Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH:14]([S:17]([N:20]1[C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:32])(=[O:19])=[O:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:14]([S:17]([N:20]1[C:24]2[CH:25]=[C:26]([C:2]3[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:5]=[C:4]([CH3:13])[CH:3]=3)[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:32])(=[O:18])=[O:19])([CH3:16])[CH3:15]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Reactant: Cc1cc(Br)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)n(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of 5-(bromo)-3-(methyl)-1-(phenyl)-pyrazole (264 mg, 1.11 mmol) in 6 mL DME add 1-isopropylsulfonyl-2-amino-benzimidazole-6-boronic acid (694 mg, 2.45 mmol). Add sodium carbonate (354 mg, 3.34 mmol) dissolved in 0.5 mL of water and trans-dichlorobis(triphenylphosphine) palladium (II) (234 mg, 0.33 mmol). Heat the mixture to 100° C. with stirring under nitrogen. After 2 hours, cool and filter over a pad of Celite® and sodium sulfate. Purify the crude product by radial chromatography eluting with 4% methanol in CH2Cl2 to yield 201 mg (46%) of the title compound. MS(ES+): m/z=396.0 (M+H)+
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][C:14]([F:17])([F:16])[F:15])[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][C:14]([F:17])([F:16])[F:15])[C:7]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(C)n(CC(F)(F)F)c2c(Cl)nncc12
Reactant: OCc1ccccc1
Product: Cc1c(C)n(CC(F)(F)F)c2c(OCc3ccccc3)nncc12
Yield: 65.2 %

Procedure:
The title compound was prepared as a white powder in 65.20% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]>C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][OH:13])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CCO)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCO)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-nitrophenyl)ethanol (200 mg, 0.94 mmol, 1.0 eq) in ethanol (10 mL) was added 10% Pd/C (50 mg) and the mixture was stirred under a H2 gas balloon at RT for 5 h. The reaction mixture was passed through a celite bed and the solvent of the filtrate evaporated to get 2-(4-amino-2-fluorophenyl)ethanol (130 mg, 75%) as a viscous oil (TLC system: EtOAc/PE (1:1), Rf: 0.2).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+].O>CO>[CH3:13][NH:14][CH2:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: CN
Reactant: Cn1ccc2ccc(C=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2ccn(C)c2c1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
1-Methyl-1H-indole-6-carbaldehyde (146 mg, 0.91 mmol) was dissolved in anhydrous methanol (4 ml). Methylamine (0.35 ml of 33% solution in ethanol, 2.81 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (4 ml). Sodium borohydride (34.9 mg, 0.92 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford methyl-(1-methyl-1H-indol-6-ylmethyl)-amine (139 mg, 87%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=8.0 Hz, 1H), 7.34 (s, 1H), 7.240 (d, J=3.6, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.345 (d, J=4.0 Hz, 1H)), 3.75 (s, 3H), 3.73 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][CH2:18][C:19]#[C:20][C:21]([OH:23])=O.[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:42])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1>O1CCCC1.N1C=CC=CC=1>[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:42][C:21](=[O:23])[C:20]#[C:19][CH2:18][O:17][CH3:16])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: COCC#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: COCC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Isobutyl chloroformate (0.432 g, 3.2 mmol) and N-methylmorpholine (0.959 g, 9.48 mmol) were added to an ice cold solution of 0.720 g (6.32 mmol) of 4-methoxy-but-2-ynoic acid in 30 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 0.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 8 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.270 g of 4-Methoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 411.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][C:33]([F:37])([F:36])[CH2:32]1>>[ClH:28].[F:36][C:33]1([F:37])[CH2:34][CH2:35][N:31]([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: FC1(F)CCN(CCCl)C1
Agent: Cl
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCN3CCC(F)(F)C3)cc12

Procedure:
6-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 62% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-3,3-difluoro-pyrrolidine hydrochloride (WO2008/86404).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C@@H:13]([CH2:19][CH2:20][CH:21]=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16].[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:12][C@@H:13]([CH2:19][CH2:20][CH:21]=[CH2:1])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C[C@@H](C)CCC=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC[C@H](C)CC(=O)OC
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
To a suspension of 23.3 g (65.2 mmol) of methyltriphenylphosphonium bromide in 120 ml of dry THF is added 36.9 ml (58.7 mmol) of 1.59 N n-butyllithium-n-hexane solution dropwise under ice cooling in a nitrogen atmosphere. After additional stirring at the same temperature for 10 minutes, the mixture was cooled to -50° C., and a solution of 5.2 g of crude aldehyde 31 (prepared in 31-(2)) in 80 ml of dry THF is added dropwise thereto. Then, the mixture is stirred at the same temperature for 10 minutes, and warmed to room temperature over an hour. To the reaction mixture is added a saturated aqueous solution of ammonium chloride, and the mixture is extracted with ether twice. The extract is washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous mangeium sulfate, and evaporated at atmospheric pressure. To the residue is added 400 ml of n-pentane and the mixture is stirred under ice cooling for 30 minutes. The precipitated triphenylphosphinoxide is removed by filtration through 100 g of silica gel. The silica gel is washed with 500 ml of mixture of ether:n-pentane=1:9. The filtrate and washing are combined and concentrated at atmospheric pressure. The residue is distilled under reduced pressure to give 2.19 g of the desired olefin 32 as an oil in 43.1% yield from compound 30.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+]=[N-].C(O)C.CCOCC>[Ni].O>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Agent: [Ni]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: NC1CCc2ccccc2NC1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-azido-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (see Example 1) (27 g) in 2B ethanol (3500 ml) stirring at room temperature under an atmosphere of nitrogen, a suspension of Raney nickel in water (50 ml, washed with 10 volumes of ethanol) was added. The mixture was stirred at room temperature for 2 hours when an additional 30 ml of Raney nickel suspension was added. After stirring for an additional 30 minutes, the catalyst was filtered off and the solvent removed under reduced pressure to give an oil which solidified on addition of ether to give 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, melting at 161°-2°.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5](=[O:26])[C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@H:13]([CH2:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1>O1CCCC1>[CH3:4][C:5]([C@@H:6]1[C@@:23]2([CH3:24])[CH2:22][CH2:21][C@@H:20]3[C@@:18]4([CH3:19])[CH2:17][CH2:16][C@:15]([OH:25])([CH3:1])[CH2:14][C@@H:13]4[CH2:12][CH2:11][C@H:10]3[C@@H:9]2[CH2:8][CH2:7]1)=[O:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.17 h

Procedure:
A solution of ferric chloride (anhydrous, 2.14 g, 13.2 mmol) in tetrahydrofuran (anhydrous, 40 mL) is cooled to −50° C. Methyl magnesium chloride (3M, 17.6 ml, 52.8 mmol) in tetrahydrofuran is added to this mixture dropwise maintaining the internal temperature below −40° C. After 10 min at −40° C., 5α-pregnane-3,20-dione (3.48 g, 11 mmol) is added in one portion with stirring. The temperature is brought to −20° C. over 30 min. and stirred 2 hours. The reaction mixture is quenched with 100 ml of 2N HCl and the product extracted with 100 ml ethyl acetate. The organic layer is washed with 2N NaOH and brine and the solvent removed in vacuo to afford crude ganaxolone (80.2% purity by HPLC (Table 1, entry 4).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH2:22][NH2:23])[N:19]=[CH:18]2)=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:23][CH2:22][C:20]2[N:19]=[CH:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([I:10])=[CH:12][CH:13]=3)[CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cn(-c2ccc(I)cc2)cn1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a mixture of 5-chlorothiophene-2-carboxylic acid (0.346 g, 2.13 mmol), (1-(4-iodophenyl)-1H-imidazol-4-yl)methanamine 9.7 (0.578 g, 1.93 mmol) and TEA (0.670 mL, 4.82 mmol) in DMF (10 mL), BOP (1.03 g, 2.33 mmol) was added. The mixture was then stirred at room temperature overnight. Water and EtOAc were added. The organic layer was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give the title compound as a solid (0.832 g). MS found for C15H11ClIN3OS: 443.9 and 445.9 ((M+H)+, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([CH:16]=O)[CH:3]=1.Cl.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:22]=1[CH2:23][O:24][NH2:25].CC([O-])=O.[Na+]>CCO>[F:19][C:20]([F:34])([F:35])[C:21]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:22]=1[CH2:23][O:24][N:25]=[CH:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11]
Reactant: NOCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=Cc1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C=NOCc1ccc(C(F)(F)F)cc1C(F)(F)F)C(F)(F)F
Yield: 57.6 %

Procedure:
A solution of N-(4-chloro-2-formylphenyl)trifluoromethanesulfonamide 24 (180 mg, 0.63 mmol), O-(2,4-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (342 mg, 1.16 mmol) and anhydrous NaOAc (141 mg, 1.72 mmol) in EtOH (10 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CHCl3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 3:7) afforded N-{2-[(2,4-bistrifluoromethylbenzyloxyimino)methyl]-4-chlorophenyl}-trifluoromethanesulfonamide 65 (192 mg, 58%), as a yellow solid. M.p. 65-67° C. 1H n.m.r. (200 MHz, CDCl3) δ 10.38, br s, 1H; 8.20, s, 1H; 7.97, s, 1H; 7.86, d, J=8.0 Hz, 1H; 7.75, d, J=8.0 Hz, 1H; 7.65, d, J=8.8 Hz, 1H; 7.35, dd, J=2.4 and 8.8 Hz, 1H; 7.28, d, J=2.4 Hz, 1H; 5.44, s, 2H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:43])[C:12](=[O:42])[C:13]([CH3:41])=[C:14]2[C:19]=1[C:18](=[O:20])[N:17](CC1C=CC(OC)=CC=1)[C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=1.[Cl-].[Al+3].[Cl-].[Cl-].CO>C1(OC)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:43])[C:12](=[O:42])[C:13]([CH3:41])=[C:14]2[C:19]=1[C:18](=[O:20])[NH:17][C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(NC(C)=O)c3)c2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: COc1ccccc1
Product: CC(=O)Nc1cccc(-n2c(=O)[nH]c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Yield: 78.1 %

Procedure:
To a suspension of N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 88 (960 mg) in anisole (10.0 ml) was added aluminum chloride (1.94 g) with stirring in a water bath. The mixture was stirred at room temperature for 37 hrs, methanol (12.0 ml) was added dropwise, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (12.0 ml), and 2N hydrochloric acid (20.0 ml) was added dropwise with stirring in a water bath. The mixture was stirred at room temperature for 1 hr, hexane (10.0 ml) was added, and the mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed with hexane, water and methanol, and dried to give N-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 89 (620 mg, yield 78.1%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@@:22]([OH:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@@:22]([OH:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([OH:16])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@](C)(O)C(=O)O)C(=O)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@](C)(O)C(=O)O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
No. 5398770 (20 mg, 0.0326 mmol) was dissolved in methanol (0.4 mL), and an aqueous solution of 1 M sodium hydroxide (65 μL, 0.065 mmol) was added. The mixture was stirred at room temperature for 2 hours. To the resulting white suspension was added an aqueous solution of 0.5 M citric acid, and the mixture was extracted with ethyl acetate. The separated organic layer was washed twice with water, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated. The residue was purified by diol thin layer chromatography (dichloromethane/methanol) to obtain the target compound as clear and colorless solid at a yield of 70%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[N:20]=[C:21](Br)[C:22]2[N:23]([CH:25]=[CH:26][N:27]=2)[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:21]3[C:22]4[N:23]([CH:25]=[CH:26][N:27]=4)[CH:24]=[C:19]([Br:18])[N:20]=3)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(N)cc21
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1ccc2ccc(Nc3nc(Br)cn4ccnc34)cc21

Procedure:
A quantity of 0.23 g (1 mmole) of 6-Amino-indole-1-carboxylic acid tert-butyl ester is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-indole-1-carboxylic acid tert-butyl ester. 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-indole-1-carboxylic acid tert-butyl ester is treated with an excess of TFA in dichloromethane at room temperature for 2 hrs. The reaction solution is evaporated in vacuo and partitioned between saturated Na2CO3 and ethyl acetate; the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(1H-indol-6-yl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CNCc1cc(Cl)cc(Cl)c1)OC
Temperature: 25 °C

Procedure:
A mixture of [(3,5-dichlorophenyl)methyl]amine (100 mg), 2-bromo-1, 1bis(methyloxy)ethane (123 μL) and K2CO3 (95 mg) in anhydrous DMF (2 mL) was processed by microwave irradiation at 150° C. for 10 min (3 cycles). The mixture was allowed to cool to rt, water was added and mixture extracted three times with AcOEt, the organic phases collected, washed with brine, dried and evaporated under vacuum to give a crude which was purified by flash cromathography eluting with CH:AcOEt=9:1 to 85:15 to afford the title compound (120 mg) as a colourless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-2-methylpyridine (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (388 mg, 72%) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([O:7][CH:8]([CH3:10])[CH3:9])[NH:3]1.[Li+].CCC[CH2-].[CH:16]([S:24](Cl)(=[O:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.CCCCCC>[CH:16]([S:24]([N:3]1[CH:4]([O:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][C:2]1=[O:1])(=[O:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CC(C)OC1CCC(=O)N1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)OC1CCC(=O)N1S(=O)(=O)C=Cc1ccccc1
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a solution of 3.53 g of 2-oxo-5-isopropyloxy pyrrolidine in 85 cm3 of anhydrous tetrahydrofuran, cooled to -10° C., 15.42 g of a 1.6M solution of N-butyllithium in hexane is added, operating at -10° to -5° C. This is agitated for 30 minutes, while cooling to -45° C., then a solution of 5 g of styrenesulphonyl chloride (CA 47, 3262c, 1953) in 35 cm3 of anhydrous tetrahydrofuran is added slowly, while operating at -45° to -40° C. After allowing a return to ambient temperature, the solvent is evaporated off under reduced pressure and the residue is chromatographed on silica, eluting with a mixture of ethyl ethyl acetate and hexane (1--1). The product obtained is crystallized from ethanol, and 3.1 g of the expected product is obtained. m.p. 92°-94° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1
Product: Clc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,6-dichloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-chloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.