Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[C:11](#[N:13])[CH3:12].Cl>O1CCOCC1>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:10])[N:1]=[C:11]([CH3:12])[N:13]=1
Reactant: Cc1cccc(N)c1C#N
Reactant: CC#N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)c2c(C)cccc2n1
Temperature: 5 °C
Reaction time: 15 h
Yield: 123.3 %

Procedure:
1. 66.2 g of 2-amino-6-methylbenzonitrile and 22 g of acetonitrile are dissolved in 750 ml of absolute dioxan and the solution is cooled to 5° C. Subsequently, a weak stream of dry hydrogen chloride is introduced for 8 h. at 5° to 7° C. The mixture is stirred at room temperature for a further 15 h. and then again cooled to 5° C. A further 11 g of acetonitrile are added thereto, hydrochloric acid gas is introduced for 8 h. and the mixture is stirred at room temperature for a further 15 h. The suspension is subsequently evaporated at 30° C. in a vacuum. The crystalline residue is triturated with 0.71 of water, cooled to 0° to 5° C. neutralized with saturated sodium hydrogen carbonate solution and filtered. The crystals are washed with water and dried in a vacuum. There are obtained 107 g of crude 4-amino-2,5-dimethylquinazoline which still contains inorganic salts. This compound melts at 198°-199° C. after recrystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].[F-].[K+].COC(=O)CCCC(C1C=CC(C(OC2C=NC(C3C=CC(C(C)(C)C)=CC=3)=CC=2)CCC(C)(C)C)=CC=1)=O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25]([C:38]3[CH:39]=[CH:40][C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:36][CH:37]=3)=[CH:26][CH:27]=2)[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(Cl)nc2)cc1
Agent: COC(=O)CCCC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)nc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)nc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-{4-[1-(6-chloro-pyridin-3-yloxy)-4,4-dimethyl-pentyl]-benzoylamino}-propionic acid methyl ester (84 mg, 0.19 mmol) in toluene:water (1:1) (2 mL) is added palladium tetrakis triphenylphosphine (22.47 mg, 0.1 mol %), 4-tert-butylphenylboronic acid (58 mg, 0.39 mmol). The reaction is purged with nitrogen and heated to reflux and the potassium fluoride (23 mg, 0.39 mmol) is added. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl acetate and then Celite is added, followed by water. This mixture is then filtered through a pad of Celite. The solution is separated in a separatory funnel and the organic layer is washed with 0.1N sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The 5-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-phenyl)-5-oxo-pentanoic acid methyl ester (80 mg, 0.15 mmol) is purified by flash column chromatography.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O.O>[CH2:8]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:30])=[CH:32][CH:33]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CS(N)(=O)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1

Procedure:
A solution of 19.0 g. of methanesulfonamide in 150 ml. of dry dimethylacetamide is added dropwise over 15 minutes to a stirred and cooled (water bath) suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide. The mixture is then stirred and heated at 60°-80° C. for 2 hours. In the meantime, a mixture of 36.2 g. of p-hexadecylaminobenzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated to an oil which is co-evaporated twice with added dioxane to remove excess thionyl chloride. To the resulting oily residue of p-hexadecylaminobenzoyl chloride hydrochloride is added, in one portion, the previously prepared mixture of sodium methanesulfonamide in dimethylacetamide. The mixture becomes very hot and is cooled briefly in a water bath and then is stirred at room temperature for 30 minutes. The mixture is filtered through a bed of diatomaceous earth and the filtrate is poured into 2 l. of water. The resulting suspension is coagulated by the addition of 250 ml. of saturated sodium chloride solution and the mixture is filtered. The product is washed with water, partially air dried and then crystallized from 1.5 l. of ethanol. The product is recrystallized twice from p-dioxane and dried in the Abderhalden at 65° C. to give 12.0 g. of the title compound as tan crystals melting point 173°-175° C.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:8]=[C:9](O)[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4]>C(#N)C>[Br:1][C:9]1[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1
Reactant: BrBr
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Solvent: CC#N
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1

Procedure:
After bromine addition, the ice bath was removed. 124 g of 3,5-di-tertbutylphenol (601 mmol) and 140 mL acetonitrile were added in one portion. The orange/white suspension converted into an orange solution upon heating. The mechanical stirrer was replaced by an egg-shape stir bar. The solution was stirred at gentle reflux temperature for three hours.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:11]1([C:10](=[N:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 15 °C
Yield: 48.8 %

Procedure:
A solution of t-butyl 2-aminoacetate (113.7 g, 866.8 mmol, 1.0 equiv) in toluene (1000 mL) was combined with benzophenone (157.9 g, 866.5 mmol, 1.0 equiv) and 4-methylbenzenesulfonic acid (14.9 g, 86.5 mmol, 0.1 equiv). The resulting solution was heated to reflux overnight. The mixture was then concentrated in vacuo to 600 mL. The mixture was cooled to 15° C. with a water/ice bath. The product precipitated and the solids were collected by filtration. The solids was washed with petroleum ether (5×150 mL) to yield t-butyl 2-(diphenylmethyleneamino)acetate (125 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(4-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(4-chlorophenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH2:1]([C:4]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[CH2:3].[OH-].[Na+].C(C1C2C(=O)C3C(=CC=CC=3)OC=2C=CC=1C)C=C>C(Cl)(Cl)Cl>[CH2:1]([C:4]1[C:5]2[O:6][C:7]3[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9](=[O:11])[C:16]=2[CH:17]=[C:18]([CH3:20])[CH:19]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C)ccc1Oc1ccccc1C(=O)O
Agent: C=CCc1c(C)ccc2oc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=CCc1cc(C)cc2c(=O)c3ccccc3oc12
Yield: 65.7 %

Procedure:
A mixture of 13.6 g (70 mmol) potassium 2-chlorobenzoate, 14.3 g (84 mmol, 1.2 equiv.) sodium 2-allyl-4-methylphenoxide, 0.8 g (8 mmol) CuCl and 2.6 g (8 mmol) tris[2-(2-methoxyethoxy]amine (TDA-1) in 200 ml anisole was heated and stirred under reflux for 3 hours. The anisole was removed under vacuum and the residue was extracted with dilute aqueous ammonia. After filtration to remove insoluble inorganics the aqueous solution was washed twice with ethyl acetate to remove remaining traces of anisole and excess 2-allyl-4-methylphenol. Acidification with conc. hydrochloric acid then gave an oil which was extracted into ethyl acetate. The organic layer was dried (Na2SO4) and the ethyl acetate was removed to give 10.6 g (47% yield) of crude 2-(2-allyl-4-methylphenoxy)benzoic acid (XVIII; R1 =H; R3 =4'-CH3), as an oil. The oil was dissolved in 50 ml of a chloroform solution of polyphosphate ester (PPE) and heated on a waterbath with the solvent being allowed to boil off. After 30 min the residue was basified with dilute sodium hydroxide solution and the oil product was extracted into petroleum ether. After being dried (Na2SO4) the solvent was removed to give 6.5 g (66% yield) of 4-allyl-2-methylxanthenone (XIX: R1 =H; R3 =2-CH3 ; m.p. (methanol) 97°-98° C. Anal. (C17H14O2) C,H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26](F)[C:27](F)=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.C1(CN2C3C=C(F)C(F)=CC=3N=C2C2C=CC=CC=2OCC2C=CC(C3NN=NN=3)=CC=2F)CCCCC1.Br[CH2:77][C:78]1[CH:85]=[CH:84][C:81]([C:82]#[N:83])=[CH:80][C:79]=1[F:86]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:77][C:78]3[CH:85]=[CH:84][C:81]([C:82]#[N:83])=[CH:80][C:79]=3[F:86])[C:10]3[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=3[N:12]=2)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: Fc1cc2nc(-c3ccccc3OCc3ccc(-c4nnn[nH]4)cc3F)n(CC3CCCCC3)c2cc1F
Product: COc1cc(Cl)ccc1-c1nc2ccccc2n1Cc1ccc(C#N)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-1H-benzoimidazole (Example 39, intermediate d) and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Yellow solid (18%). MS (Turbo Spray): m/z=392.4 (M+H).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1.[OH-].[Na+]>O1CCCC1>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])=[C:24]([CH3:29])[CH:23]=1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: Cc1cc(F)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1cc(F)ccc1NC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Cyclopropane-1,1-dicarboxylic acid (1.0 g, 8.0 mmol) was suspended in tetrahydrofuran (20 mL), and triethylamine (1.1 mL, 8.0 mmol) was added. After stirring at room temperature for 1 hr, the mixture was cooled in an ice bath. Under ice-cooling, thionyl chloride (0.58 mL, 8.0 mmol) was added dropwise, and the mixture was stirred as it was for 30 min. To this mixture was dropwise added a solution of 4-fluoro-2-methylaniline (3.9 g, 31 mmol) in tetrahydrofuran (2.0 mL) under ice-cooling, and the reaction mixture was warmed to room temperature and stirred overnight. An aqueous sodium hydroxide solution (1N, 50 mL) was added, and the mixture was washed twice with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (1N), and the mixture was extracted twice with ethyl acetate. The mixed organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane-ethyl acetate was added to the residue, and the precipitate was collected by filtration to give the title compound (1.1 g, 60%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:7][CH2:6]1)=[O:4].[Cl:20][S:21](O)(=[O:23])=[O:22]>ClCCl>[CH3:17][C:12]1[CH:13]=[CH:14][C:15]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Temperature: -5 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 2 g of 2,2,2-trifluoro-1-(4-o-tolyl-piperazin-1-yl)-ethanone (7.35 mmol) in 5 mL of dichloromethane at −5° C. were slowly added 19.7 g of chlorosulfonic acid (169 mmol). After stirring for 2 h at −5° C., the reaction mixture continued stirring for 16 h, thereby slowly allowed to warm to room temperature. After cooling to 0° C., the reaction mixture was slowly added to a water/ice mixture. The aqueous phase was extracted five times with dichloromethane, the combined organic phases washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over magnesium sulphate, filtered, and the solvent evaporated to yield 2.2 g of product as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:7]=12.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:7]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: CC(C)=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC(C)=CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21

Procedure:
The title compound was prepared as a white powder in -6.2% yeild in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(3-methyl-2-butenyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][O:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[NH:17]([CH2:19][C:20]([O:22][CH2:23][C:24]1C=CC=CC=1)=[O:21])[NH2:18].C(N(CC)CC)C.C(#N)C>C(O)C.C(=O)([O-])O.[Na+]>[CH2:13]([O:12][C:11]1[N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:14]
Reactant: NNCC(=O)OCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ncc(C(=O)OCC)c1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 14 %

Procedure:
To a solution of diethyl(ethoxymethylidene)propanedioate (3.52 g, 16.3 mmol) in ethanol (35 mL) were added benzyl hydrazinoacetate hydrochloride (3.20 g, 14.8 mmol), triethylamine (2.20 ml, 16.3 mmol) and acetonitrile (15 mL), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was diluted with diluted aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give ethyl [5-ethoxy-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]acetate (0.56 g, 14%) wherein benzyl ester was converted to ethyl ester. To a solution of the present compound (0.56 g, 2.07 mmol) in tetrahydrofuran (10 mL) was added 1N aqueous sodium hydroxide solution (2.07 mL, 2.07 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was extracted with water, and washed with ether. The aqueous layer was neutralized with 1N hydrochloric acid (2 mL), and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (401 mg, 80%) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:14][C:15]4[CH2:20][CH2:19][NH:18][CH2:17][C:16]=4[N:21]=3)[S:12][C:8]=2[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(N)C1C=CC=CC=1>O1CCCC1>[CH2:41]([O:40][C:38]([N:18]1[CH2:19][CH2:20][C:15]2[NH:14][C:13]([C:11]3[S:12][C:8]4[C:7]([N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)=[N:21][C:16]=2[CH2:17]1)=[O:39])[CH3:42]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CCOC(=O)N1CCc2[nH]c(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)nc2C1
Reaction time: 4 h
Yield: 25 %

Procedure:
To a suspension of 0.01 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride in 0.8 ml tetrahydrofurane were added at 0–4° C. 0.06 ml N-ethyldiisopropylamine and 0.003 ml ethyl chloroformate in 0.26 ml tetrahydrofurane. The mixture was refluxed over night, additional 0.06 ml N-ethyldiisopropylamine and 0.05 ml ethyl chloroformate were added and heating was continued for 4 hours. 0.015 ml benzylamine were added and the mixture was kept at 80° C. for 1 hour. Silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with ethylacetate. A second chromatography first with ethylacetate/hexane 1:1 and then with ethylacetate/methanol 9:1 yielded 0.003 g (25%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid ethyl ester as yellow solid; MS (ISP): m/e=444 (M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[O:13])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:44]1[CH:49]=[CH:48][NH:47][C:46](=[O:50])[CH:45]=1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.CC(N(C)C)=O>[CH3:19][C:16]1[S:17][CH:18]=[C:14]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:44]3[CH:49]=[CH:48][NH:47][C:46](=[O:50])[CH:45]=3)[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][NH:8]3)=[O:13])[N:15]=1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Reactant: O=c1cc(Br)cc[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cc(-c3cc[nH]c(=O)c3)cc3[nH]ncc23)cs1
Temperature: 80 °C
Yield: 4.8 %

Procedure:
N-(6-Bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (200 mg, 0.59 mmol), bis(pinacolato)diboron (166 mg, 0.652 mmol), Pd(dppf)Cl2 (48 mg, 0.06 mmol) and potassium acetate (175 mg, 1.78 mmol) were combined in a microwave vial and DMA (10 ml) was added. The solution was degassed and then heated in a Biotage initiator at 80° C. for 20 minutes. More Pd(dppf)Cl2 (48.4 mg, 0.059 mmol) was added, the solution was degassed and heated again at 80° C. for 20 minutes. 4-Bromo-2-pyridone (206 mg, 1.19 mmol), Pd(PPh3)4 (34 mg, 0.03 mmol) and sodium bicarbonate (0.89 ml, 1.78 mmol) were added to the mixture, which was heated under microwave conditions at 150° C. for 15 minutes. Saturated sodium bicarbonate (100 ml) was added to the mixture. The resulting suspension was washed three times with ethyl acetate (100 ml each). A spatula of sodium chloride was added to improve layer separation. Organics were dried and filtered with a hydrophobic frit, combined and dried under vacuum. The solid obtained was preabsorbed on silica and purified on silica (Si) 100 g using a 0-15% methanol-DCM over 60 mins. Appropriate fractions were combined and dried under vacuum. The sample was dissolved in DMSO (1 ml) and purified by MDAP (Method B) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). Pure fractions were combined and dried under vacuum to afford the title compound (10 mg).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[C:4]=1[CH3:18])=[O:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:18][C:4]1[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[O:15])=[CH:16][CH:17]=2)=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: CN1CCNCC1
Reactant: Cc1[nH]c(C=O)c(C)c1-c1ccc(C(=O)O)cc1
Product: Cc1[nH]c(C=O)c(C)c1-c1ccc(C(=O)N2CCN(C)CC2)cc1

Procedure:
4-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-benzoic acid was reacted with 1-methylpiperazine using General Amidation Procedure 1 to give 3,5-dimethyl-4-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-1H-pyrrole-2-carbaldehyde. MS m/z 326 [M+1].
Reaction SMILES: [CH:1]([P:4]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)([CH:6]([CH3:8])[CH3:7])=[O:5])([CH3:3])[CH3:2].[ClH:19].O1CCOCC1>>[ClH:19].[CH:1]([P:4]([CH2:9][CH2:10][NH2:11])([CH:6]([CH3:7])[CH3:8])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)P(=O)(CCNC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)P(=O)(CCN)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl [2-(diisopropylphosphoryl)ethyl]carbamate (585 mg, 2.11 mmol) was combined with 4.0 M HCl in 1,4-dioxane (10.0 mL, 40.0 mmol) and stirred at room temperature for 30 minutes. The solution was evaporated to dryness to afford 2-(diisopropylphosphoryl)ethanamine hydrochloride as a colorless solid. 1H NMR (DMSO-d6, 600 MHz) 8.23 (bs, 3H), 2.99-2.90 (m, 2H), 2.08-1.93 (m, 4H), 1.05 (dd, J=14.7, 7.2 Hz, 6H), 1.03 (dd, J=15.2, 7.0 Hz, 6H). MS: cal'd 178 (MH+), exp 178 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:4].[CH3:24][CH:25]1[CH2:30][CH2:29][CH:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[N:10]([C:31]([CH:28]1[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]1)=[O:32])[NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NNC(=O)C(F)(F)F
Reactant: CC1CCC(C(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(NC(=O)C(F)(F)F)C(=O)C1CCC(C)CC1
Temperature: 40 °C
Yield: 96.7 %

Procedure:
A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-[N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester (2.1 g, 6.0 mmol), 4-methyl-cyclohexanecarbonyl chloride (1.45 g, 9 mmol), DMAP (1.1 g, 9 mmol) and DCE (20 mL) was heated to 40° C. for 16 h. After cooling, the mixture was concentrated and the product was purified by silica gel chromatography 0-30% EtOAc/hexanes to give 5-(3,3-dimethyl-but-1-ynyl)-3-[N-(4-methyl-cyclohexanecarbonyl)-N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester (2.74 g, 5.8 mmol).