Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([O:30][C:31](=[O:39])[CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:29]>C(C(C)=O)C>[CH2:28]([O:30][C:31](=[O:39])[CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH2:35][CH2:34]1)[CH3:29]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: ClCCCN1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (1.5 g, 0.0055 mol, prepared similarly as described in example 1) and potassium iodide (5.4 g, 0.0327 mol) in methyl ethyl ketone (100 ml) was heated at reflux temperature for 2.5 h. Potassium carbonate (1.5 g, 0.0109 mol) and 4-piperidineacetic acid ethyl ester (1.4 g, 0.0082 mmol, described in J. Am. Chem. Soc., Vol. 75, 6249, 1953) were added and the reaction mixture was stirred at 75° C. overnight. After cooling, the reaction mixture was filtered (Hyflo) and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (150 g) using a gradient of heptane and ethyl acetate (1:1→3:7), to give 0.6 g of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)4-piperidineacetic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH:10]1[N:15]2[C:16](I)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:18]=[C:14]2[C:13](=[O:31])[NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH:10]1[N:15]2[C:16]([C:35]3[CH:36]=[CH:37][S:33][CH:34]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:18]=[C:14]2[C:13](=[O:31])[NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(I)n21
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(-c3ccsc3)n21
Yield: 54.2 %

Procedure:
To a solution of tert-butyl(2-{6-iodo-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate (100 mg, 0.177 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere, (67.9 mg, 0.531 mmol) of 3-thienylboronic acid, 7.2 mg (0.009 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium, complex with dichloromethane and 172 mg (0.531 mmol) of cesium carbonate, were subsequently added. The mixture was heated at 80° for 1 hour in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash chromatography on silica gel column (DCM/EtOAc/EtOH 6/4/0.5), and further purification by HPLC/MS preparative method 1, 50 mg (54%) of tert-butyl(2-{1-oxo-6-(thiophen-3-yl)-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate were obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:20](=[O:22])[C:19]2[CH:18]=[CH:17][C:16]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:24][CH:23]=2)[CH2:52][CH2:53]1)=[O:69]
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 62.1 %

Procedure:
DIPEA (220 mg, 0.3 mL, 0.94 mmol) was added to a stirred solution of 4-morpholin-4-yl-benzoic acid (70 mg, 0.33 mmol) in DMF (5 mL). HOBT (50 mg, 0.37 mmol) and EDCI (142 mg, 0.74 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (137 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using 60-120 silica gel and 20%-70% EtOAc in hexane as eluent) to afford 107 mg (60.8% yield) of N-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-morpholin-4-yl-benzamide, LCMS Purity: 71.5%. 1H NMR (DMSO-d6): δ 8.4 (s, 1H), 8.0 (s, 1H), 7.82 (d, 2H), 7.64 (m, 2H), 7.04 (d, 2H), 4.2 (d, 2H), 3.8-3.46 (m, 10H), 3.3 (m, 6H).
Reaction SMILES: O[C@H]1CN([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[C@H](C(OC)=O)C1.[H-].[Na+].C(Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:10]([O:9][CH2:7][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
1-Benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (6.60 g, 23.6 mmol) was dissolved in dry THF (100 mL) and cooled to 0° C. under nitrogen. Sodium hydride (1.04 g, 26.0 mmol, 60% dispersion in mineral oil) was added in portions and the mixture was stirred for 15 minutes. Tetra-n-butylammonium iodide (0.40 g, 1.0 mmol) and benzyl bromide (3.15 mL, 26.0 mmol) were added and the mixture stirred for one hour at 0° C. and then one hour at room temperature. The mixture was diluted with ethyl acetate. The organic layer was washed with water and then brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (20% to 50% ethyl acetate/hexane) to give 4.21 g (48%) of benzyl ether. LC/MS (M+H)+ m/z=370.2; 1H NMR (CDCl3) δ 7.34 (m, 10H), 5.13 (m, 2H), 4.51 (m, 3H), 4.20 (m, 1H), 3.68 (m, 2H), 3.54 and 3.78 (s, 3H), 2.45 (m, 1H), 2.11 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([CH3:24])=[CH2:23]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][C:22]([CH3:24])=[CH2:21])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=C(C)CCl
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(=O)OC)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of methyl 4-hydroxy-3-methoxybenzoate (100 g, 0.55 mol) and K2CO3 (92 g, 0.66 mol) in DMF (800 ml) was added drop wise 3-chloro-2-methyl-propene (55 g, 0.60 mol). The mixture was stirred at 60° C. overnight. TLC (EtOAc/petroleum ether=1/3) showed no starting material was present. The reaction mixture was filtered and the filtrate was added water (400 ml). The mixture was extracted with EtOAc (400 ml×3). The combined organic phase was washed with brine (400 mL), dried (Na2SO4) and concentrated to give the product (130 g, 100%) as yellow oil. The oil was used directly to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H), 7.19 (s, 1H), 6.80 (d, 1H), 5.00 (d, 2H), 4.50 (s, 2H), 3.83 (d, 6H), 1.76 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>CS(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH:12]=[CH:13][CH:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: O=C(OCc1ccccc1)N1C=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1C=CC(c2cccnc2)CC1
Temperature: 100 °C
Yield: 6.1 %

Procedure:
A solution of 1-benzyloxycarbonyl-1,2,3,4-tetrahydropyridine (8.69 g) in dimethylsulfoxide (50 mL) was treated with 3-bromopyridine (6.32 g), triethylamine (5.6 mL) and palladium(II) acetate (0.499 g). The reaction mixture was heated to 100° C. for 16 hours, cooled to the room temperature, diluted with water, and extracted with ether. The organic layer was washed with water; the combined organic layers were dried and evaporated to produce the crude product. This material was distilled under reduced pressure and the volatile material distilling at 120° C. (66.7 Pa) was removed. The remaining residue was chromatographed, with hexane:ethyl acetate (1:1) as eluent, to afford the coupled product (0.714 g); NMR (CDCl3): 1.7 (broad s, 2), 2.16 (broad m, 1), 3.5-3.7 (m, 2), 4.9-5.1 (d of m, 2), 5.2 (m, 2), 7.0-7.5 (m, 8), 8.5 (m, 2); MS: m/z=295(M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]([CH2:40]Br)[CH:31]=1.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:14]([CH2:40][C:32]2[CH:31]=[N:30][C:39]3[C:34]([CH:33]=2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:13]([CH:15]([CH3:17])[CH3:16])=[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: BrCc1cnc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1c(Sc2cc(Cl)cc(Cl)c2)nc(COCc2ccccc2)n1Cc1cnc2ccccc2c1
Reaction time: 8 h
Yield: 2.6 %

Procedure:
In tetrahydrofuran (10 ml) was dissolved 245 mg (2 mmol) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazole (101a). To this solution, a methylene chloride solution of quinolin-3-ylmethylbromide was added at room temperature with stirring, followed by addition of 200 mg (5 mmol) of sodium hydroxide and 39 mg (0.12 mmol) of n-tetrabutylammonium bromide. After stirring for 2 hours, the mixture was left overnight and worked up. The reaction mixture was distilled off under reduced pressure. The residue was extracted with methylene chloride, and the extract was washed with water and dried. The solvent was distilled off, and the residual oil was purified by silica gel column chromatography (methylene chloride-ethyl acetate). As the first eluate, 26 g (2.6%) of 2-benzyloxymethyl-4-(3,5-dichlorophenylthio)-5-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (100a) was obtained. From the subsequent eluate, 730 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (100b) suited to the next step of the reaction was obtained (yield 73%).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[C:31]1([S:37]([C:40]2[N:44]([CH3:45])[CH:43]=[N:42][C:41]=2[CH:46]=O)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:46][C:41]2[N:42]=[CH:43][N:44]([CH3:45])[C:40]=2[S:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)(=[O:38])=[O:39])=[C:20]1[CH3:29]
Reactant: Cn1cnc(C=O)c1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2ncn(C)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of triethylsilane (0.17 g), trifluoroacetic acid (0.10 g) and 1,2-dichloroethane (5.0 mL) at −5° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.022 g), 5-benzenesulfonyl-1-methyl-1H-imidazole-4-carbaldehyde (0.030 g) and 1,2-dichloroethane (3.0 mL), and the resulting mixture was stirred at room temperature overnight and then at 45° C. for 2 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried using a phase separation cartridge. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 2:5 by volume) to afford the title compound as a yellow oil (0.027 g).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:26][C:27](C)([O-:29])C.[K+].BrCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][OH:29])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)C(C)C)cnc2c(O)cccc12
Reactant: CC(C)(C)[O-]
Agent: OCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Nc1c(C(=O)C(C)C)cnc2c(OCCO)cccc12
Reaction time: 48 h

Procedure:
To a solution of 3-isobutyryl-4-(4-fluoro-2-methyl-phenylamino)-8-hydroxyquinoline (5 g, 14.8 mmol) in dry tetrahydrofuran (250 ml) was added potassium t-butoxide (2.49 g, 22.2 mmol), followed by 2-bromoethanol (3.69 g, 29.6 mmol). The stirred mixture was heated under reflux for 16 hours, then a further quantity of potassium t-butoxide (2.49 g, 22.2 mmol) and 2-bromoethanol (3.69 g, 29.6 mmol) added, and heating continued for 2 days. The solvent was evaporated, and the residue treated with aqueous sodium bicarbonate and extracted into dichloromethane. The extracts were dried and evaporated to an oil, which was purified by flash chromatography (silica gel, dichloromethane/methanol) and recrystallisation from ether to yield 3-isobutyryl-4-(4-fluoro-2-methylphenylamino-8-(2-hydroxyethoxy) (1.97 g), m.p. 183°-185°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[H-].[Na+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][O:8][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 88 %

Procedure:
3-Nitrobenzyl alcohol (5 g, 32.6 mM) was dissolved in DMF (200 ml) and cooled to 5°. Sodium hydride (60% in oil, 1.57 g, 39.2 mM) was added to the stirred solution in portions over 30 minutes, and the mixture cooled to -20°. t-Butyl bromoacetate (5.27 ml, 32.6 mM) was run in dropwise, and the mixture allowed to warm to ambient temperature overnight. Solvent was evaporated, the residue treated with water, and organics extracted into ethyl acetate. The combined organic layers were washed with water and brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a gradient from hexane/dichloromethane (95:5) to dichloromethane, to give t-butyl 3-nitrobenzyloxyacetate (7.71 g, 88%).
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)=[CH:24][CH:23]=1.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[CH:24][CH:23]=1
Reactant: O
Reactant: c1cc(-c2ccncc2)c2cc[nH]c2c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccncc2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 24.70 g, 69.50 mmol) was added portion-wise over 10 minutes to a suspension of 4-pyridin-4-yl-1H-indole (4.50 g, 23.17 mmol) in 2-methyl-2-propanol (135 mL), ethanol (90 mL) and acetic acid (45 mL). The mixture was stirred at room temperature for one hour and then acetic acid (180 mL) was added. After stirring for an additional hour, water (1 mL) and zinc dust (15.06 g, 232 mmol) were added and stirring was continued for another hour. Residual zinc dust was removed by filtration and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (500 mL) overnight. The solid that formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum dry to give 5.85 g (99%) of 4-pyridin-4-yl-1,3-dihydroindol-2-one as a light yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH2:27][CH3:28])[N:25]=[CH:24][CH:23]=2)=[C:12]([F:29])[C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([N:26]1[C:22]([C@H:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:8])=[O:9])=[C:11]([F:30])[C:12]=2[F:29])=[CH:23][CH:24]=[N:25]1)[CH3:28]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 50.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (80.0 mg, 0.133 mmol) prepared in Example 38a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (30.0 mg, 50%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH:15](C(O)=O)[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]>O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C(=O)O)C(=O)O)cc2s1
Solvent: O
Product: CCOC(=O)c1cc2ccc(CC(=O)O)cc2s1
Temperature: 200 °C

Procedure:
[2-(ethoxycarbonyl)-1-benzothien-6-yl]malonic acid (0.60 g, 1.95 mmol) was suspended in H2O (4 mL) before heating at 200° C. in a microwave reactor for 60 seconds. The suspension was diluted with H2O (50 mL) and the products extracted into EtOAc (3×75 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the product (white solid). 1H NMR (DMSO-d6) δ 12.42 (br s, 1H), 8.15 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.35 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.71 (s, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([C:34]2[CH:35]=[CH:36][C:37]3C=CS[C:38]=3[CH:42]=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:43][O:44]C1C=C(C=CC=1)C(O)=O>>[CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32](=[O:33])[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([O:44][CH3:43])[CH:42]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: COc1cccc(C(=O)/N=c2\[nH]c3cnc(OCCN4CCCCC4)cc3n2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c1

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-methoxybenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-N(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-methoxy-benzamide (42.5% yield). MS m/z=563.4 [M+H], calc 562.71 for C31H42N6O4.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O>N.CO>[CH2:7]1[C:8]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=3)=[CH:12][C:9]=2[CH2:10][CH2:11][NH:5][CH2:6]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)nc1
Agent: N
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Dissolve 6-[3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy]nicotinamide (0.306 g, 0.806 mmol) in 7.0 M NH3 in methanol (10 mL). Seal the round bottom and allow to sit without stirring. After three hours, concentrate to give the title compound (0.22 g, 100%): MS ES+ 284.1 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.010% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.2 min, 93% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:22][NH2:23]>>[CH:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([NH:23][CH3:22])[CH:3]=2)=[O:9])=[CH:11]1)([CH3:21])[CH3:20]
Reactant: CN
Reactant: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Product: CNc1cncc(C(=O)c2cn(C(C)C)c3ncncc23)c1
Yield: 13 %

Procedure:
The title compound was prepared according to the method described for Preparation 31 using (5-bromopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 94) and methylamine (20 mL) in 13% yield, 78 mg.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:4](=[O:29])[C:3]=1[C:30](OCC)=[O:31].[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[N:5]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:4](=[O:29])[C:3]=1[C:30]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:31]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-1-[(4-nitrophenyl)methyl]-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 2 and was obtained as a light yellow solid: 1H NMR (d6-DMSO) δ 10.69 (1H, br), 8.21 (1H, s), 8.10 (2H, d, J=8.7 Hz), 7.35 (2H, d, J=8.7 Hz), 7.31 (1H, s), 7.13 (3H, m), 7.07 (2H, m), 5.49 (2H, br s), 3.91 (2H, s), 3.41 (4H, m), 3.27 (3H, s); HRMS calcd for C26H24N4O6+H+: 489.1774. Found: 489.1778.