Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=O)[C:10]=2[N:11]=1)=[O:5].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>C(Cl)Cl.O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][C:16]([CH:12]1[C:10]2[N:11]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:20])[CH3:19])[S:8][C:9]=2[CH2:15][CH2:14][CH2:13]1)=[O:18]
Reactant: CC(C)(C)CC(=O)Nc1nc2c(s1)CCCC2C(=O)O
Reactant: CN(C)CCCN
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCNC(=O)C1CCCc2sc(NC(=O)CC(C)(C)C)nc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,1-Carbonyldiimidazole (CDI, 87 mg, 0.537 mmol) was added to a solution of 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (144 mg, 0.486 mmol) in CH2Cl2 (10 mL), and the resultant mixture was stirred for a period of 2 hours at room temperature. Following cooling of the suspension to 0° C., N,N-dimethyl-1,3-propanediamine (51 mg, 0.50 mmol), dissolved in CH2Cl2 (10 mL), was added dropwise over a period of 10 minutes. Following stirring for 1 hour at 0° C. and overnight at room temperature, a few drops of water were added, and the resultant mixture was extracted with CH2Cl2 (3×10 mL). Following drying of the organic phase over Na2SO4 and filtration, the solvent was removed and the residue was purified via column chromatography. The product 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid(3-dimethylaminopropyl)amide was obtained in a yield of 125 mg (corresponding to 68% of theory).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]CC=C)[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].C(OCC)(=O)C.[CH3:24][CH2:25][CH2:26]CCC>>[OH:14][C:13]1[C:12]([CH2:26][CH:25]=[CH2:24])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OC)cc1CC=C
Reactant: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Yield: 97 %

Procedure:
The product of Step A (3.2g, 13.8 mmol) was refluxed in 12-dichlorobenzene for 3 days in the presence of a catalytic amount of BHT (10 mg). Flash column chromatography of the mixture using hexane and then 10% and 20% ethyl acetate in hexane afforded 3.1 g (97%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[CH:22]=[CH:23][CH2:24]Br)#[N:19].CC(C)=O>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:24][CH:23]=[CH:22][C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[C:18]#[N:19])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: N#Cc1ccccc1C=CCBr
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#Cc1ccccc1C=CCN1CCc2nc(N)sc2CC1
Yield: 31 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 2-cyano-cinnamyl bromide (melting point: 69°-71° C.) in anhydrous dimethylformamide for 15 hours at 20° C. Yield: 31% of theory, Melting point: 140°-144° C. (acetone).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:33][N:34]([CH3:38])[C:35]([NH:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[CH:13][CH:12]=1)=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4oc(C)nc4-c4ccc(N)cc4)ccnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4oc(C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc32)cc1

Procedure:
Following the procedure described for Intermediate 31 with 4-(2-methyl-5-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1,3-oxazol-4-yl)aniline and dimethylcarbamoyl chloride provided the title product. ESMS[M+H]+: 516.2
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][OH:6].Cl[CH2:12][C:13](OCC)=[O:14].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:7]([C@@H:4]1[NH:3][C:13](=[O:14])[CH2:12][O:6][CH2:5]1)[CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)CCl
Reactant: CC(C)C[C@H](N)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)C[C@H]1COCC(=O)N1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent.
Reaction SMILES: C(CN)O.C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[C:20]([F:21])=[C:19]2[C:15]([C:16]([NH:30]C(=O)CCC)=[N:17][N:18]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:14][C:13]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[F:11][C:12]1[C:20]([F:21])=[C:19]2[C:15]([C:16]([NH2:30])=[N:17][N:18]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:14][C:13]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCCO
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(F)c(F)c21
Yield: 23.7 %

Procedure:
1.1 cm3 of ethanolamine and then 1.50 g of potassium carbonate are added to 1.6 g of N-[6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide described above, in 50 cm3 of dimethylformamide, and the mixture is refluxed for one week. The reaction medium is concentrated to dryness under reduced pressure and taken up in 150 cm3 of ethyl acetate and 75 cm3 of water. The organic phase is separated out after settling of the phases and washed successively with twice 75 cm3 of water and 50 cm3 of brine. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude oil obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40–60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 0.32 g of 6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-amine is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](N(OC)C)=[O:14].[CH3:19][Mg]Br.[Cl-].[NH4+]>CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](=[O:14])[CH3:19]
Reactant: COCOc1ccc(CC(=O)N(C)OC)c(Br)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COCOc1ccc(CC(C)=O)c(Br)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(2-bromo-4-(methoxymethoxy)phenyl)-N-methoxy-N-methylacetamide (4.30 g) in ether (93 ml) was added methyl magnesium bromide (3 M in ether, 63 mL) dropwise at 0° C. After addition, the solution was stirred at 0° C. for 1.5 hr. The mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate (100 mL×2). The organic phase was dried over anhydrous sodium sulfate, The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (23 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].C(OCC)(=O)C.S(C1C=CC(C)=CC=1)(O)(=O)=O.FC(=C(F)F)CC.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K]>C(#N)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Ag+].CN(C=O)C>[F:8][C:4](=[C:5]([F:7])[F:6])[CH2:3][CH2:2][N:37]1[C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]2[C:33]1=[O:43]
Reactant: FC(F)=C(F)CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Ag+]
Agent: CCC(F)=C(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCC(F)=C(F)F
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To 25 g (0.0896 mole) silver tosylate in 100 mL acetonitrile is slowly added 13.2 g (0.07 mole) 4-bromo-1,1,2-trifluoro-1-butene with stirring, at room temperature. The reaction mixture, protected from the light, is then heated and stirred overnight at reflux. After cooling, the precipitate is filtered off, and the solvent removed from the filtrate under vacuum. Ethyl acetate, 100 mL, is added to the residue of the filtrate and then washed three times with water and dried over magnesium sulfate. To this ethyl acetate solution of 3,4,4-trifluoro-3-butene tosylate is added 25 mL DMF and 16.7 g (0.09 mole) potassium phthalimide. This reaction mixture is stirred at reflux for 24 hrs. After cooling, the precipitate is filtered off and washed with ethyl acetate, which is combined with the filtrate, washed once with water, once with 5% NaOH solution, and then three times with water, and lastly, dried over magnesium sulfate. The solvent is removed under vacuum to yield 14.45 g N-(3,4,4-trifluoro 3-butenyl)phthalimide as a tan solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[CH3:13][O:14][C:15]([C:17]1[CH2:22][NH:21][CH2:20][CH2:19][CH:18]=1)=[O:16].Br.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:13][O:14][C:15]([C:17]1[CH2:22][N:21]([CH2:2][CH2:3][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:20][CH2:19][CH:18]=1)=[O:16]
Reactant: COC(=O)C1=CCCNC1
Reactant: BrCCC1CCc2ccccc21
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C1=CCCN(CCC2CCc3ccccc32)C1
Reaction time: 12 h

Procedure:
4.5 g (20 mmol) of 1-bromo-2-(indan-1-yl)-ethane are dissolved in 20 ml of toluene and added, at room temperature, to a solution of 4.9 g of guvacoline hydrobromide (20 mmol) and 5.7 g (44 mmol) of N,N-diisopropyl-N-ethylamine in 15 ml of dimethylformamide. The mixture is stirred at 45° under nitrogen for 12 hours. The solvents are then substantially removed under reduced pressure. The residue is rendered acidic with 2N hydrochloric acid and the aqueous solution is extracted with diethyl ether. The acidic aqueous phases are rendered basic with saturated sodium bicarbonate solution and extracted by shaking with diethyl ether. The organic phases are separated off, washed with saturated sodium chloride solution and dried over magnesium sulphate. 1-[2-(indan-1-yl)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester is obtained.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C([Si]([C:34]#[C:35][C:36]1[CH:37]=[C:38]([CH:41]=[O:42])[O:39][CH:40]=1)(C(C)C)C(C)C)(C)C.C1COCC1.[Cl-].[NH4+]>O.C(OCC)C.C(O)(=O)C>[C:35]([C:36]1[CH:37]=[C:38]([CH:41]=[O:42])[O:39][CH:40]=1)#[CH:34]
Reactant: CC(C)[Si](C#Cc1coc(C=O)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C#Cc1coc(C=O)c1
Yield: 80.4 %

Procedure:
A 1 mol/L-TBAF-THF solution (3.4 mL) was added dropwise, under ice cooling, to a mixture of 4-[(triisopropylsilanyl)ethynyl]furan-2-carbaldehyde (0.63 g) as obtained in Example 24-(1), THF (3.0 mL) and acetic acid (0.20 mL) over the course of 1.5 hours. Diethyl ether and water were added to the reaction mixture, and the mixture was adjusted to pH 5 with a saturated aqueous solution of ammonium chloride to isolate the organic layer. The extract was washed with brine, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=100/0→80/20) to obtain 4-ethynylfuran-2-carbaldehyde (brown solid) (0.22 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[N:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([C:31]2[N:30]=[N:29][C:28]([Cl:27])=[CH:33][CH:32]=2)[CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CN(c2ccc(Cl)nn2)C[C@H]1c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 65 %

Procedure:
The product of Step A, methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate (0.46 g, 1.91 mmol) was dissolved in dioxane (2 ml). DIPEA (1.33 mL, 7.64 mmol) and 3,6-dichloropyridazine (1.42 g, 9.55 mmol) were added. The reaction was conducted at 120° C. for 5 minutes and at 150° C. for 10 minutes with microwave. Then, the reaction mixture was concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/5) to give the title compound (0.44 g, 65%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O>>[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N#CCC#N
Product: N#CC(C#N)=Cc1ccc(Cl)cc1Cl

Procedure:
This material was prepared from malononitrile and 2,4-dichlorobenzaldehyde according to the procedure of M. Boehringer et al., WO 03/068748.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21]>C(#N)C>[CH3:19][N:20]([CH3:21])[C:12](=[O:13])[C:11]1[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1
Reactant: CNC
Solvent: CC#N
Product: CN(C)C(=O)C1=C(C(=O)Nc2ccc(Cl)cc2)CCCC1
Temperature: 25 °C

Procedure:
In 100 ml of acetonitrile is dissolved 3.0 g of N-(4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide. To the solution is added 1.5 g of a 40% aqueous dimethylamine solution under stirring at room temperature, followed by further stirring for 30 minutes. The solution is concentrated to dryness under reduced pressure, the resulting oily substance is dissolved in 50 ml of ether and the solution is dried with sodium sulfate. The ether layer is concentrated to dryness under reduced pressure and the resultant oily substance is allowed to crystallize by adding 50 ml of n-hexane thereto. The resultant crystals are recovered by filtration and washed with a small amount of n-hexane, whereby to yield 2.5 g of the subject compound.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([NH:7][C:8]2[C:21]3[CH2:20][CH2:19][C:18]4[N:17]=[C:16]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[NH:15][C:14](=[O:29])[C:13]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>[Pd].COCCOCCOC>[C:1]([C:3]1[CH:31]=[CH:30][C:6]([NH:7][C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[N:17]=[C:16]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[NH:15][C:14](=[O:29])[C:13]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(=O)[nH]1)-c1cccc(Nc3ccc(C#N)cc3)c1CC2
Agent: [Pd]
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Solvent: COCCOCCOC
Product: CC(C)(C)C(=O)Nc1nc2ccc3c(Nc4ccc(C#N)cc4)cccc3c2c(=O)[nH]1
Yield: 57.6 %

Procedure:
To a solution of sodium ethoxide, prepared by reacting sodium (0.28 g, 12 mmol) with ethanol (6 ml), was added guanidine hydrochloride (1.2 g, 12 mmol) and the mixture was briefly stirred at reflux. A solution of methyl 5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate (0.63 g, 1.5 mmol) in ethanol (6 ml) was added and the reaction mixture was stirred at reflux under nitrogen for 18 hours. The solution was diluted with water (50 ml), neutralized with acetic acid, and the resulting precipitate filtered and dried at 110° C. under reduced pressure. A solution of the solid in pivalic anhydride (10 ml) was refluxed for ~5 minutes and then concentrated under high vacuum. The residue was eluted on silica gel (30 g) with ethyl acetate:methylene chloride (1:9) and the resulting solid recrystallized from diethyl ether, the slurry diluted with hexane, filtered, and the solid dried at 100° C. under reduced pressure to give N-(7-(4-cyanoanilino)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.48 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.23 (s, 9H, t-butyl), 2.67 (s, 4H, ArCH2 's), 6.68 (d, J=9 Hz, 2H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.26 (t, J=8 Hz, 1H, Ar), 7.50 (d, J=9 Hz, 2H, Ar), 8.38 (d, J=8 Hz, 1H, Ar), 8.53 (s, 1H, C7 -NH), 11.28 (br s, 1H, N2H), 12.16 (br s, 1H, C3 -NH). A solution of the pivalamide (0.15 g) and 10% palladium on carbon (70 mg) in diglyme (5 ml) was stirred at reflux under nitrogen for 10 hours. Pivalic anhydride (2×0.5 ml, 4.9 mmol) was added at 5 and 9 hours. The solution was diluted with diglyme (15 ml), filtered hot through celite and concentrated under high vacuum. The residue was purified by chromatography on silica gel (15 g) eluting with ethyl acetate:methylene chloride (1:9) and then recrystallization from methanol. The solid was filtered and dried at 90° C. under reduced pressure to give N-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (86 mg). 1H NMR (DMSO-d6, 200 MHz) δ: 1.26 (s, 9H, t-butyl), 6.85 (d, J=9 Hz, 2H, Ar), 7.49-7.60 (m, 4H, Ar), 7.72 (t, J=8 Hz, 1H, Ar); 8.29 (d, J=9 Hz, 1H, Ar); 9.07 (s, 1H, C7 -NH), 9.61 (d, J=9 Hz, 1H, Ar), 11.25 (br s, 1H, N2H), 12.32 (br s, 1H, C3 -NH). Mass spectrum (CI-CH4) 412 (M+1, 100%). Anal. Calculated for C24H21N5O2.17/100H2O: C, 69.54; H, 5.19; N, 16.89. Found: C, 69.56; H, 5.23; N, 16.88.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19](I)[CH:18]=1.C(N(CC)CC)C>CN(C)C=O.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.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:21]2[CH:22]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=2[OH:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(Br)cc1I
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2O)CC1
Temperature: 75 °C

Procedure:
A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (4.03 g), 4-bromo-2-iodo-phenol (5.00 g), Pd(PPh3)2Cl2 (600 mg), copper iodide (500 mg), and triethylamine (2.35 mL) in N,N-dimethylformamide (30 mL) is heated under an argon atmosphere to 75° C. for 4 h. The reaction mixture is diluted with ice water after cooling to room temperature and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 2): tR=1.32 min; Mass spectrum (ESI+): m/z=402, 404 [M+Na]+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:24])=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:24])=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2nc3c(C(=O)NC(C)(C)C)cn(COCC[Si](C)(C)C)c3nc2Cl)sn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nc3c(C(=O)NC(C)(C)C)c[nH]c3nc2Cl)sn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
To a solution of N-tert-butyl-3-chloro-2-(3-methylisothiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 80.8 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (184 mg, 124 μL, 1.62 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (1.5 mL), methanol (0.75 mL) and ammonium hydroxide (0.2 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-3-chloro-2-(3-methylisothiazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 37.0 μmol, 46%) as a dark orange solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.76 (s, 1H), 10.91 (s, 1H), 8.30 (d, J=3.2, 1 H), 7.33 (s, 1H), 7.13 (s, 1H), 2.42 (s, 3H), 1.62 (s, 9H); MS (EI/CI) m/z: 365.0 [M+H].
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:33])CO)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[BH4-].[Na+]>C1C=CC=CC=1.C(O)C.C(OCC)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:33])=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(OCC(O)CO)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(OCCO)cc1
Reaction time: 0.25 h
Yield: 9.8 %

Procedure:
The product from Example 41A (0.6 g, 1.27 mmoles) in benzene (11.6 mL) and ethanol (11.6 mL) was treated with lead tetraacetate (0.6215 g, 1.4 mmoles) at 0° C. The reaction mixture turned from clear and colorless to light yellow and was stirred for 15 minutes. The mixture was diluted with diethyl ether (100 mL), filtered through a 1 inch pad of 1:1 Celite:silica gel and the filtrate was concentrated under reduced pressure. The residue (0.07 g, 0.16 mmoles) was dissolved in ethanol (1.0 mL) and treated with sodium borohydride (0.006 g, 0.16 mmoles). After 30 minutes, the reaction mixture was filtered through silica gel using 2:1 ethyl acetate:hexanes and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:0.1% TFA in H2O) on a YMC ODS Guardpak column to provide the title compound as a brown oil (0.055 g). 1H NMR (300 MHz, CDCl3) δ7.21 (m, 10H), 6.75 (dd, J=8.8, 1.7 Hz, 2H), 6.04 (s, 1H), 4.66 (dd, J=5.4, 3.7 Hz, 1H), 4.57 (d, J=10.3 Hz, 2H), 4.52 (d, J=10.3 Hz, 2H), 4.21 (s, 1H), 4.02 (m, 1H), 3.95 (m, 1H), 3.72 (s, 1H), 2.76 (s, 3H), 1.98 (s, 3H); MS (APCI+) m/z 441 (M+H)+.