Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:35]([CH:37]2[CH2:40][CH:39]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:38]2)=[O:36])=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:35]([CH:37]2[CH2:40][CH:39]([CH2:41][C:42]([OH:44])=[O:43])[CH2:38]2)=[O:36])=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: COc1ccc2c(c1)CCN(C(=O)C1CC(CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN(C(=O)C1CC(CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Cooled TFA (4 mL) was added to tert-butyl (R)-2-(3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (118 mg, 0.20 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into ice and aqueous sodium hydrogencarbonate solution (pH 6), and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→100% ethyl acetate/hexane) to give the title compound (70.0 mg, 0.132 mmol, 65.6%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.CC1C(C)=C(NS(C2C=CC(NC3C=C(C(O)=O)C(NC4C=CC(S(=O)(=O)NC5ON=C(C)C=5C)=CC=4)=CC=3C(O)=O)=CC=2)(=O)=O)ON=1>>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: Cc1noc(NS(=O)(=O)c2ccc(Nc3cc(C(=O)O)c(Nc4ccc(S(=O)(=O)Nc5onc(C)c5C)cc4)cc3C(=O)O)cc2)c1C
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1

Procedure:
Pigmentary 2,9-dimethylquinacridone was prepared exactly as described in comparison Example 1 except that 10% by weight, relative to the 2,5-di(4-methylanilino)terephthalic acid, of 2,5-bis[4-(3,4-dimethyl-5-isoxazolyl)sulfamoylanilino]terephthalic acid (6.8 g) was included in the ring-closure reaction. 2,9-Dimethylquinacridone (59 g) was obtained as a magenta pigment.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH:10]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19]1[CH:20]=[C:21]([CH:25]2[C:34]([CH3:36])([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:37](O)=[O:38])[CH:31]=3)[NH:26]2)[CH:22]=[CH:23][CH:24]=1)([CH3:12])[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH:10]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19]1[CH:20]=[C:21]([CH:25]2[C:34]([CH3:36])([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:37]([NH:9][S:6]([CH:3]4[CH2:5][CH2:4]4)(=[O:8])=[O:7])=[O:38])[CH:31]=3)[NH:26]2)[CH:22]=[CH:23][CH:24]=1)([CH3:12])[CH3:11]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of 60% sodium hydride (290 mg, 7.3 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (895 mg, 7.4 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (300 mg, 0.74 mmol) and 1,1′-carbonyldiimidazole (300 mg, 1.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (75 mg, 20%) as a white solid: LC/MS m/e calcd for C27H33N3O5S (M+H)+: 512.65, observed: 512.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:4][C:3]=1[C:17](=O)[CH3:18].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:28]2[C:29](=[O:30])[O:1][C:2]3[C:3]([C:17]=2[CH3:18])=[CH:4][CH:5]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=3)=[CH:24][CH:23]=1
Reactant: CC(=O)c1ccc(OCOCC[Si](C)(C)C)cc1O
Reactant: COc1ccc(CC(=O)O)cn1
Product: COc1ccc(-c2c(C)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)cn1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 9 using 1-[2-hydroxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanone and (6-methoxy-pyridin-3-yl)-acetic acid as the starting material.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][C:14]1[C:15](B(O)O)=[CH:16][S:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:15]1[C:14]([CH3:13])=[CH:18][S:17][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Cc1cscc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cscc2C)c(C)c1
Yield: 91.7 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (ABCR AV19078; 3 g; 13.10 mmol; 1 eq.), 4-methyl-3-thiopheneboronic acid (Aldrich 542393; 2.05 g; 14.41 mmol; 1.10 eq.), potassium carbonate (9.05 g; 65.48 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) in toluene (15 mL) and water (15 mL) was refluxed for 3 hours. The resulting mixture was filtered through a short pad of Celite, which was further washed with toluene. After evaporation of the solvent, the residue taken up in ethyl acetate and washed successively with sat. aq. NaHCO3, water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (2.96 g, 92%) as a brown oil.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]#[N:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]#[N:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 89 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.), conc. hydrochloric acid (0.82 g.), methanol (13.3 ml.) and tetrahydrofuran (25 ml.) were treated in a similar manner to that of Example 1-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.75 g.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>>[C:23]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: C[C@@H](NC(=O)c1ccnc(N)n1)c1cccc(C(F)(F)F)c1
Product: CCC(=O)Nc1nccc(C(=O)N[C@H](C)c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound is prepared from (R)-2-amino-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.06 mmol, Step-1) and propionyl chloride (18 mg, 0.19 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=O)[C:20]3=[O:27])(=[O:16])=[O:15])[CH2:4][CH2:3]1.Cl[CH2:29][C:30]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:14]([C:17]2[CH:25]=[CH:24][C:23]3[N:22]4[CH2:29][C:30]5([CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:35][N:36]=[C:21]4[C:20](=[O:27])[C:19]=3[CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:7]1
Reactant: N#CC1(CCl)CCCC1
Reactant: CN1CCN(C[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C(=O)C(=O)N3)CC1
Product: CN1CCN(C[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C(=O)C2=NCC4(CCCC4)CN23)CC1

Procedure:
The title compound was prepared as a light brown foam from 5-({(2S)-2-[(4-methylpiperazin-1-yl)methyl]pyrrolidin-1-yl}sulfonyl)-1H-indole-2,3-dione and 1-(chloromethyl)cyclopentanecarbonitrile (Syn. Comm. 20(12) 1757, 1990), using a procedure similar to that of steps 2-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES+) m/z 486.2 [M+H].
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)[S:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:17]>CO>[NH2:17][CH:6]([C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)c1cccs1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)CC(N)c1cccs1
Temperature: 80 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
Ru(OCOCH3)2((S)-segphos)(45.0 mg, 0.543 mmol), methyl 2-(2-thenoyl)acetate (1.00 g, 5.428 mmol), ammonium acetate (0.418 g, 5.428 mmol) and methanol (5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled down to room temperature and further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo and the residue was purified by silica gel chromatography (eluent hexane ethyl acetate/triethylamine=50/50/5) to give methyl (+)-3-amino-3-thiophen-2-yl-propionate (270 mg) as a colorless oil in 26.8% yield. The resulting methyl (+)-3-amino-3-thiophen-2-yl-propionate was converted into methyl 3-(4-nitrobenzoylamino)-3-thiophen-2-yl-propionate, and the enantiomeric excess of the product was found to be 95.7% ee by HPLC analysis using a SUMICHIRAL OA-4100 column (available from SUMIKA CHEMICAL ANALYSIS SERVICE LTD.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1.[OH-].[Na+].[NH2:28]O.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:21][NH:28][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
Trans-methyl 2-(4-chlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (184 mg, 0.50 mmol) (from example 27, step 1) was dissolved in MeOH (2 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.147 mL, 0.50 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.031 mL, 0.50 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (2.58 mL, 15.46 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-(4-chlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (155 mg, 92%) as a slightly yellow oil. MS m/z 337 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br>C1COCC1>[C:10]1([CH3:15])[C:9]([C:4]2[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1-c1ccccc1CBr
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1C

Procedure:
2,2'-Bis(bromomethyl)-1,1'-biphenyl (3.40 grams, 10 mmole) was added to the addition funnel and dissolved in 10 mL of dry THF. The dibromo compound may be obtained by the free radical catalyzed halogenation of 2,2'-bitolyl. The flask containing the dibenzophospholyl anion is chilled with a water-ice bath. The mixture was stirred vigorously as the dibromo compound was added dropwise to the chilled solution over 30 minutes. The solution color lightened by the end of the addition. The resulting mixture was allowed to stir at room temperature for an additional five hours. Methanol (5 mL) was added to quench out any remaining anion and resulted in a pale yellow mixture.
Reaction SMILES: C(Cl)CCl.C(N(C(C)C)CC)(C)C.C(N)C1C=CC=CC=1.[CH3:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]2[C:35](O)=O)=[O:28])=[CH:25][CH:24]=1.[CH2:40]([NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][C:51]=1[NH-:57])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([N:47]1[C:48](=[O:49])[C:50]2[C:51](=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=2)[N:57]=[C:35]1[CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][N:29]1[C:27](=[O:28])[C:26]1[CH:38]=[CH:39][C:23]([CH3:22])=[CH:24][CH:25]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: [NH-]c1cc(Cl)ccc1C(=O)NCc1ccccc1
Reactant: Cc1ccc(C(=O)N2CCCCC2C(=O)O)cc1
Solvent: NCc1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCCCC2c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 47 %

Procedure:
Formula 205 where T is a covalent bond; W, X, Y and Z are —C═; U—V is —N(R6)—CReRf—CRgRh—; R1, R2, R4 and Ra to Rh are H; Rand R6 is p-methyl-benzoyl: A mixture of the compound of Formula 203 (2.66 g, 6.7 mmol), 1M NaOH (27 mL), methanol (54 mL), and dioxane (36 mL) was stirred at room temperature for 7 hours. The solvents were evaporated and the residue portioned between dichloromethane (75 mL), saturated NaCl (50 mL), and concentrated HCl (3 mL). The layers were separated and the organic layer dried over MgSO4 and concentrated under vacuum to give the corresponding compound of Formula 204, 4-chloro-2-[1-(4-methyl-benzoyl)-piperidine-2-carbonyl]amino}-benzoic acid, which was carried forward without further purification. This crude product was redissolved in dichloromethane and treated with EDC (3.84 g, 20 mmol), and diisopropylethylamine (3.50 mL, 20 mmol). After stirring 20 minutes, benzylamine (2.20 mL, 20 mmol) was added and the mixture stirred overnight at room temperature. The mixture was washed with water (2×50 mL) and 1M HCl, dried over MgSO4, filtered and concentrated under vacuum to give 1.5 g (47% yield) of the desired product of Formula 205, 1-(4-methyl-benzoyl)-piperidine-2-carboxylic acid (2-benzylcarbamoyl-5-chloro-phenyl-amide, a crude product that was found to be 80% pure by reverse phase HPLC. The product was taken on without further purification. LRMS (MH+) m/z 491.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])C[C:4](=[O:9])[O:3]1.C(O)C=C.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:20]([C:19]1([CH2:18][CH:17]=[CH2:16])[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])[CH:15]=[CH2:21]
Reactant: Cc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: C=CCO
Product: C=CCC1(CC=C)C(=O)OC(C)(C)OC1=O

Procedure:
There were supplied to a 50 mL-round bottom flask 7.69 g of MOLECULAR SIEVES 3A, 35 mL of toluene, 49.7 mg of the above-produced Pd(OC6H5)3, 5.04 g of 2,2-dimethyl-1,3-dioxane-4,6-dione, and 4.9 ml of allyl alcohol, and the resultant mixture was stirred for 2 hours at 80° C. in an atmosphere of a nitrogen gas. The reaction mixture was filtered, and toluene contained in the filtrate was distilled away. The resultant residue was purified according to a column chromatography having a stationary phase of silica gel and a mobile phase of a mixed solvent consisting of 8 parts by weight of hexane and 1 part by weight of ethyl acetate, thereby obtaining 6.22 g of clear and oily isopropylidene diallylmalonate (monomer).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:6]([C:8]1[N:13]([CH2:14][C:15]2([CH2:18][C:19](O)=[O:20])[CH2:17][CH2:16]2)[C:12](=[O:22])[NH:11][C:10](=[O:23])[C:9]=1[CH:24]([CH3:26])[CH3:25])=[O:7])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>C1COCC1.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:6]([C:8]1[N:13]([CH2:14][C:15]2([CH2:18][C:19]([NH:44][CH2:43][C:42]3[CH:45]=[CH:46][C:39]([O:38][CH3:37])=[CH:40][CH:41]=3)=[O:20])[CH2:16][CH2:17]2)[C:12](=[O:22])[NH:11][C:10](=[O:23])[C:9]=1[CH:24]([CH3:26])[CH3:25])=[O:7])#[N:2]
Reactant: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2(CC(=O)O)CC2)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)CC2(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)CC2)cc1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a stirred solution of {1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-acetic acid (90 mg, 0.22 mmol) in THF (5 mL) cooled in an ice bath, were added oxalyl chloride (38 μL, 0.44 mmol) and one drop of DMF. After stirring for 1 hr., the mixture was evaporated in vacuo. The residue was dissolved in THF (8 mL) and p-methoxy benzylamine (261 μL, 2 mmol) was added. After stirring for 1 hr., the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (2:1): Rf=0.25 fraction was collected) to give 97 mg (83%) of 2-{1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-N-(4-methoxy-benzyl)-acetamide (84) as a white solid. 1H-NMR (200 MHz, CDCl3) δ 0.40-0.46 (4H, m), 1.12 (3H, d, J=6.6 Hz), 1.23 (3H, d, J=6.6 Hz), 2.00 (1H, d, J=15.4 Hz), 2.25 (1H, m), 2.48-2.55 (4H, m), 3.45 (1H., d, J=15.4 Hz), 3.80 (3H, s), 3.90 (1H, d, J=15.4 Hz), 4.34-4.39 (2H, m), 6.69 (1H, m), 6.83-6.90 (2H, m), 7.22-7.30 (2H, m), 7.81 (1H, s), 8.01 (1H, s), 8.07 (1H, s), 9.81 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[Cl:47])[CH2:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:42]([NH:41][CH2:40][C:39]2[CH:44]=[CH:45][C:46]([Cl:47])=[C:37]([Cl:36])[CH:38]=2)=[O:43])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.170 g, 0.42 mmol) and triethylamine (0.12 mL, 0.86 mmol) were combined in CH2Cl2 (2 mL). 3,4-Dichlorobenzyl isocyanate (0.08 mL, 0.52 mmol) was added, and the reaction was stirred at room temperature for 15 minutes. After concentrating, the crude material was purified by silica gel chromatography (20-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])(=[O:21])=[O:20])[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)=[O:4].Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C.C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])(=[O:20])=[O:21])[CH:7]=[C:8]([C:36]2[N:35]=[C:34]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:33]=[CH:32][N:37]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Reactant: Clc1ncnc(Nc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ncnc(Nc3ccccc3)n2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 80 °C
Yield: 33.9 %

Procedure:
In a 10 mL flask was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (1.0 equivalent, 0.34 mmol, 149 mg), (4-chloro-[1,3,5]triazin-2-yl)-phenyl-amine (1.1 equivalent, 0.37 mmol, 78 mg), tetrakistriphenylphosphine palladium (0.2 equivalent, 0.07 mmol, 80 mg), sodium carbonate (1 mL, 2 N), methanol (1 mL) and benzene (5 mL). The resulting mixture was heated at 80° C. for 2 hours then diluted in ethyl acetate and washed with water, brine. The organic layer was dried over sodium sulfate then concentrated under vacuum. The crude mixture was then purified by prep HPLC to afford 55 mg of the title compound. HPLC, Rt=8.8 min, FIA, ES+=478.1.
Reaction SMILES: [CH3:1][C@@H:2]([OH:7])[CH2:3][C@H:4]([OH:6])[CH3:5].[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31](Cl)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1.O>CN(C=O)C>[F:39][C:9]([F:8])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31]([O:6][C@H:4]([CH3:5])[CH2:3][C@H:2]([OH:7])[CH3:1])=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Reactant: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](C[C@@H](C)O)Oc1ccc2nc(C(=O)Nc3nc4cc(-c5cccc(C(F)(F)F)c5)ccc4[nH]3)cn2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.1 %

Procedure:
To a solution of (2R,4R)-(−)-pentanediol (31.2 mg) in dry DMF (1 mL) NaH (12 mg, 60% dispersion in mineral oil) was added, and the mixture was stirred at room temperature for 20 minutes under nitrogen. To this mixture 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (45.6 mg) was added. The reaction was monitored by LCMS until substantially complete. Then, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, purified by column chromatography to obtain 6-((1R,3R)-3-hydroxy-1-methyl-butoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (25.2 mg). LCMS (m/z): 526.1. 1H NMR (400 MHz, CDCl3) δ 8.39 (1H, s) 7.89 (1H, s) 7.45-7.85 (7H, m) 6.79 (1H, d) 5.42 (1H, ddd) 3.95 (1H, d) 2.18 (1H, brs) 1.91 (1H, ddd) 1.69-1.79 (1H, m) 1.44 (3H, d) 1.26 (3H, d)