Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[SH:43].CN(C=O)C>O>[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][C:2]1[C:3]([O:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3
Reactant: Nc1ccccc1S
Reactant: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Sc1ccccc1N)C(=O)c1ccccc1-2
Temperature: 125 °C

Procedure:
A 500 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 52.5 g (0.11 mole) of 3-bromo-2-(1-isobutyl-3-methylbutoxy)-7H-benzo[de]anthracene-7-one (4), 9.2 g (0.087 mole) sodium carbonate, 16.0 g (0.13 mole) 2-aminothiophenol and 170 g DMF. The mixture was agitated well and heated at 120-130° C. for three hours. The reaction was cooled to 25° C. and 300 g water was added. The reaction mixture was extracted twice with 250 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator. The yield of crude product was 55 g of a dark brown oil which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[N:13]1([C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: CCO
Product: CCOC(=O)c1cccnc1N1CCNCC1

Procedure:
10.0 g of ethyl 2-chloronicotinate were reacted with 27.8 g of piperazine in 400 ml of ethanol analogously to Example 18a, 6.9 g (54%) of the product being obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH2:28][OH:29])=[CH:25][C:24]=2[CH:30]=1)=[NH:19].C(N=C=NCCCN(C)C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CS(C)=O.O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([CH2:28][OH:29])=[CH:25][C:24]=4[CH:30]=3)[N:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: N=C(NO)c1ccc2oc(CO)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc4oc(CO)cc4c3)no2)cc1OCC
Temperature: 120 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
A mixture of 3,4-diethoxybenzoic acid (0.21 g; 1 mmol), the product of Step C (0.2 g; 0.97 mmol) and hydrochloride salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.22 g; 1.15 mmol) in anhydrous dimethylsulfoxide (DMSO) (2 ml) was stirred for 20 min at ˜40° C. under N2. To it 1 M tetra-n-butylammonium fluoride (TBAF) in terahydrofuran (THF) (0.4 ml) was added and the resulting mixture was stirred for 1 h at ˜120° C., then overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between EtOAc (15 ml) and H2O (5 ml). The organic phase was washed with brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.13 g; 34%), as greyish solid. 1H-NMR (CDCl3) 8.36 (d, 1H, J=3 Hz); 8.09 (dd, 1H, J=3, 9 Hz); 7.79 (dd, 1H, J=3, 9 Hz); 7.68 (d, 1H, J=3 Hz); 7.55 (d, 1H, J=9 Hz); 6.98 (d, 1H, J=9 Hz); 6.73 (s, 1H); 4.8 (s, 2H); 4.2 (m, 4H); 2.02 (s, 1H); 1.51 (m, 6H);
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:10]([NH2:11])=[C:9]([I:17])[CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[C:19](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:10]([NH:11][CH3:19])=[C:9]([I:17])[CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1noc(C)c1-c1cc(I)c(N)c([N+](=O)[O-])c1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNc1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Yield: 59.3 %

Procedure:
Into a flask containing 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline (1000 mg, 2.78 mmol, 1 equiv) is added DMF (15 mL, 0.2 M) before adding cesium carbonate (1.4 gm, 4.17 mmol, 1.5 equiv.) and idomethane (260 μL, 4.17 mmol, 1.5 equiv). After an hour, the reaction was quenched with water and the reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification was carried out by flash column chromatography to furnish 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (615 mg, 60%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])(=[O:27])=[O:26])[N:21]=[C:20]([C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:36])[F:37])(=[O:27])=[O:26])[N:21]=[C:20]([C:38]2[CH:39]=[CH:40][C:41]([NH:42][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:43][CH:44]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2C(F)(F)F)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2C(F)(F)F)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
Phenyl chloroformate (0.535 mL, 4.26 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[[2-(trifluoromethyl)phenyl]sulfonylmethyl]pyrimidin-2-yl]aniline (1.4 g, 2.84 mmol) and sodium hydrogen carbonate (0.358 g, 4.26 mmol) in dioxane (20 mL) at 5° C. under nitrogen. The resulting mixture was stirred at RT for 2 hours then the reaction mixture diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.70 g).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])(O)=O.[Na+]>CC(C)=O.O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Cyanuric chloride (2.22 g, 12.0 mmol) in acetone (50 mL) was added to well-stirred ice water (72 mL). To the resulting fine slurry at 0° C. was slowly added a solution of 1-Boc-piperazine (2.24 g, 12.0 mmol) in acetone (20 mL). A solution of NaHCO3 (1.0 g) in water (20 mL) was slowly added to the mixture, which was subsequently stirred at 0° C. for an additional 2.5 h. The resulting precipitate was collected by filtration, washed with water, and dried to yield a white solid, which was used without further purification.
Reaction SMILES: [N+]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[C:5]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:11]1([C:9]2[O:10][C:6]3[C:7]([N:8]=2)=[CH:17][CH:18]=[C:4]2[C:5]=3[CH2:19][C:20](=[O:22])[NH:21]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1c([N+](=O)[O-])ccc2nc(-c3ccccc3)oc12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(ccc3nc(-c4ccccc4)oc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (6-nitro-2-phenyl-benzoxazole-7-yl)-acetonitrile (66 mg 0.23 mmol) (Starting Material 7) was suspended in concentrated H2SO4 /H2O (1/1, 2 mL)) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (3 mL) heated at reflux was added excess zinc dust (120 mg, 1.85 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-oxazolo[5,4-e]indol-7-one. (Yield 17 mg, 30%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>ClCCl>[CH2:18]([O:17][C:15]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CSCCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCSCC1
Temperature: 25 °C
Yield: 4.2 %

Procedure:
To a solution of thiomorpholine (5 g, 1 mol. equiv.) and triethylamine (5.4 g, 1.1 mol. equiv.) in dichloromethane (200 ml) at 0° C. under nitrogen was slowly added benzyl chloroformate (8.68 g, 1.05 mol. equiv.) over fifteen minutes. The reaction was then allowed to warm to room temperature and stirred for a further sixteen hours. The reaction was washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried using magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane to give the title compound (10 g). TLC=Rf 0.3 (silica, dichloromethane). Found: C, 59.24; H, 6.49; N, 5.78. C12H15NO2S requires C, 59.12; H, 6.23: N, 5.70%.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=C.C[OH:27]>>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]2=[C:5]3[C:4]=1[CH2:1][CH:2]([OH:27])[N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)[C:6]3=[N:7][CH:8]=[N:9]2
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Reactant: CO
Product: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine (0.17 g, 0.42 mmol) (from Example 17, Step E, supra) in methanol (50 mL) at −78° C. was passed a continuous stream of 03 until the color of the solution became blue. The reaction solution was then purged with argon, and methyl sulfide (5 mL) (Aldrich) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The solution was concentrated, the residue was dried in vacuo to give the desired 7,8-dimethoxy-4-(3-bromo-phenyl)-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol as a crude brown oil. (Yield 0.16g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([O:13]CC)=O)=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].[NH3:16]>>[NH2:1][C:2]1[C:3]([C:11]([NH2:16])=[O:13])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1ccnc(C(=O)OCC)c1N
Reactant: N
Product: CCCc1ccnc(C(N)=O)c1N
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of ethyl 3-amino-4-n-propylpyridine-2-carboxylate (Preparation 5; 7.4 g, 0.035 mol) and liquid ammonia (60 ml) was heated in an autoclave at 100° C. for 18 hours. The mixture was allowed to cool and the ammonia to evaporate, then the residue was crystallized from methanol to give the title compound as a colourless solid (4.84 g, 76%), m.p. 139-141° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([N:37]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH3:38])=[O:36])[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([N:37]([C:39]2[CH:40]=[CH:41][C:42]([NH:43]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:44][CH:45]=2)[CH3:38])=[O:36])[CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)N(C)c2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[N—(N-methylpiperazinomethylcarbonyl)-N-methyl-amino]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.OS(O)(=O)=O.[I:24](O)(=O)(=O)=O.II>C(O)(=O)C>[Cl:1][C:2]1[C:3]([I:24])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(I)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a solution of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1 g, 3.87 mmol) prepared as described in Example 16, Part G, in acetic acid (30 mL) was added H2SO4 (0.021 mL, 0.387 mmol) and periodic acid (0.881 g, 3.87 mmol). The solution was heated at 80° C. for 20 min then iodine (0.294 g, 1.160 mmol) was added. The mixture was stirred for another 3 h at 80° C. The solution was cooled to room temperature then concentrated under reduced pressure. EtOAc was added to the residue and the layer was washed with saturated aqueous NaHCO3 then H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 8-chloro-9-iodo-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.2 g, 3.12 mmol, 81% crude yield) as an off-white solid. The material was carried on without further purification. LC/MS (ESI) m/e 385.0 [(M+H)+, calcd for C14H11ClIN2O, 385.0]; LC/MS retention time (method B): tR=1.09 min.
Reaction SMILES: COC1C=CC(P(=S)=[S:10])=CC=1.[S:12]1[C:16]2[C:17]([C:21]([NH2:23])=O)=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1>C1(C)C=CC=CC=1>[S:12]1[C:16]2[C:17]([C:21](=[S:10])[NH2:23])=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: NC(=O)c1cccc2nnsc12
Reactant: COc1ccc(P(=S)=S)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1cccc2nnsc12
Yield: 56.4 %

Procedure:
A suspension of 2.42 g of p-methoxyphenylthiono-phosphine sulfide and 1.79 g of benzo-1,2,3-thiadiazole-7-carboxamide in 95 ml of toluene is refluxed under a nitrogen atmosphere for 6 hours. The mixture is then evaporated in vacuo and the residue is suspended in ethyl acetate and filtered off. The filtrate is recrystallized from ethyl acetate/tetrahydrofuran with added active charcoal. 1.1 g of yellow crystals of melting point 129°-131° C. result.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[CH3:12][C:4]1[CH:3]=[C:2]([O:1][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: Clc1ncccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Oc2ncccn2)cc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 2.15 g, 13.1 mmol), 2-chloropyrimidine (1.00 g, 8.73 mmol), copper (55.0 mg, 0.87 mmol), and potassium carbonate (3.62 g, 26.2 mmol) in 17.5 mL of DMF was stirred at 100° C. for 3.0 h. The reaction mixture was cooled to room temperature, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% EtOAc in hexanes as eluant) to give 1-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)ethanone (6-1, 1.16 g) as white solids in 55% yield: 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=4.5 Hz, 2 H), 7.05 (t, 1 H), 6.87 (s, 2 H), 2.49 (s, 3 H), 2.27 (s, 6 H).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([OH:10])=[N:9][C:4]2=[CH:3][CH:2]=1.[Br:11]N1C(=O)CCC1=O>ClCCl.CN(C=O)C>[Br:11][C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][C:8]([OH:10])=[N:9][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccn2nccc2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Oc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.9 %

Procedure:
A mixture of pyrazolo[1,5-a]pyrimidin-5-ol (Example 1, Step 1, 28.3 g, 210 mmol) and N-bromosuccinimide (37.3 g, 210 mmol) in dichloromethane (200 mL) and DMF (300 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was concentrated and the product was precipitated using Et2O. The solids were collected by filtration and dried to afford 3-bromopyrazolo[1,5-a]pyrimidin-5-ol (40.4 g, 90%). LCMS (APCI−) m/z 211, 213 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[S:26](N)([NH2:29])(=[O:28])=[O:27]>O1CCOCC1>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][S:26]([NH2:29])(=[O:28])=[O:27])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: NS(N)(=O)=O
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)C)c(C)c1
Solvent: C1COCCO1
Product: Cc1cnc(CN(CCCCNS(N)(=O)=O)Cc2ncccc2C(C)C)c(C)c1
Temperature: 25 °C
Yield: 37.1 %

Procedure:
A solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-isopropyl-pyridin-2-ylmethyl}-butane-1,4-diamine (110 mg, 0.328 mmol) and sulfamide (94 mg, 0.98 mmol) in 1,4-dioxane (6 mL) was refluxed for 25 hours then cooled to room temperature and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 51 mg (35%) of COMPOUND 152 as a white foam. 1H NMR (CDCl3) δ 1.03 (d, 6H, J=6.6 Hz), 1.42-1.50 (m, 2H), 1.59-1.66 (m, 2H), 2.15 (s, 3H), 2.28 (s, 3H), 2.58 (t, 2H, J=6.6 Hz), 2.93-3.03 (m, 3H), 3.70 (s, 2H), 3.73 (s, 2H), 5.15 (br s, 2H), 6.04 (br s, 1H), 7.16 (dd, 1H, J=7.8, 4.8 Hz), 7.25 (s, 1H), 7.54 (dd, 1H, J=7.8, 1.0 Hz), 8.25 (s, 1H), 8.41 (dd, 1H, J=4.8, 1.0 Hz); 13C NMR (CDCl3) δ 18.29, 18.37, 21.98, 23.60 (2 carbons), 27.53, 27.73, 42.81, 53.61, 57.69, 58.48, 123.28, 132.37, 133.15, 133.93, 139.23, 144.17, 146.13, 146.64, 154.10, 155.82; ES-MS m/z 420 (M+H). Anal. Calcd. For C21H33N5O2S.0.3CH2Cl2.0.5H2O: C, 56.34; H, 7.68; N, 15.42; S, 7.06. Found: C, 56.69; H, 7.45; N, 15.05; S, 6.76.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)[C:9]([N:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2)C)=O>CO.O>[CH3:9][NH:11][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2
Reactant: CN(C(=O)C(F)(F)F)c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1ccc2[nH]ncc2c1
Yield: 100.2 %

Procedure:
Potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of 2,2,2-trifluoro-N-(1H-indazol-5-yl)-N-methylacetamide (3.80 g, 15.6 mmol) in a mixture of methanol (95 ml) and water (16 ml) at room temperature, and the resulting mixture was refluxed for 1.5 hours. Then, the reaction solution was concentrated and the resulting residue was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-methyl-1H-indazol-5-amine (2.30 g, 100%).
Reaction SMILES: C[CH:2]([N:6]([CH:14](C)[C:15]([O-:17])=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O-:5])=O.[NH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][NH2:25].CC(C)=O>C(O)C>[CH2:7]([N:6]1[CH2:2][C:3](=[O:5])[NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][C:15](=[O:17])[CH2:14]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C(=O)[O-])N(Cc1ccccc1)C(C)C(=O)[O-]
Reactant: NCCNCCN
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1CN(Cc2ccccc2)CC(=O)NCCNCCN1
Yield: 14.4 %

Procedure:
To a solution of 31.2 g dimethyl-N-benzyliminodiacetate in 2.5 l of dry ethanol at reflux under nitrogen was added dropwise 12.8 g of diethylenetriamine in 160 ml of dry ethanol. Reflux was carried out for a total of 137 hours. The solution was evaporated under reduced pressure leaving a yellow paste. Trituration with acetone left 5.2 g of the desired product as a colorless solid. 13C NMR (methanol, ppm vs TMS): 173.130.5, 129.130.5, 129.6, 128.8, 64.0, 46.3, 38.7. Mass spectrum (CI): m/e 291 (M+H) and 289 (M-H).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4]C[CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:55])CC2)CC1>>[OH:55][CH:5]1[CH2:4][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid 153 (see example 123) and amine 21.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14]OS(C)(=O)=O)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[CH:22][CH:21]=2)[N:9]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[NH:36]([CH2:14][C:12]1[CH:13]=[C:8]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])[N:9]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])=[CH:24][CH:25]=2)[N:11]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CNc2ccccc2)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.5 %

Procedure:
1-[4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (105 mg, 0.21 mmol) dissolved in a solution of DCM (5 mL) was added to aniline (0.097 mL, 1.06 mmol) and stirred at RT for 18 h. The mixture was vacuumed to dryness and purified by prep-HPLC (basic) to give the desired material (41 mg) as a white solid.