Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]1([C:24]#[C:25][C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C:5]3=[O:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1CC2(CCCOC2)Oc2ccc(C#Cc3ccccc3)cc21
Temperature: 80 °C
Yield: 90.5 %

Procedure:
An oven dried 3-necked round bottom flask equipped with condenser was charged with 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (223 mg, 0.75 mmol), TEA (3 mL) and DEA (0.8 mL) under N2 atmosphere. To this solution was added CuI (5.7 mg, 0.03 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol) and PPh3 (16 mg, 0.06 mmol). The system was degas once again, then phenylacetylene (0.41 mL, 3.75 mmol) was added and the mixture was heated to 80° C. (oil bath) with stirring. The reaction was evaporated after 12 h and the residue was purified by flash chromatography (12 g silica gel, eluted with EA in hexane in a gradient of 0-25%, v/v) to afford 6-(phenylethynyl)-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (216 mg, yield: 90%). MS ESI+ve m/z 319 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.[CH2:22]=[C:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:15]
Reactant: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 96 %

Procedure:
Into a 200-ml four-necked flask, were charged 22.2 g of 2-methyl-4-t-butyl-5-hydroxyphenylacetic acid, 100 ml of toluene and 1 ml of concentrated sulfuric acid, and isobutene was blown into the mixture at 50° to 60° C. for a period of 3 hours. After completion of the reaction, the reaction mixture was freed from the catalyst (sulfuric acid) by washing with water and freed from the solvent under reduced pressure to obtain 26.7 g (96% yield) of yellow t-butyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate, which was recrystallized from n-hexane to obtain white crystals melting at 105.0° to 106.0° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=O)[CH2:16][CH:15]1[C:27](=O)[NH2:28])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[NH2:28][CH2:27][CH:15]1[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:14]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(C(N)=O)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccccc2)C(CN)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
1M Lithium aluminium hydride in tetrahydrofuran (112 ml, 0.112 mol) was added dropwise to a stirred solution of (RS)-1-benzyl-4-(tert-butyloxycarbonyl)-2-carbamoylpiperazine (D1) (15 g, 0.047 mol) in anhydrous tetrahydrofuran (300 ml) at room temperature under argon. On complete addition the reaction mixture was stirred at room temperature for 0.5 h, then at reflux for a further 1.5 h. The mixture was cooled to room temperature and treated sequentially with water (19.5 ml), 2N sodium hydroxide (22.5 ml) and water (19.5 ml) dropwise. Sodium sulphate was added and the resultant stirred for 0.3 h, filtered and the filtrate evaporated in vacuo to give the title compound (10.3 g, 100%).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[S:7][CH:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[S:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C=C(c2cccs2)SC1c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Oc1cc(-c2cccs2)sc1-c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of crude (III) in benzene (35 ml) at room temperature was added 2,3-dichloro-5,6-dicyano-1,4-benzoguinone (1.0 g, 0.0048 mmol) all at once, and the mixture was allowed to stir overnight at ambient temperatures. The mixture was then filtered, the volatiles removed (hi-vac), and the residue chromatographed on silica gel (methylene chloride/hexane) to yield 0.35 g of the title compound. M.S. (M+)=300; NMR: consistent. ##STR25##
Reaction SMILES: O=[C:2]([CH3:6])[C:3](=[S:5])[NH2:4].[Br:7][C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12][C:11]2=[NH:23]>C(#N)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12][C:11]12[NH:4][C:3](=[S:5])[C:2]([CH3:6])=[N:23]1
Reactant: N=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Reactant: CC(=O)C(N)=S
Solvent: CC#N
Product: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)NC1=S

Procedure:
2-Oxopropanethioamide (Intermediate 2, 289 mg, 2.80 mmol) and 6-bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-imine (Example 45 Step 2, 331.4 mg, 1.12 mmol) were dissolved in acetonitrile (3 mL) and heated using MW for 20 min to 120° C. The solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in heptane but co-eluted with byproducts. The not completely pure product was used as a mixture in the next step.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=[S:3].[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37](=O)[CH2:38]Br>CCO>[Cl:33][C:34]1[CH:35]=[C:36]([C:37]2[N:1]=[C:2]([N:4]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=3)[CH2:5][CH2:6][C:7]3[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:18])([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=3)[S:3][CH:38]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Reactant: O=C(CBr)c1cccc(Cl)c1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc(-c3cccc(Cl)c3)cs2)cc1
Yield: 60.6 %

Procedure:
A solution of ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (162 mg; 0.35 mmol) and 3-chlorophenacyl bromide (82 mg; 0.35 mmol) in EtOH (4 ml) was heated to reflux for 12 hr. Upon cooling the mixture was concentrated and the residue purified by flash chromatography using ethyl acetate-hexane mixtures (5–50% gradient) to afford ethyl 2-[4-(2-{[4-(3-chlorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (128 mg; 61% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C([N:15](CC)CC)C.[C:20]1([S:26](Cl)=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1.[CH:23]1[CH:24]=[CH:25][C:20]([S:26]([NH2:15])=[O:27])=[CH:21][CH:22]=1
Reactant: CCN(CC)CC
Reactant: O=S(Cl)c1ccccc1
Agent: c1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Product: NS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.90 g of 1-(2-pyridyl)piperazine in 150 ml of dichloromethane containing 4.59 ml of triethylamine is added dropwise with stirring under nitrogen a solution of 4.82 g of benzenesulfinyl chloride in 50 ml of dichloromethane. The reaction mixture is stirred for 3 hours at room temperature, diluted with 100 ml of dichloromethane, and washed with 150 ml water and 100 ml 5% potassium carbonate. The organic layer is dried over sodium sulfate and evaporated in vacuo to give a yellow crystalline solid. Recrystallization from ethanol affords 4.14 g of 1-(2-pyridyl)piperazine-4-benzenesulfinamide as a colorless crystalline solid, mp 83°-86° (soften 81°). A second crop (1.24 g) is obtained by concentration of the mother liquors, total yield: 5.38 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[C:40]([CH3:41])=[C:39]([C:42]#[CH:43])[N:38]=[C:37]1[CH3:44]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:43]#[C:42][C:39]2[N:38]=[C:37]([CH3:44])[N:36]([C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])[C:40]=2[CH3:41])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1nc(C)n(-c2ccc(F)cc2F)c1C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-4-iodo-pyridine (0.21 g, 1 mmol) was dissolved in 10 mL of dry THF and 0.29 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (5 mg, 0.03 eq) and bis(triphenylphosphine)palladium(II)chloride (24 mg, 0.05 eq) were added, and the reaction mixture was stirred at room temperature for 10 min. 1-(2,4-Difluoro-phenyl)-4-ethynyl-2,5-dimethyl-1H-imidazole (0.16 g, 1 mmol) and Copper(I)iodide (3 mg, 0.02 eq) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 10 mL water and extracted three times with ethyl acetate (10 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (n-heptane/ethyl acetate 1:1) and recrystallized from diethyl ether. The desired product was obtained as a white solid (0.1 g, 42%), MS: m/e=344.0 (M+).
Reaction SMILES: Br[C:2]1[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:4][N:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[C:6]=1[NH2:7].[CH3:21]B1OBOBO1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:17]([C:3]1[C:2]([CH3:21])=[C:6]([NH2:7])[N:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:4]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CB1OBOBO1
Reactant: COc1cccc(C)c1-n1nc(C(C)(C)C)c(Br)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C)c1-n1nc(C(C)(C)C)c(C)c1N
Temperature: 155 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of 4-bromo-3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-amine (2.6 g, 7.68 mmol) in DMF (15 mL) was added methylboroxine (6.66 mL, 46.08 mmol), [1,1′-bis(diphenylphosphino)-butane]palladium (II) dichloride (481.97 mg, 0.80 mmol), and potassium carbonate (3.3 g, 23.04 mmol). The reaction mixture was stirred for 18 h at 155° C. The reaction was diluted with water (100 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 90% hexane/EtOAc, to afford the product (1.7 g, 77%) as a pure white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.24 (s, 9H), 1.96 (s, 3H), 1.99 (s, 3H), 3.71 (s, 3H), 4.25 (s, 2H), 6.85 (d, 1H), 6.94 (d, 1H), 7.23-7.29 (m, 1H). ES-MS m/z 274.2 (MH+); HPLC RT (min.) 1.78.
Reaction SMILES: Cl.Cl.[CH2:3]1[CH:7]2[CH2:8][NH:9][CH2:10][CH:6]2[CH2:5][N:4]1[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[S:23][C:24]4[C:25]([N:30]=3)=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][C:15]=2[O:14][CH:13]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[O:48]1[CH2:52][CH2:51][CH:50]([C:53](O)=[O:54])[CH2:49]1>CN(C=O)C>[O:48]1[CH2:52][CH2:51][CH:50]([C:53]([N:9]2[CH2:10][CH:6]3[CH:7]([CH2:3][N:4]([CH2:11][C:12]4[C:16]5[CH:17]=[CH:18][C:19]([O:21][C:22]6[S:23][C:24]7[C:25]([N:30]=6)=[N:26][CH:27]=[CH:28][CH:29]=7)=[CH:20][C:15]=5[O:14][CH:13]=4)[CH2:5]3)[CH2:8]2)=[O:54])[CH2:49]1
Reactant: O=C(O)C1CCOC1
Reactant: c1cnc2nc(Oc3ccc4c(CN5CC6CNCC6C5)coc4c3)sc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(C1CCOC1)N1CC2CN(Cc3coc4cc(Oc5nc6ncccc6s5)ccc34)CC2C1
Yield: 44.5 %

Procedure:
A solution of 2-[3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-benzofuran-6-yloxy]-thiazolo[4,5-b]pyridine dihydrochloride (50 mg, 0.11 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbdiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (73 mg, 0.54 mmol), N-methylmorpholine (33 mg, 0.32 mmol), and tetrahydro-furan-3-carboxylic acid (13 mg, 0.11 mmol) in DMF (0.4 mL) was stirred at rt. Upon reaction completion, the mixture was concentrated, re-dissolved in DMF and purified using reverse phase HPLC to provide the title compound (24 mg, 45%). MS (ESI): mass calculated for C26H26N4O4S, 490.17; m/z found, 491.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=8.0, 1.5, 1H), 7.70 (dd, J=8.5, 2.9, 1H), 7.59 (dd, J=5.6, 3.4, 2H), 7.27-7.18 (m, 2H), 4.08-3.95 (m, 1H), 3.94-3.60 (m, 7H), 3.53-3.42 (m, 1H), 3.40-3.26 (m, 1H), 3.17-3.06 (m, 1H), 2.99-2.77 (m, 2H), 2.71-2.46 (m, 4H), 2.29-2.14 (m, 1H), 2.14-1.99 (m, 1H).
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][N:10]([C@H](C3C=CC=CC=3)C)[C@@H:9]2[C:21]([NH2:23])=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O>CO.[Pd]>[N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][NH:10][C@@H:9]2[C:21]([NH2:23])=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](CN2CCOCC2)[C@H]1C(N)=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NC(=O)[C@H]1NCC[C@H]1CN1CCOCC1

Procedure:
A mixture of (2S,3S)-3-morpholin-4-ylmethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Stage 37.2) (1.046 mmol) and 10% Pd on charcoal, wet with 50% H2O (Aldrich 330108) (0.105 mmol) in MeOH (5 mL) was hydrogenated for 6.5 h at rt. The reaction mixture was then filtered through a Fluoropore Membrane Filter (0.2 μm FG) and evaporated. The residue was dissolved in CH2Cl2 and evaporated to dryness to afford the title compound as colorless oil. ESI-MS: [M+H]+ 214; TLC: Rf=0.14 (200:20:1 CH2Cl2/MeOH/conc. NH4OH).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:21][C:9]=2[C:8]1=[O:28]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:7]([CH3:6])[C:8](=[O:28])[C:9]2[CH:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][C:10]1=2)=[O:4]
Reactant: CN1C(=O)c2cnc(-c3ccccc3)nc2Nc2ccccc21
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CN1C(=O)c2cnc(-c3ccccc3)nc2N(C(=O)CCl)c2ccccc21

Procedure:
1.6 ml (20 mmols) of chloroacetyl chloride are added dropwise at room temperature to a suspension of 3 g (10 mmols) of 6-methyl-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 30 ml of absolute toluene, and the mixture is then heated under reflux for 3 hours. After cooling, the precipitate which has been deposited is filtered off, and the filtrate is evaporated. The residue is stirred thoroughly with diethyl ether; yield: 3.3 g (86%) with m.p. 189° to 190° C. (from 2-butanone).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN1CCOCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and morpholine following the procedure outlined in Example 15. 1H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 8.83 (s, 1H), 8.77 (s, 2H), 7.88 (d, 1H), 7.04 (d, 1H), 4.79 (s, 1H), 3.97 (t, 2H), 3.79 (s, 3H), 3.52 (app t, 4H), 2.29 (br, 4H), 2.22 (t, 2H), 1.74 (m, 2H), 1.39 (m, 4H), 1.30 (m, 2H); MS (ESI): 521.3.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:25]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26]1>>[O:25]1[CH2:29][CH2:28][CH:27]([CH2:30][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]4[CH2:24][C:23]5[CH:22]=[CH:21][N:20]=[CH:19][C:18]=5[CH2:17]4)=[O:15])=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)[CH2:26]1
Reactant: O=CC1CCOC1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Product: O=C(Nc1ccc(C2CCN(CC3CCOC3)CC2)cc1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 926, substituting N-(4-(piperidin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide and tetrahydrofuran-3-carbaldehyde for isobutraldehyde. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.33 (s, 1H), 7.44 (m, 3H), 7.13 (m, 2H), 4.78 (m, 4H), 3.71 (m, 2H), 3.61 (q, J=7.6 Hz, 1H), 3.36 (m, 2H), 2.96 (m, 2H), 2.40 (m, 1H), 2.27 (m, 2H), 96 (m, 3H), 1.72 (m, 2H), 1.66-1.46 (m, 3H); MS (ESI(+)) m/e 407 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N+:7]([O-])=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:12].P(Cl)(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:15])[N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1sc2c[n+]([O-])ccc2c1Br
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Cl)nccc2c1Br
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3-Bromo-2-methylthieno[2,3-c]pyridine-N-Oxide (0.500 g, 2.05 mmol) was dissolved in chloroform (10 mL) and treated with phosphorous oxychloride (0.955 ml, 10.2 mmol). The reaction was heated to 70° C. while stirring. After 3 hours, the volatiles were removed in vacuo and the residual phosphorous oxychloride was azeotroped with toluene. The resulting residue was taken up in DCM and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20-60% EtOAc in hexanes to give 3-bromo-7-chloro-2-methylthieno[2,3-c]pyridine as a yellow solid. MS (M+H)+ 263.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.O>CN(C)C=O>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(Nc1ccc(OCCN2CCCC2)cc1)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C1CCCCC1)N(Cc1cccc(F)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of cyclohexanecarboxylic acid (4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-amide (0.250 g, 0.79 mmol) in 5 mL N,N-dimethylformamide at 0° C. was added sodium hydride (0.041 g of a 60% dispersion in mineral oil, 1.03 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and 3-fluorobenzyl bromide (0.117 mL, 0.95 mmol) was added. The reaction mixture was stirred at room temperature for 24 hr. and water was added. The aqueous solution was washed with ethyl acetate (2×). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography (methylene chloride to 5% methanol/methylene chloride) afforded the title compound. MS 425.2 (M+1)+
Reaction SMILES: ClC1C=CC(S(Cl)(=O)=O)=CC=1C(F)(F)F.COC(C1C(N)=CC=CN=1)=O.ClC1C=CC(S(NC2C(C#N)=NC=C(C)C=2)(=O)=O)=CC=1C(F)(F)F.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([NH:61][C:62]2[C:63]([C:69]([OH:71])=[O:70])=[N:64][CH:65]=[C:66](C)[CH:67]=2)(=[O:60])=[O:59])=[CH:54][C:53]=1[C:72]([F:75])([F:74])[F:73].[Li+].[OH-]>N1C=CC=CC=1.C1COCC1>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([NH:61][C:62]2[C:63]([C:69]([OH:71])=[O:70])=[N:64][CH:65]=[CH:66][CH:67]=2)(=[O:59])=[O:60])=[CH:54][C:53]=1[C:72]([F:74])([F:73])[F:75]
Reactant: Cc1cnc(C(=O)O)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: COC(=O)c1ncccc1N
Agent: Cc1cnc(C#N)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Prepared from 0.60 g (2.17 mmol) of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride and 0.30 g (1.97 mmol) of 3-amino-pyridine-2-carboxylic acid methyl ester in 3 mL pyridine using the procedure used to prepare 4-chloro-N-(2-cyano-5-methylpyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide in the preparation of Intermediate 6. The solvent was switched to THF, followed by the addition of 1 M aqueous LiOH and the mixture stirred for 1 hour. The pH of the mixture was adjusted to neutral and the product was extracted with ethyl acetate. LC-MSD, m/z for C13H8ClF3N2O4S [M+H]+=380.9, 383.0; HPLC retention time: 1.8 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[Br:1][C:2]1[C:3]([NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[N:6][CH:7]=1
Reactant: Nc1c(Br)cnc(Cl)c1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(c2ncc(Br)c(N)c2[N+](=O)[O-])CC1
Temperature: 130 °C
Yield: 64.9 %

Procedure:
A 20 mL microwave reaction tube was charged with 5-bromo-2-chloro-3-nitropyridin-4-amine (1.0 g, 3.9 mmol), N-methylpiperazine (0.78 g, 7.8 mmol) and anhydrous ethanol (15 mL). The resulting solution was heated at 130° C. for 1 h in a Biotage microwave reactor. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 10% MeOH in CH2Cl2, to afford 0.80 g (64%) of the product as a white solid. MS m/z: 316 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:16][CH:17]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ethyl acetate (50 mL) solution of tert-butyl [4-(hydroxymethyl)benzyl]carbamate (3.0 g), manganese dioxide (20.0 g) was added. The reaction solution was stirred at room temperature for one hour. The reaction solution was filtered through celite (trade name). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=8:2→7:3) to obtain the title compound having the following physical properties (2.3 g).