Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:41](=O)[C:40]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=3[C:34]2=[O:43])=[CH:29][C:28]=1[CH:44]1[S:48][CH:47]([CH3:49])[CH2:46][S:45]1.[C:50]1(C)C=CC=CC=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:41](=[CH:50][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:40]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=3[C:34]2=[O:43])=[CH:29][C:28]=1[CH:44]1[S:48][CH:47]([CH3:49])[CH2:46][S:45]1
Reactant: Cc1ccccc1
Reactant: CC1CSC(c2cc(N3C(=O)C4=C(CCCC4)C3=O)ccc2Cl)S1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CC=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(C2SCC(C)S2)c1
Temperature: 25 °C

Procedure:
1.75 g of (ethoxycarbonylmethylene)triphenylphosphorane were added to a solution of 1.90 g of 2-[4-chloro-3-(4-methyl-1,3-dithiolan-2-yl)phenyl]-4,5,6,7-tetrahydro-2H-isoindol-1,3-dione in 50 ml of toluene. The solution obtained was then refluxed for 5 hours, after which a further 5.25 g of (ethoxycarbonylmethylene)triphenylphosphorane were added in two portions. The reaction mixture was refluxed for a total of 6 hours and then cooled to about 25° C. After separating off solid components and solvent, the residue was treated with diisopropyl ether. The substance crystallizing from diisopropyl ether was separated off and the filtrate was chromatographed on silica gel (eluent: CH2Cl2). Yield : 0.7 g of the title compound as an 85:15 E/Z isomer mixture.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:13][O:14][C:15](=[O:37])[C:16]1[CH:21]=[C:20](Br)[CH:19]=[C:18]([CH3:23])[C:17]=1[N:24]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:25]>>[CH3:13][O:14][C:15](=[O:37])[C:16]1[CH:21]=[C:20]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:19]=[C:18]([CH3:23])[C:17]=1[N:24]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:25]
Reactant: C#CCCCCCCCCCC
Reactant: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Product: CCCCCCCCCCC#Cc1cc(C)c(N(C)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Yield: 73 %

Procedure:
Following the procedure of Example 351, using 1-dodecyne instead of ethynyl biphenyl, 1.0 g (2.336 mmol) of the product of Example 202 gives 0.874 g (73%) of the alkyne as a brown oil. Electrospray Mass Spec: 514.4 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17][C:16](=O)[O:15][C:13]2=[O:14]>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:13](=[O:14])[C:12]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCCCn1ccnc1
Solvent: CCO
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCCn1ccnc1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
A mixture of 1.53 g of 1H-imidazole-1-pentanamine, 1.63 g of isatoic anhydride and 15 ml at ethanol was stirred for 20 hours and concentrated. The viscous residue was mixed with 10 ml of ethyl chloroformate and heated for 1.5 hours in an oil bath at 95° C. The mixture was dissolved in ethanol, reconcentrated, mixed with 2.0 g of potassium hydroxide and 50 ml of ethanol and heated at reflux temperature for 3 hours. The reaction mixture was concentrated, dissolved in water and treated with acetic acid to pH 6-7. The insoluble material was collected by filtration and recrystallized from ethanol to obtain the desired product, mp 160°-162° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].[CH3:13][C:14]1[C:15]([CH2:23][OH:24])=[CH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[CH:22]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH:11]=[O:12].[CH3:13][C:14]1[C:15]([CH:23]=[O:24])=[CH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[CH:22]=1
Reactant: Cc1cc2sccc2cc1CO
Reactant: Cc1c(CO)ccc2sccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1c(C=O)ccc2sccc12
Product: Cc1cc2sccc2cc1C=O

Procedure:
In 17 ml of chloroform is dissolved 1.7 g of a mixture of 4-methylbenzo[b]thiophene-5-methanol and 6-methylbenzo[b]thiophene-5-methanol, and 4.1 g of manganese dioxide is added thereto at room temperature. Thereafter, the resulting mixture is refluxed for one hour. After the reaction, insolubles are removed from the resulting reaction mixture by filtration and the filtrate obtained is concentrated under reduced pressure. The residue obtained is purified by a moderate pressure column chromatography [eluent:hexane:toluene=1:1], to obtain 0.65 g of 4-methylbenzo[b]thiophene-5-carbaldehyde as colorless solid and 0.48 g of 6-methyl-benzo[b]thiophene-5-carbaldehyde as colorless solid.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].C(O)(=O)C(O)=O.[CH2:30]([NH:33][NH2:34])[CH2:31][CH3:32]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:34][N:33]2[CH2:30][CH2:31][CH3:32])=[CH:14][CH:15]=1
Reactant: CCCNN
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Product: CCCn1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Yield: 52.8 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and propylhydrazine oxalate (0.164 g, 1.0 mmol) to give 0.075 g of product as a pink solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>ClCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][Br:43]
Reactant: Cc1ccc(-c2nc(Cc3cccc(CO)c3)c(C)o2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(Cc3cccc(CBr)c3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}-benzyl alcohol (3.52 g) was dissolved in 60 ml of dichloromethane. After addition of 3.77 g of triphenylphosphine and 5.17 g of carbon tetrabromide, the mixture was stirred for 30 minutes at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 3.96 g of the objective compound as colorless crystals. M.p. 101–102° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[NH:22][C:23](=O)[CH2:24][CH3:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[N:22]=[C:23]2[CH2:24][CH3:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCc1nc2cc(F)ccc2n1C1CCN(Cc2ccccc2)CC1
Yield: 96.3 %

Procedure:
N-[2-(1-Benzyl-piperidin-4-ylamino)-5-fluorophenyl]-propionamide (7 g) in glacial acetic acid (70 ml) was heated at reflux for 1 h. After cooling the residue was dissolved in ethyl acetate (100 ml) and water (50 ml) was then added. The mixture was made alkaline with K2CO3, and the organic layer separated, washed with water, then dried and concentrated in vacuo. The resulting oil was purified by flash chromatography (9:1 DCM:MeOH) to yield 6.4 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C:5]([CH3:39])([CH3:38])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[N:31][C:32]([O:35][CH2:36][CH3:37])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=1.[CH2:56](O)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:40])[C:5]([CH3:38])([CH3:39])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[N:31][C:32]([O:35][CH2:36][CH3:37])=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:13][C:12]([O:21][CH2:56][C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=1)=[CH:11][CH:10]=2)[CH3:2]
Reactant: CCO
Reactant: Cc1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(-c2ccc(OCC)nc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc(C)cn3)ccc2n1Cc1ccc(-c2ccc(OCC)nc2)cc1
Temperature: 35 °C

Procedure:
3-{3-tert-Butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-hydroxy-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (1313.2 g) was dissolved in acetonitrile (20.0 L) in a 50 L reaction flask under nitrogen, and the mixture was stirred and heated to 30-40° C. Cesium carbonate (2118.67 g) was added, followed by 2-chloro-5-methylpyridine hydrochloride (497.17 g), and the temperature was increased to 70-80° C. over 2 hours. After heating at 70-80° C. for 4 hours, no starting material was seen by tlc analysis, and the mixture was cooled to 55° C. and concentrated. The residue was dissolved in dichloromethane (2 L) and water (2 L) and transferred to a flask containing dichloromethane (4 L) and water (4 L). The original flask was rinsed twice with dichloromethane (2 L) and water (2 L), and the combined material was then diluted with an additional 3 L of dichloromethane and 6 L water to a total volume of 13 L of dichloromethane and 16 L of water. The mixture was agitated for 10 minutes and allowed to separate over 10 minutes. The organic layer was separated, and additional dichloromethane (9 L) was added to the aqueous layer. The mixture was agitated for 6 minutes and allowed to separate over 5 minutes. The organic layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (433.07 g) and silica gel, thiol derivatized (91.17 g). The mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2″ pad of Celite. The flask was rinsed with dichloromethane (2.6 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material. Ethanol (9.2 L) was added to the solids, and the mixture was stirred slowly for 17 hours and filtered. The isolated solids were dried in a drying oven at 45° C. under vacuum for 2 days to give the desired product (1459.4 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>C1COCC1>[ClH:36].[ClH:36].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:13]=2)[CH:16]=1
Reactant: CN(C)CCN
Reactant: CCOC(=O)Cl
Reactant: Cc1csc(Nc2cc(Oc3cccc(C(=O)O)c3)ccn2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3cccc(C(=O)NCCN(C)C)c3)ccn2)n1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
3-(2-(4-Methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol) and THF (2 mL) were combined according to the method of Example 32. The reaction mixture was cooled to 0° C., ethyl carbonochloridate (0.03359 mL, 0.3513 mmol) was added, and the reaction mixture was stirred at 0° C. for 30 minutes. N1,N1-dimethylethane-1,2-diamine (0.1006 mL, 0.9164 mmol) in THF (2 mL) was added to afford N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzamide dihydrochloride (0.07 g, 48.23% yield) as off white solid. 1H NMR (CDCl3) δ 8.97 (bs, 1H), 8.16 (d, 1H), 7.99 (m, 2H), 7.52 (t, 1H), 7.23 (d, 1H), 6.92 (bs, 1H), 6.39 (s, 1H), 3.90 (m, 2H), 3.37 (m, 2H), 2.92 (s, 6H), 2.38 (s, 3H); Mass spectrum (esi) m/z=398 (100) (M+H).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20](Br)[CH:21]=[CH2:22].C(=O)(O)[O-].[Na+].C(Cl)[Cl:30]>>[ClH:30].[CH2:22]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1)[CH:21]=[CH2:20]
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Reactant: C=CCBr
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCN1CCOC(c2ccccc2)(c2ccccc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the stirred solution of 5.06 g of 7,7-diphenyl-hexahydro-1,4-oxazepine in 50 ml of methylene chloride, 2.6 g of allyl bromide are added, followed by 40 ml of 10% aqueous sodium bicarbonate and the mixture is stirred for 24 hours at room temperature. The organic layer is separated, washed with water, dried, filtered and evaporated. The residue is taken up in acetone, the solution acidified with hydrogen chloride in acetone and diluted with diethyl ether, to yield the 4-allyl-7,7-diphenyl-hexahydro-1, 4-oxazepine hydrochloride melting at 246° to 247°.
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([C:8]1[O:12][C:11]([C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](=[NH:30])[NH:25]OC(=O)C)=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[CH:10][CH:9]=1)=[NH:7])(=[O:3])[CH3:2].C(O)C>C(O)(=O)C.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[O:14][C:13]([C:11]3[O:12][C:8]([C:6]([NH2:7])=[NH:5])=[CH:9][CH:10]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=1)(=[NH:25])[NH2:30]
Reactant: CC(=O)ONC(=N)c1ccc(-c2ccc(-c3ccc(C(=N)NOC(C)=O)o3)o2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N=C(N)c1ccc(-c2ccc(-c3ccc(C(=N)N)o3)o2)cc1
Reaction time: 4 h
Yield: 67 %

Procedure:
To a solution of 7 (246 mg, 0.6 mmol) in glacial acetic acid (8 mL), and ethanol (20 mL) was added 10% palladium on carbon (60 mg). The mixture was placed in a Parr hydrogenation apparatus at 50 psi for 4 h at room temperature. The mixture was filtered through hyflo and the filter pad washed with water. The filtrate was evaporated under reduced pressure and the precipitate was collected and washed with ether to give 8a in 67% yield, mp 240-242° C. 1H NMR (D2O/DMSO-d6); δ 1.80 (s, 2×CH3), 7.06 (d, J=3.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 7.36 (d, J=3.6 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H). Calcd for C16H14N4O2-2.0AcOH-2.4H2O: C, 52.48; H, 5.87; N, 12.23. Found. C, 52.28; H, 5.49; N, 11.91.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[NH2:11][C:12]([C:14]1[C:18]([NH:19][C:20](=O)[C:21]2[CH:26]=[C:25]([I:27])[CH:24]=[N:23][C:22]=2[O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:17]([CH2:34][CH3:35])[N:16]([CH2:36][CH2:37][O:38][CH3:39])[N:15]=1)=[O:13].C(OCC)(=O)C>C(O)CCC>[CH2:29]([O:28][C:22]1[C:21]([C:20]2[NH:11][C:12](=[O:13])[C:14]3[C:18](=[C:17]([CH2:34][CH3:35])[N:16]([CH2:36][CH2:37][O:38][CH3:39])[N:15]=3)[N:19]=2)=[CH:26][C:25]([I:27])=[CH:24][N:23]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOc1ncc(I)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Yield: 42.3 %

Procedure:
Potassium hexamethyldisilazide (46 mg, 0.23 mmol) was added to N-[3-(aminocarbonyl)-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-butoxy-5-iodonicotinamide (Preparation 13) (100 mg, 0.19 mmol) in degassed n-butanol (2 mL) and the solution stirred under a nitrogen atmosphere. The reaction was heated at reflux for 9 h and then cooled. The butanol was removed in vacuo and the residue partitioned between dichloromethane and 1N hydrochloric acid. The organic phase was separated and washed with brine, dried (MgSO4) and concentrated to give a white solid. Trituration with ethyl acetate gave the title compound (40 mg, 42%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])=[C:20]([F:38])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[CH:39][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7](=[O:8])[NH:6][C:4]([C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:5])[S:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])=[C:20]([F:38])[CH:19]=1
Reactant: CCOC(=O)C(C)(SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(=O)OCC
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
2,6-Difluorobenzoylisocyanate (3 g) in a 1:1 (v/v) mixture of toluene and petroleum ether (10 ml) was added to a solution of the compound produced by Example 3 (7.6 g) in the same solvent (15 ml), over 30 minutes at 15°-20° C. The solution was stirred for 6 hours at ambient temperature and the solvent was removed by evaporation. Column chromatography on silica using a 1:1 (v/v) mixture of diethyl ether and petroleum ether yielded the title compound as a gum (9.5 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Br.Br.Br.[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][NH:37][CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]>>[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][N:37]([CH2:6][C:5]6[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=6)[CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc(F)cc3)C4)n[nH]c2c1
Yield: 5.3 %

Procedure:
The title compound was prepared from 4-fluoro-benzaldehyde (25 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method A to afford 3.4 mg of the title compound.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>C(O)C>[CH2:6]([NH:3][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1)[CH2:7][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Product: CCCCCCNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
101 g of triethylamine and subsequently 50 g of n-hexylamino are placed into 600 ml of distilled anhydrous ethanol. An amount of 79 g of 2-chloro-5-nitropyridine is added portionwise at room temperature in the course of 15 minutes. The mixture is then heated to reflux temperature, whereby it goes into solution at 60° C. The solution is stirred for 24 hours at the reflux temperature and afterwards cooled to room temperature; the solution is poured into ice/water, and the formed precipitate filtered off. The 2-n-hexylamino-5-nitropyridine obtained after recrystallisation from ethanol/water melts at 56°-57° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pt](=O)=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCN2C=CN=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CCO
Product: O=S1(=O)CCN2CCNC(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 33 %

Procedure:
A mixture of 9-(4-phenoxyphenyl)-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (96.0 mg), and platinum(IV) oxide (15.0 mg) in EtOH (5 mL) was stirred at room temperature for 2.5 hr under H2. The mixture was added with NH silica gel, concentrated, purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc), then recrystallized from EtOAc—IPE to give the title compound (32.0 mg) as white powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7]([C:9]1(Cl)[CH2:15][CH:14]2[N:11]([C:12](=[O:16])[CH2:13]2)[CH:10]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:8])(=[O:3])[CH3:2].N12CCCCC1C=NCCC2>C(OCC)(=O)C>[C:1]([NH:4][CH2:5][CH2:6][S:7]([C:9]1[CH2:15][CH:14]2[N:11]([C:12](=[O:16])[CH2:13]2)[C:10]=1[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCS(=O)C1(Cl)CC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOC(C)=O
Product: CC(=O)NCCS(=O)C1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
A solution of benzyl 3-(2-acetamidoethylsulphinyl)-3-chloro-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (62) (0.010 g) in ethyl acetate (1 ml) was treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (0.0037 g) under an argon atmosphere. It was stirred at room temperature for 15 minutes and then washed with brine and dried over sodium sulphate. The solution was concentrated to give benzyl 3-(2-acetamidoethylsulphinyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (63) (0.007 g) as a colourless gum; νmax (CHCl3) 3400, 2980, 2920, 1795, 1920, 1670, 1600 and 1515 cm-1 ; νmax (ethanol) 305 nm; τ(CDCl3) 2.5-2.8 (5H, m, phenyl), 4.76 (2H, s, benzyl CH2), 5.6-5.9 (1H, m, C5-H), 6.3-7.3 (8H, m, C4-H2, C6-H2, NCH 2 CH2S) and 8.14 (3H, s, COCH3).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=O)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:5]1)(=O)C.CO.[OH-].[NH4+:35].C([O-])(=O)C.[NH4+]>CN(C)C=O>[C:18]([CH2:17][CH2:16][NH:15][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)=[O:14])(=[O:20])[NH2:35]
Reactant: [NH4+]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)NCCC(=O)OC(C)(C)C)ccc21
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)CCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A sealed tube containing tert-butyl 3-{[1-acetyl-3-(4-fluorophenyl)-1H-indazol-5-yl]carbonylamino}propanoate (115 mg, 0.270 mmol) and methanol saturated with ammonium hydroxide (2 mL) was heated to 80° C. for 18 hours. The solution was condensed to give an oil. The oil was dissolved in dimethyl formamide (5 mL) with N—N′-carbonyldiimidazole (110 mg). The solution was allowed to stir for two hours at ambient temperature. Ammonium acetate (160 mg) was added and the reaction mixture was allowed to stir at ambient conditions under nitrogen for 18 hours. The mixture was condensed and extracted with 5% sodium bicarbonate and ethyl acetate. The extracts were dried over sodium sulfate, filtered and condensed to give the title compound (17 mg, 19% yield) after purification by preparative-HPLC. 1H NMR (DMSO-d6) δ 8.65 (br s, 1H), 8.47 (s, 1H), 8.00 (m, 2H), 7.84 (d, 1H), 7.59 (d, 1H), 7.43 (br, 1H), 7.35 (t, 2H), 6.84 (s, 1H), 3.45 (m, 2H), 2.39 (m, 2H); ES-MS (m/z) 327[M+1]+.