Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: Cc1ccccc1
Solvent: CCO
Product: CCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-butoxyphenyl borate (0.45 g) and potassium carbonate (0.58 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.12 g), and the mixture was refluxed for 20 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) to give colorless crystals of methyl 7-(4-butoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (672.6 mg).
Reaction SMILES: C(N(CC)CC)C.O[C@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@@H:10]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)S(Cl)(=O)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>ClCCl.O.CN(C=O)C>[N:35]([C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@@H:10]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccccc2O[C@H](c2ccccc2)[C@H]1O
Agent: O=S(=O)(Cl)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.667 g, 16.472 mmol) was added via syringe to a stirred solution of (2R,3R)-3-hydroxy-2-phenyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (64c) (2.532 g, 9.922 mmol) in dichloromethane (90 mL) under nitrogen at −40° C. Next trifluoromethanesulfonyl chloride (2.541 g, 15.080 mmol) was added slowly via syringe and the mixture kept at −25° C. for 2 h. Additional triethylamine (1.667 g, 16.472 mmol) was added followed by trifluoromethanesulfonyl chloride (2.541 g, 15.080 mmol) and the reaction was kept for 8 h at −25° C. Again, additional triethylamine (1.667 g, 16.472 mmol) was added via syringe followed by trifluoromethanesulfonyl chloride (2.541 g, 15.080 mmol) and the reaction was kept for 24 h at −25° C. The solvent was evaporated without heating under reduced pressure and the residue dissolved in DMF (25 mL). Sodium azide (3.000 g, 46.15 mmol) was added to the stirred DMF solution at −10° C. and the reaction was allowed to warm to ambient temperature. After 2 h the reaction was diluted with water (300 mL) and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and then with brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography an silica gel eluting with 30:1 (v/v) dichloromethane: ethyl acetate to afford the title compound as an off-white solid. TLC Rf=0.35 (20:1 (v/v) dichloromethane: ethyl acetate). 1H NMR (300 MHz, CDCl3) δ4.45 (d, 1H, J=6 Hz), 5.56 (d, 1H, J=6 Hz), 7.00-7.07 (m, 1H), 7.10-7.26 (m, 3H), 7.40-7.46 (m, 3H), 7.51-7.61 (m, 3H). MS APCI, m/z=253 (M+1-N2). LC/MS: 2.25 min. [α]D25=−179° (c=5.0, CHCl3)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:13][CH:22]=[C:20]([CH2:19][Cl:18])[N:14]=2)[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2cccc(OCc3ccccc3)c2)n1
Yield: 26 %

Procedure:
In substantially the same manner as in Reference Example 31, 3-benzyloxybenzamide was allowed to react with 1,3-dichloroacetone to give 2-(3-benzyloxyphenyl)-4-chloromethyloxazole. The yield was 26%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 49-50° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:19]
Reactant: BrCCOc1ccccc1
Reactant: COC(=O)c1ccc2ccccc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccccc2c1OCCOc1ccccc1
Yield: 85.1 %

Procedure:
To 22.81 g cesium carbonate and 7.08 g methyl 1-hydroxy-2-naphthoate in 70 ml abs. DMF was added 7.39 g (2-bromo-ethoxy)-benzene and the mixture was reacted for 16 h at 80° C. The reaction was poured unto ice, neutralized with 2 M hydrochloric acid, and extracted with ethyl acetate twice. The combined organic phases were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The resulting residue was purified by crystallization from pentane to yield 9.60 g of 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:36][CH2:35][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH2:33][CH3:34])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[CH3:46][O:47][CH:48]([O:56][CH3:57])[CH2:49][NH:50][CH:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:18][CH2:19][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH2:33][CH3:34])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:35][CH2:36]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([N:50]([CH:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)[CH2:49][CH:48]([O:56][CH3:57])[O:47][CH3:46])=[O:11]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
Reactant: COC(CNC1CCCC1)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)N(CC(OC)OC)C5CCCC5)c4Cl)CC3)C2)cs1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid (9.8 g) in DCM (100 mL) was added Hunig's Base (9.58 mL). The reaction was stirred for 10 mins before the addition of N-(2,2-dimethoxyethyl)cyclopentanamine (4.12 g) followed by HATU (7.65 g). After 1 h, the reaction mixture was diluted with DCM (200 mL) and washed with saturated sodium bicarbonate (300 mL) followed by water (300 mL). The DCM solution was dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by silica chromatography, eluting with 2 to 5% 7N/NH3/methanol in dichloromethane to afford 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)-N-cyclopentyl-N-(2,2-dimethoxyethyl)propanamide (12.0 g) as a pale yellow gum.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[NH:16][C:15](=[O:24])[N:14]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]3=[O:30])[CH:9]=1)=O.C([NH2:33])=O.C[O-].[Na+]>CN(C)C=O>[CH3:29][S:26]([NH:25][N:14]1[C:13](=[O:30])[C:12]2[C:17](=[CH:18][C:19]([C:20]([F:22])([F:21])[F:23])=[C:10]([N:8]3[CH:9]=[C:5]([C:3]([NH2:33])=[O:2])[N:6]=[CH:7]3)[CH:11]=2)[NH:16][C:15]1=[O:24])(=[O:27])=[O:28]
Reactant: NC=O
Reactant: COC(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3cnc(C(N)=O)c3)cc2c1=O
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A solution of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methyl ester (50 mg, 0.112 mmol) and formamide (0.15 ml, 0.374 mmol) in 5 ml of dimethylformamide is heated to 120° C. and sodium methylate (6 mg, 0.112 mmol) is added under stirring. After two hours at 120° C. the solution is cooled to room temperature, evaporated in vacuo and the residue chromatographed to give 30 mg (0.069 mmol, 62%) of amorphous 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H -imidazole-4-carboxylic acid amide, ES-MS: m/z 433 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:6].[Cl-].[NH4+]>CCOCC>[CH3:6][CH:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH3:1])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:4]
Reactant: CC(C)N1CCCc2cc(C=O)ccc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1ccc2c(c1)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.9 ml (15 mmol) of a 3.0M ethereal solution of methylmagnesium bromide was diluted with 15 ml of ether. An ethereal solution of 2.0 g (10 mmol) of 1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde was dropped into the dilution prepared above at room temperature. The obtained mixture was stirred at room temperature for one hour, followed by the addition of an aqueous solution of ammonium chloride. The resulting mixture was extracted with thyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum to give 2.1 g of the title compound as a brown oil.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[N:22]([NH2:23])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:33](Cl)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:11][CH2:12][C:13]1[N:22]([NH:23][C:33](=[O:35])[CH3:34])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 2-carbobenzoxyaminomethyl-3-amino-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (2.36 g) in dimethylformamide (15 ml), acetyl chloride (0.79 g) is added, and the resultant mixture is stirred at room temperature for 5 hours and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The organic layer is washed with water and evaporated to give 2-carbobenzoxyaminomethyl-3-acetamido-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][S:8][CH:7]([C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:23]([OH:25])=O)=[O:12])[CH2:6]1.C[CH2:31][N:32](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN>CN(C=O)C>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][S:8][CH:7]([C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:23](=[O:25])[NH:32][CH3:31])=[O:12])[CH2:6]1
Reactant: O=C(O)c1n[nH]c2ccc(NC(=O)C3CN(Cc4ccccc4F)CCS3)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1n[nH]c2ccc(NC(=O)C3CN(Cc4ccccc4F)CCS3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4-(2-fluorobenzyl)thiomorpholine-2-carboxamido)-1H-indazole-3-carboxylic acid (41 mg, 0.1 mmol) and DIEA (35 μL) in DMF was added HATU (38 mg, 0.1 mmol). The resulted solution was stirred for 10 min before methyl amine hydrochloride (13 mg, 0.2 mmol) and DIEA (17 μL) in DMF (0.5 mL) was added. The reaction mixture was stirred at room temperature for overnight and was purified using prep-HPLC to give the desired product (14 mg). LC-MS: 428.27 [M+H].
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:37][O:38][C:39](=[O:40])[C:41]1[CH:46]=[CH:45][C:44]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:43][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 71.7 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 1.0 g, 1.92 mmol), 4-methoxycarbonylphenylboronic acid (0.86 g, 4.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (134 mg, 0.02 mmol) in dioxane (16 mL) was added an aqueous sodium carbonate solution (2 M, 2.4 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-benzoic acid methyl ester (0.67 g, 72%) as a white solid: LC/MS m/e calcd for C28H26N2O4S [M+H]+ 487.59, observed 487.0.
Reaction SMILES: [ClH:1].[C:2]1([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH2:29])=[NH:28])[CH2:20][CH2:19]3)=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[ClH:1].[C:2]1([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH2:29])=[NH:28])[CH2:22][CH2:23]3)=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)c1cccc(C2CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N=C(N)c1cccc(C2CCN(C(=O)c3cncc(CCc4ccccc4)c3)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
A solution of 3-[1-(5-phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzamidine hydrochloride (Example 46) (150 mg) in ethanol (5 ml), treated with 10% palladium on carbon (15 mg) and stirred at ambient temperature under an atmosphere of hydrogen for 5 hours. The reaction mixture is filtered through a short pad of hyflo and concentrated under vacuum to give the title compound as a colourless oil (150 mg). 1H NMR (DMSO, 500 MHz) δ8.48 (m, 2H), 7.78 (s, 1H), 7.65 (m, 3H), 7.59 (m, 1H), 7.20 (m, 5H), 4.63 (br m, 1H), 3.57 (br m, 1H), 3.18 (br m, 1H), 2.90 (m, 6H), 1.70-1.90 (br m, 4H). EI MS M++H: 413.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[Br:14][C:11]1[CH:10]=[N:9][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:13][CH:12]=1
Reactant: C1COCCN1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
Potassium carbonate (0.34 g) was added to a solution of 2-chloro-5-bromo-pyrimidine (0.5 g) in DMF (20 ml). The reaction mixture was stirred at rt for 15 min. Morpholine (0.2 g) was added and the reaction mixture was stirred at rt for 2 h. The excess DMF was removed by evaporation and the residue was partitioned between H2O/EtOAc (30:30 ml) The EtOAc layer was dried (MgSO4) and evaporated to dryness to give the sub-title compound as a cream solid (0.2 g). LCMS electrospray(+ve) 246 (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:13]I>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:13]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: CI
Product: COc1ccccc1OC(F)(F)F
Reaction time: 17 h
Yield: 78 %

Procedure:
2-Trifluoromethoxyanisole was prepared from 2-trifluoromethoxyphenol by following Method C in 78% yield. Methyl iodide was used in this reaction as an alkylating agent and the reaction was conducted at room temperature for 17 h. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:17])[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1>C1(C)C=CC=CC=1>[NH2:17][C:10]1[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(-c2cn3ccnc3c(N)n2)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: Nc1nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)cn2ccnc12

Procedure:
(FIG. 1) Procedure: A mixture of 1.00 eq. of 6-(4-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamine, 1.50 eq. of phenylisocyanate, and 2.00 eq. of N-methylmorpholine, in toluene is mixed at room temperature for 2 hr. The mixture is partitioned between 1 N NaOH and ethyl acetate and extracted three times. The organic extracts are combined and dried over MgSO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (50% ethyl acetate/hexanes) to yield 8.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:21]2[C:29]3[C:24](=[C:25]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)([CH2:19][CH3:20])[CH:17]=[O:18])=[CH:12][CH:11]=1>CS(C)=O.C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:21]2[C:29]3[C:24](=[C:25]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)([CH:17]2[CH2:4][O:18]2)[CH2:19][CH3:20])=[CH:12][CH:11]=1
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)cc1)(C1CO1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C

Procedure:
To a solution of NaH (41 mg, 0.764 mmol, 60% in oil) in DMSO (15 mL) at 0° C. was added trimethylsulfoxonium iodide (235 mg, 1.07 mmol) divided into several portions. The mixture was stirred at room temperature until the mixture became clear. To the solution of tert-butyl 1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indol-4-ylcarbamate (210 mg, 0.509 mmol), as described in Example 21 Step B, in THF (15 mL) was added the upper solution dropwise at 0° C. Then the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a colorless solid. LC/MS m/z=448.9[M+Na]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[C:10]1([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[Cl:5][CH2:6][C:7]([C:13]1[CH:14]=[CH:15][C:10]([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:11][CH:12]=1)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)NCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NCCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
Aluminium chloride (1.63 g) was dissolved in 1,2-dichloroethane (15 mL). Chloroacetylchloride (0.732 mL) was added to the mixture at 0° C., and stirred additionally for 20 minutes, then N-(2-phenylethyl)acetamide (1 g) in 1,2-dichloroethane (5 mL) was added dropwise. The mixture was stirred for 1 hour at room temperature, and then poured into ice water. The mixture was extracted with chloroform, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The solid was washed with ethyl acetate and ethyl ether, and dried in vacuo to give N-{2-[4-(2-chloroacetyl)phenyl]ethyl}-acetamide as a white powder (1.18 g, 80.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N:9]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[NH:1]([C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)[NH2:9]
Reactant: O=N[O-]
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
To a stirred, ice cooled solution of 3-aminophenol (2.00 g, 18.3 mmol) in concentrated HCl (20 mL) was added dropwise a solution of sodium nitrite (1.33 g, 19.24 mmol) in H2O (10 mL), ensuring the internal temperature did not exceed 10° C. After 10 min, a solution of tin (II) chloride (7.645 g, 40.3 mmol) in concentrated HCl (10 mL) was added dropwise, and the ice bath removed. After stirring at RT for 45 min, the reaction was basified to pH 10 with careful addition of 10 M NaOH solution (50 mL), and then extracted with EtOAc (3×). The organic extracts were dried over MgSO4, concentrated in vacuo and triturated with Et2O to afford the title compound as a brown solid (353 mg, 16%). 1H NMR (300 MHz, d6-DMSO): 3.83 (2H, br s), 5.96-6.02 (1H, m), 6.15-6.21 (1H, m), 6.22 (1H, t, J=2.2 Hz), 6.52 (1H, br s), 6.84 (1H, t, J=8.0 Hz), 8.91 (1H, br s).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].C(=O)([O-])O.[Na+].[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][NH:8][C:17](=[O:19])[CH3:18])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CCOC(CCCN)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(CCCNC(C)=O)OCC
Temperature: 0 °C
Reaction time: 6 h

Procedure:
35.8 g (0.2 mol) of 4-aminobutyraldehyde-diethylacetal (90%) are dissolved in 600 ml of dichloromethane, 300 ml of saturated sodium hydrogen carbonate solution are added, and the mixture is cooled to 0° C. 17 ml (0.24 mol) of acetyl chloride are added dropwise at 0°-5° C., and the mixture is stirred for a further 6 hours at 0°-5° C. The organic phase is separated off and the aqueous phase is extracted twice more with dichloromethane. The organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation in a rotary evaporator. The residue is purified by chromatography on silica gel with ethyl acetate. 4-(N-acetylamino)butyraldehyde-diethylacetal is obtained in the form of a yellowish oil.