanone, 1 part of a solution of thiophene in methanol 4% and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the ethanedioate salt in a small amount of 2-propanone and ethanol. After cooling, the salt was filtered off and crystallized from ethanol. The product was filtered off and dried, yielding 2 parts (23.9%) of N-(1-cyclohexylhexahydro-1H-azepin-4-yl)-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5 -b]pyridin-2-amine ethanedioate(1:2), hemihydrate; mp. 136.1° C. (compound 206).
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([S:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:2]3[N:21]=[C:5]4[C:6]([S:10][C:11]5[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(=O)Nc1ccc(Sc2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(=O)Nc1ccc(Sc2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)cc1

Procedure:
4-{4-[8-(4-Acetylamino-phenylsulfanyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-[4-(2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-ylsulfanyl)-phenyl]acetamide and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.023 g, 10%). MP=226-228° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.2 (s, 1H), 9.69 (s, 1H), 8.62 (d, 1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.49 (m, 2H), 7.12 (m, 2H), 6.91 (m, 1H), 4.18 (bs, 2H), 2.78 (bs, 2H), 2.58 (m, 1H), 2.04 (s, 3H), 1.66 (m, 2H), 1.51 (m, 2H), 1.42 (s, 9H). MS=559 (MH)+.
Reaction SMILES: O[C@H:2]([C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C@@H:3]([NH:5][C:6](=[O:15])[O:7]CC1C=CC=CC=1)[CH3:4].Cl>[OH-].[K+].CO.C1COCC1>[CH3:4][C@H:3]1[C@@H:2]([C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[O:7][C:6](=[O:15])[NH:5]1
Reactant: Cc1csc([C@@H](O)[C@H](C)NC(=O)OCc2ccccc2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1csc([C@H]2OC(=O)N[C@H]2C)n1

Procedure:
A solution of benzyl [(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate (53.4 mg, 0.174 mmol) in 7.5 N aqueous KOH (1 mL), MeOH, (2 mL) and THF (4 mL) was stirred at room temperature overnight. The reaction mixture was acidified with 3N HCl and extracted with EtOAc (3×20 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the product. LCMS calc.=199.1; found=199.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 6.92 (s, 1H), 6.82 (s, 1H), 5.91 (d, J=8.2 Hz, 1H), 4.39-4.35 (m, 1H), 2.44 (s, 3H), 0.95 (d, J=6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH2:22][CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25].[H-].[Na+]>>[NH2:27][C:24]([CH3:26])([CH3:25])[CH2:23][NH:22][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: CC(C)(N)CN
Agent: [H-]
Agent: [Na+]
Product: CC(C)(N)CNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (79.2 mg, 0.2 mmol) in 1,2-diamino-2-methylpropane (Aldrich, 3 mL, 28.4 mmol) was added NaH (Aldrich, 90%, 36 mg, 1.4 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated under reflux for 1 hour. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (silica gel, 5% methanol in ethyl acetate) to afford 5-(2-amino-2-methyl-propylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a brown solid. (Yield 4.4 mg, 6.5%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([CH:12]2[CH2:17][CH2:16][C:15]([OH:26])([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[CH2:9]1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[NH2:7][CH:8]1[CH2:9][N:10]([CH:12]2[CH2:13][CH2:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)([OH:26])[CH2:16][CH2:17]2)[CH2:11]1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)OC(C)(C)C)C3)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2(O)CCC(N3CC(N)C3)CC2)cn1

Procedure:
{1-[4-Hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-carbamic acid tert-butyl ester (less polar isomer from Step A, 5.50 g, 14.6 mmol) in DCM (10 mL) and TFA (10 mL) at room temperature was stirred for 2 hours. The solvent was removed and dried under vacuum to give the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CCC.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>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[C:3]([OH:9])=[CH:4][C:5]([OH:6])=[CH:7][CH:8]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: Oc1ccc(Br)c(O)c1
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: O
Solvent: CCCCO
Product: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 4-bromoresorcinol (10.1 g) in 1-butanol (200 mL) were added 2-fluoro-5-methoxyphenylboronic acid (10.8 g), tetrakis(triphenylphosphine)palladium(0) (3.00 g) and 2.0 M aqueous sodium carbonate solution (54 mL), and the mixture was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.6 g) as a pale-yellow oil.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]2[C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][C:21]=1[F:28])=[O:9])=C.Cl>>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]2[C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][C:21]=1[F:28])=[O:9]
Reactant: C=COCCONC(=O)c1cc2ccncn2c1Nc1ccc(SC)cc1F
Agent: Cl
Product: CSc1ccc(Nc2c(C(=O)NOCCO)cc3ccncn23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 7-(2-fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide in IMS was added aqueous hydrochloric acid (4 N, 0.5 mL). The reaction was stirred at room temperature for 1 hour then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (5 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×5 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% DCM in methanol) to yield the title compound as an off-white solid (73 mg, 56%). 1H NMR (DMSO-d6): 11.31 (1H, s), 8.65 (1H, s), 7.85 (1H, s), 7.42-7.37 (2H, m), 7.15 (1H, dd, J=12.10, 2.09 Hz), 6.82-6.79 (1H, m), 6.73 (1H, s), 6.06 (1H, t, J=8.82 Hz), 4.66 (1H, s), 3.75 (2H, dd, J=5.34, 4.47 Hz), 3.46 (2H, t, J=4.82 Hz), 2.36 (3H, s). LCMS (Method A): RT=7.35 min, M+H+=377.