Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[CH:11]=[N:10][CH:9]=[N:8][C:7]=2[NH:6][CH:5]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:6]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[C:4]([Br:3])=[CH:5]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Brc1c[nH]c2ncncc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(Br)c2cncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To suspension of NaH (60% in mineral oil, 34 mg, 0.85 mmol) in DMF (1.5 mL) at 0° C. under nitrogen atmosphere was added a solution of 5-bromo-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.71 mmol) in DMF (1.5 mL). The reaction mixture was stirred at 0° C. for 30 min and tert-butyl bromoacetate (104 μL, 0.71 mmol) was slowly added. The mixture was further stirred at RT for 30 min, then poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. MS (UPLC/MS): 312.3/314.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C(=O)([O-])O.[Na+].[C:16](Cl)(Cl)=[S:17]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:16]=[S:17])=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N=C=S)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 4-methoxy-2-methylaniline (2.51 mL, 19.7 mmol) and saturated aqueous sodium hydrogen carbonate (13.5 ml) in tetrahydrofuran (13.5 mL) was added thiophosgene (1.50 mL, 19.7 mmol), and the mixture was stirred at 0° C. for 30 min. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-10% ethyl acetate/n-hexane gradient mixture. The desired fractions were concentrated in vacuo to give the title compound as a colorless oil (2.80 g, 15.6 mmol, 79%).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:37]1([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([S:44]([CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:46])=[O:45])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=S(=O)(Cc1ccccc1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.7 mg) obtained in Example 25 and α-toluenesulfonyl chloride (17.2 mg) were reacted and treated in the same manner as in the method described in Example 30 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([NH:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:8]([CH3:9])[C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([NH:24][CH3:25])=[O:23])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CNC(=O)c1ccc(C)c(N)c1
Reactant: CN(CC(C)(C)C)c1ncnc(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
(6-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-methyl-amine (1.0 mmol) was dissolved in p-dioxane (2 mL), and 3-amino-4,N-dimethyl-benzamide (0.2 g, 1.2 mmol) and DIEA (0.3 mL) were added. The resulting mixture was heated to 80° C. for overnight. The product (0.31 g, yield 80%) was purified by column silica gel chromatography. MS (m/z): 387 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][NH:23][C:24](=[NH:26])[CH3:25])=O)=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[NH:26][C:24]([CH3:25])=[N:23][N:22]=4)=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(=N)NNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)ccc2C)cc1
Solvent: Cc1ccccc1C
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)[nH]1

Procedure:
N-Cyclopropyl-4′-[(2-ethanimidoylhydrazino)carbonyl]-6-methyl-1,1′-biphenyl-3-carboxamide (intermediate 46) (80 mg) in xylene (15 ml) was heated at 190° C. under Dean-Stark conditions for 4 hours. The xylene was decanted from the precipitated solid and the solid washed with cyclohexane. The solid was applied to a bond-elut (silica) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvents under vacuum, N-cyclopropyl-6-methyl-4′-(5-methyl-1,3,4-triazol-2-yl)-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:25])([CH3:24])[C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:20]([CH3:25])([CH3:24])[CH:21]=[CH:22][C:23]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCC2=C1C=CC2(C)C
Product: CC1C2=C(CCN1C(=O)c1cc3ncc(Br)cn3n1)C(C)(C)C=C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-[2]pyrindine to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:11]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)c(Cl)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,5-dichloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(Br)(C)=O.[CH:5]([C:8]1[C:9]([C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10][C:11]([O:16]C)=[N:12][C:13]=1[O:14]C)([CH3:7])[CH3:6]>>[CH:5]([C:8]1[C:13](=[O:14])[NH:12][C:11](=[O:16])[NH:10][C:9]=1[C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH3:7])[CH3:6]
Reactant: COc1nc(OC)c(C(C)C)c(-c2cnc3ccccc3c2)n1
Agent: CC(=O)Br
Product: CC(C)c1c(-c2cnc3ccccc3c2)[nH]c(=O)[nH]c1=O
Temperature: 70 °C
Yield: 47.4 %

Procedure:
In a 10 mL round bottom flask, 1 mL AcBr was added to 3-(5-Isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-quinoline (14 mg, 0.045 mmol). The reaction mixture was heated at 70° C. for 2 hours. The reaction mixture was concentrated down and purified by reverse phase prep HPLC (MeCN/water) to give a white powder (6 mg, 47%). LC-MS shows 280.3 (M−1).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[NH:16][C:15](=[O:21])[N:14]([CH2:22][CH2:23][CH3:24])[C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.CCN(CC)CC>CS(C)=O.CCOC(C)=O>[O:21]=[C:15]1[N:14]([CH2:22][CH2:23][CH3:24])[C:13]2[N:12]=[C:11]([C:6]34[CH2:7][CH2:8][C:3]([CH:2]=[O:1])([CH2:10][CH2:9]3)[CH2:4][CH2:5]4)[NH:19][C:18]=2[C:17](=[O:20])[NH:16]1
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc21
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-3-propyl-3,7-dihydro-purine-2,6-dione (2.70 g, 8.13 mmol) was dissolved in 40 mL of DMSO. Pyridine-SO3 (3.88 g, 3 eq) was added, followed by Et3N (7.4 mL, 7 eq) at rt. The resulting reaction mixture was stirred at rt for 18 h. It was then diluted with EtOAc and washed with 5% aq citric acid, H2O, brine, dried (Na2SO4) and concentrated under reduced pressure to afford 900 mg of the desired aldehyde.
Reaction SMILES: C[O-].[Na+].[C:4](=O)(OC)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH:14]=[O:15])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH:25]1[CH:30]=[CH:29][C:28](CBr)=[CH:27][CH:26]=1>CO.O>[CH2:4]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH:7]=1)[CH:14]=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)Oc1ccc(OC)c(C=O)c1
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(OCc2ccccc2)cc1C=O
Reaction time: 0.75 h
Yield: 98 %

Procedure:
To a stirred solution of sodium methoxide (257 mg. 4.8 mmol) in MeOH (20 mL) at room temperature was added 3-formyl-4-methoxyphenyl methyl carbonate (6, 1.0 g, 4.8 mmol). The resulting orange solution was stirred for 45 min and concentrated to dryness. The residue was dissolved in DMF (2 mL) and treated with K2CO3 (1.3 g, 9.4 mmol) and BnBr (0.57 mL, 4.8 mL). The reaction mixture was stirred for 15 h and it was poured into water (20 mL). The precipitate was collected, washed with water and dried in vacuo to afford the title compound (1.13 g, 98%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.44 (s, 1H), 7.49-7.41 (m, 3H), 7.40-7.36 (m, 2H), 7.35-7.30 (m, 1H), 7.21 (dd, J=9.1, 3.2 Hz, 1H), 6.95 (d, J=9.1 Hz, 1H), 5.05 (s, 2H), 3.90 (s, 3H); ESI MS m/z 243 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[C-:35]#[N:36].[Na+]>CS(C)=O>[CH3:33][Si:31]([CH3:34])([CH3:32])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:11][CH2:12][C@H:7]([CH2:6][C:35]#[N:36])[CH2:8][CH2:9]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: [C-]#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Agent: [Na+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CC#N)CC4)c3)ncnc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) and sodium cyanide (0.050 g, 0.0010 mol) and DMSO (1.0 mL) were mixed. The mixture was stirred at 60° C. for 24 hours, at which time LCMS analysis showed most of the starting material had been consumed. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 437, 1H NMR(CDCl3): δ 8.90 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.43 (m, 1H), 3.60 (m, 2H), 2.45 (d, 2H, J=7.6 Hz), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)Cl.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>CCOC(C)=O.O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C(Cl)CCCCBr
Reactant: OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(CCCCBr)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a dry, nitrogen purged 100 mL round bottomed flask was added benzyl alcohol (2.98 g, 0.027 mol), triethylamine (2.79 g, 0.027 mol) and CH2Cl2 (50 mL). The solution was stirred and cooled to 0° C. and 5-bromovaleryl chloride (5.00 g, 0.025 mol) added dropwise. A white suspension formed and this mixture was stirred at 0° C. for 0.5 h then warmed to rt over 1 h. After stirring at rt for 15 h, the suspension was poured into water (100 mL) and the phases separated. The aqueous layer was extracted with CH2Cl2 (1×100 mL) and the combined CH2Cl2 layers were dried over Na2SO4. Filtration and concentration produced a light brown suspension, which was diluted with EtOAc (50 mL) and then re-filtered. After concentration, the resulting amber oil was chromatographed on silica gel using 10% EtOAc in hexanes to give 6.79 g (100%) of Preparation 12 as a clear, colorless oil. Rf=0.80 (SiO2, 50% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3): δ=7.33 (m, 5H), 5.11 (s, 2H), 3.38 (t, J=6.5 Hz, 2H), 2.38 (t, J=7.0 Hz, 2H), 1.88 (m, 2H) and 1.79 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCCC2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCCC2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.5 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(1-piperidinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 14) (334 mg, 0.77 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a beige solid (266 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([N:16]([CH3:17])[CH3:15])=[O:13])=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COc1ccc(NCC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(NCC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a stirred suspension of 2-((4-methoxyphenyl)amino)acetic acid (18) (45 g, 0.25 mol) and dimethylamine hydrochloride (40.5 g, 0.5 mol) in acetonitrile (1 L) at 0° C., was added DIPEA (174 ml, 0.99 mol) followed by HATU (99 g, 0.26 mol). The reaction mixture was stirred at RT for 1 h, and then partitioned between EtOAc (1 L) and 5% NaH2PO4 (aq.) (250 mL), the organic layer was washed with sat. NaHCO3 (aq.) (3×300 mL), and 3M HCl (aq.) (4×250 mL). The combined acidic extracts were cooled to 0° C. and solid NaOH was added to pH 14 and the aqueous phase was extracted with EtOAc (3×400 mL), the combined organics were washed with brine (500 mL) dried (MgSO4), filtered and solvents removed in vacuo to give 2-((4-methoxyphenyl)amino)-N,N-dimethylacetamide (19) (37.1 g, 71%) as a brown solid: m/z 209 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 6.74-6.70 (m, 2H), 6.65-6.59 (m, 2H), 5.10 (br s, 1H), 3.81 (s, 2H), 3.64 (s, 3H), 3.01 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][N:8]=1>CCOC(C)=O>[NH2:1][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][N:8]=1
Reactant: FC(F)(F)COc1ccc(CBr)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCc1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C
Yield: 54.6 %

Procedure:
Dissolve sodium azide (270 mg, 4.0 mmol) in DM (30 mL). Cool the solution to 0° C., then add 2-bromomethyl-5-(2,2,2-trifluoroethoxy)-pyridine (440 mg, 1.6 mmol) at 0° C. Slowly heat the mixture from 0° C. to 80° C. over 30 min. Cool the reaction, dilute with EtOAc (100 mL) and wash with 10% aqueous NaCl (3×25 mL). Collect the organic layer and concentrate in vacuo to a volume of 50 mL. Transfer the solution to a pressure vessel. Add 10% Pd/C (Degussa type E101, 50% water by wt, 500 mg) and pressurize the vessel under hydrogen (10 psi) for 1 h with stirring. Filter the mixture through Celite® and wash filter cake with warm methanol followed by DCM. Concentrate in vacuo, then purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound (180 mg, 54%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][CH:12]=C)[C:6]=2[CH:14]=1.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][CH:12]=[O:16])[C:6]=2[CH:14]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)sc2ccc(Cl)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-chloro-3-(2-propen-1-yl)-1,3-benzothiazol-2(3H)-one (0.43 g, 1.9 mmol) (0.43 g, 1.9 mmole) was dissolved in 1,4-dioxane (20 ml) and water (22 ml) was added. Sodium periodate (0.94 g, 4.4 mmol) was added followed by 4% osmium tetroxide in water (2.1 ml) and stirred at rt for 30 mins after which time a heavy precipitate had formed. Water (20 ml) was added followed by more sodium periodate (1.9 g, 8.9 mmol) and the mixture stirred at rt for 18 h. The mixture was concentrated in-vacuo to a small volume and partitioned between water (50 ml) and DCM (2×50 ml). The organics were separated and dried. Chromatography on silica gel eluting with a gradient of 25-100% ethyl acetate/40-60 petroleum ether gave 0.21 g, 48%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[S:14][C:15]([C:18](O)=O)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:35][C:36]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([NH2:40])=[O:39]>N1C=CC=CC=1.CN(C=O)C>[C:38]([C:37]1[C:36]2[N:35]=[C:18]([C:15]3[S:14][C:13]([C@H:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:17][CH:16]=3)[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)(=[O:39])[NH2:40]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(C(=O)O)s1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 16B (2.4 g) in pyridine (20 mL) and DMF (20 mL) was added CDI (1.6 g), and the mixture was stirred at 40° C. for 1 hour. 2,3-Diaminobenzamide dihydrochloride (1.8 g) was added, and the mixture stirred at ambient temperature overnight and concentrated. The concentrate was stirred in of acetic acid (20 mL) at 80° C. for 4 hours and concentrated. The concentrate was partitioned between ethyl acetate and saturated sodium bicarbonate solution, and the extract was washed with water and concentrated. The concentrate was purified by flash chromatography on silica gel with 40-80% ethyl acetate in hexane.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:29]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:29])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Fc1cc(F)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1
Solvent: ClC(Cl)Cl
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of yellow mercuric oxide (0.74 g, 0.036 mol), N-[3-(2,4,6-trifluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.27 g, 0.003 mol) and methanolic ammonia solution (40 ml) was stirred for 1 day at room temperature. The solvent was removed-in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent, trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 0.63 g (52%), m.p. 161°-162 ° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7](/[CH:10]=[CH:11]/[C:12](OC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7](/[CH:10]=[CH:11]/[CH2:12][OH:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C/C(=O)OC)n1Cc1ccccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCc1ncc(/C=C/CO)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-propenoate (Example 11, Method A) (0.5 g, 1.5 mmol) in dry tetrahydrofuran (10 mL) held at -78° C. under argon was treated dropwise with a solution of diisobutyl aluminum hydride in toluene (3.30 mmol, 2.2 mL of 1.5 M). The mixture was allowed to warm to ambient temperature and stirred an additional 17 hours. Excess reducing agent was quenched with methanol and water, dilute acetic acid and methylene chloride were added, and the organic layer was washed with sodium bicarbonate solution, dried and concentrated to 0.507 g of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH:7]([CH3:11])[C:8](Cl)=[O:9].[Cl-].[NH4+]>ClCCl>[Br:6][CH:7]([CH3:11])[C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: CC(Br)C(=O)Cl
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(Br)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
Pyrrolidine (0.12 mol, 8.3 g) was added to stirred solution of 2-bromopropanoyl chloride (0.58 mol, 10 g) in dichloromethane (200 ml) at 0° C. After 0.5 hour, the reaction mixture was warmed to room temperature, stirred for 2 hours, and saturated ammonium chloride solution (20 ml) was added. The solvent was evaporated and the mixture was extracted with ethyl acetate (200 ml). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=55:1) to give 2-bromo-1-(pyrrolidin-1-yl)propan-1-one (9.8 g, 93%). LCMS (M+H+) m/z: calcd 205.01. found 205.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH2:39][CH3:40])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([Br:29])[CH:31]=[CH:32][C:33]=3[O:38][CH2:39][CH3:40])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOc1ccc(Br)cc1C=O
Product: CCOc1ccc(Br)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 5-bromo-2-ethoxy benzaldehyde. MS (ESI) m/z 591.