Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:22]([O:24]CC1C=CC=CC=1)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:32]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:33](C(O)=O)[CH2:34][CH2:35][C:36](=[O:38])[NH2:37].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CO.CN(C=O)C>[NH:32]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:33]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(N)=O)C(=O)O
Reactant: CN(C(=O)CNC(=O)OCc1ccccc1)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 15 h

Procedure:
0.85 g of Z-Gly-MePhe-NHNHCONH2 is subjected to catalytic reduction in methanol, dissolved in 10 ml of DMF, and after ice-cooling, 0.50 g of BOC-(D)-Gln-OH, 0.40 g of HONB and 0.45 g of DCC are added. The mixture is stirred for 15 hours, the precipitated DCU filtered off and the solvent distilled off. The residue is dissolved in n-butanol, washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is distilled off, treated with ether and filtered to obtain a powder. Yield 0.82 g; m.p. 124°-128° C.; [α]D24 -36.5° (c=1.0, DMF); Rf1 0.11.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=O)C.[CH3:13][NH:14]N.CC(O)=O>CC(O)(C)C>[CH3:13][N:14]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:2]1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CNN
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: Cn1ncc2c1CCCC2=O
Yield: 44.4 %

Procedure:
To a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (55 g crude, 300 mmol) in t-BuOH (400 ml) was added methylhydrazine solution (35 g, 40% aqueous solution, 304 mmol) and AcOH (20 ml) at room temperature. The resulting mixture was heated to reflux for 3 h under nitrogen protection. After cooling, the mixture was concentrated in vacuo and the residue was purified by column chromatograph on silica gel (petroleum ether/ethyl acetate=1/1 v/v %) to give 1-methyl-6,7-dihydro-1H-indazol-4(5H)-one (20 g, two steps: 44%). MS-ESI (m/z): 151 (M+1)+ (Acq Method: 0-60AB_2 min; Rt: 0.90 min)
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:40].O>O1CCOCC1>[OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26]([CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:32])([F:33])[F:34])=[O:40])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CO
Solvent: O
Solvent: C1COCCO1
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[8-(4,4,5,5,5-pentafluoropentylthio)octyl]-2,3-dihydro-4H-benzopyran (53 mg, 0.095 mmol) was dissolved in 1,4-dioxane (1.2 ml), methanol (1.2 ml) and water (0.3 ml). NaIO4 (24 mg, 0.11 mmol) was added dropwise thereto, and the reaction mixture was stirred for 8 hours at room temperature and then filtered. The filtrate was concentrated and the residue was subjected to column chromatography (n-hexane:ethyl acetate=2:1) to obtain 38 mg (yield: 70%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)=[O:31]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH:16]([CH3:20])[C:17]([O:19][CH2:29][C:30](=[O:31])[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:37]=2)=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: CC(C(=O)O)C1(NC(=O)OCc2ccccc2)COC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C(=O)OCC(=O)c1ccc(C(F)(F)F)cc1)C1(NC(=O)OCc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
2-(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)propanoic acid (Preparation 28, 1.5 g, 5.37 mmol) and triethylamine (1.12 mL, 8.06 mmol) were stirred in ethyl acetate (50 mL). 2-Bromo-1-[4-(trifluoromethyl)phenyl]ethanone (1.51 g, 5.64 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (2.19 g, 88%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.COCCOC>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].O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc3ccccc3n2)cc1
Yield: 68.6 %

Procedure:
2-Chloroquinoline (5.0 g, 31 mmol) and 4-methoxyphenylboronic acid (5.5 g, 36 mmol) were dissolved in a solvent mixture containing 40 mL ethylene glycol dimethyl ether and 60 mL water containing 12.0 g K2CO3. To the stirred solution was added 1.6 g tetrakis(triphenylphosphine)palladium(O) and the mixture refluxed under N2 overnight. The cooled reaction mixture was then removed of water, extracted with methylene chloride three times. The combined organic phase was washed with portions of brine and then dried with anhydrous sodium sulfate, filtered, and evaporated of solvent to give 2-(p-methoxyphenyl)quinoline (5.0 g) after column chromatography (20% ethyl acetate in hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:26]=[C:27]([CH3:39])[C:28]3[N:32]=[C:31]([C@@H:33]4[CH2:37][CH2:36][CH2:35][O:34]4)[NH:30][C:29]=3[CH:38]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:39][C:27]1[C:28]2[N:32]=[C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][O:34]3)[NH:30][C:29]=2[CH:38]=[C:25]([O:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)[CH:26]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12

Procedure:
50 mg (0.23 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]-imidazole and 0.08 mL (0.46 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT and for 2 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 1M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](OC(OCC)OCC)C>ClCCCl.C1CCN2C(=NCCC2)CC1>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][CH:25]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)[N:1]=[CH:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Reactant: CCOC(OCC)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: COc1cc(-n2cnc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A solution of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide [Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) was treated with triethylorthoformate (2 ml) and the mixture heated to 80° C. for 16 hours. The mixture was cooled, 1 drop of DBU added and the mixture evaporated. The residue was subjected to flash chromatography on silica gel eluting with (methanol-dichloromethane-aqueous ammonia) to give the title compound;
Reaction SMILES: ICl.[OH:3][CH2:4]C(CO)OCN1C=C(C=C)C(=O)NC1=O.[OH:20][CH2:21][CH2:22][O:23][CH2:24][N:25]1[CH:32]=[C:31]([CH:33]([N:36]=[N+:37]=[N-:38])[CH2:34][I:35])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>C(Cl)(Cl)Cl.CO>[OH:20][CH2:21][CH:22]([CH2:4][OH:3])[O:23][CH2:24][N:25]1[CH:32]=[C:31]([CH:33]([N:36]=[N+:37]=[N-:38])[CH2:34][I:35])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: [N-]=[N+]=NC(CI)c1cn(COCCO)c(=O)[nH]c1=O
Reactant: C=Cc1cn(COC(CO)CO)c(=O)[nH]c1=O
Agent: ClI
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [N-]=[N+]=NC(CI)c1cn(COC(CO)CO)c(=O)[nH]c1=O
Yield: 29.6 %

Procedure:
Reaction of iodine monochloride (72.0 mg, 0.44 mmol) with 9a (95 mg, 0.39 mmol), using the procedure described for the preparation of 2c, and purification of the product by silica gel column chromatography using chloroform-methanol (90:10, v/v) as eluent afforded 10c as a syrup (48 mg, 29.6%).
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:15]=3[CH:16]=2)[O:8][C:7](=[O:25])[C:6]=1[CH3:26])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[C:21]([C:19]1[CH:18]=[CH:17][C:15]2[CH:16]=[C:12]([C:9]3[O:8][C:7](=[O:25])[C:6]([CH3:26])=[C:5]([OH:4])[C:10]=3[CH3:11])[O:13][C:14]=2[CH:20]=1)([OH:23])=[O:22]
Reactant: COC(=O)c1ccc2cc(-c3oc(=O)c(C)c(OC(C)=O)c3C)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(-c2cc3ccc(C(=O)O)cc3o2)oc(=O)c(C)c1O

Procedure:
A mixed solution of 4-acetyloxy-3,5-dimethyl-6-(6-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one (85 mg) and K2CO3 (45 mg) in MeOH (5 ml) and H2O (1 ml) was stirred at room temperature for one hour, and then the reaction solution was rendered acidic with a 1 N hydrochloric acid aqueous solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/MeOH=5/1) to obtain 6-(6-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Temperature: 50 °C
Yield: 38.1 %

Procedure:
A mixture of intermediate 1 (3.0 g), potassium carbonate (3.70 g), 1-(chloromethyl)-4-(methylsulfonyl)benzene (2.74 g) and DMF (20 mL) was heated at 50° C. for 24 hours. The mixture was allowed to cool then poured into water (50 mL) and extracted with dichloromethane (100 mL). The extracts were combined, evaporated under reduced pressure and the residue purified (SiO2 chromatography, eluting with 2% methanol in dichloromethane) to give the sub-titled compound (2.0 g).
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][CH2:3]1.[Br:12][CH2:13][CH2:14][CH2:15]Br>>[CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]([CH2:15][CH2:14][CH2:13][Br:12])[CH2:3]1
Reactant: CC1CNc2ccccc2O1
Reactant: BrCCCBr
Product: CC1CN(CCCBr)c2ccccc2O1
Yield: 42.9 %

Procedure:
From 2-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.5 g, 1 eq, 30.2 mmol) obtained in step (iii) above, and 1,3-dibromo propane (30 ml, 10 eq, 300 mmol) and following the procedure of step (iv), preparation 17 title compound (3.5 g, yield 48%) was obtained as viscous oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>C1(O)CCCCC1>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([F:26])[CH:20]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Solvent: OC1CCCCC1
Product: COC(=O)c1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OC
Temperature: 130 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
4-Chloro-7-methoxy-6-methoxycarbonylquinoline (1.4 g, 5.5 mmol) was dissolved in cyclohexanol (30 ml) and 4-chloro-2-fluoroaniline (0.786 g, 5.8 mmol) was added. The mixture was heated at 130° C. for 1 hour then at 160° C. for 3hours. The solvent was removed by evaporation and the residue was purified by flash chromatography eluting with methylene chloride/ethylacetate (100/0 increasing to 50/50). The solvent was removed by evaporation and the solid was triturated with ether/isohexanes. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-methoxycarbonylquinoline (570 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].I[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CNc1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 49.9 %

Procedure:
A mixture of 2,4-dichloroaniline (20.2 g, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18.1 g, 0.13 mol) in DMF (200 ml) was heated under nitrogen at 100° C. overnight. After cooling to rt, water was added and the mixture extracted with ether (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (Heptane:EtOAc 90:10-80:20) afforded 13.6 g (50%) of the title compound as a brown solid.
Reaction SMILES: NC1C=CC(C(F)(F)F)=CC=1N[C:13]([C:15]1[N:16]=[C:17]([NH:20][C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[S:18][CH:19]=1)=[O:14].NC1C=C(C(F)(F)F)C=CC=1NC(C1N=C(NC2C(Cl)=CC=CC=2Cl)SC=1)=[O:42]>>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:17]1[S:18][CH:19]=[C:15]([C:13]([OH:14])=[O:42])[N:16]=1
Reactant: Nc1ccc(C(F)(F)F)cc1NC(=O)c1csc(Nc2c(Cl)cccc2Cl)n1
Reactant: Nc1cc(C(F)(F)F)ccc1NC(=O)c1csc(Nc2c(Cl)cccc2Cl)n1
Product: O=C(O)c1csc(Nc2c(Cl)cccc2Cl)n1

Procedure:
N-[2-Amino-5-(trifluoromethyl)phenyl]{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}carboxamide and N-[2-amino-4-(trifluoromethyl)phenyl]{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}carboxamide. According to the procedure described in step (f) of Example 11, the title compounds were obtained from 2-[(2,6-dichlorophenyl)amino]-1,3-thiazole-4-carboxylic acid (339 mg, 1.18 mmol, prepared analogously to the procedures described in Example 3) and 4-(trifluoromethyl)-1,2-phenylenediamine (207 mg, 1.18 mmol, Lancaster) as a light brown solid. MS (ESI, pos. ion) m/z: 447 (M+1).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1.Cl>O1CCCC1.O>[CH3:28][S:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:26][CH:25]=1
Reactant: CSc1ccc(-c2oncc2CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(-c2oncc2CCC(=O)O)cc1
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of diethyl malonate (10.3 g) in tetrahydrofuran (80 ml) was gradually added sodium hydride (60%, oil, 2.34 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-methylthiophenyl)isoxazole (7.00 g) in tetrahydrofuran (70 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (50 ml) and acetic acid (100 ml), and heated under reflux for 5 hr. The reaction mixture was concentrated, and water was added to the residue to give colorless crystals (4.68 g, yield 61%) of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionic acid. The crystals were recrystallized from ethyl acetate-isopropyl ether to give a colorless prism. melting point: 124–125° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]([OH:14])=O)[C:6]=2[N:7]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[Cl:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:33]([Cl:32])[CH:34]=3)=[O:14])[C:6]=2[N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Nc1nc(-c2ccco2)c2nnn(CC(=O)O)c2n1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2nnn(CC(=O)Nc3cccc(Cl)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
A suspension of (5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)acetic acid (140 mg, 0.5 mmol) in DMF (1 mL) was treated with carbonyl diimidazole (81 mg, 0.5 mmol), stirred at room temperature for 1 h, treated with 3-chloroaniline (53 μL, 0.5 mmol) and the mixture heated to 50° C. for 16 h. The reaction mixture was cooled, diluted with water (3 mL) and filtered to give the title compound (94 mg, 48%) as a cream solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[O:31][CH:30]=[N:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O>[O:31]1[C:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:8]4[CH2:9][CH2:10][CH2:11][N:7]4[CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:15][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28][N:29]=[CH:30]1
Reactant: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cnco3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cnco3)cc2)cc1
Temperature: 50 °C
Yield: 10.7 %

Procedure:
To a solution of the product (90 mg, 0.21 mmol) from step 2 in 4:1 mixture of MeOH/water (2 mL) was added 2M solution of NaOH (124 uL 0.25 mmol). Reaction mixture was heated at 50° C. for 16 h. Solvent was removed in vacuo, residue was dissolved in water and pH was adjusted to 4-5 with 1M HCl solution. Then product was extracted with EtOAc, washed with water, brine, dried over anhydrous MgSO4 and concentrated to give the title compound (9.5 mg, 11%): MS; m/z 423.8 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.20-1.30 (m, 2H), 1.82-2.25 (m, 6H), 2.73 (t, 2H, J=7.2 Hz), 3.17 (br, 2H), 3.75 (br, 1H), 4.21-4.27 (m, 2H), 7.01 (dd, 2H, J1=6.8 Hz. J2=2.4 Hz), 7.07-7.08 (m, 4H), 7.59 (s, 1H), 7.71 (dd, 2H, J1=6.8 Hz, J2=2.4 Hz), 8.41 (s, 1H); HPLC (UV); 86%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CO>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]=[O:10])=[C:6]([NH:17][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:7]=1
Reactant: CCCCCN
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Solvent: CO
Product: CCCCCNc1nc(N)nc(Cl)c1C=O

Procedure:
A mixture of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (30 g), pentylamine (18.5 ml) and TEA (22 ml) in MeOH (600 ml) were heated under reflux for 3 h then partitioned between EtOAc/water. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with ether/iso-hexane to afford the subtitle compound, 20 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=2)[CH:13]=O)[CH:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH2:13][C:12]2[CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(-c2ccnc(Cl)n2)cc1C=O
Product: COc1ccc(-c2ccnc(Cl)n2)cc1CNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Intermediate 86 was coupled with 4-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product was >95% pure and had the expected M+H+ of 433.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)[CH:14]=[CH:13][C:12]=2[O:25][CH3:26])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.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>[CH3:24][C@H:19]1[NH:20][C@@H:21]([CH3:23])[CH2:22][N:17]([C:15]2[CH:14]=[CH:13][C:12]([O:25][CH3:26])=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[F:27])=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=2)[CH2:18]1
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccccc2F)s1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-thiophenesulfonamide (E122) (150 mg, 0.33 mmol) and (2-fluorophenyl)boronic acid (91 mg, 0.65 mmol) in DME (3 ml) was added potassium tert-butoxide (329 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.033 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then reduced in vacuo, azeotroped with toluene (×3) and purified using SCX then mass directed autoprep HPLC to afford the title product (E124). MS (ES+) m/e 476 [M+H]+.