Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:14]([NH2:16])=O)[C:10](=O)[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[N:11]=[N:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]=1[C:14]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Solvent: O
Product: N#Cc1cc(-c2ccccc2)nnc1Cl
Temperature: 80 °C

Procedure:
1.5 g of the product obtained in Example 1 are dissolved in 20 ml of phosphorus oxychloride and the solution is then heated at 80° C. for 5 hours. The mixture is poured into 50 ml of water. A precipitate appears, which is filtered off and dried.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18](=[O:30])[CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOC(C)=O.CCCCCC>ClC1C=CC=CC=1Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[CH:22]=[C:21]3[CH2:20][CH2:19][C:18](=[O:30])[C:17]=23)=[CH:12][CH:11]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C#CC(=O)CC/C=C/c2ccc(Cl)cc2)cc1
Solvent: CCCCCC
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2c3c(cc4ccc(Cl)cc24)CCC3=O)cc1

Procedure:
To a 10-20 mL microwave irradiation vial equipped with a stir bar was added compound 14b (0.18 g, 0.41 mmol) in 1,2-dichlorobenzene (10 mL). The reaction was irradiated with stirring at 225° C. for 60 min until complete by TLC (AcOEt/n-hexane 1:9). The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then AcOEt/n-hexane 1:9 to collect the pure product. The title compound was isolated as a white solid in a quantitative yield (0.19 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@:7]1([CH3:14])[C:11]([OH:13])=[O:12])=[O:5].[H][H]>CO.[Pd]>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@:7]1([CH3:14])[C:11]([OH:13])=[O:12])=[O:5]
Reactant: [H][H]
Reactant: C[C@]1(C(=O)O)CCCN1C(=O)c1c(N)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: C[C@]1(C(=O)O)CCCN1C(=O)c1c(N)cccc1N

Procedure:
366 mg (1.25 mmol) (R)-1-(2-amino-6-nitro-benzoyl)-2-methyl-pyrrolidine-2-carboxylic acid are dissolved in 50 mL methanol and combined with 40 mg palladium on charcoal (10% Pd). The reaction mixture is hydrogenated for 9 h at 5 bar hydrogen pressure and at 25° C. Then the catalyst is filtered off, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the end point.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13]C1C=CC=CC=1.[N:20]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.S(=O)(=O)(O)O.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:20]
Reactant: FC(F)(F)c1cc(Cl)c(Nc2ccccc2)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 107.5 %

Procedure:
2,6-Dichloro-4-trifluoromethylphenylaniline (4.3 g) (described in U.S. Pat. No. 3,850,955) was dissolved, with stirring, in glacial acetic acid (23 ml). A solution of sodium nitrite (1.5 g) in concentrated sulphuric acid (11 ml) was then added at 55°-60° C. The solution thus obtained was cooled to 0°-5° C. and a solution of stannous chloride (16.4 g) in concentrated hydrochloric acid (14 ml) was added with vigorous stirring. A cream-coloured solid precipitated. The mixture was filtered and the solid obtained was added to a mixture of aqueous ammonium hydroxide solution and ice. The mixture thus obtained was extracted with diethyl ether (6×500 ml) and the combined ethereal extracts were dried over sodium sulphate, filtered and evaporated to dryness to give 2,6-dichloro-4-trifluoromethylphenylhydrazine (3.7 g), m.p. 54°-56° C., in the form of a colourless crystalline solid. By proceeding in a similar manner, but replacing the 2,6-dichloro-4-trifluoromethylaniline by 2-chloro-4-trifluoromethylaniline (described in U.S. Pat. No. 3,850,955), there was prepared:
Reaction SMILES: [C:1]([Cl:4])(=O)C.Cl.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CO>[ClH:4].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:1])=[O:12]
Reactant: NCCCCC(=O)O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: COC(=O)CCCCN

Procedure:
Acetyl chloride (5 mL) was added into methanol (150 mL) to prepare hydrogen chloride in methanol solution, and 5-aminopentanoic acid (1 g) was added. The mixture was kept at the room temperature overnight, and evaporated to isolate methyl 5-aminopentanoate hydrochloride. A mixture of the methyl 5-aminopentanoate hydrochloride (251 mg), cinnamoic acid (74 mg), HBTU (168 mg), diisopropylethylamine (0.87 mL), and dimehylformamide (2 mL) was kept at the room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water twice (10 mL each) followed by brine (10 mL), dried (Na2SO4), and evaporated to isolate (4-methoxycarbonyl)butyl cinnamamide (1, 100 mg). A mixture of (4-methoxycarbonyl)butyl cinnamamide (1, 100 mg), benzaldehyde phenylhydrazone (2, 113 mg), chloramine-T trihydrate (160 mg), and methanol (2 mL) were heated under refluxing for 22 hours. The reaction mixture was diluted with 50% ethyl acetate in n-hexanes (40 mL), filtered, and evaporated. The residue was purified by column chromatography (silica gel 20 g, eluent: 0 to 10% ethyl acetate gradient in hexanes) to isolate methyl 5-(1,3,5-triphenyl-4,5-dihydro-pyrazole-4-carbonyl) aminopentanoate (3, 13 mg) and methyl 5-(1,3,4-triphenyl-4,5-dihydro-pyrazole-5-carbonyl)aminopentanoate (4, 103 mg). Regiochemistry of each isomer was identified by 1H- and 13-C NMR chemical shifts of the CH adjacent to the amide carbonyl. 5-(1,3,5-Triphenyl-4,5-dihydro-pyrazole-4-carbonyl)aminopentanoic acid (5, FN1-9U) were obtained from 3 by a standard ester hydrolysis condition as shown in the preparation of FN1-2. MS: 464.9 (M+Na), 442.9 (M+H), 325.8, 297.9. 5-(1,3,4-Triphenyl-4,5-dihydro-pyrazole-5-carbonyl)aminopentanoic acid (6, FN1-9S) were obtained from 4 by a similar manner to the preparation of FN1-2. MS: 464.9 (M+Na), 442.9 (M+H), 325.8, 297.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>C(Cl)Cl>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.18 g (54 mmol) of 5-aminoindane and 10.9 g (108 mmol) of triethylamine in 40 mL of CH2Cl2 is cooled to 5° C. Acetic anhydride (7.63 g, 81 mmol) is added carefully dropwise. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is poured into 1 N HCl to acidify it and is then extracted with EtOAc. The organic layer is evaporated in vacuo. Toluene is added to the residue and the mixture is evaporated in vacuo to give 5-acetylaminoindane that was used without purification. 5-Acetylaminoindane (8.8 g) is dissolved in a solution of 26 mL of HOAc and 126 mL of acetic anhydride, and cooled to 0° C. Nitric acid (8.3 mL) is added carefully dropwise to the solution so as to control the temperature of the exothermic reaction. The mixture is stirred for an additional 30 minutes and is poured onto ice and filtered. The solid is washed with water and dried in a vacuum oven overnight to give 5-acetylamino-6-nitroindane that is used without further purification. A mixture of this solid in 230 mL of 6 N HCl is heated to reflux for 4 hours. The mixture is neutralized with Na2CO3 (152 g) in 1000 mL of H2O. The solids are filtered and dried overnight in a vacuum oven to give 5-amino-6-nitroindane.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[O:29][CH2:30][CH3:31])[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:32])C.[Li+].[OH-]>>[CH2:34]([O:33][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[O:29][CH2:30][CH3:31])[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:32])[C:4]([OH:36])=[O:3])[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(F)cc3OCC)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)O)c(C)c2)c(C)o1

Procedure:
In analogy to the procedure described in example 1 g], [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid as colorless solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[N-:22]=[N+:23]=[N-:24].[Li+]>CN1CCCC1=O.O>[N:22]([CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Agent: Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)Cn1c(CN=[N+]=[N-])nc2c(N)nc3ccccc3c21

Procedure:
2-Chloromethyl-1(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (2.5 g; 0.0077 mol, Example 10) was suspended in N-methylpyrrolidone (15 mL). A solution of lithium azide (2.3 g) in water (45 mL) was added to the suspension. The resulting mixture was heated on the steam bath for 2 hr and then diluted with water (about 45 mL). The tan solid was washed with water and dried to yield 1.4 g (60.9%) of crude product. The solid was recrystallized from ethanol to give a pure product m.p. 174-178° C. Analysis: C, 61.0; H, 5.8; N, 33.2. Found: C, 60.9; H, 5.6; N, 32.6.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)O[C:37](=O)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]1=2)=O>ClCCl>[O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]([O:19][CH2:37][C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: O=C([O-])c1ncccc1-c1ccc(CCCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CCCc1ccc(-c2cccnc2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-[4-(3-hydroxypropyl)phenyl]pyridine-2-carboxylate (245 mg, 0.704 mmol) in dichloromethane (3 ml) and pyridine (357 uL, 3.52 mmol) was added a solution of Dess-Martin periodinane (358 mg, 0.845 mmol) in dichloromethane (3 mL). After stirring at rt for 30 min, the reaction was quenched by addition of a mixture of 15% Na2S2O3 (2 mL) and saturated NaHCO3 (3 mL). The organic layer was separated and the aqueous layer was extracted by ethyl acetate (3×). The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated, and the residue was purified by flash column chromatography on silica gel eluting 10-50% ethyl acetate in hexanes) to afford the title compound. LC-MS: m/e 346 (M+H)+. 1HNMR (CDCl3, 500 MHz): δ 9.86 (1H, t, J=1.5 Hz), 8.68 (1H, dd, J=4.5, 1.7 Hz), 7.76 (1H, dd, J=8.0, 1.7 Hz), 7.48 (1H, dd, J=8.0, 4.5 Hz), 7.30 (3H, m), 7.26 (2H, d, J=8.0 Hz), 7.19 (2H, d, J=8.0 Hz), 7.14 (2H, dd, J=7.5, 2.0 Hz), 5.22 (2H, s), 3.00 (2H, t, J=7.5 Hz), 2.82 (2H, t, 7.5 Hz).
Reaction SMILES: [C:1]([C:5]1[C:13]2S[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.CC[O:27]C(C)=O>CCO>[NH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]2[O:27][CH2:11][C:10]([CH3:14])([CH3:15])[C:9]=2[CH:8]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2c1SCC2(C)C
Reactant: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reaction time: 3 h

Procedure:
A suspension of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-nitro-benzothiophene (2.6 g, 8.8 mmol) in absolute EtOH (60 mL) is hydrogenated at 40 psi of H2 pressure on a Parr hydrogenation apparatus for 3 h at 22° C. The reaction is judged complete by TLC (hexane:EtOAc, 19:1; visualized with Dragendorff reagent). The reaction mixture is filtered through Celite and evaporated to yield the title compound as a purple solid, which is used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CC(C)=O>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cc1ccc(OCCCCl)cc1
Temperature: 80 °C
Yield: 93 %

Procedure:
A solution of 4-hydroxyphenylacetone (4.5 g, 30 mmol) and potassium carbonate (4.14 g, 3.0 eq.) in 50 mL of acetone was stirred under N2 as 1-bromo-3-chloro-propane was added dropwise. The reaction was heated to 80° C. overnight. The mixture was then filtered through celite, washed with acetone and concentrated to afford 1-[4-(3-chloro-propoxy)phenyl]propan-2-one (6.3 g, 93% yield): MS m/z 227 (M+H).
Reaction SMILES: [Si]([O:8][C:9]([C:18]1[CH:48]=[CH:47][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])=[O:39])=[C:33]([Cl:46])[CH:32]=3)=[O:30])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])(C(C)(C)C)(C)C.[F-].[K+]>O1CCCC1>[Cl:46][C:33]1[CH:32]=[C:31]([C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([C:9]([OH:8])([C:14]([F:16])([F:15])[F:17])[C:10]([F:12])([F:13])[F:11])=[CH:48][CH:47]=3)[CH2:28][CH2:27]2)=[O:30])[CH:36]=[CH:35][C:34]=1[NH:37][C:38]([NH:40][CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])=[O:39]
Reactant: CC(C)(O)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(O)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
To a stirring solution of 1-(4-(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)benzyl)piperazine-1-carbonyl)-2-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)urea (0.262 mmol, 190 mg) in tetrahydrofuran (1 mL) was added potassium fluoride (50% weight on celite) (0.524 mmol, 60.9 mg). The resulting suspension was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite and concentrated under vacuum. The resulting residue was purified by SCX chromatography, followed by column chromatography (5-10% methanol in dichloromethane) to afford the title compound (55.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:3]=12.[CH3:35][N:36]([CH3:46])[C:37]([C:39]1[CH:44]=[N:43][CH:42]=[C:41](Cl)[N:40]=1)=[O:38].C(=O)(O)[O-].[Na+]>C(#N)C.C1(C)C=CC=CC=1.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:35][N:36]([CH3:46])[C:37]([C:39]1[CH:44]=[N:43][CH:42]=[C:41]([C:7]2[C:2]([Cl:1])=[C:3]3[C:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[CH:18][N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:4]3=[N:5][CH:6]=2)[N:40]=1)=[O:38]
Reactant: CN(C)C(=O)c1cncc(Cl)n1
Reactant: CC1(C)OB(c2cnc3c(c(-c4ccc(F)cc4)cn3COCC[Si](C)(C)C)c2Cl)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1cncc(-c2cnc3c(c(-c4ccc(F)cc4)cn3COCC[Si](C)(C)C)c2Cl)n1
Temperature: 110 °C
Yield: 62.3 %

Procedure:
45 mg (84 mmol) of 4-chloro-3-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine, 5 mg (6 μmol) of (1,1′-bis(diphenylphosphino)ferrocene palladium(II)-dichloride dichloromethane adduct and 25 mg (0.13 mmol) of 6-chloro-pyrazine-2-carboxylic acid dimethylamide were dissolved in a mixture of 1 mL of acetonitrile and 1 mL of toluene. 2 mL of a saturated aqueous solution of sodium bicarbonate was added and the resulting mixture heated in closed vial to 110° C. for 18 h. The aqueous layer was removed and the organic phase evaporated. The residue was purified by flash chromatography on silica gel using a gradient of 10% v/v of methanol in ethyl acetate and hexanes to afford 46 mg (81 μmol, 97%) of 6-[4-chloro-3-(4-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazine-2-carboxylic acid dimethylamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:27])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:41])([F:40])[F:28])=[CH:31][CH:32]=3)=[CH:21][CH:20]=2)=[O:26])[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1ccc(C(F)(F)F)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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 86.4 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{[(4-bromobenzoyl)amino]methyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 455-1 and 4-trifluoromethylphenylboric acid (363 mg) were dissolved in dioxane (8 mL) and 2 M aqueous sodium carbonate solution (4 mL), tetrakis(triphenylphosphine)palladium (73 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (590 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])[CH:7]=1.[I-:20].[Na+].C[Si](C)(C)N[Si](C)(C)C.CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[CH2:18]([C:5]1[CH:4]=[CH:3][C:2]([I:20])=[CH:7][C:6]=1[CH:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH:10]([CH2:11][CH2:12]2)[C:9]1=[O:17])[CH3:19]
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1COCCO1
Product: CCc1ccc(I)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 180 °C
Yield: 99.6 %

Procedure:
To a microwave vial is added 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (1.00 g, 3.11 mmol), sodium iodide (0.93 g, 6.23 mmol), hexamethyldisilazane (0.45 g, 3.11 mmol), copper(I) iodide (0.03, 0.15 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.044 g, 0.31 mmol) then degassed dioxane (5 ml). After purging with nitrogen the mixture is heated at 180° C. for 1 hour under microwave irradiation. The mixture is cooled to room temperature, quenched with 2M hydrochloric acid and extracted with dichloromethane (×2). Organic fractions are combined, washed with saturated aqueous sodium metabisulfite, dried over magnesium sulfate then filtered. The filtrate is concentrated in vacuo, then purified by flash column chromatography (20% to 100% ethyl acetate/hexane eluant ratio) to afford 3-(2-ethyl-5-iodophenyl)bicyclo[3.2.1]-octane-2,4-dione (1.14 g, 100%) as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:7]2=[N:6][C:5]=1[CH3:14])#[N:2].C(N([CH2:20][CH3:21])CC)C>CO>[C:1]([CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][C@H:11]3[C:20]4[C:21](=[CH:1][CH:3]=[CH:4][CH:5]=4)[CH2:7][C@@H:12]3[OH:13])[C:7]2=[N:6][C:5]=1[CH3:14])#[N:2]
Reactant: Cc1nc2c(O)cccn2c1CC#N
Reactant: CCN(CC)CC
Solvent: CO
Product: Cc1nc2c(O[C@H]3c4ccccc4C[C@@H]3O)cccn2c1CC#N
Yield: 18.8 %

Procedure:
750 mg 3-cyanomethyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine are reacted, analogously to the method described in Example 21, with 210 mg (-)-1R,2S-indenoxide and 400 mg triethylamine in aqueous methanol (60 ml methanol+15 ml water) at room temperature. After 3 days the solution is evaporated and the residue taken up in 50 ml water. The precipitate is filtered off and purified by chromatography over silica gel (mobile phase: ethyl acetate/methanol=10:1). After evaporation the residue is precipitated from methylene chloride/cyclohexane. 120 mg of the title compound is isolated. [α]D22 =+113° (c=1, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[Br:16]Br>C(Cl)Cl>[NH2:1][C:2]1[C:13]([Br:16])=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: BrBr
Reactant: CCN(CC)Cc1cc(OC)ccc1N
Solvent: ClCCl
Product: CCN(CC)Cc1cc(OC)cc(Br)c1N

Procedure:
2-Amino-3-bromo-N,N-diethyl-5-methoxy-benzylamine was prepared from 2-amino-N,N-diethyl-5-methoxy-benzylamine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [CH2:1]([C:5]([CH2:10][OH:11])([CH2:8][SH:9])[CH2:6][SH:7])[CH:2](C)[CH3:3].C(OCC(CCC)(CO)CO)C1C=CC=CC=1>>[OH:11][CH2:10][C:5]([CH2:1][CH2:2][CH3:3])([CH2:8][SH:9])[CH2:6][SH:7]
Reactant: CC(C)CC(CO)(CS)CS
Agent: CCCC(CO)(CO)COCc1ccccc1
Product: CCCC(CO)(CS)CS

Procedure:
2-hydroxymethyl-2-n-propyl-propan-1,3-dithiol was prepared in an analogous manner to 2-i-butyl-2-hydroxymethyl-propan-1,3-dithiol starting from 2-benzyloxymethyl-2-n-propyl-propan-1,3-diol.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1O>>[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C[C@@H]1CCCC[C@H]1O
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@@H]1C)C(C)=O
Yield: 8.5 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (3.48 g) was reacted with trans-2-methylcyclohexanol as described in Example 4a, method 3 to give the title compound (0.476 g, 8.5%), as a colourless liquid, νmax (film) 2930, 1740 and 1690 cm-1, δH (CDCl3) 0.95 (3H, d, J 6.9 Hz), 1.34 (3H, t), 1.3-2.1 (9H, m), 2.40 (3H, s), 4.36 (2H, q), and 4.39 (1H, m).