Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound which contains less than 10% of the Z isomer as a white foam, MS (ESI+): m/z=445.05 [M+H]+.
Reaction SMILES: [C:1]([S:9]/[CH:10]=[CH:11]\[C:12](Cl)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[C:16]#[CH:17].C(N(CC)CC)C.Cl>ClCCl>[CH2:15]([NH:18][C:12](=[O:13])/[CH:11]=[CH:10]\[S:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]#[CH:17]
Reactant: O=C(Cl)/C=C\SC(=O)c1ccccc1
Reactant: C#CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)/C=C\SC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a stirred, cooled (0° C.) solution of 0.70 g (0.0039 mol) of cis-3-(benzoylthio)propenoyl chloride in 40 ml of dichloromethane under nitrogen was added dropwise 0.21 ml (0.0039 mol) of propargylamine as a solution in 10 ml of dichloromethane. After 15 min, 0.43 ml (0.0039 mol) of triethylamine was added dropwise. The reaction was allowed to stir at 0° C. for 2 h, poured into 10% aqueous hydrochloric acid, and extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, and dried over magnesium sulfate. Filtration and removal of solvents gave 0.49 g (65% yield) of N-(2-propynyl)-cis-3-(benzoylthio)acrylamide as a white powder, m.p. 131°-134° C., as described in Table 1.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]1[C:15]([O:17][CH3:18])=[O:16])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:18][O:17][C:15]([C@@H:10]1[C@@H:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH2:12][CH2:11]1)=[O:16]
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CCC=C[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
438 mg of (1S, 2R)-2-benzoyl-1-methoxycarbonylcyclohex-4-ene was dissolved in 2.5 ml of trifluoroacetic acid. To the solution, 2.5 ml of triethylsilyl hydride (Et3SiH) was added at 50° C., and the solution was stirred for 30 minutes at the same temperature. After the solution was allowed to stand to return to room temperature, a saturated sodium bicarbonate solution was added, and the water layer was extracted with ether. Then, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and the residure was subjected to silica gel column chromatography (ether:hexane=4:96), thereby obtaining 221 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:18]3[N:23]=[C:22]([NH:24][C:25]4[C:26]([C:27](=[O:28])[NH:29][CH3:30])=[CH:31][CH:32]=[CH:33][C:34]=4[F:35])[C:21]([Cl:36])=[CH:20][N:19]=3)=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COC(=O)N1CCCOc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a white foam (71 mg, 37%). LCMS (m/e) 501 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.48-9.34 (m, 2H), 8.61-8.52 (m, 1H), 8.20 (s, 1H), 7.55-7.37 (m, 3H), 7.33-7.25 (m, 1H), 7.14-7.07 (m, 1H), 6.99-6.91 (m, 1H), 4.03-3.87 (m, 2H), 3.73-3.44 (m, 5H), 2.74 (d, 3H, J=4.4 Hz), 1.96-1.82 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]([C:16]([CH3:24])([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12](OC)=[O:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C[O-].[Na+]>C(O)C>[CH3:23][C:16]([N:10]1[CH2:11][C:12]([OH:13])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:9])([CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CN(C(=O)Cc1ccccc1)C(C)(C)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(c1ccccc1)N1CC(O)=C(c2ccccc2)C1=O
Yield: 45.5 %

Procedure:
10 g (30 mmol) of methyl 2-(N-phenylacetyl-α,α-dimethylbenzylamino)acetate was dissolved in 100 ml of ethanol, and 17.4 g (90 mmol) of a methanol solution of 28% sodium methylate was added thereto. The mixture was refluxed under heating for 0.5 hour. The reaction solvent was distilled off under reduced pressure, and the residue was poured into ice water and acidified with 10% hydrochloric acid. Precipitated crude crystals were collected by filtration and recrystallized from ethanol to obtain 4.0 g (yield: 46%) of the desired compound.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3]([S:9](=[O:10])(=[O:11])[NH:12][C:13]3[C:14]2=[CH:15][CH:16]=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 4 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-methyl-N-quinolin-8-yl-benzenesulfonamide (Intermediate 294) (520 mg, 1.67 mmol), t-butyl nitrite (0.29 ml, 2.5 mmol), AcOH (5.2 ml) and THF (5.2 ml) gave the title compound (20 mg, 5%) after purification by column chromatography with DCM/MeOH (99.7:0.3) as the eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([O:40][CH2:41][C:42](O)=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=3)[C:22]([O:40][CH2:41][C:42]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCC(=O)N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxymethoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto is added morpholine (30 μl). After addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (66 mg) and 1-hydroxybenzotriazole hydrate (46 mg) under ice-cooling, the mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1) to give (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(morpholin-4-yl)-2-oxoethoxy]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (138 mg). MS (m/z): 727 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)[N:3]=1.[F-:31].[K+].[F-].[Na+].C1OCCOCCOCCOCCOCCOC1>CCOCC.O>[F:31][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)[N:3]=1
Reactant: [F-]
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(Cl)n2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(F)n2)cc1
Yield: 53.2 %

Procedure:
0.20 g (0.5 mmol) of 2-chloro-3-octyl-6-(4-octyloxyphenyl)pyridine is heated together with 0.5 g of potassium fluoride, 0.5 g sodium fluoride and 0.02 g of 18-crown-6 in a sealed tube at 200° C. for 18 hours. The reaction mixture is taken up in ether/water, the organic phase is washed with water, dried over sodium sulfate, filtered, the solvent is distilled off, the residue is purified by chromatography (silica gel, 8:2 hexane/ethyl acetate) and recrystallized from acetonitrile, giving 0.11 g of 2-fluoro-3-octyl-6- (4-octyloxyphenyl ) pyridine. ##STR16##
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22](O)=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(CC)CC.O.[CH3:31][CH2:32][CH2:33][CH2:34]CC>>[C:1]1([NH:7][C:8]2([C:22](=[O:23])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CCCCC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a stirred and cooled (-5° C.) suspension of 16.2 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid in 525 parts of dry 1,1'-oxybisethane, are added dropwise 228.5 parts of 1-lithiumbutane solution 20% in hexane at 0° C. Upon completion, stirring is continued for 3 hours at 0° C. The reaction mixture is decomposed by addition of 300 parts of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 2.5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is dissolved in 2,2'-oxybispropane and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from petroleum-ether, yielding 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]-1-pentanone; mp. 71.3° C.
Reaction SMILES: [C:1]1([C:7](=[N:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>>[C:1]1([C:7](=[N:17][O:18][CH2:19][C:20]([OH:22])=[O:21])[C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CON=C(c1ccccc1)c1cc2ccncc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CON=C(c1ccccc1)c1cc2ccncc2[nH]1

Procedure:
[[[Phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]acetic acid was prepared by treating tert-butyl[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]acetate (Example 58) (18 mg, 0.05 mmol) with trifluoroacetic acid (1 mL) as an off white solid after concentration: mp 68-73° C.; ESI MS m/z 296 [C16H13N3O3+H]+; HPLC (Method A) 98.9% (AUC), tR=15.7 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(C1(N[C:34]([CH:36](NC(N2CCOCC2)=O)CC(C)(C)C)=[O:35])CC(C2C=CC=CC=2)NC(C2C=CC=CC=2)C1)#N.C(C1(NC(C(NC(N2CCOCC2)=O)CC2CCCCC2)=O)CCN(C)CC1C)#N>C(O)(=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:34](=[O:35])[CH3:36])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CC(c2ccccc2)NC(c2ccccc2)C1
Agent: CC1CN(C)CCC1(C#N)NC(=O)C(CC1CCCCC1)NC(=O)N1CCOCC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC(C)=O)cc1

Procedure:
Methyl-4-(acetylamino-methyl)-benzoate was prepared from acetic acid and methyl 4-(aminomethyl)benzoate using a method analogous to that of Example 1-part (d). The crude N-acyl ester was saponified using a method analogous to that of Example 1-part (c). The crude product was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:61])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([OH:60])[CH2:45]2)[CH:7]([CH3:62])[CH2:6][CH2:5][C:4]1=[O:63])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:61])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([OH:60])[CH2:45]2)[CH:7]([CH3:62])[CH2:6][CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: [H][H]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-cinnamyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (16 mg in 2 ml ethanol) is added 2 mg of 5% rhodium on carbon catalyst. The reaction flask is fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 30 minutes, the mixture is filtered over diatomaceuis earth, concentrated and purified by preparative TLC on silica gel to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH:36][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1
Reactant: CN(C)CCN
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)NCCN(C)C)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (83 mg, 0.2 mmol), N1,N1-dimethylethane-1,2-diamine (19 mg, 0.22 mmol), 1-methyl-1H-imidazole (66 mg, 0.8 mmol) and EDCI (153 mg, 0.8 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 h then concentrated. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:20) and further purified by Prep-TLC (silica gel, methanol:dichloromethane=1:10) to afford N-(2-(dimethylamino)ethyl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (41 mg, 42%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.89 (s, 1H), 8.48 (s, 1H), 8.13 (dd, 1H, J1=6.9 Hz, J2=1.8 Hz), 8.02-7.97 (m, 2H), 7.65-7.60 (m, 2H), 7.45 (t, 1H, J=8.1 Hz), 6.31 (d, 1H, J=7.5 Hz), 6.10 (d, 1H, J=8.1 Hz), 4.29-4.25 (m, 1H), 3.76-3.72 (m, 2H), 3.66-3.60 (m, 1H), 3.54-3.40 (m, 1H), 3.19-3.15 (m, 2H), 2.81 (s, 6H), 2.25-2.00 (m, 3H), 1.75-1.73 (m, 1H), 1.17 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 485, tR=1.062 min, HPLC: 99.08% at 214 nm, 99.16% at 254 nm, tR=4.868 min.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.13 min; [M+H]+=475.08.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:31][C:29]3[CH:28]=[CH:27][C:25]4[N:26]=[C:22]([N:21]([CH2:20][CH2:19][N:18]([CH3:17])[CH3:33])[CH3:32])[S:23][C:24]=4[CH:30]=3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(OC2CCCCC2)cc1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(OC4CCCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following Method A, using 4-cyclohexyloxy benzoic acid (0.20 g, 0.91 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.17 g, 0.68 mmol) to afford the 0.15 g (36%). LC/MS: Retention time=5.23 min; (m/z): calcd for C25H32N4O2S: 453.6; found: 453.0.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:23]=[CH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:23]=[CH:22]4)=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCn1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Product: CCCCCCCCn1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 95 %

Procedure:
This compound was synthesized as a white amorphous solid from 4m (50.2 mg, 0.108 mmol) in 48% aqueous HBr (1.0 mL) in 95% yield by following general procedure 1.4: MALDI-MS: 450.3 (M+H+), 472.3 (M+Na+).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[N:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]([CH2:12][O:13][CH3:14])=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:4]=1[C:22](OC)=[O:23].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O1CCCC1.O>[CH3:26][N:2]([CH3:1])[C:3]1[N:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[C:6]([CH2:12][O:13][CH3:14])=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:4]=1[CH2:22][OH:23]
Reactant: COCc1c(C(C)C)nc(N(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1c(C(C)C)nc(N(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2.8 ml (9.8 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 1.83 g (4.9 mmol) of the compound from Example 13 in 10 ml of dry tetrahydrofuran at 25° C. and the mixture is stirred overnight at 60° C. After cooling to 20° C., a solution of 10 g of potassium sodium tartrate in 20 ml of water is added dropwise cautiously and the mixture is extracted three times with 100 ml of ethyl acetate each time. The combined organic phases are washed once with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][CH:30]([F:41])[O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:34]1[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH:30]([F:41])[F:29])[CH:33]=1
Reactant: OB(O)c1cncc(OC(F)F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(OC(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.17 mmol) were added 48 mg (0.26 mmol) of (5-(difluoromethoxy)pyridin-3-yl)boronic acid, 13 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex and 170 μl of a 2M aqueous solution of cesium carbonate in dioxane. The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 100% hexane/AcOEt, 0-8% AcOEt/MeOH) to give 70 mg (81% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.Cl.[CH3:12][C:13](=O)CC(=O)C.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:9]=[C:12]([CH3:13])[NH:8][C:6]=2[CH:7]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(Br)cc(N)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(C)cc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
To a solution of 5-bromo-3-methylbenzene-1,2-diamine (201 mg, 1.00 mmol) in EtOH (15 mL) was added 5 N HCl (4 mL). The mixture was heated at reflux before addition of 2,4-pentanedione (200 mg, 0.21 mL, 2.0 mmol). Heating was continued for 45 minutes before analysis indicated the reaction was complete. The reaction was cooled to room temperature, neutralized with saturated aqueous NaHCO3 and extracted with CHCl3. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, concentrated and dried to afford 6-bromo-2,4-dimethyl-1H-benzimidazole (217 mg, 96%).