Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH2:19]([NH:21][CH2:22][CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[CH3:20]>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:25]3[CH2:26][CH2:27][CH:23]([CH2:22][NH:21][CH2:19][CH3:20])[CH2:24]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCNCC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CC)C1
Yield: 53.5 %

Procedure:
1 00 g (3.69 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-napthyridine-3-carboxylic acid, 100 ml acetonitrile and 1.42 g (11.08 mmole) of N-ethyl-3-pyrrolidinemethanamine were stirred for three days at room temperature. The reaction mixture was then filtered, and the precipitate washed with water, ethanol/ether (1:3), and finally with ether until dry to give 0.715 g of 1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8 -napthyridine-3-carboxylic acid, mp 229.5°-231.5° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]2=[O:30])=[CH:9][CH:8]=1)(=O)=O.[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2B(O)O)[CH:36]=[CH:35][CH:34]=1.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.CC#N>[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:14]3=[O:30])=[CH:11][CH:12]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)n(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c2ncccc21
Reactant: OB(O)c1cccc2cccnc12
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: CC#N
Product: C[Si](C)(C)CCOCn1c(=O)n(-c2ccc(-c3cccc4cccnc34)cc2)c2ncccc21
Temperature: 150 °C
Yield: 85.7 %

Procedure:
The mixture of 4-(2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl trifluoromethanesulfonate (500 mg), 8-quinolineboronic acid (265 mg), Pd(Ph3P)4 (35.4 mg), 2 M Na2CO3 (1.02 mL) and CH3CN (10 mL) was heated at 150° C. for 20 min under microwave irradiation. The mixture was diluted with sat.NaHCO3aq. at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-(4-quinolin-8-ylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (410 mg) as white crystals.
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)=[O:2].C[Li].[CH3:17]COCC>O1CCCC1>[OH:2][CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)[CH3:17]
Reactant: CC(C)c1ccc(C=O)c(=O)c(O)c1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(C)O)c(=O)c(O)c1
Temperature: -78 °C

Procedure:
7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (2.00 g, 10 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to -78° C. in a dry ice/acetone bath. A solution of methyllithium the ether (1.4M, 15 ml) was added dropwise to the solution, then dry ice/acetone bath was removed and stirring was continued until the insolubles were dissolved. An aqueous saturated ammonium chloride was added to the reaction mixture and extracted with methylene chloride. The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate and solvent was distilled off to give 2.18 g of 7-(α-hydroxyethyl)-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-l-one as a reddish brown oil (yield: quantitative).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A suspension of methyl 3-(4-benzyloxyphenyl)propanoate in ethanol (200 ml) and THF (100 ml) was treated with an aqueous solution of potassium hydroxide (6.7 g, 1.5 N, 101.2 mmol). The mixture was stirred at 60° C. for 1.5 hours, cooled to room temperature, adjusted to pH 3-4 with 1N HCl. The solvent was removed in vacuo to give the title material (12.8 g, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([NH:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:15])[C:8]([CH3:11])=[CH:9][N:10]=1
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Reactant: NCCc1cccnc1
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCCc1cccnc1

Procedure:
3-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 3-(2-aminoethyl)pyridine essentially according to the procedure of Example 1, Step K. It was characterized as the hydrochloride salt. Mass Spectrum: Found: (M+1) 429.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13]2)=[O:8].C1(C)C=CC(S(O[CH2:34][C@@H:35]2[O:37][CH2:36]2)(=O)=O)=CC=1.O>CN(C)C=O>[O:37]1[CH2:36][C@@H:35]1[CH2:34][O:18][C:17]1[C:9]([CH:7]=[O:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCOC(=O)c1cc2c(C=O)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C=O)c(OC[C@H]3CO3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
Potassium carbonate (0.89 g) was added under nitrogen to a stirred solution of ethyl 4-formyl-5-hydroxyindole-2-carboxylate (1.50 g) in dry dimethylformamide (40 ml). A solution of (R)-glycidyl 4-toluenesulphonate (1.47 g) in dry dimethylformamide (30 ml) was then added and the mixture stirred at ambient temperature for 10 minutes, then at 60° C. for 3 hours. The mixture was poured into water (400 ml) and extracted with ethyl acetate (3×200 ml). The combined extracts were washed with brine (6×200 ml), dried over magnesium sulphate and the solvent evaporated under reduced pressure. The brown solid residue was purified by flash column chromatography on silica eluting with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate to give ethyl (R)-5-(2,3-epoxypropoxy)-4-formylindole-2-carboxylate (1.07 g) as an off-white solid; m.p. 152-154° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[F:30][C:31]([F:35])([F:34])[CH2:32][OH:33]>O1CCOCC1.CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([O:33][CH2:32][C:31]([F:35])([F:34])[F:30])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCC(F)(F)F)c3)nc12

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 2,2,2-trifluoroethanol in dioxane and DMF. ES-MS m/e (%): 491 (M+Na+, 81), 469 (M+H+, 100).
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:28][C:25]([F:26])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:11]3[CH2:12][CH2:13][CH2:14][CH:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: c1ccc(C2CCCNCC2)cc1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Agent: Cl
Product: FC(F)(Cl)c1nnc2ccc(N3CCCC(c4ccccc4)CC3)nn12
Yield: 69 %

Procedure:
A mixture of 4-phenylazepane hydrochloride and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 331 to give 3-[chloro(difluoro)methyl]-6-(4-phenylazepan-1-yl)[1,2,4]triazolo[4,3-b]pyridazine in 69% yield.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:25][C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OC(C)C)(=O)C>[Cl:25][C:26]1[C:31]([NH:32][CH:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:17])[CH2:19][CH2:20]2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1cccnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: O=C(OCc1ccccc1)N1CCC(Nc2cccnc2Cl)CC1

Procedure:
560 mL (7.25 mol) TFA were added dropwise to 930 g (3.99 mol) N-benzyloxycarbonyl-4-piperidone and 466 g (3.63 mol) 2-chloro-3-aminopyridine in 9.5 L isopropyl acetate at approx. 15° C. 922 g (4.35 mol) sodium triacetoxyborohydride were added batchwise. The mixture was stirred until the reaction was complete. At RT the reaction mixture was combined with 860 mL sodium hydroxide solution (2 mol/L). The organic phase was separated off, washed with 5 L water and evaporated down.
Reaction SMILES: C1(P([C:14]2[CH:19]=[CH:18]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(O)(C)C.[Cl:36][C:37]1[C:45]2[C:40](=[N:41][C:42]([S:46][CH3:47])=[N:43][CH:44]=2)[NH:39][N:38]=1>C1COCC1>[Cl:36][C:37]1[C:45]2[C:40](=[N:41][C:42]([S:46][CH3:47])=[N:43][CH:44]=2)[N:39]([CH:19]([CH3:18])[CH3:14])[N:38]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CSc1ncc2c(Cl)n[nH]c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CSc1ncc2c(Cl)nn(C(C)C)c2n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Triphenylphosphine (387 mg, 1.5 mmol) was dissolved in THF (15 mL) and the solution was cooled to −78° C. Diethyl azodicarboxylate (225 uL, 1.5 mmol) was added slowly to the reaction mixture. The reaction was stirred for 5 min and then isopropanol was added (115 uL, 1.5 mmol) dropwise. After stirring an additional 5 min. the 3-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (305 mg, 1.6 mmol) was added as a solid. The resulting suspension was kept at −78° C. for 5 min then the cooling bath was removed. The reaction was stirred for 3 hours at room temperature. After concentration the desired 3-Chloro-1-isopropyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine was obtained by column chromotography (0–5% MeOH/methylene chloride); 1H-NMR (CDCl3): • 1.46 (d, 1H), 2.66 (s, 3H), 4.53 (q, 6H), 8.87 (s, 1H); LC/MS (m/e)=243.0 (MH+), Rt=2.25 min.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].Cl.[CH:25]1([C:28]2[CH:29]=[C:30]([CH3:40])[C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:32][CH:33]=2)[CH2:27][CH2:26]1>>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:21])=[O:22])[CH:13]=[CH:12][C:8]=1[C:9]([N:37]1[CH2:36][CH2:35][N:34]([C:31]2[C:30]([CH3:40])=[CH:29][C:28]([CH:25]3[CH2:27][CH2:26]3)=[CH:33][N:32]=2)[CH2:39][CH2:38]1)=[O:10]
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCCS2(=O)=O)CC1
Yield: 37 %

Procedure:
Using 2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 34 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (141 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (115 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[OH:27])/[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccccc2)c2ccccc2)cc(F)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccccc2)c2ccccc2)=N/O)cc(F)n1

Procedure:
In analogy to example 1, step 2, from 1-(2-fluoro-6-methyl-pyridin-4-yl)-3,3-diphenyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white oil, MS (ESI+): m/z=335.1553 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH:28]1[C:33]([O:35][CH3:36])=[O:34]>C(#N)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:30]2[CH2:31][CH2:32][NH:27][CH:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29]2)=[CH:4][CH:5]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1CNCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Yield: 25.1 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.61 mmol, 1.553 g), potassium carbonate (13.82 mmol, 1.910 g) and methyl piperazine-2-carboxylate dihydrochloride (4.61 mmol, 1 g) were combined and stirred at room temperature overnight in acetonitrile (25 mL). The reaction mixture was filtered and the solid washed with ethyl acetate. The organic was concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (eluant dichloromethane/methanol/ammonia 95/5/0.5) to afford the title compound (464 mg).
Reaction SMILES: [CH:1]1([CH:7]([OH:19])/[CH:8]=[CH:9]/[CH:10]2[CH2:17][CH2:16][CH:15]3[CH:11]2[CH2:12][CH2:13][C:14]3=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.O>CN(C)C=O>[Si:24]([O:19][CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)/[CH:8]=[CH:9]/[CH:10]1[CH2:17][CH2:16][CH:15]2[CH:11]1[CH2:12][CH2:13][C:14]2=[O:18])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC2C(/C=C/C(O)C3CCCCC3)CCC12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)C1CCCCC1
Yield: 96.8 %

Procedure:
A mixture of (E)-2-(3-cyclohexyl-3-hydroxyprop-1-enyl)bicyclo[3,3,0]octan-6-one (41 mg), prepared as described in Reference Example 13, and in the form of (±)-(E)-2β-(3-cyclohexyl-3α-hydroxyprop-1-enyl)bicyclo[3,3,0]octan-6-one, tert-butyldimethylchlorosilane (35 mg), and imidazole (29.5 mg) in dimethylformamide (0.25 ml) was stirred at ambient temperature for 3 hours. Water (2.5 ml) was added and the mixture was extracted with diethyl ether. The combined ethereal extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give (E)-2-(3-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one (57 mg), in the form of (±)-(E)-2β-(3α-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[N:14][CH:15]=1)([O-:9])=[O:8].[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([NH:19][S:16]([C:12]1[CH:13]=[N:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:17])=[O:18])(=[O:22])[CH3:21]
Reactant: NS(=O)(=O)c1cncc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)NS(=O)(=O)c1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 10 ml. of a 10% aqueous sodium carbonate solution of 0.5g. of 5-nitro-3-pyridinesulfonamide was added dropwise 1g. of acetyl chloride at 0° C. The mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate. The extract was purified by silica gel chromatography to give 0.26g. of the desired product. m.p. 176° - 178° C.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[S:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1c[nH]c2ccccc12
Reactant: COc1ccc(S)cc1
Product: COc1ccc(Sc2[nH]c3ccccc3c2C(C)C)cc1
Yield: 72 %

Procedure:
coupling 3-isopropylindole with 4-methoxybenzenethiol to give 3-isopropyl-2-(4-methoxyphenylthio)indole (yield: 72% of pure product);
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][S:8][CH2:9][CH:5]2[C:4](=[O:10])[N:3]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[O:28]=[S:8]1[CH2:9][CH:5]2[C:4](=[O:10])[N:3]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:2](=[O:1])[N:6]2[CH2:7]1
Reactant: N#Cc1ccc(N2C(=O)C3CSCN3C2=O)c2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc(N2C(=O)C3CS(=O)CN3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
To a solution of 17B (62 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) was added 3chloroperoxybenzoic acid (46 mg, 0.2 mmol). The reaction was stirred at RT for 2 h, then quenched with 5% aqueous Na2S2O3 and extracted with CH2Cl2 (2×) and EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with EtOAc/hexane (2:3) to give 6 mg of the title compound (reacemate) as a white solid. HPLC: 97% at 4.0 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 326 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[CH2:17](C(CC)(CC)C([O-])([O-])[O-])[CH3:18]>C(OC(=O)C)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=[C:17]2[CH3:18])=[CH:10][CH:11]=1)#[N:16]
Reactant: N#Cc1ccc(Nc2ccncc2N)cc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2n1-c1ccc(C#N)cc1

Procedure:
A mixture of 3-amino-4-(4'-cyanophenyl)aminopyridine (9.31 g, 44.3 mmol), triethyl-orthoacetate (40 ml) and acetic anhydride (30 ml) was heated at reflux for 2 hours under nitrogen, cooled, then concentrated under reduced pressure. The brown residue was dissolved in 1M hydrochloric acid and washed with ethyl acetate (200 ml). The aqueous layer was rendered basic with saturated aqueous ammonia and extracted with dichloromethane (3×200 ml). The combined extracts were washed with water, dried (MgSO4) and concentrated to give 1-(4-cyanophenyl)-2-methylimidazo[4,5-c]pyridine, 6.5 g, as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11]C1C3C(=CC(OCC4CCNCC4)=CC=3)N=CN=1)=[CH:6][CH:5]=2.C(OC([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44][O:45][C:46]2[CH:55]=[C:54]3[C:49]([C:50](OC4C=C5C(=CC=4)NC(C)=C5)=[N:51][CH:52]=[N:53]3)=[CH:48][C:47]=2[O:67][CH3:68])[CH2:39][CH2:38]1)=O)(C)(C)C>>[CH3:68][O:67][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][C:46]=1[O:45][CH2:44][CH2:43][CH:40]1[CH2:39][CH2:38][NH:37][CH2:42][CH2:41]1)[N:53]=[C:52]([O:11][C:7]1[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]3)[N:51]=[CH:50]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCC5CCNCC5)ccc34)ccc2[nH]1
Product: COc1cc2cnc(Oc3ccc4[nH]c(C)cc4c3)nc2cc1OCCC1CCNCC1
Yield: 87 %

Procedure:
Using an analogous procedure to that described for the synthesis of 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline, (prepared as described in Example 122), 7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (400 mg, 0.75 mmol), (prepared as described in Example 126), was used to give 6-methoxy (2-methylindol-5yloxy)-7-(2-(piperidin-4-yl)ethoxy)quinazoline (284 mg, 87%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[O:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:17][CH2:18]1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCOCC1
Temperature: 98 °C
Reaction time: 23 h
Yield: 90.6 %

Procedure:
A 3-neck flask (200 mL) was charged with 1-fluoro-2-nitro-4-trifluoromethylbenzene (1.59 g, 7.61 mmol), 4-aminotetrahydropyran (1.00 g, 9.89 mmol), and pyridine (16 mL), and this was stirred at 98° C. for 23 hours. The yellow oil produced was allowed to cool, distilled water (approx. 20 mL) was added with stirring, and the precipitated crystals were filtered off. These were washed with distilled water and dried with heating at reduced pressure to yield the title compound (2.00 g, 90.5% yield) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]4[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18]1)=[N:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[CH2:36]([C@@H:38]1[O:40][CH2:39]1)[Cl:37]>C1COCC1.CO>[Cl:37][CH2:36][C@H:38]([OH:40])[CH2:39][N:13]([CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:34][CH3:35])[N:9]=2)[N:4]=[CH:3][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1
Reactant: COc1ccc2ncc(F)c(CNCCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Reactant: ClC[C@H]1CO1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(CN(CCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)C[C@@H](O)CCl)c2n1
Temperature: 70 °C
Yield: 52 %

Procedure:
A solution of the compound of Example 78 (0.135 g, 0.27 mmol) in THF/MeOH (1:1, 2 mL) was treated with (R)-epichlorohydrin (0.032 mL, 1.5 eq.). The mixture was heated at 70° C. overnight, concentrated in vacuo and purified by FC (EA/MeOH 19:1+1% NH4OH) to give the title compound as a colourless foam (0.1 g, 52% yield).