Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2=[N:6][C:7]([S:10][CH3:11])=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:13].[CH2:14](Cl)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>CC#N>[CH3:1][C:2]1[N:12]=[C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[C:7]([S:10][CH3:11])=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:13]
Reactant: CSc1ccc2c(C)c(C)[nH]c2n1
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Product: CSc1ccc2c(C)c(C)nc-2n1CC(=O)c1ccccc1
Yield: 41.2 %

Procedure:
A mixture of 2,3-dimethyl-6-methylthiopyrrolo[2,3-b]pyridine (100 mg, 0.5 mmol) and phenacyl chloride (804 mg, 5 mmol) in 3 ml CH3CN was refluxed for 72 h. The solvent was evaporated and the residue chromatographed (silica, CH2Cl2 /MeOH;59/5). Pure fractions were pooled, evaporated, and taken up in 100 ml CH2Cl2. The organic layer was washed with 25 ml 2M HCl, dried over MgSO4, and evaporated leaving 64 mg (35%) pure product as the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([C:9]#[N:10])C(O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:9]#[N:10]
Reactant: N#CC(Cc1ccccc1Cl)C(=O)O
Solvent: CN(C)C=O
Product: N#CC=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
Into a 1-liter, three-necked flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet is placed 138.5 g (0.66 mole) of 2-(o-chlorobenzyl)cyanoacetic acid and 220 ml of dry N,N-dimethylformamide. The mixture is stirred and slowly heated under nitrogen to reflux and held there for 6 hours. The resulting yellow mixture is allowed to cool under nitrogen overnight at room temperature. A precipitate (approximately 0.5 g) that forms is filtered off and the filtrate is poured into 1 liter of water. The organic layer is taken up in three 330-ml portions of ethyl ether/hexane (1:1 v/v), and the solutions are combined and washed once with 150 ml of water. The ethyl ether/hexane solution is dried over anhydrous magnesium sulfate, filtered and evaporated on a rotary evaporator. The residual liquid is distilled under reduced pressure through an insulated 12-inch Vigreux column with the product being collected at 82° C.-85° C./0.3 mm Hg as a colorless liquid identified by infrared, 'H and 13C nuclear magnetic resonance. The yield is 94.7 percent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.N>C(O)C.[Ni]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH2:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccc2cc[nH]c2c1
Yield: 97 %

Procedure:
A mixture of 1H-indole-6-carbonitrile (prepared by the literature procedure: Batcho, A. D.; Leimgruber, W. Organic Syntheses 1985, 63, 214-225; 1.50 g, 10.6 mmol), Raney an nickel and concentrated aqueous ammonia (4 mL) in ethanol (50 mL) was hydrogenated at atmospheric pressure overnight. The mixture was filtered through Celite® and the filter cake was washed thoroughly with ethanol, while taking care not to allow the catalyst to become dry. The combined filtrates were concentrated to give 1H-indole-6-methanamine (1.50 g, 97% yield).
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[CH3:20][O:19][C:12]1[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: COc1cc2c(cc1S(C)(=O)=O)CCN(C(C)=O)CC2
Agent: Cl
Product: COc1cc2c(cc1S(C)(=O)=O)CCNCC2

Procedure:
Alternatively, 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with 3N hydrochloric acid to give 8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. Refluxing this compound with 48% hydrobromic acid gives 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>CCCCCC>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: CC(C)=CC(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Yield: 81.3 %

Procedure:
A mixture of 53 g of 1,1,1-trichloro-2-hydroxy-4-methyl-3-pentene, 28 g of acetic anhydride, and 1.23 ml of pyridine was heated at 95°-100° for one hour. The reaction mixture was then dissolved in 500 ml of hexane. This solution was washed thrice with 150 ml portions of water and dried over anhydrous magnesium sulfate. After stripping the hexane, the residue was distilled under reduced pressure, yielding 52 g of 1,1,1-trichloro-2-acetoxy-4-methyl-3-pentene; bp 85°-90°/4-4.3 mm. An nmr spectrum of this product was consistent with the assigned structure.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([Cl:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].[NH:27]([C:29]1[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1)[NH2:28].S(=O)(=O)(O)N.CC(O)=O>CCO>[Cl:19][C:13]1[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=[C:11]([N:6]2[CH:5]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:4]3[C:1]([CH3:2])=[N:28][N:27]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:8]=3[C:7]2=[O:10])[CH:12]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: COc1ncccc1NN
Agent: NS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
To a stirred solution of 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-chloro-1-methylpyridin-2(1H)-one (Step 57.1) (250 mg, 0.636 mmol) and TEA (0.115 ml, 0.827 mmol) in EtOH (2 ml) was added 3-hydrazinyl-2-methoxypyridine (Step 71.1) (115 mg, 0.827 mmol) and the reaction mixture was stirred 1 hr at 90° C. Sulfamic acid (93 mg, 0.954 mmol) and AcOH (2 ml) was added and the reaction mixture was stirred 3 hr at 115° C. The reaction mixture was concentrated under reduced pressure, quenched with a saturated aq. NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAC. The residue was further purified by SFC (column Propyl-pyridyl-urea, gradient 13-18% in 6 min_total 11 min) and triturated in hexane/Et2O (2:1) to afford the title product (13 mg, 0.026 mmol, 4% yield) as white solid. tR: 4.55 min (HPLC 1); tR: 1.04 min (LC-MS 2); ESI-MS: 496 [M+H]+ (LC-MS 2); Rf=0.41 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.02 (s, 3H) 3.43 (s, 3H) 3.89 (s, 3H) 6.24 (s, 1H) 7.15-7.22 (m, 1H) 7.32-7.37 (m, 2H) 7.40-7.45 (m, 2H) 7.88-7.96 (m, 3H) 8.28-8.33 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[N:26][OH:27])=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH2:10]([O:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][C:25]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:27][N:26]=2)=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)nc2)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
To a solution of 3-ethynyl-pyridin-2-ylamine (400 mg, 3.39 mmol) described in Manufacturing Example 1-2-3 in anhydrous tetrahydrofuran (20 mL) was added (2-benzyloxy-pyridin-5-yl)-acetohydroximoyl chloride (2.50 g, 9.03 mmol) under nitrogen atmosphere at room temperature. Triethylamine (1.89 mL, 13.6 mmol) was then added dropwise thereto, and stirred for 1.5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3 then 1:2) to obtain the title compound (315 mg, 26%).
Reaction SMILES: Cl.C([O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:21][CH:22]3[CH2:27][CH2:26][CH:25]([CH:28]([NH2:37])[C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)=[C:17]([Cl:20])[CH:18]=2)[CH:13]=[CH:12][N:11]=1)C1C=CC=CC=1.C(#N)C.O>C(O)(C)C>[NH2:37][CH:28]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:25]1[CH2:24][CH2:23][CH:22]([O:21][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][C:17]=2[Cl:20])[C:10](=[O:9])[NH:11][CH:12]=[CH:13]3)[CH2:27][CH2:26]1
Reactant: COc1ccc(C(N)C2CCC(Oc3cc4ccnc(OCc5ccccc5)c4cc3Cl)CC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C(N)C2CCC(Oc3cc4cc[nH]c(=O)c4cc3Cl)CC2)cc1
Reaction time: 8 h

Procedure:
A 2M aqueous solution of hydrochloric acid (3.8 mL) was added to a solution of C-[4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-C-(4-methoxy-phenyl)-methylamine (36, 40 mg, 0.08 mmol) in isopropanol (4 mL). The reaction mixture was stirred overnight. Isopropanol was removed under reduced pressure and the remaining aqueous solution freeze dried to give crude product as an amorphous powder. This was treated twice with acetonitrile/water and freeze dried to give the desired product as a colourless hydrochloride salt. The relative stereochemistry was not assigned.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[F:35][CH:36]([F:39])[CH2:37]O>C(#N)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[C:7]=2[CH2:6][O:5][CH2:37][CH:36]([F:39])[F:35])=[O:24])[CH2:28][CH2:27]1
Reactant: OCC(F)F
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCC(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (204 mg, 0.5 mmol) obtained in Example 126a), potassium carbonate (69 mg, 0.5 mmol, 1.0 eq.) and 2,2-difluoroethanol (0.5 ml) were suspended in acetonitrile (3 ml), and the suspension was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (160 mg, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[C:9](=[O:14])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15])#[CH:2].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[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>[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]#[C:1][C:3]2[CH:12]=[C:11]([OH:13])[C:10]3[C:9](=[O:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=3[CH:4]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CCC2=O
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CCC3=O)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 67, 1.58 g, 7.4 mmol), 4-iodo phenyl acetic acid methyl ester (2.2 g, 7.94 mmol), triethyl amine (12 mL), copper(I)iodide (0.38 g, 1.99 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.2 g, 1.71 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 16% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (2.1 g, 78%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:14]3[C:22](=[CH:23][C:24]=2[CH:25]([CH3:27])[CH3:26])[O:21][C:17]2([CH2:20][CH2:19][CH2:18]2)[CH2:16][C:15]3=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:43])CC)C.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([F:43])[C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:14]3[C:22](=[CH:23][C:24]=2[CH:25]([CH3:26])[CH3:27])[O:21][C:17]2([CH2:18][CH2:19][CH2:20]2)[CH2:16][C:15]3=[O:28])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 110 mg (0.23 mmol) of 6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A) are dissolved in 2.3 ml of toluene, 36 μl (0.27 mmol) of diethylaminosulfur trifluoride are added slowly at −78° C. and the mixture is stirred at −78° C. for 1 h. The temperature is then slowly increased to −60° C. After 2 h, water is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 12:1). This gives 92 mg (83% of theory) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](Cl)=[O:12])[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:20][CH:19]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:30])[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)c1ccc(CCN)cc1
Reactant: O=C(Cl)c1cccc2cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(CCNC(=O)c2cccc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.0 g Quinoline-8-carbonyl chloride (m.p. 156°-160° C.) are added to 6.0 g ethyl 2-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride in 50 ml methylene chloride and a solution of 7 ml triethylamine in 20 ml methylene chloride slowly added dropwise at 0° C. The reaction mixture is thereafter stirred for 2 hours at ambient temperature, subsequently shaken out 6 times with 2 N aqueous sodium hydroxide solution and twice with 2 N hydrochloric acid, and the methylene chloride phase is then dried and evaporated. The residue is taken up with diethyl ether, undissolved material is filtered off and the diethyl ether is evaporated. Ethyl 2-{4-[2-(quinoline-8-carboxamido)-ethyl]-phenyl}-propionate (oil) remains behind in a yield of 8.0 g (91% of theory). This ester is saponified with 2.0 g sodium hydroxide in 50 ml 80% ethanol by heating under reflux for 2 hours. The reaction mixture is thereafter evaporated to dryness, the residue is taken up in water and diethyl ether, the layers are separated and the aqueous layer acidified. The 2-{4-[2-(quinoline-8-carboxamido)-ethyl]-phenyl}-propionic acid obtained is again reprecipitated by dissolving in dilute aqueous sodium bicarbonate solution and acidifying with hydrochloric acid, whereafter it is recrystallized from 50% isopropanol and then from toluene. The yield is 2.3 g (31% of theory); m.p. 143°-144° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[NH2:17][C:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:3][CH2:2][NH:1][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCn1cnc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A mixture of 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.40 g, 1.76 mmol) and anhydrous pyridine (60 mL) was heated until a clear solution was obtained. The solution was then cooled with an ice bath. Benzoyl chloride (0.25 g, 1.76 mmol) was added. The reaction mixture was maintained at ambient temperature overnight and then concentrated under vacuum. The residue was slurried with water (200 mL) and a solid was isolated by filtration. This material was recrystallized from isopropyl alcohol to provide 0.15 g of N1-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]benzamide as a white powder, m.p. 295° C. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (t, J=6.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.75(d, J=8.0 Hz, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0, 1H), 7.41 (t, J=8.0 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 6.28 (broad s, 2H), 4.80(t, J=7.0 Hz, 2H), 3.80(q, J=6.0 Hz, 2H); MS (EI) m/e 331.1429 (331.1433 calcd for C19H17N5O).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19](/[CH:22]=[CH:23]/[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2cnc(/C=C/Cc3ccccc3)cn2)sc1C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cnc(CCCc3ccccc3)cn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 56 %

Procedure:
Part B. To a solution of 4-methyl-2-[5-((E)-3-phenyl-propenyl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (20 mg, 0.05 mmol, 1.0 equiv) in ethyl acetate was added Pd/C (15 mg, 10%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 60 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 4-methyl-2-[5-(3-phenyl-propyl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (12 mg, 60%). 1H NMR (400 MHz, CD2Cl2) δ 9.25 (s, 1H), 8.38 (s, 1H), 7.14-7.35 (m, 10H), 6.20 (bs, 1H), 4.58 (d, J=4.0 Hz, 2H), 2.87 (t, J=8.0 Hz, 2H), 2.72 (s, 3H), 2.69 (t, J=8.0 Hz, 2H), 2.07-2.13 (m, 2H); HRMS (M+H)+=429.17.
Reaction SMILES: O[N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.CS(Cl)(=O)=O.C(N(C(C)C)C(C)C)C>C1COCC1>[O:5]1[C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:8][CH:4]1[C:3]([Cl:14])=[NH:2]
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(Cl)C1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in an ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (3 L). The filtrate was concentrated and the residue was purified over silica gel (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle, washed with hexanes (about 1000 mL) and dried to afford (R)-N-methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([S:15](=[O:17])(=[O:16])[NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:3][C:2]=1[CH3:1])=[O:14]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)C(F)(F)F
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2nccs2)ccc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 75.5 %

Procedure:
Synthesized according to general procedure 70. Under an N2 atmosphere, a mixture of 3-methyl-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (7.5 g, 24.9 mmol) and 2-aminothiazole (2.49 g, 24.9 mmol), and pyridine (15 mL) was stirred at RT for 19 h. Purification via silica gel chromatography using 0-10% MeOH in CH2Cl2 gave 2,2,2-trifluoro-N-(2-methyl-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (6.87 g, 76%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=366.1; tR=1.13 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH-].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].C(OCC)(=O)C>O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[O:15][CH2:3][CH2:2][Br:1]
Reactant: BrCCBr
Reactant: Oc1c(Br)cccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: BrCCOc1c(Br)cccc1Br
Yield: 55.9 %

Procedure:
1,2-Dibromoethane (5.0 ml, 58 mmol) was added to a solution of sodium hydroxide (2.5 g, 63 mmol) and 2,6-dibromophenol (14.5 g, 57.6 mmol) in 45 ml of water. The mixture was stirred under reflux for 20 hours and then extracted with ether. The combined organic layers was dried over Na2SO4, filtered and concentrated to give colorless oil. Silica gel chromatography using a gradient of ethyl acetate in hexanes to afforded 1,3-dibromo-2-(2-bromo-ethoxy)-benzene (11.55 g, 57% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[OH:37][CH:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][NH:28][C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:25])[CH2:32][CH2:33]1
Reactant: NCCN1CCC(O)CC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCCN2CCC(O)CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 57.2 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with 1-(2-amino-ethyl)-piperidin-4-ol (54 mg, 1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 69.8 mg (57%) of the titled compound as a yellow solid.