Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:14]2([CH2:19][O:20][C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[C:23]([CH3:38])[CH:22]=3)[CH2:18][CH:17]=[CH:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:8]>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:14]2([CH2:19][O:20][C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)=[C:23]([CH3:38])[CH:22]=3)[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:8]
Reactant: COC(=O)CCNC(=O)c1ccc(C2(COc3cc(C)c(-c4ccc(C(F)(F)F)cc4)c(C)c3)CC=CC2)s1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCNC(=O)c1ccc(C2(COc3cc(C)c(-c4ccc(C(F)(F)F)cc4)c(C)c3)CCCC2)s1
Reaction time: 0.83 h
Yield: 93 %

Procedure:
A solution of 3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.0828 g, 0.148 mmol) in EtOH (2.0 mL) is treated with 10% palladium on carbon (16 mg), flushed with H2, and stirred under 1 atm pressure for 50 min. The mixture is then filtered through Celite® and concentrated. to provide 3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopentyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.0770 g, 93%) as a white foam. MS (ES): 558.3 [M−H]−.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([F:34])[C:25]=4[F:35])=[N:21][C:20]=3[CH3:36])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[F:35][C:25]1[C:26]([F:34])=[C:27]([C:30]([F:32])([F:31])[F:33])[CH:28]=[CH:29][C:24]=1[C:22]1[S:23][C:19]([CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[CH2:7][C:6]([OH:37])=[O:5])=[CH:12][CH:13]=2)=[C:20]([CH3:36])[N:21]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], {6-[2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid as yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:22]1([C:28]2[CH:33]=[CH:32][C:31](O)=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH:22]1([C:28]2[CH:33]=[CH:32][C:31]([O:1][CH2:2][C:3]3[N:8]=[CH:7][C:6]([N:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]4)=[CH:5][CH:4]=3)=[CH:30][C:29]=2[C:35]([F:36])([F:37])[F:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)nc2)CC1
Reactant: Oc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(COc3ccc(C4CCCCC4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
tert-Butyl 4-(6-hydroxymethyl-pyridin-3-yl)-piperazine-1-carboxylate (0.22 mmol), 4-Cyclohexyl-3-trifluoromethyl-phenol (0.22 mmol, synthesized in a similar manner as described in a previous example), 1,1′-azodicarbonyl dipiperdine (0.33 mmol) and Ph3P (0.33 mmol) are mixed in DCM (2 mL). The reaction mixture is stirred at room temperature for 17 h and then partitioned between saturated Na2CO3 solution and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic extracts are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (6:5 hexanes/EtOAc) to give tert-butyl 4-[6-(4-cyclohexyl-3-trifluoromethyl-phenoxymethyl)-pyridin-3-yl]-piperazine-1-carboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:18](Cl)=[O:19]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:18]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH3:13])=[O:11])=[O:19]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C1Cc2ccccc2N1
Product: COC(=O)C1Cc2ccccc2N1C(=O)c1ccc(Cl)c(Cl)c1
Yield: 82.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 72A, methyl indoline-2-carboxylate (Lee, S. et al., Eur. J. Org. Chem., 38:459-471 (2003)) (3.23 g, 18.3 mmol) and 3,4-dichlorobenzoyl chloride (4.21 g, 20.1 mmol) were converted to the title compound (5.30 g, 83%) after purification using flash column chromatography (gradient from 0% to 5% EtOAc/CH2Cl2). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 7.67 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.41-7.37 (m, 1.5H), 7.23-7.20 (m, 1.5H), 7.04-7.01 (m, 2H), 5.31-5.08 (m, 1H), 3.77-3.75 (m, 3H), 3.62-3.55 (m, 1H), 3.24-3.19 (m, 1H); MS(ESI+) m/z 350.1 (M+H)+.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH:4]=[CH:3][O:2]1.[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:7]1([S:13][CH:3]2[CH2:4][O:5][C:1](=[O:6])[O:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1occo1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCC(Sc2ccccc2)O1

Procedure:
In 70 mL of tetrahydrofuran (THF), 3 g of vinylene carbonate and 5.1 g of benzenethiol were dissolved, and then 4.7 g of triethylamine was added. The mixture was refluxed under an argon atmosphere for 4 hours. When the reaction was finished, the solvent was removed through distillation under reduced pressure, and the resulting material was subjected to the column chromatography on silica gel (eluted with 20% hexane/ethylacetate) and purified to obtain a target product, 4-phenylsulfanyl-[1,3]dioxolan-2-one.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>>[CH3:1][S:2][C:3]1[S:4][C:5]([C:15]2([OH:18])[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)=[CH:6][N:7]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CSc1nccs1
Product: CSc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-methylsulfanyl-thiazole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.CCOCC>O1CCOCC1>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([C:4]([CH2:3][O:2][CH3:1])=[O:5])=[C:15]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: Cc1ccccc1N
Reactant: COCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Yield: 82.8 %

Procedure:
3-methoxyacetyl-4-chloro-8-methoxyquinoline (19.0 g, 0.07 mol) and o-toluidine (9.0 ml, 0.08 mol) were heated under reflux in 1,4-dioxan (250 ml) for 1 hour. The solvent was removed and the residue taken up in dichloromethane, washed with dilute hydrochloric acid, sodium hydrogen carbonate solution, and brine. Evaporation of the solvent gave an oil, which afforded 8-methoxy-3-methoxymethylcarbonyl-4-(2-methylphenylamino)quinoline (19.5 g, 81%) as yellow crystals from ether, m.p. 122°-3°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@:14]([OH:16])([CH3:15])[C@@H:13]([CH3:17])[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[OH:16][C@:14]1([CH3:15])[C@@H:13]([CH3:17])[CH2:12][NH:11][CH2:10][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of benzyl (3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate (81 mg, 0.21 mmol) in MeOH (4.0 mL), 10 wt % Pd on carbon (29 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 h. The reaction mixture was filtered through a pad of diatomaceous earth (eluted with MeOH), and then concentrated under reduced pressure. The resulting crude product was used directly in the next step without further purification (46 mg, 88%). LCMS calc. for C12H25N2O3 (M+H)+: m/z=245.2. found 245.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([Cl:32])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Br)C.C1COCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[C:24]([Cl:32])[CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(Cl)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(Cl)c1
Yield: 72.1 %

Procedure:
According to the previously described general procedure (GP12C), treatment of 8-[2-(3-chloro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.070 g; 3.546 mmol) with 1M ethylmagnesium bromide in THF (15.6 ml; 15.6 mmol; 4.4 eq.) afforded 8-[2-(3-chloro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.170 g; 72%) as a pale yellow oil. LC-MS: tR=0.95 min.; [M+H]+=457.98 g/mol.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:26][CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1CCC1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NC4CCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure as above, the acid 3 (50 mg, 0.18 mmol) was reacted with cyclobutanamine (CAS-2516-34-9) (0.03 mL, 0.35 mmol), HATU (103 mg, 0.35 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-cyclobutyl-5-fluorobenzamide 6. LC/MS (ESI+): m/z 338 (M+H). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=7.3 Hz, 1H), 8.63 (d, J=10.3 Hz, 1H), 8.55 (dd, J=7.6, 5.1 Hz, 2H), 8.47-8.40 (m, 1H), 8.29 (d, J=12.0 Hz, 1H), 8.19 (dd, J=15.7, 10.5 Hz, 1H), 8.04 (s, 1H), 7.73 (d, J=9.2 Hz, 1H), 4.47 (dq, J=15.8, 7.9 Hz, 1H), 2.36-2.21 (m, 2H), 2.21-2.03 (m, 2H), 1.84-1.61 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)#[N:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.67 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 30 mg (0.75 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 147 mg (0.75 mmol) of 4-cyanobenzyl bromide was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][CH2:21]Br.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:21][CH2:20][CH2:19]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: BrCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g of ethyl 4-nitrophenylacetate are dissolved in 100 ml of DMF, added dropwise to a suspension of 4.97 g of sodium hydride in 20 ml of DMF with ice-cooling and stirred for 30 min. 6.6 ml of 1,3-dibromopropane are subsequently added, and the mixture is stirred at 23° C. for 12 h. The reaction mixture is subsequently stirred into a mixture of 100 ml of 1 N hydrochloric acid and 200 g of ice. The mixture is washed four times with 100 ml of ethyl acetate each time, the combined organic phases once with 100 ml of sodium chloride solution, dried over sodium sulfate and, after filtration, evaporated to dryness in vacuo. The residue is purified by column chromatography (reversed phase). Yield: 5.5 g (46%) of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate; LC-MS retention time: 2.21 min (“nonpolar” gradient);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:30][C:26]4[CH:25]=[C:24]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:29]=[CH:28][CH:27]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ccccc5)c4)ncnc3[nH]2)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (60.0 mg, 0.179 mmol) and biphenyl-3-ylamine (30.5 mmol, 0.180 mmol) in nBuOH (3 mL) was heated to 80° C. (bath temp.) for 17 h. The solvent was evaporated, water/NaHCO3 solution was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined extracts were washed with brine and dried over MgSO4. MgSO4 was filtered off, the filtrate was concentrated, and the residue was chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-9)→1% MeOH in CH2Cl2 (10-19)→2% MeOH in CH2Cl2 (20-30)]. Fr.17-26 were combined and dried in vacuo overnight. One obtained the title compound as off-white solid. MS (ES+): m/z 468.1 (100) [MH+]. HPLC: tR=3.2 min (ZQ2000, nonpolar—5 min). 1H NMR (CDCl3, 400 MHz): δ=1.50 (s, 9H), 2.44-2.55 (brs, 2H), 3.61-3.71 (m, 2H), 4.13-4.22 (m, 2H), 6.15 (s, 1H), 6.24 (s, 1H), 7.11 (brs, 1H), 7.37 (t, J=7.4 Hz, 1H), 7.40-7.52 (m, 4H), 7.60-7.67 (m, 3H), 7.80 (t, J=1.6 Hz, 1H), 8.43 (s, 1H), 11.83 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)CCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:23]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: C1COCCN1
Reactant: COc1cc2nc(N3CCN(c4ccnc(Cl)n4)CC3)nc(N)c2cc1OC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4ccnc(N5CCOCC5)n4)CC3)nc(N)c2cc1OC
Yield: 35.4 %

Procedure:
4-Amino-6,7-dimethoxy-2-[4-(2-chloropyrimidin-4-yl)-piperazino] quinazoline (2.0 g, 5.0 mmole) and morpholine (1.1 g, 12.6 mmole) in n-butanol (150 ml) were heated in a bomb at 160° C. for 19 hours. The solvent was evaporated in vacuo and the residue partitioned between 5% methanol in chloroform and 5N sodium hydroxide solution. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel (20 g, "Kieselgel" (Trade Mark) 60H) eluting with chloroform. Appropriate fractions were combined and evaporated in vacuo. Crystallization from ethyl acetate gave 0.8 g of the desired product, m.p. 232°-233° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][OH:36].[H-].[Na+]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][C:29]([O:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccnc2)cc(OC)c1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(OCCN(C)C)nc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (100 mg, 0.21 mmol), prepared using procedures similar to those described above in Example 1, 2-(dimethylamino)ethanol (50 μL, 0.50 mmol) and dry DMF were combined and 60% NaH in oil (80 mg, 2.0 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethoxy)pyridine-3-sulfonamide (23 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, 1H), 8.73 (s, 1H), 8.38 (dd, 1H), 7.40 (dd, 1H), 7.31 (m, 3H), 7.14 (m, 2H), 6.85 (d, 1H), 6.12 (m, 1H), 4.56 (m, 2H), 3.76 (s, 6H), 3.43 (m, 2H), 2.77 (s, 6H). MS (EI) m/z for C25H28N6O5S: 525.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1>CN1CCCC1=O.O>[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:2]2[CH:3]=[C:4]([N:21]([CH:31]3[CH2:33][CH2:32]3)[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:37][CH2:36]1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Temperature: 120 °C

Procedure:
6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (9 g, 18.6 mmol) was combined with trans-1,4-diaminocyclohexane (31.9 g, 279 mmol) in N-methyl-2-pyrrolidinone (50 mL) and heated at 80° C. for 16 hours and at 120° C. for 6 hrs. The reaction was cooled to room temperature, and water (200 mL) was added, and the solid collected via Buchner filtration. The crude product was purified with silica gel chromatography using a stepwise gradient of 10% methanol/chloroform to 25% methanol/chloroform/1% triethylamine to isolated foamy solid. The solid was suspended in water (400 mL) and collected with Buchner filtration (2×50 mL water wash) and dried for 16 hrs under reduced pressure to afford 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (10.2 g, 18.18 mmol, 98% yield) as a off white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.77 minutes. [M+H]=561.16.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:8]1[O:10][CH2:9]1>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:7][CH:8]([OH:10])[CH2:9][N:1]2[CH2:6][CH2:5][N:4]([CH2:9][CH:8]([OH:10])[CH2:7][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(OCC2CO2)cc1
Solvent: CO
Product: OC(COc1ccc(Cl)cc1)CN1CCN(CC(O)COc2ccc(Cl)cc2)CC1

Procedure:
While 9.3 g of piperazine is refluxed in 50 ml of methanol with stirring, 10 g of p-chlorophenyl glycidyl ether are added dropwise over a period of 1.5 hours. After the addition has been completed, the mixture is refluxed with stirring for a further 1.5 hours, and then concentrated to dryness under reduced pressure. The residue is dissolved in dilute hydrochloric acid and extracted with ethyl acetate. The water layer is rendered basic with sodium hydroxide, extracted first with benzene from which there can be obtained N,N'-bis[3-(4-chlorophenoxy)-2-hydroxypropyl]piperazine, and then with n-butanol. The butanol extracts are washed with water and the solvent then removed by distillation under reduced pressure to yield 10.0 g of N-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperazine as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([O-:21])=O.[NH3:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([NH2:22])=[O:21]
Reactant: N
Reactant: CCCOc1ccccc1-c1cc(C)c(C(=O)[O-])c(=O)[nH]1
Product: CCCOc1ccccc1-c1cc(C)c(C(N)=O)c(=O)[nH]1

Procedure:
1,2-dihydro-4-methyl-2-oxo-6-(2-propoxyphenyl)-pyridine-3-carboxylate (0.53 g) and saturated methanolic ammonia (25 ml) was heated in a sealed vessel at 70°-85° C. for 34 hours. The residue after evaporation was triturated with methanol (10 ml) to give a solid, 0.28 g, m.p. 239°-242° C. Recrystallization from ethanol afforded the title compound, 0.18 g, m.p. 244°-246° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(C(F)(F)F)cc1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 4-(trifluoromethyl)-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C14H11F3N2O2, 297. Found 297.