Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:40][CH3:41])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[O:40][CH3:41]
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5ccc(C(C)=O)s5)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 34, 40 mg, 0.093 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (16 mg, 0.115 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 74% yield (0.038 g, 0.0686 mmol).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:38])([F:37])[C:7]1[CH:8]=[C:9]([NH:21][C:22]([N:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]3[CH:31]=[C:32]([O:35]C)[CH:33]=[CH:34][C:25]2=3)=[O:23])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(=O)=O.CC(C)=O.C(Cl)Cl>[F:37][C:6]([F:5])([F:38])[C:7]1[CH:8]=[C:9]([NH:21][C:22]([N:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]3[CH:31]=[C:32]([OH:35])[CH:33]=[CH:34][C:25]2=3)=[O:23])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1
Reactant: COc1ccc2c(c1)CCCCN2C(=O)Nc1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)N3CCCCc4cc(O)ccc43)cc2C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 38 ml BBr3 (1 M in CH2Cl2) is cooled in dry ice and acetone. Then 1.828 g (3.8 mMol) of 7-methoxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid [3-trifluoromethyl-4-(4-methylpiperazin-1-ylmethyl)-phenyl]-amide in 20 ml CH2Cl2 are added dropwise. The mixture is stirred for 90 min at −78° C., warmed up (−40 to −30° C.) and then stirred at this temperature for 3.5 h. The solution is poured into a mixture of 300 g ice, 150 ml sat. Na2CO3 solution and 200 ml EtOAc, the aqueous phase separated off and extracted twice with EtOAc. The organic layers are washed with water (2×) and brine, dried (Na2SO4) and concentrated after addition of 15 g SiO2. The resulting powder is put on top of a SiO2 chromatography column. Eluation with EtOAC/EtOH 19:1→EtOAC/EtOH/Et3N 90:10:1 gives the title compound: MS: [M+1]+=463; Anal.: C,H,N,F.
Reaction SMILES: N1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[S:8](=[O:21])(=[O:20])[N:7]=2)C=CN=C1.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>>[CH:22]([NH:26][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:15][C:9]=2[S:8](=[O:21])(=[O:20])[N:7]=1)([CH2:24][CH3:25])[CH3:23]
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ccc(C(F)(F)F)cc21
Reactant: CCC(C)N
Product: CCC(C)NC1=NS(=O)(=O)c2cc(C(F)(F)F)ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide was treated with sec-butylamine according to the general procedure Method A to give the title compound; m.p. 234-236° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]([F:38])([F:37])[C:30](=O)[C:31](OCC)=[O:32]>C(O)C>[O:32]=[C:31]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:12][CH:11]=3)[C:7]=2[N:8]=[C:30]1[C:29]([F:38])([F:37])[F:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)c2ccccc12
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3[nH]c(=O)c(C(F)(F)F)nc23)c2ccccc12
Temperature: 25 °C

Procedure:
To tert-butyl 4-(2,3-diaminopyridin-4-yloxy)naphthalen-1-ylcarbamate (1.00 g, 2.73 mmol) dissolved in 20 mL of anhydrous ethanol under argon and at reflux was added the ethyl trifluoropyruvate (697 mg, 0.50 mL, 4.10 mmol). The reaction mixture was stirred at reflux for 3 hours. After cooling at RT, a precipitate was formed, filtered off and rinsed with Et2O. tert-butyl 4-(3-oxo-2-(trifluoromethyl)-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)naphthalen-1-ylcarbamate was obtained as a white solid (116 mg, 0.246 mmol, 9%). The filtrate was evaporated under vacuum. The residue was chromatographed (eluent: CH2Cl2/EtOAc: 4/1 towards 0/1) to afford the second isomer as a slightly yellow solid (540 mg, 1.14 mmol, 42%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([F:25])[CH:17]=1.[OH-].[Na+].O>O1CCCC1>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[C:18]([F:25])[CH:17]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
1-(3,5-Dimethylpyridin-2-yl)piperazine (2.42 g) described in Preparation Example 79 was dissolved in tetrahydrofuran (32 mL), 4-bromo-2-fluorobenzoyl chloride (3.0 g) and 1N aqueous sodium hydroxide solution (15 mL) were added, and the mixture was stirred at room temperature. The reaction mixture was poured into water under cooling, 4N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine added 4N aqueous sodium hydroxide solution and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (4.39 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]>Br>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3ccccc23)CC1
Agent: Br
Product: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Yield: 75 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(4-methoxyphenyl)isoquinoline (1.50 g) obtained in Example 10 was dissolved in 48% hydrobromic acid (15 ml) and reacted at 120° C. for 1.5 hr. The reaction solution was evaporated to a final half volume, and ice-cooled. The resulting precipitates were collected by filtration, and then washed with a small amount of ice-cold water. The precipitates were treated with a 2N aqueous solution of sodium hydroxide, followed by collecting the precipitates by filtration, washed with water and ether/n-hexane, and then dried in warm air, to give the title compound (1.08 g, yield; 75%).
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][CH3:15])[N:8]=1>CN(C)C=O>[Cl:6][C:7]1[CH:12]=[C:11]([O:2][CH3:1])[N:10]=[C:9]([S:14][CH3:15])[N:8]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(SC)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.4 %

Procedure:
3.86 g of 28% sodium methoxide methanol solution was added dropwise over 20 minutes to a solution of 3.9 g of 4,6-dichloro-2-methylthiopyrimidine in 20 ml of N,N-dimethylformamide at 0° C. Then the mixture was stirred at room temperature for 7 hours. 20 g of ice was added to the mixture, then white precipitate was collected by suction filtration, and the solid was washed with water. The solid was dissolved in ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 3.18 g of 4-chloro-6-methoxy-2-methylthiopyrimidine.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH3:5][CH:6]([CH3:23])[CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH:21]=O>CO>[CH3:3][O:2][N:4]=[CH:21][C:9]1[N:8]([CH2:7][CH:6]([CH3:23])[CH3:5])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CON
Reactant: CC(C)Cn1c(C=O)nc2cnc3ccccc3c21
Agent: Cl
Solvent: CO
Product: CON=Cc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
Methoxylamine hydrochloride (0.659 g, 7.90 mmol) was added to a stirred suspension of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde (1.00 g, 3.95 mmol) in methanol (10 mL), and the reaction was stirred at room temperature overnight. The methanol was removed under reduced pressure, and the residue was diluted with saturated aqueous sodium bicarbonate (50 mL). The resulting mixture was extracted with dichloromethane (3×30 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.16 g of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde O-methyloxime as a pale yellow oil that solidified upon standing.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[S:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=[O:12])=O.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:2]([C:3]1[O:12][C:11](=[O:13])[CH:10]=[C:9]2[C:8]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=3[S:6][C:5]=12)([CH3:21])([CH3:20])[CH3:1]
Reactant: COc1ccc2sc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2sc3c(C(C)(C)C)oc(=O)cc3c2c1
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 0.460 g [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]acetic acid from the Step C above, 0.345 g HOBt hydrate, and 0.504 g EDC HCl salt. This mixture was dissolved in 15 mL anhydrous DMF and 0.582 g DIEA was added. The mixture turned bright yellow. After standing at room temperature overnight, the mixture was poured into water and extracted with ether several times. The combined ether extract was washed with water (4×), 5% NaHCO3, and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the title compound as a bright yellow solid. 1H NMR (CDCl3, 500 MHz) 7.49 (d, 8.7 Hz, 1H), 7.35 (d, 2.5 Hz, 1H), 7.20 (dd, 2.5 & 8.9 Hz, 1H), 6.65 (s, 1H), 3.92 (s, 3H), 1.51 (s, 9H). LC-MS: 3.77 min. (m/Z=289.3).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)c4ccccc4)cc3)cc2)CC1
Yield: 6.6 %

Procedure:
The title compound (3.0 mg, 7%) was prepared from [4-(phenylcarbonyl)phenyl]boronic acid (22.6 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to example 9, Step 3. LRMS (ESI), m/z 480 (M+Na).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]1[CH2:16][O:15][CH2:14][C@@H:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].O.NN>C(O)C>[NH2:3][C@@H:12]1[CH2:16][O:15][CH2:14][C@@H:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1COC[C@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1COC[C@H]1N
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl ((3R,4S)-4-(1,3-dioxoisoindolin-2-yl)tetrahydrofuran-3-yl)carbamate (13.08 g, 39.4 mmol) was dissolved into ethanol (98 mL, 0.4 M)). Hydrazine monohydrate (1.97 g, 39.4 mmol) was added, and the reaction was stirred 30 minutes at 50° C. and then 2 hours at 75° C. The reaction was then cooled to room temperature and the white solid was removed by filtration. The filtrate was concentrated down and dried, then treated with ethanol (about 15 mL). Additional white solid was removed by filtration, then filtrate was concentrated down and dried to yield tert-butyl ((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate as a thick, clear oil (8.724 g at 90% purity; 99%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:38][CH3:39])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:40])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.[C:50](Cl)(=[O:53])[CH:51]=[CH2:52].C([O-])(O)=O.[Na+]>O.C(Cl)Cl>[CH3:39][O:38][C:27]1[CH:28]=[C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:30]=[CH:31][C:26]=1[NH:25][C:22]1[N:23]=[CH:24][C:19]2[CH:18]=[CH:17][C:16](=[O:40])[N:15]([C:11]3[CH:10]=[C:9]([NH:8][C:50](=[O:53])[CH:51]=[CH2:52])[CH:14]=[CH:13][CH:12]=3)[C:20]=2[N:21]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(Nc4ccc(N5CCOCC5)cc4OC)nc32)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49.1 %

Procedure:
8-(3-Aminophenyl)-2-((2-methoxy-4-morpholinophenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one 2,2,2-trifluoroacetate (2b, 63 mg, 0.11 mmol) was treated with DCM (5.0 mL), cooled to 0° C. and treated with DIEA (0.06 mL, 0.34 mmol) and acryloyl chloride (9.16 μL, 0.113 mmol) and stirred at 0° C. for 40 min. The reaction mixture was treated with ice and water and then a saturated solution of NaHCO3. It was extracted with DCM (3×25 mL), dried over Na2SO4, filtered and concentrated. The crude residue was purified on a Gilson prepatory HPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5μ, 20-95% 0.1% TFA/CH3CN in 0.1% TFA/water) affording N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (2) (26 mg, 0.054 mmol, 47% yield) as a light orange amorphous solid after concentration of the sample containing fractions, treatment with a saturated solution of NaHCO3, extraction with DCM (3×25 mL), drying over Na2SO4, filtration and drying under vacuum. m/z (ESI, +ve ion) 500.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 8.88 (1H, s), 8.04 (1H, d, J=9.6 Hz), 7.66-7.70 (1H, m), 7.64 (1H, d, J=8.2 Hz), 7.45 (1H, t, J=8.0 Hz), 6.94-7.00 (1H, m), 6.90 (1H, d, J=8.6 Hz), 6.67 (1H, d, J=9.6 Hz), 6.59 (1H, d, J=2.5 Hz), 6.42-6.51 (1H, m), 6.40 (1H, dd, J=8.8, 2.5 Hz), 6.22-6.32 (1H, m), 5.77-5.82 (1H, m), 3.71-3.80 (4H, m), 3.63 (3H, s), 3.04-3.14 (4H, m).
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](I)[CH:31]=3)=[CH:24][C:23]=2[C:39]([F:42])([F:41])[F:40])[CH2:17][CH2:16]1>>[OH:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:31]=3)=[CH:24][C:23]=2[C:39]([F:42])([F:41])[F:40])[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cccnn12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 563 m/z (M+H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13][CH3:14])=[O:12])=[O:7])=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1(C)C=CC=CC=1>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:16]=[CH:15][C:5]([C:6]([C@@H:8]3[CH2:10][C@H:9]3[C:11]([O:13][CH3:14])=[O:12])=[O:7])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 85 °C
Yield: 66.3 %

Procedure:
Methyl trans-2-(4-bromobenzoyl)cyclopropanecarboxylate (1.33 g, 4.70 mmol) and 4-amino-phenyl boronic acid (0.98 g, 5.64 mmol) were combined in a dry flask under argon. Toluene (25 mL), EtOH (10 mL), and 3 M aqueous Na2CO3 (7 mL, 20 mmol) were added, and the resulting solution was degassed for 30 minutes by using a flow of argon. Then [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1 complex with dichloromethane (383 mg, 0.47 mmol) was added, and the resulting mixture was heated at 85° C. for 16 h. The mixture was cooled to rt, then diluted with EtOAc and passed through a Celite® pad. The solvent was removed by rotary evaporation. Water and EtOAc were added, and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage Flash 40M) using 33 to 40% ethyl acetate in hexane to afford methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]-cyclopropanecarboxylate (0.92 g, 66%). 1H NMR (400 MHz, CD2Cl2) δ 1.60 (m, 21), 2.35 (m, 1H), 3.22 (m, 1H), 3.73 (s, 3H), 6.80 (m, 2H), 7.51 (m, 2H), 7.68 (m, 2H), 8.05 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[S:25][C:26]([CH3:30])=[C:27]([CH3:29])[N:28]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[S:25][C:26]([CH3:30])=[C:27]([CH3:29])[N:28]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: Cc1nc(N)sc1C
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Product: Cc1nc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)sc1C
Yield: 87 %

Procedure:
2,5-Dihydro-2,5-dimethyl-N-(4,5-dimethyl-2-thiazolyl)-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from methyl 2,5-Dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indol-3-carboxylate 1,1-dioxide and 2-amino-4,5-dimethyl-thiazole with a yield of 87% of theory; M.p. 265° C. (decomposition).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:14]=[C:13]([Cl:24])[C:12]=1[C:25](Cl)=[O:26]>>[Cl:10][C:11]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:24])[C:12]=1[C:25]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:26])[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[O:23]
Reactant: COCCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: c1cc2cc[nH]c2cn1
Product: COCCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3cnccc23)c(Cl)c1

Procedure:
3,5-Dichloro-N-(2-methoxyethyl)-4-(1H-pyrrolo[2,3-c]pyridin-3-ylcarbonyl)benzamide was prepared from 1H-Pyrrolo[2,3-c]pyridine and 2,6-dichloro-4-(2-methoxyethylcarbamoyl)benzene carbonyl chloride (Compound No. 14).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:16].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:26])[CH2:21][CH2:20]1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:26])[C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[O:13])=[CH:9][C:8]=1[CH3:16]
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCS1(=O)=O
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)c(C)c3)CC2)cc1
Yield: 10.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-methylbenzoic acid (268 mg) described in Preparation Example and (piperidin-4-yl)(p-tolyl)methanone hydrochloride (252 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (50 mg) was obtained.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]2[N:45]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[O:11])[C:5]=3[N:44]=2)[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(C(=O)N2CCOCC2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C(=O)N2CCOCC2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-(morpholine-4-carbonyl)-cyclohexanone (16 mg, 0.06 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (17 mg, 0.045 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (5 mg, 25%). MS ISP (m/e): 449.4 (100) [(M+H)+].
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[C:27]([C:29]1[CH:38]=[C:37]2[C:32]([C:33]([CH3:45])([CH3:44])[CH2:34][CH2:35][C:36]2=[C:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:45][C:33]1([CH3:44])[C:32]2[CH:31]=[CH:30][C:29]([C:27]#[C:28][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:38][C:37]=2[C:36](=[C:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: C#Cc1ccc2c(c1)C(=C(CC)CC)CCC2(C)C
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=C(CC)CC)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 235 mg (0.94 mmol) of 7-ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound X) was converted into the title compound using 236 mg (0.85 mmol) of ethyl 4-iodobenzoate, 57 mg (0.3 mmol) of cuprous iodide and 220 mg (0.31 mmol) of bis(triphenylphosphine)palladium(II) chloride.