Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:25])[N:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:18][O:19][CH2:20][C:13]=4[C:12]([C:26]4[S:30][CH:29]=[N:28][CH:27]=4)=[C:9]3[C:10]=2[CH:11]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Sn](CCCC)(CCCC)CCCC)[N:35]=1>C1(C)C=CC=CC=1.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:21]([N:16]1[C:15](=[O:25])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:31][CH3:32])[C:2]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[N:35]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:26]3[S:30][CH:29]=[N:28][CH:27]=3)[C:13]=2[CH2:20][O:19][CH2:18][CH2:17]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(F)n1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cccc(F)n1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Yield: 72.7 %

Procedure:
A solution of 80 mg of 11i, 90 mg of 2-fluoro-6-tributylstannylpyridine and 25 mg of Pd(PPh3)4 in 5 ml of degassed toluene was heated at 110° C., under N2 atmosphere, during 48 hr. The reaction mixture was applied to a silica gel column and eluted with a gradient of heptane/acetone. The isolated product was treated with diethyl ether and provided 60 mg of 11k as white crystalline material; Mp: 232-234° C.; Rf 0.45 (heptane/acetone 1/1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(Cl)(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])=[CH:13][CH:14]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Nc2ccc(O)cc2)c(C(C)=O)c1

Procedure:
1-[2-(4-Hydroxyphenylamino)-5-methoxyphenyl]ethanone [XIV; R=5-CH3O, R"=H, OH at 4-position] was prepared by hydrogenation of 1-[2-(4-benzyloxyphenylamino)-5-methoxyphenyl]ethanone according to the procedure of Example 5, part (b), and obtained in the form of an orange powder, m.p. 118°-119° C. after chromatography on silica gel with chloroform eluant.
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:5])=[O:4].C(O)(=O)C>O1CCOCC1.C(O)C.O1CCOCC1>[N+:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])CCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
In a 500 mL two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel, NaBH4 (5.33 g, 0.140 mol) was suspended in 1,4-dioxane/ethanol (100 mL/30 ml). ≈-Nitrostyrene (3, 10.0 g, 67.0 mmol) in 1,4-dioxane (100 mL) was added dropwise to the solution over 45 minutes, keeping the temperature below 30° C. A fine slurry formed during the addition. After the addition the reaction mixture was stirred overnight, then ice/water (125 mL) was added, and a 50% solution of acetic acid was added to neutralize excess NaBH4; the clear solution was then concentrated in vacuo and the residue was dissolved in water and extracted twice with CH2Cl2. The organic phase was washed with water (2×30 mL) and brine (1×30 mL), dried (Na2SO4), filtered and evaporated in vacuo obtaining 4 (8.40 g, 83%) as yellow oil. ESI-MS: 152 (MH+) (Calc. for C8H9NO2: 151).
Reaction SMILES: O1CCCC1.[Br-].[F:7][C:8]([F:13])([F:12])[C:9]([Zn+])=[CH2:10].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>CCCCCC>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:9]([C:8]([F:13])([F:12])[F:7])=[CH2:10])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]
Reactant: FC(F)(F)c1cc(I)ccc1Cl
Reactant: C=C([Zn+])C(F)(F)F
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
In a nitrogen atmosphere, to 53 mL of a 1M tetrahydrofuran solution of 1-trifluoromethylethenyl zinc bromide prepared according to a method described in the literatures, 7.1 g of 2-chloro-5-iodobenzotrifluoride and 0.65 g of dichlorobis(triphenylphosphine) palladium (II) were added and the resultant mixture was stirred while heating the mixture to reflux for 2.5 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 200 mL of hexane was added to the reaction mixture, followed by filtering off the deposited insoluble substance. The resultant filtrate was washed with water (50 mL×1) and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 4.8 g of the objective substance as a colorless oily substance.
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[C:5](N)[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.C(N(CC)CC)C>[CH2:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: Nc1c2c(cc3c1CCC3)CCC2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1c2c(cc3c1CCC3)CCC2
Temperature: 25 °C
Yield: 113.8 %

Procedure:
To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (77 grams) in tetrahydrofuran (1.5 L) and triethylamine (68.3 mL) was added triphosgene (43.9 grams) in one portion. The mixture was heated to reflux for ½ hour, then cooled to room temperature. The tetrahydrofuran was removed under reduced pressure, and the residue was taken up in pentane and filtered through a plug of silica gel. Removal of the pentane in vacuo afforded 80 grams of a white solid, m.p. 35.0-36.2° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([CH3:41])[CH:33]=1>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[C:34]([CH3:41])[CH:33]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: Cc1cc(F)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(F)ccc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 9.2 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 4-fluoro-2-methyl-phenylboronic acid (30 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 72 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (5 mg, 9%). LC-MS m/e 419.28 (M+H+)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:13]2[CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10][C:9]2=[N:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[CH2:18][CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: CCCc1cc(I)ccc1N=C1NCC2(CCCC2)S1
Product: CCCc1cc(I)ccc1N=C1SC2(CCCC2)CN1C1CCCC1

Procedure:
2-n-Propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. The aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-n-propylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=[C:32]([C:38]([F:41])([F:40])[F:39])[N:31]=2)[CH:25]=1>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH:37][CH2:36][C:35]2[C:30]([C:26]3[CH:25]=[C:24]([CH3:42])[CH:29]=[CH:28][CH:27]=3)=[N:31][C:32]([C:38]([F:41])([F:39])[F:40])=[CH:33][CH:34]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a stirred solution of phenyl 3-fluoro-4-(methylsulfonamidomethyl)-phenylcarbamate (67 mg, 0.198 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (53 mg, 0.198 mmol) in acetonitrile were added 4-dimethylaminopyridine (24 mg, 0.198 mmol). The reaction mixture was stirred for 15 h at 50° C. The mixture was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(2-Fluoro-4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)methanesulfonamide (example 27) (72 mg) was obtained as 72% yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2ncccc2c1
Temperature: 0 °C
Yield: 72.5 %

Procedure:
Dissolve 6-quinolinecarboxamide (1.5 g, 8.95 mmol) in DCM (50 mL), add triethylamine (2.7 g, 26.8 mmol) and cool the reaction mixture to 0° C. Add trifluoroacetic acid anhydride (2.4 g, 11.16 mmol) to the reaction mixture and stir for 10 min at 0° C. Quench the reaction mixture with water (20 mL) and separate the organic layer. Extract aqueous layer with DCM (2×15 mL). Combine the organic extracts and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the desired intermediate as a white solid (1.0 g, 73%). GC-MS m/z: 154 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])=[CH:19][CH:20]=2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCBr
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(OCCCCCl)cc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
Combine 4-benzyloxy-4'-hydroxybenzophenone (9.12 g, 30.0 mmol) and sodium hydroxide (1.8 g, 45 mmol) in water (35 mL). Add tetrabutylammonium hydrogensulfate (1.02 g, 3.0 mmol). Add 1-bromo-4-chlorobutane (5.2 mL, 45 mmol). Heat to reflux. After 3 hours, cool the reaction mixture to give a solid. Collect the solid by filtration, rinse with water, and dry to give 4-benzyloxy-4'-(4-chlorobutyloxy)benzophenone: Rf =0.32 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:8]12
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (89.0 mg, 0.382 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (111.0 mg, 0.458 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (200 ul, 1.1 mmol). To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile (79 mg, 0.420 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (54.2 mg, 35.2%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (br. s., 1H), 8.46 (d, J=2.3 Hz, 1H), 7.83 (dd, J=9.1, 2.5 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.55-3.70 (m, 4H), 3.34 (s, 2H), 2.59 (td, J=12.6, 2.4 Hz, 1H), 2.40 (t, J=4.8 Hz, 4H), 2.03 (d, J=12.6 Hz, 1H), 1.84 (d, J=12.1 Hz, 1H), 1.63 (d, J=13.6 Hz, 1H), 1.29-1.56 (m, 3H). [M+H] calc'd for C22H25N7O, 404. found, 404.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[C:54]([CH3:59])=[N:55][O:56][C:57]=3[CH3:58])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[C:54]([CH3:59])=[N:55][O:56][C:57]=3[CH3:58])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Cc1noc(C)c1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5c(C)noc5C)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 41 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-4-(4-((3,5-dimethylisoxazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (20 mg, 0.049 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.14 mmol, 0.14 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.053 mmol, 7 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 42%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.26 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.63 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 3.40 (s, 2H, CH2), 3.72 (s, br, 4H, piperazine N(CH2)2), 3.88 (s, 3H, OCH3), 7.08 (d, J=8.8 Hz, 2H, methoxyphenyl H-2 & H-6), 8.12 (d, J=8.7 Hz, 2H, methoxyphenyl H-3 & H-5), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.03 (s, br, 1H, imidazo[4,5-b]pyridine NH); LC (Method B)-MS (ESI, m/z): Rt=3.29 min—497, 499 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 497.1301, calculated for C23H25BrN6O2 (M+H)+: 497.1301.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:11][CH:10]3[CH2:12][CH2:13][CH:7]2[CH2:8][CH2:9]3)[CH2:2]1.C([O-])(=O)C.[Na+].[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>CC(C)=O.O>[Cl:19][CH2:20][CH2:21][C:22]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:11][CH:10]3[CH2:12][CH2:13][CH:7]2[CH2:8][CH2:9]3)[CH2:2]1)=[O:23]
Reactant: C1CNCC2(C1)CC1CCC2CC1
Reactant: O=C(Cl)CCCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCCl)N1CCCC2(CC3CCC2CC3)C1

Procedure:
An amount of 2.0 g (0.0112 mole) of spiro[bicyclo [2.2.2]octane-2,3'-piperidine] is added, with ice cooling and with stirring, to a suspension of 2.4 g of sodium acetate in 30 ml of acetone and 10 ml of water; there is then added dropwise to the formed mixture at 0°-5° 1.8 g (0.014 mole) of 3-chloropropionyl chloride. An addition is subsequently made to the mixture, at 0°-5°, of 70 ml of water, whereupon the reaction product precipitates in liquid form. The mixture is extracted three times with 50 ml of methylene chloride each time. The methylene chloride extracts are washed separately in each case once with saturated sodium bicarbonate solution and twice with water; they are then dried over sodium sulphate and afterwards concentrated in vacuo (ca. 12 Torr) to obtain 1'-(3-chloropropionyl)-spiro[bicyclo[2.2.2]octane-2,3'-piperidine].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH:24]=[CH2:25])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][NH2:31].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH:24]=[CH2:25])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:5])[CH3:2]
Reactant: COCCN
Reactant: C=CCn1c(=O)c(C(=O)OCC)c(Cl)c2cnc(-c3ccccc3)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCn1c(=O)c(C(=O)OCC)c(NCCOC)c2cnc(-c3ccccc3)nc21

Procedure:
To 0.9 g. (0.0024 mole) of 8-allyl-5-chloro-7,8-dihydro-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in 30 ml. of ethanol was added 0.17 g. (0.0024 mole) of 2-methoxyethylamine and 0.25 g. (0.0024 mole) of Na2CO3. This mixture was heated at reflux for 4 hours, then filtered and the filtrate chilled. Yellow crystals formed and were collected on a filter. Recrystallization from ethanol gave 0.5 g. of product--m.p. 155°-158° C.
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:20])[C:5]1([C:15]([O:17]CC)=[O:16])[CH2:10][C:9](=[CH2:11])[CH2:8][CH:7]([C:12]([O-:14])=[O:13])[NH:6]1.Cl>C(O)C>[F:20][CH:4]([F:3])[C:5]1([C:15]([OH:17])=[O:16])[CH2:10][C:9](=[CH2:11])[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[NH:6]1
Reactant: C=C1CC(C(=O)[O-])NC(C(=O)OCC)(C(F)F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C1CC(C(=O)O)NC(C(=O)O)(C(F)F)C1
Temperature: 25 °C
Reaction time: 30 h
Yield: 76.3 %

Procedure:
1.3 ml of 2N sodium hydroxide were added to a solution of 190 mg of the product of Example 13 (Isomer B) in 7 ml of ethanol and the mixture was stirred at ambient temperature for 30 hours and then neutralized to about pH 5 with 2N hydrochloric acid. After evaporating to dryness, the residue was taken up in 5 ml of water, then chromatographed on Dowex resin followed by elution with water. After evaporation to dryness, 140 mg of the product were taken up in 200 ml of water, filtered and lyophilized to obtain 130 mg of the desired product with a Rf=0.4 Butanol-acetic acid-water (4-2-2).
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.C(O)C.[NH2:15]OS(O)(=O)=O>O>[NH2:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nn1ncc2ccccc21
Temperature: 55 °C
Yield: 47.3 %

Procedure:
To a solution of 2.2 g(55 mmol) of sodium hydroxide in 30 ml of water was added 1.33 g(10 mmol) of 1H-indazole and ethanol was slowly added at 50° C. until the reaction mixture was dissolved thoroughly. The resulting mixture was heated to 55° C. and 2.83 g(25 mmol) of hydroxylamine-O-sulfonic acid was slowly added over 30 min with vigorous stirring followed by further stirring for 30 min. After completion of reaction, the resulting precipitate was filtered off, and the filtrate was extracted with dichloromethane(30 ml×2), dried over anhydrous magnesium sulfate and concetrated under the reduced pressure. The concentrate was chromatographed over silica gel using 10% ethyl acetate/dichloromethane as an eluent. The fractions containing the desired product were concentrated under the reduced pressure and crystallized from benzene/petroleum ether to give 0.63 g of the desired compound(47%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:6][C:3]=1[CH:4]=[O:5].C([OH:22])(C)(C)C.C(Cl)Cl.CC(=CC)C.[O-]Cl=O.[Na+]>O.CC#N.CC#N.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:6][C:3]=1[C:4]([OH:22])=[O:5]
Reactant: COCCCOc1cc(C=O)c(Cl)cc1OC
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)O)c(Cl)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4-methoxy-5-(3-methoxy-propoxy)-benzaldehyde (1.08 g, 3.55 mmol) in a 3:1 mixture of tert-butanol/CH2Cl2 (20 mL) is added 2-methyl-2-butene (0.74 g, 5.32 mmol), followed by dropwise addition of a solution of NaClO2 (0.67g, 7.10 mmol) and NaH2PO4 (0.67 g, 4.26 mmol) in water (14 mL) over 15 min at room temperature, and stirring is continued overnight. The reaction mixture is poured into ice/saturated aqueous NaHCO3 solution, the water phase is washed with AcOEt. The ice-cold aqueous layer is acidified with HCl 37% to form a white precipitate which is filtered off, washed with ice-cold water and dried in vacuo. The compound is obtained as white solid. MS: 273.0 [M−H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.25 min. 1H-NMR (CDCl3): δ 1.96 (m, 2H), 3.25 (s, 3H), 3.47 (m, 2H), 3.85 (s, 3H), 4.03 (m, 2H), 7.10 (s, 1H), 7.39 (s, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[F:26][CH:27]([F:36])[CH2:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>>[F:26][CH:27]([F:36])[CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([NH:21][C:17]2[C:18]([NH2:20])=[N:19][C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=4[F:1])[N:6]=3)=[N:15][CH:16]=2)[CH2:31][CH2:30]1
Reactant: O=C1CCN(CC(F)F)CC1
Reactant: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1NC1CCN(CC(F)F)CC1

Procedure:
200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were reacted in analogy to the method in example 88A with 1-(2,2-difluoroethyl)piperidin-4-one. After purification by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient), this gave 219 mg of the title compound (76% of theory).