Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[C:8]([CH3:14])[C:7]=2[CH:15]=1)#[N:2].[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]3)=[O:13])=[C:8]([CH3:14])[C:7]=2[CH:15]=1)#[N:2]
Reactant: Cc1c(C(=O)O)oc2ccc(C#N)cc12
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)oc2ccc(C#N)cc12

Procedure:
In the same manner as in Example 1 (2), 5-cyano-3-methyl-2-benzofurancarboxylic acid (312 mg, 1.55 mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (380 mg, 1.66 mmol) were condensed to give 534 mg of t-butyl trans-[4-[(5-cyano-3-methyl-2-benzofuranyl) carbonylamino]cyclohexyloxy]acetate as a colorless solid (84%).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl.[C@@H:34]1([NH2:38])[CH2:36][C@@H:35]1[NH2:37].[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([C:49](O)=[O:50])=[CH:43]2>CN(C)C=O>[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([C:49]([NH:37][C@@H:35]1[CH2:36][C@@H:34]1[NH2:38])=[O:50])=[CH:43]2
Reactant: N[C@@H]1C[C@@H]1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
1-Hydroxybenzotriazole monohydrate (377 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (642 mg) and diisopropylethylamine (1.95 ml) were added to cis-1,2-cyclopropanediamine hydrochloride (J. Med. Chem., 1998, Vol. 41, pp. 4723-4732) (405 mg) and a solution of 5-chloroindole-2-carboxylic acid (546 mg) in N,N-dimethylformamide (10 ml) at room temperature, and the mixture was stirred for 50 hours. After the reaction mixture was concentrated under reduced pressure, dichloromethane (50 ml) and a saturated solution (200 ml) of sodium hydrogencarbonate were added to separate colorless solid deposited by filtration. An organic layer of the filtrate was separated and the water layer was extracted with dichloromethane. After the resultant organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain residue. The residue was purified by medium-pressure flash column chromatography on silica gel (dichloromethane:methanol=100:7→10:1) to obtain the title compound (110 mg) as a colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[OH:4][CH2:3][C@@H:2]([NH:1][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](N)CO
Solvent: ClCCl
Product: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of D-Ser-OMe (LXXXVIII) in dry DCM was added TEA (1.2 eq). After the solution became clear, trityl chloride (1 eq in dry DCM) was added dropwise and stirred for 2 hours. The reaction mixture was washed with 2M HCl, brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give the crude product as a colorless oil. The oil crystallized from Et2O/hexane to produce pure (R)-methyl 3-hydroxy-2-(tritylamino)propanoate (LXXXIX) as white solid (85% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:19]([NH:21][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@H](N)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: C[C@H](NC(=O)C(C)(C)C)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1 using (2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine (60 mg, 0.16 mmol) and pivaloyl chloride (0.078 mL, 0.64 mmol).
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)#[CH:7].CN(C)[CH:27]=[O:28].Cl>CCCCCC.O1CCCC1>[CH:27]([C:7]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:28]
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CC=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.75 ml (0.80 mmol) of 1.6 molar n-butyllithium solution in n-hexane are added dropwise at 0° C. to 2.48 g (9.80 mmol) of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene in 25 ml of tetrahydrofuran. After 1 hour, this solution is added dropwise to 0.83 ml of dimethylformamide in 20 ml of tetrahydrofuran, the mixture is stirred at room temperature for 1 hour, acidifed by means of aqueous hydrochloric acid and partitioned between ether and water, and the organic phase is dried and evaporated. Chromatography on silica gel using n-hexane/dichloromethane (1:1) gives 1.75 g of 1-(formylethynyl)-4-(trans-4-pentylcyclohexyl)benzene, ##STR39## which is stirred for 2 hours at room temperature with 1.05 g (6.49 mmol) of diethylaminosulfur trifluoride in 10 ml of dichloromethane. After partitioning between water and dichloromethane, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel using n-heptane, giving 0.89 g of product ##STR40## having the phase sequence
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([O:16][CH2:23][CH3:24])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1c(CC(=O)O)c(=O)oc2cc(O)ccc12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(C)c2ccc(O)cc2oc1=O
Temperature: 25 °C
Yield: 92 %

Procedure:
7-Hydroxy-4-methylcoumarin-3-acetic acid (1) (1 gm, 4.3 mmol) was suspended in anhydrous ethanol (15 mL), concentrated sulfuric acid (1.5 mL) was added and the mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with 5% NaHCO3 (5×50 mL), water (2×50 mL), saturated NaCl (2×50 mL) dried with sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to give 1.04 gm (4.0 mmol, 92% yield of 2 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C[O-].[Na+].CO.C(O)(=O)C>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:11])=[CH:10][C:14](=[O:15])[C:13]([F:20])([F:19])[F:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: O=C(C=C(O)c1ccc(F)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 40.0 g (0.256 moles) 2', 4'-difluoroacetophenone (commercially available) in 400 mL diethyl ether at 0° C. was added 40 mL (0.405 moles) ethyl trifluoroacetate. At 5° C., 80 mL of a 25% wt. sodium methoxide in methanol (0.37 moles) were added over 15 minutes. The reaction mixture was stirred overnight at 25° C. The mixture was poured over 300 mL ice water and 21.3 mL (0.37 moles) acetic acid were added. The organic layer was washed two times with water, dried over anhydrous MgSO4, and concentrated in vacuo to give 62.85 g (97%) 4-(2,4-difluorophenyl)-1,1,1-trifluoro-4-hydroxy-3-buten-2-one as a yellow oil; 1HNMR (CDCl3) ppm: 6.61 (s,1H), 6.87 (m, 1H), 6.97 (m, 1H), 7.97 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][O:21][CH2:22][CH3:23])[N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=3[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[C:14]1[CH2:20][O:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCn1c(COCC)nc2c(N)nc3ccc(Br)cc3c21
Reactant: OB(O)c1cccnc1
Product: CCCCn1c(COCC)nc2c(N)nc3ccc(-c4cccnc4)cc3c21

Procedure:
8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (8%-10% methanol in CH2Cl2 gradient) followed by recrystallization from isopropanol (3×) and chromatography as above afforded 1-butyl-2-ethoxymethyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 220-222° C.
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[Sn:15](C)C.C[Sn](C)C>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:11][C:9]1([CH3:12])[C:8](=[O:13])[C:7]2[C:2]([Sn:15])=[CH:3][CH:4]=[CH:5][C:6]=2[O:10]1
Reactant: C[Sn](C)C
Reactant: CC1(C)Oc2cccc(Br)c2C1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cccc([Sn])c2C1=O

Procedure:
In a slight variation in the method to the 2,4-diamino-5,6-disubstituted-5-deazapteridine described above, using a method taught by A. Pidcock et al (J. Organometallic Chem. 1981, 215, 49-58), 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone is reacted with hexamethylditin in the presence of tetrakis(triphenylphosphine)palladium(O) in toluene, yielding (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)tin. The organometallic derivative is then reacted with 2-amino-3-cyano-5-iodo-4-methylpyridine, again in the presence of tetrakis(triphenylphosphine)palladium(O) in toluene, affording the corresponding 2-amino-3-cyano-5-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)-4-methylpyridine. This compound is then cyclized with guanidine in ethanol, as previously described, yielding the corresponding 2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)-5-deazapteridine. Example 9 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:70][CH2:71][C:72]([NH2:74])=[O:73]>CN(C=O)C>[NH2:74][C:72](=[O:73])[CH2:71][NH:70][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=4[F:25])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:37][CH3:38])[N:9]=2)[CH:28]=1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(N)=O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and glycinamide (11.1 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 31%). LC-MS m/z 578 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[Br:8][C:9]1[C:14]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:13][C:12]([NH:28][C:29](=O)[O:30]C(C)=C)=[C:11]([F:35])[CH:10]=1.CN1CCCC1>O1CCOCC1>[Br:8][C:9]1[C:14]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:13][C:12]([NH:28][C:29]([NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])=[O:30])=[C:11]([F:35])[CH:10]=1
Reactant: CC(C)(C)CCN
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(Br)cc1F
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3Br)c(C)nc2n1
Temperature: 65 °C
Yield: 97.4 %

Procedure:
Treat a solution of 3,3-dimethylbutan-1-amine (0.080 g, 0.790 mmol) and prop-1-en-2-yl (4-bromo-2-fluoro-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (0.244 g, 0.527 mmol) in dioxane (5 mL) with 1-methylpyrrolidine (4.48 mg, 0.053 mmol), heat at 65° C. for 3 h, then cool to RT overnight. Collect the resulting solid via filtration; concentrate the filtrate to dryness and purify via silica gel chromatography (10-30% EtOAc/DCM). Combine the two solids to afford the title compound (260 mg, 97% yield). MS (m/z): 506.1/508.1 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (434 mg, 87%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CNC1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([NH:33][CH3:32])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CNC1CCNC1
Product: CNC1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N-methylpyrrolidin-3-amine. MS(m/e): 400.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(-c2ccccc2)c(F)c1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccccc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
2,4-Difluorobiphenyl (21.2 g, 111 mmol) was dissolved in chloroform (120 mL) and chlorosulfonic acid (12.5 mL, 188 mmol) was added dropwise. The reagents were stirred overnight at room temperature. The reaction was concentrated in vacuo and the residue was taken up into EtOAc (100 mL) and washed with water (3×25 mL). The organics were shaken with brine, whereupon a flocculent solid formed. This was filtered and washed with EtOAc and dried to give 2′,4′-difluorobiphenyl sulfonic acid as an off-white solid (12.1 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][C:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]3)=[N:18][N:17]2[CH:40]=1)=O)C>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][N:25]([C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]([F:36])([F:38])[F:37])[CH2:26][CH2:27]4)=[N:18][N:17]3[CH:40]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Product: O=C(Nc1ccc(F)cc1)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 57 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to 4-fluoroaniline in place of isoamylamine to react with 6-[4-(2-trifluoromethyl-benzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 57% yield (0.065 g). m.p. 115-117° C. 1H NMR (300 MHz, CDCl3) δ 9.1 (s, 1H), 8.22 (s, 1H), 7.74-7.5 (m, 6H), 7.35-7.33 (m, 1H), 7.08-6.95 (m, 2H), 6.9 (d, J=7.6 Hz, 1H), 4.06-3.94 (m, 1H), 3.93-3.81 (m, 1H), 3.7-3.53 (m, 2H), 3.51-3.4 (m, 2H), 3.6-3.27 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 160.8, 160.2, 157.6, 154.9, 137.8, 135.7, 134.3, 134.2, 134.1, 134.0, 132.4, 129.5, 127.2, 126.9, 126.8, 126.7, 126.5, 125.4, 121.2, 121.1, 118.7, 115.8, 115.5, 112.2, 46.2, 46.1, 45.6, 41.2. MS (ES+) m/z 513.3 (M+1).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[NH:10][N:9]=1)=[O:7])C>CO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:11]2[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(CCc2ccc(OC)cc2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCc2cc(C(=O)O)n[nH]2)cc1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 25.4 mmol) was added to a stirring, room temperature solution of 23 (1.391 g, 5.07 mmol) in MeOH (12.7 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (30 min): The reaction was concentrated and then dissolved in 10 mL H2O. The reaction was extracted with a small amount of EtOAc, then the aqueous layer was made acidic (pH=2) with the dropwise addition of 10% aq. HCl. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.3771 g of relatively pure 24. 24 was further purified by recrystallization from warm MeOH to obtain 0.1317 g of pure 24. No attempts were made to recover remaining 24 from the mother liquor. 1H (CD3OD, 400 MHz): 7.07 (2H, d, J=8.2 Hz), 6.84 (2H, d, J=8.6 Hz), 6.53 (1H, s), 3.73 (3H, s), 2.97-2.84 (4H, m) ppm. 13C (CD3OD, 100 MHz): δ 164.86, 159.60, 148.26, 143.15, 134.01, 130.36, 114.81, 107.50, 55.60, 35.67, 29.10 ppm.
Reaction SMILES: CO.[CH3:3][C:4]1([CH3:12])[CH2:10][C:9](=[O:11])[NH:8][C:6](=[O:7])[CH2:5]1.[OH-].[K+].S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:27][CH2:28][N:29]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][N:31]=[C:30]1[CH3:37]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:37][C:30]1[N:29]([CH2:28][CH2:27][N:8]2[C:9](=[O:11])[CH2:10][C:4]([CH3:12])([CH3:3])[CH2:5][C:6]2=[O:7])[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][N:31]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: CC1(C)CC(=O)NC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)CC(C)(C)CC1=O

Procedure:
A solution is prepared from 240 parts of methanol, 14 parts of 3,3-dimethylglutarimide, and 6.5 parts of potassium hydroxide. The solvent is evaporated to leave a residual syrup which is mixed with 95 parts of dimethylformamide, Then, a solution of 32 parts of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole tosylate in 190 parts of dimethylformamide is added. The mixture becomes dark green-black immediately. It is then stirred and warmed at 90°-110° C. for about 1 hour before it is cooled and diluted slowly to a total volume of 100 parts with toluene. The precipitate which forms is removed by filtration and washed. The solvent is evaporated from the toluene-dimethylformamide filtrate under reduced pressure and the residue is dissolved in 80 parts of acetone, diluted with 280 parts of ether, mixed with charcoal, and filtered. The solvent is evaporated from the filtrate under reduced pressure and the residual oil is diluted with 140 parts of ether and made to crystallize. The precipitate which forms is separated by filtration and dried. The solid is then dissolved in an excess of warm acetone and treated with charcoal. The resulting filtrate is diluted with 35 parts of ether and crystallization is initiated. The precipitate which forms is separated by filtration, washed with ether and then with acetone. The resulting filtrate is then concentrated to a volume of 40 parts and cooled. The precipitate which forms is separated by filtration, washed, and then dried to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-3,3-dimethylglutarimide melting at about 153°-154.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.[K+].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH-:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C.O>CS(C)=O>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:6]([Cl:14])[N:5]=[C:4]([S:15][CH3:16])[N:3]=2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(Cl)c(-c2ccccc2)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Reaction time: 24 h
Yield: 87.4 %

Procedure:
2.77 g 4,6-dichloro-2-methylthio-5-phenylpyrimidine was dissolved in 50 ml DMSO and 3.42 g 4-tert-butylbenzenesulfonamide potassium salt and 1 ml Hünig's base was added. Stirring was continued for 24 h. The mixture was poured onto 400 ml water, washed with diethylether and acidified with conc. hydrochloric acid. The product precipitated and was filtered off and dried in vacuo to give 4 g of 4-tert.-butyl-N-(6-chloro-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl)-benzenesulfonamide. LC-MS: tR=6.29 min, [M+1]+=448.17; 459.17.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]=[O:14])=[CH:7][CH:8]=1
Reactant: OC/C=C/C=C/c1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Yield: 92 %

Procedure:
(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadien-1-ol was treated with active manganese dioxide in the same manner as in Reference example 22 to obtain the title commound in a yield of 92%.