Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2nccn2Cc2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1

Procedure:
To a solution of 5 mmol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 100 ml of ethyl alcohol is added 0.5 g of 10% Pd/C and 10 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography to give the desired product as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:16])=[N:12]2)=[CH:7][CH:6]=1)=O.[NH3:17]>>[OH:15][C:14]1[C:5]([C:3]([NH2:17])=[O:2])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:16])[CH:10]=[CH:9]2
Reactant: COC(=O)c1ccc2ccc(C)nc2c1O
Reactant: N
Product: Cc1ccc2ccc(C(N)=O)c(O)c2n1

Procedure:
8-Hydroxy-2-methyl-7-quinolinecarboxylic acid methyl ester is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:21])=[O:22])=[CH:24][CH:25]=1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl)-piperdine-4-carboxylic acid was prepared starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl)-piperdine-4-carboxylic acid ethyl ester (3.14 g, 6.42 mmol) dissolved in THF:methanol 3:1 (100 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 2.37 g (80%); white solid; mp 205° C.; MS: 461.9 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([N:15]=1)=[C:13]1[C:8]([CH:9]=[CH:10][C:11](=O)[N:12]1C)=[CH:7][CH:6]=2.P(Br)(Br)([Br:20])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Br:20][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[CH:3][C:2]([Br:1])=[N:15]3)[N:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cn1c(=O)ccc2ccc3ccc(Br)nc3c21
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Brc1ccc2ccc3ccc(Br)nc3c2n1
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 81.3 %

Procedure:
Under a stream of argon, to compound (9) (8.4 g; 29.1 mmol), phosphorus oxybromide (3.25 g; 174 mmol) and phosphorus pentachloride (15.4 g; 35.8 mmol) were added in an ice bath. The reaction temperature was raised to 65 to 75° C., and the resulting reaction mixture was stirred for 5.5 hours. The reaction mixture was cooled in an ice bath and evaporated under reduced pressure. Excess phosphorus oxybromide was removed and the resulting reaction concentrate was poured into ice water, and was made alkaline with concentrated aqueous ammonia. While solids which precipitated out were separated by filtration, they were washed with water to give crude title compound (10). The crude compound (10) was dried, and separated and purified by silica gel column chromatography (SiO2 300 g) (CHCl3/methanol=50/1 to 40/1 to 30/1) to give 8 g (yield: 81%) of the title compound (10).
Reaction SMILES: Cl.[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[C:3]([NH2:5])=[NH:4].Cl.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28](O)[OH:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[OH:29]
Reactant: N=C(N)NCCCCCCC(N)=O
Reactant: NCCCNCCCCNC(=O)C(O)O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCCNCCCN
Temperature: 60 °C

Procedure:
A mixture of 10.0 g (45.0 m moles) of 7-guanidinoheptanamide hydrochloride, 13.1 g (45.0 moles) of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride, and 3.2 g (15 m moles) of citric acid in water (100 ml) was evaporated to dryness to give a syrup which contained 1.0 g of water. The resulting syrup was heated at 60° C. for 8 hours.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:49]([O:50]CC2C=CC=CC=2)[C@H:48]([O:58][C@@H:59]2[O:88][C@H:87]([CH3:89])[C@@H:78]([O:79]CC3C=CC=CC=3)[C@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]2[O:61]CC2C=CC=CC=2)[C@@H:47]([CH2:90][O:91]CC2C=CC=CC=2)[O:46][C@@H:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16](C(OCC3C=CC=CC=3)=O)[O:17][CH2:18]2)[C@H:14]([O:30]CC2C=CC=CC=2)[C@@H:13]1[O:38]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[C@@H:59]1([O:58][C@@H:48]2[C@@H:47]([CH2:90][OH:91])[O:46][C@H:10]([O:11][C@@H:12]3[C@@H:19]([CH2:18][OH:17])[C@@H:15]([NH2:16])[C@H:14]([OH:30])[C@H:13]3[OH:38])[C@H:9]([OH:8])[C@H:49]2[OH:50])[O:88][C@H:87]([CH3:89])[C@@H:78]([OH:79])[C@H:69]([OH:70])[C@H:60]1[OH:61]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3[C@H]4CON(C(=O)OCc5ccccc5)[C@H]4[C@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](N)[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
The compound (115 mg, 86.8 μmol) synthesized in Example 15 (15a) was dissolved in methanol (20 mL) and ethyl acetate (1 mL) and hydrochloric acid (10 μL) and 20% palladium hydroxide-carbon (115 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 4 hours. After celite filtration, the solvent was distilled off under reduced pressure and the residue was purified by ion exchange resin (Dowex 50w×8) column (water-5% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound (30 mg, 73%) as a colorless amorphous.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>C(Cl)(Cl)Cl>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: O=CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C=O)CC3)ncc2c1=O
Yield: 83 %

Procedure:
A mixture of 8.4 g of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine, 6.9 g of formylpiperazine and 160 cm3 of chloroform is heated under reflux for 1 hour. After cooling, the solution is washed with water and dried and the solvent is evaporated. The oily residue crystallises on being taken up to 100 cm3 of isopropyl ether. The solid is filtered off and recrystallised from 50 cm3 of ethanol and yields 8.9 g (82%) of 2-(4'-Formylpiperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine which melts in two stages; melting point 195°C, solidification, followed by m.p. 204°C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH2:6][C@H:5]2[CH2:26][C@@H:3]1[C:4]2([CH3:28])[CH3:27].C(N(CC)CC)C.[C:36]1([CH2:42][CH2:43][C:44](Cl)=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:36]1([CH2:42][CH2:43][C:44]([N:8]([CH:9]2[CH2:10][CH2:11][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH2:13][CH2:14]2)[C@H:7]2[CH2:6][C@H:5]3[CH2:26][C@H:3]([C:4]3([CH3:28])[CH3:27])[C@@H:2]2[CH3:1])=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1ccc(C2CCC(N[C@H]3C[C@H]4C[C@@H]([C@@H]3C)C4(C)C)CC2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2CCC(N(C(=O)CCc3ccccc3)[C@H]3C[C@H]4C[C@@H]([C@@H]3C)C4(C)C)CC2)cc1
Reaction time: 24 h

Procedure:
To a solution of EXAMPLE 45C (192 mg, 0.5 mmol), triethylamine (0.077 mL, 0.55 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) in tetrahydrofuran (5 mL) was added 3-phenylpropanoyl chloride (0.082 mL, 0.55 mmol), and the reaction was stirred for 24 hours. The residue was chromatographed on silica gel using 20-50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.O[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:11][O:10][C:8]([C@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)=[O:9]
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reaction time: 3 h

Procedure:
2.20 g of methyl cis-4-hydroxycyclohexanecarboxylate (13.88 mmol, 1 eq.), 2.70 g of tert-butyl 4-hydroxybenzoate (13.88 mmol, 1 eq.) and 5.46 g of triphenylphosphine (20.82 mmol, 1.5 eq.) are placed in 30 mL of tetrahydrofuran at room temperature. 4.04 mL of diisopropyl azodicarboxylate (20.82 mmol, 1.5 eq.) are added dropwise to the reaction medium with stirring. After 3 hours at room temperature, the medium is concentrated to dryness and taken up in diethyl ether. The triphenylphosphine oxide is filtered off. The organic phase is washed successively with sodium hydroxide solution and then with water, dried over sodium sulfate, filtered and evaporated to give a residue. This residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 10% to 50%. 1.6 g of tert-butyl trans-4-(4-methoxycarbonylcyclohexyloxy)benzoate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3([C:27](=[O:30])[NH:28][CH3:29])[CH2:26][CH2:25]3)[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:23][C:24]2([C:27]([NH:28][CH3:29])=[O:30])[CH2:25][CH2:26]2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][NH:32][CH3:33])[CH:9]=1
Reactant: CNC(=O)C1(COc2cccc(S(=O)(=O)n3cc(CN(C)C(=O)OC(C)(C)C)cc3-c3ccccc3F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC3(C(=O)NC)CC3)c2)c1
Reaction time: 1 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-((1-(methylcarbamoyl)cyclopropyl)methoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 5d (100 mg, 0.18 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of 1 mL of trifluoracetic acid, and then the reaction solution was stirred for 1 h. 10 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 1-((3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)methyl)-N-methylcyclopropylcarboxamide 5 (20 mg, a yellow oil) in 24% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[O:25]1[CH:28]([CH3:29])[C:26]1([CH3:30])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH:28]([C:26]([OH:25])([CH3:30])[CH3:27])[CH3:29])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: CC1OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(n1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O)C(C)(C)O
Temperature: 85 °C
Reaction time: 48 h
Yield: 20.1 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (300 mg, 0.84 mmol), prepared as described in Example 1, in 0.6 mL of DMF was added 2,3-epoxy-2-methylbutane (4.8 mg, 0.056 mmol), followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated at 85° C. for 16 h. After this time, an additional 10 mg of K2CO3 and 2,3-epoxy-2-methylbutane (4.8 mg, 0.056 mmol) were added. The reaction was allowed to continue stirring at 85° C. for an additional 48 h. The reaction was cooled to RT and filtered. The collected solution was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(3-hydroxy-3-methylbutan-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (5 mg, 20% yield) as a yellow oil. MS [M+H]+: found 443; 1H NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 7.39-7.27 (m, 6H), 7.14 (dd, 2H), 4.55 (q, 1H), 1.52 (d, 3H), 1.34 (s, 1H), 1.23 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:6][C:5]=1[CH3:28].[OH-].[K+].Cl>O1CCCC1.CO.O>[Br:10][C:8]1[C:7]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:18])([F:19])[F:17])[O:13][N:12]=2)=[CH:6][C:5]([CH3:28])=[C:4]([CH:9]=1)[C:3]([OH:29])=[O:2]
Reactant: COC(=O)c1cc(Br)c(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 5-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (Example I22) (290 mg) in tetrahydrofuran (3 ml) was added a solution of potassium hydroxide (1.53 g) in methanol (3 ml) and water (3 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was acidified by addition of aqueous hydrochloric acid (4N). The aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×10 ml) and brine, dried over sodium sulfate, and concentrated to afford 5-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (220 mg) as a white foam. 1H-NMR (CDCl3, 400 MHz): 8.20 (s, 1H), 7.30-7.50 (m, 4H), 4.20 (d, 1H), 3.80 (d, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:5][C:6]=1[CH2:7][OH:8]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1nc(Oc2ccccc2)sc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(Oc2ccccc2)sc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of [4-methyl-2-(phenyloxy)-1,3-thiazol-5-yl]methanol (X-3a) (0.109 g, 0.492 mmol) and MnO2 (0.22 g, 2.56 mmol) in chloroform (2.5 mL) was stirred at RT for 2 h. More MnO2 was added (0.22 g) and continued to stir overnight. Additional MnO2 was added (0.40 g), and the mixture stirred for 3 days. The mixture was filtered through a pad of Celite, and the Celite was washed with EtOAc. The filtrate was concentrated, and the crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a colorless oil (0.086 g, 80%). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.46 (t, J=8.0 Hz, 2H), 7.33 (t, J=7.4 Hz, 1H), 7.29-7.27 (m, 2H), 2.60 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.[NH2:14][NH2:15]>O1CCOCC1>[Cl:12][C:5]1[N:4]=[N:3][C:2]([NH:14][NH2:15])=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=1
Reactant: NN
Reactant: CS(=O)(=O)c1cc(Cl)nnc1Cl
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(Cl)nnc1NN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,6-Dichloro-4-methanesulfonylpyridazine(W4.126; 660 mg, 2.9 mmol) was dissolved in 1,4-dioxane (5 ml) and hydrazine hydrate (295 μl, 5.8 mmol) was added. The mixture was stirred at RT for 4 h, then concentrated, and the residue was purified by flash chromatography (dichloromethane:ethyl acetate). Yield: 200 mg
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[NH:11][C:10]1=[O:26].[C:27](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:27][N:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)=[CH:13][C:14](=[O:15])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[F:1])[C:10]1=[O:26]
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(-c2cccc(C(F)(F)F)c2)[nH]c(=O)n1-c1ccc(Cl)cc1F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2cccc(C(F)(F)F)c2)cc(=O)n(-c2ccc(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.8 %

Procedure:
1.00 g of 3-(2-fluoro-4-chlorophenyl)-6-(3-trifluoromethylphenyl)-2,4(1H,3H)-pyrimidinedione was dissolved in 10 ml of dimethylformamide, followed by addition of 0.48 g of anhydrous potassium carbonate and 0.48 g of methyl iodide, and stirring of the solution at room temperature for 4 hours. The resulting reaction solution was poured into water and the precipitated crystals were filtered out and dried to obtain 0.90 g of the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[NH:15][C:14](=O)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[N:15]=1
Reactant: Cc1cc(C)cc(Nc2nccc(=O)[nH]2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)cc(Nc2nccc(Cl)n2)c1
Temperature: 100 °C

Procedure:
2-(3,5-Dimethyl-phenylamino)-3H-pyrimidin-4-one (2.01 g, 9.34 mmol) was dissolved in POCl3 (8.70 ml, 93.4 mmol) and the mixture was heated to 100° C. in a round bottom flask equipped with a reflux condenser and a drying tube. After 5 hours the reaction was cooled to room temperature and concentrated in vacuo. The residue was quenched by the addition of sat NaHCO3 (aq) and was extracted 3× with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (dissolved sample in DCM, eluted with 85:15 hexane/EtOAc) to afford 4-chloro-N-(3,5-dimethylphenyl)pyrimidin-2-amine (4-3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][Mg]Br.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:15])[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To the product from step A (5.42 g, 23.2 mmol) in 100 mL of tetrahydrofuran was added methylmagnesium bromide (11.6 mL, 34.8 mmol) drop-wise. After stirring at ambient temperature for 25 min, 1N hydrochloric acid was added and the mixture extracted with two portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to provide the title compound which was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.84 (d, J=1.9 Hz, 2H); 7.58 (d, J=1.8 Hz, 1H); 2.63 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCOC.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:32]3[CH:31]=[N:30][C:29]([Cl:28])=[CH:34][CH:33]=3)[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(-c3ccc(Cl)nc3)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To the solution of 0.30 g (0.84 mmol) (R)-2-(3-bromo-benzyl)-morpholine-4-carboxylic acid tert-butyl ester (example 97, intermediate (d)) in 12 mL 1,2-dimethoxyethane 97 mg (84 μmol) tetrakis(triphenylphosphine)palladium(0) were added. After 30 min. 0.48 g (3.0 mmol) 2-chloropyridine-5-boronic acid and 0.22 g (2.1 mmol) sodium bicarbonate dissolved in 6 mL water were added successively and the reaction stirred for 2.5 h under reflux. After cooling down to room temperature the reaction mixture was poured on saturated aqueous potassium carbonate solution and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography using MPLC on silica gel with ethyl acetate: n-heptane (1:1) as eluant to give the compound as colorless oil (35%).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][C:6]=1[CH3:29])C.[OH-].[Na+]>C(O)C>[CH2:22]([O:21][C:8]1[CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([C:4]([OH:30])=[O:3])=[C:6]([CH3:29])[CH:7]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCc2ccccc2)cc(OCCCc2ccccc2)c1C(=O)O

Procedure:
Ethyl-4-benzyloxy-2-methyl-6-(3-phenyl-propoxy)-benzoate (0.57 g, 1.4 mmol) and 10 N sodium hydroxide (1.4 mL, 14 mmol) are combined in ethanol (6 mL) and heated at reflux for 6 hours. The solvent is removed in vacuo and dichloromethane is added to the residue. Then 1 N hydrochloric acid is added to acidify the mixture to pHI. The aqueous layer is extracted once with dichloromethane and the combined organic layers washed once with water. The organic layer is dried over magnesium sulfate and the solvent removed in vacuo to give the title compound as a tan solid. The solid is recrystallized from ethyl acetate/petroleum ether to provide an analytically pure sample; m.p. 109-111° C., 1H NMR (300 MHz, CDCl3) δ 7.18-7.41 (m, 10H), 6.55 (d, 1H), 6.41 (d, 1H), 5.07 (s, 2H), 4.10 (t, 2H). 2.81 (t, 2H), 2.62 (s, 3H), 2.16-2.21 (m, 2H); MS (EI) 376 (M)+.