Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.I[CH:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29]4)[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Product: CC(C)(C)OC(=O)N1CC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Yield: 100.7 %

Procedure:
Following the general method as outlined in Intermediate 16, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 812 mg; 2.38 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (674 mg; 2.38 mmol), 1.19 g (100%) of the title compound was obtained as a yellow solid, which was used directly without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][CH:16]2[C:19](O)=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:24]1[CH:28]=[C:27]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[CH:26]=[N:25]1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][CH:16]2[C:19]([N:30]([CH2:29][C:27]2[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[CH:28]=2)[C:31]2[CH:32]=[CH:33][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:35][CH:36]=2)=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2ccc(OCc3ccccc3)cc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(OCc4ccccc4)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 60.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 7-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as starting materials, 7-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.61 g) was obtained. melting point: 100-101° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CN(C=O)C.CC#N>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(-c2ccncc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C1=C(c2ccccn2)CCN(Cc2ccccc2)C1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A Solution of 2 g (12.8 mmol) of 4-(2-pyridyl)pyridine (Aldrich) and 2.18 g (12.8 mmol) of benzylbromide in 15 mL of DMF and 15 mL of CH3CN was stirred at 95° C. for 4 h. The reaction mixture was then concentrated and redissolved in 20 mL of methanol. To the reaction mixture at 0° C. was added 0.95 g, (25.6 mmol) of NaBH4 and the reaction mixture was stirred for 1 h. The reaction was quenched with 6N HCl, and was partitioned between CH2Cl2 and 1N NaOH. The aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified chomatography [silica, CH2Cl2:ethyl acetate:(2M NH3 in MeOH), 100:100:2] to give 3.2 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[Si:15]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1.CCCCCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:22][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH:24]=2)[OH:27])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 4-bromothioanisole (10.0 g, 49.0 mmol) in 60 mL of anhydrous tetrahydrofuran was cooled to -78° C. under nitrogen and 32 mL (49 mmol) of 1.55M n-butyllithium in hexane was was added dropwise at a rate to maintain temperature below -60° C. The reaction was stirred an additional 15 minutes after addition was complete, and a solution of crude 3-(tert-butyldimethylsilyloxy)benzaldehyde (11.6 g, 49 mmol) in 50 mL of dry tetrahydrofuran was added dropwise over 20 minutes. The reaction was stirred another 30 minutes and quenched at -78° C. with saturated aqueous ammonium chloride. After warming to room temperature, the reaction was diluted with 200 mL of diethyl ether and washed with 50 mL of water and 50 mL of saturated aqueous sodium chloride. After drying over sodium sulfate, the solvent was removed to give 17.5 g (99%) of crude (4-methylthio-phenyl)(3-tert-butyldimethylsilyloxyphenyl)methanol as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[C:3]([NH:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: NC1CCCC1
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1NC1CCCC1
Yield: 47 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (30 mg, 7.6 μmol) and cyclopentylamine (1 ml) were heated in a microwave oven (170-° C.: 30 min). The excess amine was removed in vacuo and the residue dissolved in acetonitrile (1 ml) with a drop of TFA. This mixture was subjected to semi-preparative HPLC-C18. The appropriate fractions were pooled and evaporated in vacuo. The residue was dissolved in EtOAc (5 ml). This solution was washed with saturated aqueous NaHCO3 (5 ml) and brine (2 ml). The organic phase was dried (MgSO4) and evaporated in vacuo and the residue recrystallized from methanol to afford the pure product (16 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12](Cl)(=O)[C:13](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].C=C>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:13][CH2:12]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc(Br)ccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A single neck 3 liter round bottom flask under an Ar atmosphere was charged with 4-bromobenzeneacetic acid (250.0 g, 1.15 mol), methylene chloride (1.5 L) and dimethylformamide (0.5 mL). This magnetically stirred solution was cooled to 0° C. and treated dropwise with oxalyl chloride (156 mL, 1.74 mol). The reaction was allowed to reach room temperature and stirred 16 h. The reaction was concentrated on a rotary evaporator to approximately 1 L of volume. A separate dry 5 liter 3 neck round bottom flask under Ar, fitted with gas inlet tube, overhead stirrer, and digital thermometer was charged with methylene chloride (1.5 L) and AlCl3 (312.0 g, 2.34 mol). This suspension was cooled to 0° C. and stirred while the above solution of acid chloride was added to it slowly via cannula. When the addition was complete, ethylene gas was introduced for 1-2 h. to the vigorously stirred suspension while maintaining the internal temperature at 15° C. Upon completion by HPLC, the reaction was warmed to room temperature and stirred for 0.5 h. The mixture was recooled to 0° C. and cautiously quenched slowly with water (1.5 L). The layers were separated, and the aqueous one washed with methylene chloride (500 mL). The organic portion was washed with 2N aqueous HCl (2×800 mL), brine (400 mL), and saturated aqueous NaHCO3 (2×800 mL). Each aqueous extract was washed with the same 500 mL methylene chloride extract from above. The methylene chloride extracts were combined, dried (Na2SO4), filtered, and concentrated to approximately 500 mL of volume. This was then added to 5.0 L of hexane warmed to 50° C. The methylene chloride was distilled off and the hot solution decanted from an insoluble brown tar. The solution was allowed to cool to 25° C. and placed in the freezer overnight. The precipitate was collected and washed with hexane (200 mL), and dried in vacuo to give 229.0 g of 6-bromo-3,4-dihydro-2(1H)-napthalenone as a pale yellow solid (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[Cl-].[Cl-].[Cl-].[Al+3].[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[N:36]=[N:37][NH:38][N:26]=4)[CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Oc2ccnc(-c3nn[nH]n3)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-[(2-cyanopyridin-4-yl)oxy]phenyl}propanamide (0.300 g, 0.67 mmol), aluminum trichloride (1.0 M in hexanes, 2.0 mL, 2.0 mmol), and sodium azide (0.131 g, 2.0 mmol) in DMF was heated at 100° C. for 3 days. The mixture was concentrated and purified by column chromatography to give A-57 which was converted to the bishydrochloride salt (29 mg). 1H NMR (400 MHz, CD3OD; bis HCl salt) δ: 8.66 (d, 1H), 8.03 (d, 1H), 7.93 (d, 1H), 7.66 (dd, 1H), 7.52 (t, 1H), 7.45 (d, 1H), 7.41 (dd, 1H), 7.37 (d, 1H), 7.21-7.24 (m, 1H), 7.12-7.17 (m, 1H), 3.10 (t, 2H), and 2.75 (t, 2H). LCMS, FA: Rt=1.48 min, [MH+ 489.3].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: CCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 204 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-ethyl-4,5,6,7-tetrahydroindazol-4-one (0.44 g), aminoguanidine hydrochloride (0.19 g), concentrated hydrochloric acid (0.24 ml), water (0.24 ml) and ethanol (40 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated. The resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-3-ethyl-4-guanidinoimino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 27) (0.6 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1>>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[C:23]([F:31])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)c2c(c1)OC(C)(CO)C2
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)c(F)c3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (232a) and 2-amino-5-picoline. 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1 H) 8.22 (d, J=8.59 Hz, 1 H) 8.12 (d, J=2.02 Hz, 1 H) 7.93 (t, J=8.46 Hz, 1 H) 7.58 (dd, J=8.34, 2.02 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 7.13 (d, J=1.26 Hz, 1 H) 6.88 (dd, J=8.84, 2.27 Hz, 1 H) 6.82 (dd, J=10.86, 2.27 Hz, 1 H) 3.76 (d, J=5.56 Hz, 1 H) 3.64 (d, J=7.33 Hz, 1 H) 3.21 (s, 3 H) 2.81 (d, J=16.67 Hz, 1 H) 2.33 (s, 3 H) 1.97 (d, J=1.52 Hz, 1 H) 1.47 (s, 3 H); LCMS for C24H23FN2O6S m/z 487.00 (M+H+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][OH:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][O:24][N:26]1[C:27](=[O:36])[C:28]2=[CH:35][CH:34]=[CH:33][CH:32]=[C:29]2[C:30]1=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCOCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCOCc1ccccc1
Yield: 99.1 %

Procedure:
Diethyl azodicarboxylate (15.6 ml 99.4 mmol) added to a solution of 3-benzyloxy-1-propanol (15 g, 90.4 mmol), N-hydroxyphthalimide (14.7 g, 90.1 mmol) and triphenylphosphine (23.7 g, 90.4 mmol) in tetrahydrofuran (450 ml). After 16 hours at 20° C. the solvent was removed under reduced pressure and the residue chromatographed on silica gel (eluted with hexane:acetone, 3:1) to yield the title compound as a yellow oil (27.8 g, 99%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([Cl:27])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+].CO>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([Cl:27])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCOc1ccc(CC(Cl)C(=O)O)cc1)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate (0.94 g), 10% aqueous sodium hydroxide solution (5 mL) and methanol (15 mL) was stirred at room temperature for 1.75 hrs. The mixture was then diluted with water (400 mL) and washed with dichloromethane (300 mL). The aqueous layer was acidified to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate (2×250 mL). The combined ethyl acetate extracts were washed with water (500 mL), brine (500 mL), dried (MgSO4) and evaporated. The residue was crystallised from dichloromethane-hexane to afford the title compound, mp 142°-3° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].N1C=CC=CC=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>ClCCl>[S:14]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: C#CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
5-hexyn-1-ol (14 g), pyridine (20 ml) and dichloromethane (60 ml) were mixed and cooled to 0° C. Tosyl chloride (30 g:1.1 equivalent) was added portion wise over 20 minutes. After 5 hours at 0° C., the reaction was transferred to a separating funnel and washed with 2N HCl (2×50 ml) and saturated sodium bicarbonate (2×50 ml). These were back extracted with dichloromethane (1×25 ml) and the combined organic layers washed with water (1×50 ml). After drying (Na2SO4), the liquid was filtered off and the solvent evaporated to leave the product--33.4 g (93%)--of sufficient purity to be used for the next step.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH:7]=[N:6]2.Br[CH:16]([CH2:22][CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C>[CH2:20]([O:19][C:17]([CH2:16][CH2:22][CH2:23][CH2:24][CH2:25][N:9]1[C:10]2[C:5](=[CH:4][C:3]([Cl:2])=[C:12]([Cl:13])[CH:11]=2)[N:6]=[CH:7][C:8]1=[O:14])=[O:18])[CH3:21]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCCCn1c(=O)cnc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 10.5 %

Procedure:
Under a nitrogen atmosphere sodium (0.148 g, 6.42 mmol) was dissolved in 50 ml of abs. ethanol and 6,7-dichloroquinoxalin-2(1H)-one (1.20 g, 5.58 mmol) (Liebigs Ann. Chem., (1982), 754) was added. The mixture was stirred until the compound dissolved, and ethyl 2-bromohexanoate (1.30 ml, 7.1 mmol) was added. The reaction mixture was refluxed for 72 h, cooled to room temperature, then poured onto crushed ice and acidified by dilute hydrochloric acid (pH=2). The precipitated compound was extracted with ethyl acetate and purified by column chromatography on silica gel (eluent 15% THF in heptane) to afford 0,21 g of 1-((1-ethoxycarbonyl)pentyl)-6,7-dichloroquinoxalin-2(1H)-one 1H-NMR(DMSO-d6):δ 0.78(t, 3H), 1.1(t, 3H), 1.15-1.35(m, 4H), 2.0-2.25(m, 2H), 4.02-4.18(m, 2H), 5.58-5.75(m, 1H), 8.02-8.36(broad, 1H), 8.18(s, 1H), 8.33(s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([N:29]=[C:30]=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>C(Cl)Cl>[F:17][C:18]([F:32])([F:33])[C:19]1[CH:20]=[C:21]([NH:29][C:30]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Br:1])[CH:9]=2)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1-c1c(Br)cnn1C
Yield: 46.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 3,5-bis(trifluoromethyl)phenyl isocyanate (0.036 g, 24.0 μL, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 13 (0.030 g, 0.06 mmol, 43%) as a white solid. LCMS m/z (%)=537 (M+H79Br, 99), 539 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.77 (s, 1H), 8.42 (s, 1H), 8.22 (s, 2H), 7.73 (dd, J=2.5, 9.0 Hz, 1H), 7.51 (s, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(O)nc1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(Cl)nc1C(=O)OCC
Yield: 30 %

Procedure:
The title compound was prepared as described in Example 7, but employing a solution of diethyl 2-hydroxypyrimidine-4,5-dicarboxylate (1.0 g, 4.2 mmol) and POCl3 (7.7 g, 50 mmol) resulting in a 30% yield (0.32 g); 1HNMR (CDCl3) δ 9.09 (d, 1H), 4.35 (m, 4H), 1.30 (m, 6H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[F:41])[CH:26]=4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C=O>C(O)=O>[F:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]4)[CH:18]=3)[CH:24]=2)[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(-c4cc(-c5ccccc5F)nc5ncccc45)c3)cn2)CC1
Agent: C=O
Solvent: O=CO
Product: CN1CCC(n2cc(-c3cncc(-c4cc(-c5ccccc5F)nc5ncccc45)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 286 mg (0.52 mmol) 4-(4-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (synthesis see example 8) in 1.7 ml formic acid was treated with 124 mg (1.56 mmol) 35% aqueous formaldehyde solution and heated to 80° C. The reaction mixture was stirred at this temperature for two hours. The volume of the reaction mixture was reduced under vacuum and the residue was partitioned between 2 N NaOH and dichloromethane. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(2-fluoro-phenyl)-4-{5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine as colourless solid; HPLC/MS: 1.37 min, [M+H] 465.