Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[C:27]([O:33][CH3:34])[C:28]([O:31][CH3:32])=[N:29][CH:30]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Reactant: COc1cc(Br)cnc1OC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1cc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cnc1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
To a glass vial was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 7) (1.00 g, 3.12 mmol), 5-bromo-2,3-dimethoxypyridine (0.82 g, 3.75 mmol), sodium tert-butoxide (0.46 g, 4.68 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.11 g, 0.13 mmol), 2-di-t-butylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.18 mmol) and anhydrous toluene (10 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 18 h at 80° C. Allowed to cool and filtered through a celite pad. The filtrate was diluted with EtOAc (50 mL) and washed with brine (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. Purified by flash column chromatography on silica gel with EtOAc/MeOH, 98/2 to 92/18 to give (S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow foam (1.05 g, 74% yield). LCMS: [M+H]+=458.1, Rt(4)=1.02 min.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5].[CH2:23]([Mg]Br)[CH3:24].CCOCC>O1CCCC1.[Cl-].[NH4+]>[CH3:21][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[O:10][C:6]=1[C:4](=[O:5])[CH2:23][CH3:24]
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C

Procedure:
4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methoxy-methyl-amide (1.0 g, 3.18 mmol) is stirred in tetrahydrofuran (15 mL) at −78° C. ethyl magnesium bromide, 3M/ether (2.1 mL, 4.14 mmol) is added and the mixture is warmed to room temperature. The mixture is diluted with aqueous saturated ammonium chloride and washed with ethyl acetate (three 50 mL portions). The combined ishes are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified over silica eluting with 7:3 hexanes:ethyl acetate to afford 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-one as an ivory solid, 0.70 g, 78%. MS (M++1) 284.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14](N)=[O:15]>O>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:14]([OH:15])[N:13]=[C:4]2[OH:6]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: NC(N)=O
Solvent: O
Product: COc1ccc2nc(O)nc(O)c2c1
Yield: 71.6 %

Procedure:
2-Amino-5-methoxybenzoic acid (5.090 g, 30.45 mmol) was heated with urea (18.300 g, 304.50 mmol) to 150° C. for 24 h. Water (150 mL) was cautiously added to the melt and allowed to cool. The resulting precipitate was filtered off and dried to give a solid (4.189 g, 72%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O>>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1nc2ccccc2o1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4nc5ccccc5o4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-benzoxazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-benzoxazol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][CH2:21][N:22]1[CH2:28][CH:27]2[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]2)[CH2:23]1>>[ClH:19].[ClH:18].[CH:27]12[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]1)[CH2:23][N:22]([CH2:21][CH2:20][N:12]1[CH2:13][CH2:14][C:9]3[C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:28]2
Reactant: CCc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Product: CCc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 68 %

Procedure:
Prepared by the method described for Example 1 from 8-ethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.5 g, 0.024 moles) and 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (5.5 g, 0.025 moles). Recrystallization from ethanol gave the product (7.4 g), mp 295°-300° C.
Reaction SMILES: [Cl-].BrBr.[Cl:4][CH:5]1[CH:13]=[CH:12][CH:8]([C:9]([Cl:11])=[O:10])[CH:7]([C:14]([Cl:16])=[O:15])[CH2:6]1>ClC1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([C:14]([Cl:16])=[O:15])[C:8](=[CH:12][CH:13]=1)[C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)C1C=CC(Cl)CC1C(=O)Cl
Agent: BrBr
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=C(Cl)c1ccc(Cl)cc1C(=O)Cl
Temperature: 135 °C

Procedure:
To a 1-l three-necked flask, equipped with a mechanical stirrer, a condenser with a gas outlet and an equa-pressured addition funnel, is charged 241.5 g (1 mole) of 4-chloratetrahydrophthaloyl chloride and 36 g of chlorobenzene. The mixture is heated to 100°-110° C. with stirring. Bromine, 320 g (2 moles) is added dropwise into the solution in a sub-surface manner. The color dissipates quickly and an evolution of gas occurs. When approximately 240 g of bromine has been added, the pot temperature is raised to 135° C. The addition of bromine continues until completion. The pot temperature is then raised to 165°-170° C. for 2-4 fours. during this period, an additional amount of bromine, such as about 10 to 15 g, may be added to complete the conversion of 4-chlorotetrahydrophthaloyl chloride. A good yield of 4-chlorophthaloyl chloride will be obtained from the distillation of the mixture.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](OC)=[O:10]>C1COCC1>[F:7][C:8]([F:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:9][OH:10]
Reactant: COC(=O)C(F)(F)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
Add lithium aluminum hydride (5.18 mL, 5.18 mmol, 1M solution in THF) to a solution of methyl difluorophenylethanoate (0.964 g, 5.18 mmol, prepared by following the procedure described in J. Org. Chem. 1995, 60, 5174-5179) in anhydrous THF (10 mL) at 0° C. Stir the mixture at room temperature for 45 min. Cool to 0° C. and quench with EtOAc and then water. Separate the organic phase and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate (0.8 g, 98%) that was used without any further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([NH:11][C:12]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=2)[CH:4]=1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.S(C)C>[NH2:8][C:7]1[C:6]2[C:5]([N:11]=[C:12]3[C:13]=1[C:14](=[O:18])[CH2:15][CH2:16][CH2:17]3)=[CH:4][C:3]([Cl:2])=[CH:10][CH:9]=2
Reactant: N#Cc1ccc(Cl)cc1NC1=CC(=O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CSC
Solvent: C1CCOC1
Product: Nc1c2c(nc3cc(Cl)ccc13)CCCC2=O
Yield: 47.5 %

Procedure:
In 200 ml of tetrahydrofuran were combined 5.00 g of 4-chloro-2-(3-oxocyclohexen-1-yl)aminobenzonitrile hydrochloride, 4.88 g (2 eq) milled anhydrous K2CO3, and 0.36 g (0.1 eq) of CuBr.(CH3)2S used as a catalyst. The mechanically stirred mixture was refluxed overnight. It was then evaporated to a residue and extracted with several portions of MeOH. The MeOH extract was evaporated and the residue was chromatographed on silica gel and then the purified product was recrystallized from EtOAc to yield 2.07 g (47%) of a solid, melting point 285°-287° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:7][CH:8]=1)#[N:2].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:12][CH2:11][CH2:10][NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(C#N)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NCCN)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 g (15.25 mmol) of tert-butyl {2-[(5-cyanopyridin-2-yl)amino]ethyl}carbamate (Example 12A) are dissolved in 150 ml of dichloromethane, and 17.39 g (152.5 mmol) of trifluoroacetic acid are slowly injected. The mixture is stirred at RT for 16 h and then all volatile constituents are removed in vacuo. 4.3 g (91% of theory) of the product are obtained as a resin.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][C:14]1=[O:22].Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].[Cl-].[NH4+].Cl>O1CCCC1.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:13][C:14]1=[O:22])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1Cc2ccccc2O1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(CC1C(=O)Oc2ccccc21)OCc1ccccc1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7.53 g of diisopropylamine in 150 ml of anhydrous tetrahydrofuran is cooled under a stream of nitrogen to -60° C. 46.6 ml of a 1.6M solution of n-butyllithium in hexane is added dropwise at this temperature. When the addition is complete, the temperature of the reaction medium is allowed to rise to 5° C., the mixture is stirred for 10 minutes at this temperature and cooled to -80° C. and a solution of 10 g of 2,3-dihydro-2-benzofuranone in 150 ml of anhydrous tetrahydrofuran is added dropwise. The mixture is maintained for 10 minutes at -80° C. and then for 10 minutes at -60° C. It is cooled again to -80° C. and a solution of 18.8 g of benzyl bromoacetate in 16.05 g of hexamethylphosphorotriamide is added. The temperature is allowed to rise to 20° C., and the reaction mixture is stirred for 1 hour at this temperature and hydrolyzed at 0° C. using 26 ml of saturated ammonium chloride solution. The medium is then poured into 2.5 l of 1% strength hydrochloric acid solution. The precipitate is filtered off and dissolved in 200 ml of benzene, the organic phase is washed with water and dried over anhydrous sodium sulfate and the solvent is evaporated off. The residue is recrystallized in petroleum ether.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[C:28]([CH3:33])=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[C:28]([CH3:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1ncccc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Product: Cc1cc(-c2cccnc2C)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 3-Bromo-2-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=325.2 (M+H)+.
Reaction SMILES: [NH2:1]CCN1CCNCC1.[Cl:10][CH2:11][CH2:12][C:13]([N:15]=[C:16]=[O:17])=[O:14]>>[Cl:10][CH2:11][CH2:12][C:13]([NH:15][C:16]([NH2:1])=[O:17])=[O:14]
Reactant: NCCN1CCNCC1
Reactant: O=C=NC(=O)CCCl
Product: NC(=O)NC(=O)CCCl
Yield: 263 %

Procedure:
In the same way, reaction of 6.5 g (50 mmols) of N-(2-aminoethyl)piperazine with 14.3 g (106 mmols) of 3-chloropropionyl isocyanate gives a quantitative yield of 19.8 g of the 3-chloropropionyl urea of the formula ##STR10## Melting point: 125°-130° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[CH3:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]([OH:22])[C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([NH:2][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH3:34])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:17][CH:16]=2)=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Agent: Cl
Product: CCCCC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and n-valeroyl chloride by using the same techniques as in Example 41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(OCCBr)c(Cl)c1
Temperature: 85 °C
Yield: 77.2 %

Procedure:
To a solution of 2-chloro-4-methylphenol (500 mg, 3.62 mmol) in acetonitrile (20 mL) was added 1,2-dibromoethane (3.29 g, 17.53 mmol) followed by cesium carbonate (2.28 g, 7.01 mmol). The resulting mixture was heated at 85° C. for 48 h, then cooled to rt. The solution was filtered through a Celite® pad. The Celite® was washed with acetone and the combined eluents were concentrated under reduced pressure to give the title compound as a white solid (697 mg, 76%). GC/MS (EI) m/z 248 (M)+, RT 7.33 min.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[N:7]=1.[H-].[Na+].[C:13](=O)([O:21]C1C=CC=CC=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)=O.Cl>CN(C)C=O.O1CCCC1.ClCCl>[Cl:8][C:6]1[N:7]=[C:2]([NH:1][C:13](=[O:21])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: Cn1cc(Cl)nc(N)c1=O
Agent: Cl
Agent: O=C=O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cc(Cl)nc(NC(=O)Oc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-5-chloro-1-methyl-2(1H)-pyrazinone (11.17 g, 0.070 mol) in anhydrous N,N-dimethylformamide (90 mL) was treated with oil-free sodium hydride (3.4 g, 0.154 mol). After stirring at room temperature for 1 hour, the mixture was cooled with the aid of a dry ice-acetone bath while a solution of diphenyl carbonate (16.49 g, 0.077 mol) in N,N-dimethylformamide (60 mL) was added as rapidly as possible. A wet ice bath was substituted for the dry ice bath, and the reaction mixture was stirred at approximately 0° C. for 3 hours. The mixture was allowed to briefly warm to room temperature, and was then poured into a stirred mixture of ice (350 g), concentrated hydrochloric acid (42 mL); dichloromethane (318 mL), and tetrahydrofuran (32 mL). The layers were separated, and the aqueous layer was extracted with 10:1 dichloromethane-tetrahydrofuran (5×100 mL). The combined organic solutions were dried (Na2SO4), and the solvent was rotary evaporated. After the residue was taken up in toluene, further rotary evaporation left a tan solid. This solid was taken up in dichloromethane, absorbed onto silica gel and then chromatographed using a 5:1 mixture of dichloromethane-ether as eluant. Rotary evaporation of the appropriate fractions left 9.70 g of phenyl (6-chloro-3,4-dihydro-4-methyl-3-oxopyrazin-2-yl)carbamate as a crystalline solid melting at 175°-177° C.
Reaction SMILES: C([O:3][P:4]([CH:7]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[P:8](=[O:11])([OH:10])[OH:9])(=[O:6])[OH:5])C.C[Si](I)(C)C>C(Cl)(Cl)(Cl)Cl>[O:18]=[C:15]1[CH2:14][CH2:13][N:12]([CH:7]([P:8](=[O:9])([OH:10])[OH:11])[P:4](=[O:3])([OH:5])[OH:6])[CH2:17][CH2:16]1
Reactant: CCOP(=O)(O)C(N1CCC(=O)CC1)P(=O)(O)O
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCN(C(P(=O)(O)O)P(=O)(O)O)CC1
Temperature: 27.5 °C
Reaction time: 5 h
Yield: 28.6 %

Procedure:
7.7 g of 4-oxopiperidinomethylene bisphosphonic acid ethyl ester and 12 ml of trimethylsilyl iodide (specific gravity: 1.41) were stirred at 0° C. for 30 minutes in 120 ml of CCl4. Then, the reaction solution was distilled under reduced pressure. To the residue, 50 ml of water and 200 ml of CH3OH were added, and the mixture was stirred at a temperature of from 25 to 30° C. for 5 hours. The reaction solution was distilled, and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give 2.0 g (yield: 37%) 4-oxopiperidinomethylene bisphosphonic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH:13]([CH3:17])[C:14](Cl)=O>>[Cl:12][CH:13]([C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=2[N:1]=1)[CH3:14]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: CC(Cl)C(=O)Cl
Product: CC(Cl)c1nc2c(F)cccc2c(=O)o1

Procedure:
A mixture of 9.3 g of 2-amino-3-fluoro-benzoic acid and 18,6 ml of α-chloropropionyl chloride was refluxed for 3 hours and excess acid chloride was distilled off. The residue was concentrated under reduced pressure at 70° C. for 2 hours to obtain 2-(1-chloroethyl)-8-fluoro-4H-3,1-benzoxazine-4-one which was used as is for the next step.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[N:22]=[CH:21][N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:19]=4)[CH:16]=3)[N:11](C3CCCCO3)[N:10]=2)=[CH:5][CH:4]=1.C(Cl)Cl.ClC1C=C(C=CC=1)C(OO)=[O:56]>CCOC(C)=O>[NH:19]1[C:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:6]2[CH:7]=[CH:8][C:3]([S:2]([CH3:1])=[O:56])=[CH:4][CH:5]=2)=[N:22][CH:21]=[N:20]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
A mixture of 4-methylthio-1-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}benzene (136 mg, 0.214 mmol), 1.00 mL CH2Cl2, and 3-chloroperoxybenzoic acid (Aldrich, 77% purity, 48.1 mg, 0.214 mmol based on 77% purity, 1.00 equiv.) was stirred at room temperature for 30 minutes. The reaction was diluted with EtOAc, washed with 2×sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude concentrate was heated in 5.00 mL of MeOH and 5.00 mL of 6.0 N aq. HCl at 65° C. for 17.5 h. The mixture was poured onto 6.0 N aq. NaOH and extracted with 2×EtOAc. The aqueous layer was neutralized to pH=6.0 with 6.0 N aq. HCl, and extracted with 2×EtOAc. The combined organics were dried (Na2SO4), filtered, and concentrated. Purification by prep HPLC afforded the title compound (7.2 mg, 10.4% yield): 1H NMR (CDCl3/CD3OD) δ 8.78 (s, 1H), 8.45–7.98 (m, 4H), 7.86 (d, 2H), 7.72 (d, 1H), 2.89 (s, 3H); ES-MS (m/z) 324 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][C:33](Cl)=[O:34])[CH3:29]>C1COCC1>[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:34])[CH3:29]
Reactant: CCN(CC)CCC(=O)Cl
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)CCN(CC)CC)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 3-(diethylamino)propanoyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J=7.45 Hz, 3H) 1.23 (t, J=7.20 Hz, 6H) 1.28-1.37 (m, 2H) 2.19-2.29 (m, 2H) 2.88 (t, J=7.07 Hz, 2H) 3.18 (ddd, J=12.69, 6.82, 6.51 Hz, 4H) 3.38-3.42 (m, 2H) 6.78 (s, 1H) 7.54-7.62 (m, 1H) 7.71 (d, J=8.59 Hz, 2H) 7.79-7.90 (m, 4H) 8.09 (d, J=8.34 Hz, 1H) 9.12 (s, 1H) 10.57 (s, 1H); ESI-MS: m/z calc'd for C28H33N5O2S 503.66. found 504.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.B.O1CCCC1>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)Cc2ccc(Cl)nc2)cc1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc(NCCc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 500 mL reaction flask containing 2-(6-chloropyridin-3-yl)-N-p-tolylacetamide (12 g, 46 mmol; Example 117A) in tetrahydrofuran (200 mL) was treated with 1 M borane-tetrahydrofuran (100 mL, 100 mmol; Aldrich) and then heated to reflux with stirring for 16 hours. After cooling the reaction mixture to room temperature, it was quenched with ethanol, concentrated and purified by flash chromatography (silica gel, hexanes/ethyl acetate, 2:1) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.19 (s, 3H), 2.89 (t, J=7 Hz, 2H), 3.35 (t, J=7 Hz, 2H), 6.56 (d, J=8 Hz, 2H), 6.93 (d, J=8 Hz, 2H), 7.37 (d, J=8 Hz, 1H), 7.70 (dd, J=8, 2 Hz, 1H), 8.21 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 247 (M+H)+.