Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[NH:11][C:10](=[O:12])[C:9]2[CH2:8][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1.N([O-])=[O:24].[Na+]>C(O)(=O)C.O>[C:13]([C:7]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][C:4]2[NH:3][C:2](=[O:24])[NH:11][C:10](=[O:12])[C:9]=2[CH2:8]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2nc(N)[nH]c(=O)c2C1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCc2[nH]c(=O)[nH]c(=O)c2C1

Procedure:
To a solution of 2-Amino-6,6-dicarboethoxy-5,6,7,8-tetrahydro-4(3H)-quinazolinone (75 g) in acetic acid (250 mL) at reflux was added a solution of sodium nitrite (75 g) in water (100 mL) in a dropwise fashion over a period of 45 min. The solution was cooled and the solvent removed in vacuo. The subsequent addition of 300 mL of water precipitated a solid which was collected and dried to yield 6,6-Dicarboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:35]([CH:32]1[CH2:34][CH2:33]1)(=[O:37])=[O:36]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. cyclopropansulfonyl chloride (10 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 24 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropansulfonamide (percentage yield: 96%), was obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>>[CH2:7]([N:8]1[C:12]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=[N:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Cn2cncn2)cc1
Reactant: CC(C)C=O
Product: CC(C)C(O)c1ncnn1Cc1ccccc1
Yield: 71 %

Procedure:
1-(1-Benzyl-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-ol was synthesized in a manner similar to that of procedure 21 B but using 1-(phenylmethyl)-1H-1,2,4-triazole and isobutyraldehyde as the starting materials. The product was isolated as a white solid in 71% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:51][O:52][CH:53]1[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]1.C(O)(=O)C>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:56]3[CH2:57][CH2:58][CH:53]([O:52][CH3:51])[CH2:54][CH2:55]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: COC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCC(OC)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (400 mg, 0.78 mmol) (example 1), sodium triacetoxyborohydride (260 mg, 1.23 mmol), 4-methoxycyclohexanone (100 mg, 0.78 mmol) (J. Am. Chem. Soc. 5190, 89, 1967) and acetic acid (56 mg, 0.93 mmol) in tetrahydrofuran (30 ml). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (94:6:0.3) to give the title compound as a mixture (3:2 ratio) of diastereoisomers (118 mg) as a foam. MS: 603 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8](C(O)=O)[CH:7]=[N:6][N:5]2[CH:14]=1.O=P(Cl)(Cl)Cl.C([N:23](C(C)C)CC)(C)C.N.Cl[CH2:31][Cl:32]>>[Cl:32][C:31]1[C:4]2[N:5]([CH:14]=[C:2]([F:1])[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:9]([NH2:23])=[O:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: ClCCl
Reactant: O=C(O)c1cnn2cc(F)cc2c1O
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)c1cnn2cc(F)cc2c1Cl
Temperature: 120 °C
Yield: 81 %

Procedure:
To a slurry of 6-fluoro-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylic acid (0.400 g, 2.039 mmol) in POCl3 (15.64 g, 102 mmol) was added diisopropylethylamine (0.39 mL, 2.24 mmol) and the resulting mixture was heated at 120° C. for 3 h with stirring. The reaction was cooled to rt and concentrated to remove the excess POCl3 and the resulting residue was dissolved in dichloromethane (15 mL) and reconcentrated and the process was repeated 2 more times to afford a brown oil. This material was dissolved in dichloromethane (10 mL) and the solution was added dropwise via pipette into a 0° C. well stirred solution of ammonia in dichloromethane (˜100 mL, prepared by extracting 100 mL of conc. Aq ammonium hydroxide with 3×30 mL portions of dichloromethane). After the addition was complete, the mixture was concentrated under vacuum and water was added to give a slurry which was filtered to collect the precipitated solid. The solid was rinsed with additional water and dried to afford 355 mg (81%) of the title compound as a yellow solid. HPLC (condition B): retention time=2.05 min. LCMS (condition B): m/z 197 +ve.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][C:3]=1[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>O>[C:34]([O:33][C:31](=[O:32])[CH2:30][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][C:3]=1[CH3:17])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1cc(Sc2ccc(O)c(C)c2)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Sc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried 100 mL round-bottomed flask was charged with bis-(4-hydroxy-3-methylphenyl)-sulfide (8.6 g, 34.9 mmol), finely powdered Cs2CO3 (11.9 g, 36.7 mmol), and anhydrous DMF (35 mL). Next, tert-butyl bromoacetate (5.2 mL, 34.9 mmol, Aldrich) was added dropwise, and the reaction was stirred vigorously overnight at room temperature. The reaction was poured into 500 mL of water and extracted with 3×50 mL of methylene chloride. The combined organics were washed with 2×150 mL of water, dried over Na2SO4, and concentrated to a slightly yellow oil. The mixture was then purified by flash chromatography (SiO2 gel 60, eluted with 10% hexanes in DCM-5% hexanes in DCM-100% DCM). The fractions containing only desired product 1.1 were combined and concentrated to a white solid (3.5 g). The mixed fractions were combined, concentrated, and resubjected to the same chromatography conditions to yield an additional 2.0 g of pure 1.1. 1H NMR (400 MHz) (CDCl3) δ 7.13 (2H, m); 7.06 (2H, m); 6.70 (1H, d, J=8.3 Hz); 6.59 (1H, d, J=8.4 Hz); 4.50 (2H, s); 2.23 (3H, s); 2.20 (3H, s); 1.48 (9H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]([CH3:38])[C:15](=[O:37])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:33]3[N:32]=[C:31]([CH3:34])[NH:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]([CH3:38])[C:15](=[O:37])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:33]3[N:32]=[C:31]([CH3:34])[NH:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCNC(C)=O)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of N-[2-(4-aminobut-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (120 mg) in dichloromethane (10 ml) was added acetic anhydride (23.8 mg) and the mixture was stirred at ambient temperature for 1 hour. The solution was washed with water and brine and dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column (2% methanol in chloroform) and the product was solidified with diethyl ether to give N-[2-(4-acetylaminobut-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (87 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:20]=1.C(O)C.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([OH:13])[C:10]3[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(O)C2
Reaction time: 1.5 h

Procedure:
17.8 G. of 3-methoxy-8-(methylthio)-dibenzo[b,f]thiepin-10(11H)-one is suspended in 150 ml. of ethanol and reacted with 38 g. of sodium borohydride. The reaction mixture is stirred for 90 minutes, and subsequently treated with water and extracted with ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated, whereby there is obtained 10,11-dihydro3-methoxy-8-(methylthio)-dibenzo[b,f]thiepin-10-ol having a melting point of 122°-124°.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=[C:3]([C:18](O)=[O:19])[CH:2]=1.B#B>O1CCCC1.O>[OH:19][CH2:18][C:3]1[CH:2]=[CH:1][C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)c2ccccc2C=Cc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mix 2.8 gm. of dibenzo[b,f]thiepin-3-carboxylic acid-5,5-dioxide, 50 ml. of tetrahydrofuran, and 30 ml. of 1 N diborane in tetrahydrofuran. Stir at room temperature for 1 hour. Dilute the reaction mixture with water, and extract into ether. Evaporate the ether extract to dryness. Stir the residue in ether, and filter to obtain the title product (m.p., 156°-158° C.).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:22]([O:24][CH2:25]Cl)[CH3:23]>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:22]([O:24][CH2:25][N:6]1[CH:7]=[C:2]([I:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])[CH3:23]
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: CCOCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [I-]
Solvent: ClCCl
Product: CCOCn1cc(I)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
In 50 ml of dichloromethane, 4.76 g (20 mmol) of 5-iodouracil was suspended and added with 11 ml (45 mmol) of bistrimethylsilylacetamide and stirred for 15 minutes at room temperature to form a homogeneous solution. This solution was added with 2.04 ml (22 mmol) of chloromethyl ethyl ether and 60 mg of tetra-n-butylammonium iodide and heated under reflux for 3 hours. After the solvent was evaporated under reduced pressure, the residue was added with water to produce crystals, which were taken by filtration. The crystals were washed by suspending them in hot methanol and recovering them by cooling and filtration to obtain 5.43 g of 1-(ethoxy-methyl)-5-iodouracil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:13]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>O.CS(C)=O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ncccc1C(=O)O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1cccnc1N
Yield: 52.4 %

Procedure:
2-Aminonicotinic acid (5.0 g), WSC (10 g), HOBt (7.3 g), ammonium chloride (5.8 g), diisopropylethylamine (28 g), and DMSO (100 mL) were stirred for 16 hours at room temperature. Water was added and then extraction was performed with ethyl acetate and THF. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate) to obtain the titled compound (2.6 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=O.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:23](=[O:26])([O-])[O-].[K+].[K+].[I-].[K+].Cl>O.CN(C=O)C>[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]([CH2:2][C:18]3[CH:21]=[CH:22][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=3)[C:23]2=[O:26])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Cn2c(=O)n(Cc3ccc(C(C)(C)C)cc3)c3ccccc32)cc1
Temperature: 75 °C
Yield: 43.1 %

Procedure:
To a solution of benzimidazolinone (1.5 g, 11.2 mmol) in abs. DMF (25 mL) there were added 4-tert-butylbenzyl bromide (1.8 mL, 9.8 mmol), potassium carbonate (2.76 g, 20 mmol), and a catalytic amount of potassium iodide under a blanket of argon. The reaction mixture was heated to 75° C. over a period of 2 h. Following cooling, the reaction mixture was poured into a solution of H2O (200 mL) and 2N hydrochloric acid solution in H2O (10 mL). The resulting mixture was extracted with EtOAc (5×40 mL), the combined organic phases were washed with sat. NaCl solution (2×30 mL), dried over Na2SO4, and the solvent was removed in vacuo. The residue was taken up in chloroform (50 mL), and the resulting solid matter was isolated by filtration. The filtrate was concentrated in vacuo. The residue was purified by means of column chromatography (SiO2, cyclohexane/EtOAc 2:1), and there were obtained 1,3-bis(4-tert-butylbenzyl)-1,3-dihydrobenzimidazol-2-one (O) (0.9 g, mp: 164-168° C.) and the desired product 1-(4-tert-butylbenzyl)-1,3-dihydrobenzimidazol-2-one (N) (615 mg, 22% of theory, mp: 179-180° C.) as the more polar substance.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.[CH3:33][C:34]1[N:35]=[C:36]([CH2:39][NH2:40])[NH:37][CH:38]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][CH2:39][C:36]1[NH:37][CH:38]=[C:34]([CH3:33])[N:35]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1c[nH]c(CN)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c[nH]c(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)n1
Reaction time: 1 h
Yield: 21.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), C-(4-methyl-1H-imidazol-2-yl)-methylamine hydrochloride (5.15 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((4-methyl-1H-imidazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (5.5 mg, 10.07 μmol, 21.71% yield): LCMS=525.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (2 H, d, J=8.53 Hz), 7.48-7.72 (8 H, m), 6.64 (1 H, d, J=1.00 Hz), 5.17 (1 H, s), 4.28-4.53 (2 H, m), 2.18 (3H, d, J=1.00 Hz); HPLC peak RT=2.5 min (Method E).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[NH2:29][CH2:30][CH2:31][OH:32]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:29][CH2:30][CH2:31][OH:32])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: NCCO
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)NCCO)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and 2-aminoethanol following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.59 (s, 1H), 8.34 (s, 1H), 8.04 (d, 1H), 7.50-7.62 (m, 3H), 7.08-7.25 (m, 2H), 3.80 (t, 2H), 3.63 (t, 2H), 3.07-3.16 (m, 4H), 2.51 (s, 3H), 2.32 (s, 3H). LRMS [M+H]=415.2
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:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[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:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][N:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(OCCN4CCCCC4)cc3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40.2 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.01-7.90 (m, 4 h), 7.57 (s, 1H), 7.42 (t, 1H, J=7.8 Hz), 7.05-7.01 (m, 2H), 6.21 (d, 1H, J=7.8 Hz), 6.04 (d, 1H, J=8.7 Hz), 4.30-4.20 (m, 3H), 3.70-3.64 (m, 1H), 3.53-3.45 (m, 1H), 2.84 (t, 2H, J=6.2 Hz), 2.56 (brs, 4 h), 2.20-2.03 (m, 3H), 1.78 (brs, 1H), 1.67-1.62 (m, 4 h), 1.50-1.48 (m, 2H), 1.27 (d, 3H, J=6.3 Hz). LC/MS: 498 [M+H]+, tR=1.13 min. HPLC: 99.24% at 214 nm, 99.34% at 254 nm, tR=5.70 min.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:5]=1.Cl.C[O:24][C:25]([C:27]1([NH2:36])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:26]>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:36][C:27]2([C:25]([OH:26])=[O:24])[CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:35]2)=[O:21])=[CH:5][C:6]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COC(=O)c1ccc(OC)c(C(=O)c2ccccc2C)c1
Agent: Cl
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(=O)c1ccccc1C

Procedure:
The compound of step 1 was hydrolyzed in analogy to example 2 and the obtained acid reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 2 of example 13. The obtained ester was hydrolyzed in analogy to example 2.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[CH3:24])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3
Reactant: CN(C)CCCCl
Reactant: O=C1CC2CCc3ccc(F)cc3C2=NN1c1ccc(O)cc1
Product: CN(C)CCCOc1ccc(N2N=C3c4cc(F)ccc4CCC3CC2=O)cc1

Procedure:
By conducting reactions and treatments in the same manner as in Example 1 using 9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one and 3-dimethylaminopropyl chloride, there is obtained 9-fluoro-2-[4-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, m.p. 118°-120° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.Cl[C:22]1[C:27]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH2:34])[N:29]=2)=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:1][C:2]1[C:3]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:22]3[C:27]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH2:34])[N:29]=4)=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:18][CH:19]=2)=[N:4][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccccc2)nc1Nc1ccc(O)cc1
Reactant: Nc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cn(-c2ccccc2)nc1Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A resealable reaction tube was charged with 4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenol (0.12 g, 0.45 mmol), 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (0.09 g, 0.45 mmol), cesium carbonate (0.30 g, 0.91 mmol), and DMSO (2.26 ml, 0.2 M). The reaction vessel was sealed and the mixture stirred at 130° C. for 16 h. The reaction was cooled to RT, diluted with 1 ml DMSO and passed through a PTFE acrodisc filter via syringe. The residue was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA), and the product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(2-(4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a tan solid. MS m/z=436.2 [M+H]+. Calc'd for C25H21N7O: 435.48.