Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(C1[CH:27]=[N:28]C(N2CCC(OC3C=CNC(=O)C=3)CC2)=NC=1)C.[F:46][C:47]1[CH:52]=[CH:51][C:50](S(C)(=O)=O)=[CH:49][C:48]=1[F:57]>>[F:46][C:47]1[C:48]([F:57])=[C:49]([N:20]2[CH:21]=[CH:22][C:17]([O:16][CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=4)[CH2:11][CH2:12]3)=[CH:18][C:19]2=[O:23])[CH:50]=[CH:51][C:52]=1[C:27]#[N:28]
Reactant: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(C#N)c(F)c4F)c(=O)c3)CC2)nc1

Procedure:
Example 253 was prepared according to procedures described in Example 248 substituting 4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (prepared according to procedures described in Example 173 Step C) for 4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one and substituting 2,3,4-trifluorobenzonitrile (Oakwood) for 1,2-difluoro-4-(methylsulfonyl)benzene. 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (s, 2 H), 7.35-7.53 (m, 1 H), 7.21-7.35 (m, 1H), 7.03 (d, J=7.03 Hz, 1 H), 6.01 (dd, J=7.65, 2.64 Hz, 1H), 5.93 (d, J=2.51 Hz, 1H), 4.43-4.54 (m, 1 H), 4.05-4.19 (m, 2 H), 3.50-3.66 (m, 2 H), 2.34 (t, J=7.53 Hz, 2 H), 1.93-2.11 (m, 2 H), 1.72-1.83 (m, 2 H), 1.42-1.56 (m, 2H), 0.87 (t, J=7.28 Hz, 3 H). MS (ESI) 452 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[NH2:29][C@H:30]([C:36]([OH:38])=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][NH2:35].[CH3:39][P:40]([NH2:43])(=[O:42])[O-:41].C([N:47]([CH:50](C)C)CC)(C)C>CN(C=O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[NH2:29][C@H:30]([C:36]([OH:38])=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:50]([NH2:47])=[NH:43].[CH3:39][P:40]([NH2:43])(=[O:41])[O-:42]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CP(N)(=O)[O-]
Solvent: CN(C)C=O
Product: N=C(N)NCCCC[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of (15) (0.131 g, 0.216 mmol) stirring at room temperature under argon in anhydrous DMF (2.0 ml), 1-H-pyrazole-1-carboxamidine. HCl (32 mg, 0.216 mmol) was added followed by diisopropylethylamine (28 ml, 0.216 mmol). The reaction mixture was stripped slightly on a rotovap then rotated overnight without vacuum at room temperature. After removing DMF in vacuo the reaction residue was dissolved in dichloromethane and applied to a flash silica gel column. An isocratic system of 20% MeOH/dichloromethane, 2% NH4OH followed by treatment with Dowex OH− (300 mg) in MeOH gave 80 mg of desired product (yield, 57%). P NMR (s, 31.99 ppm), mass spec. calcd=648.91, found=649.48.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:35])[CH:32]=4)[C:27]([S:42][CH3:43])=[CH:26]3)=[N:23][CH:24]=2)=[CH:15][CH:14]=1>ClCCl.CN(C=O)C.ClCCl>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[N:23][C:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:35])[CH:32]=4)[C:27]([S:42]([CH3:43])=[O:6])=[CH:26]3)=[N:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: CSc1cn(-c2ncc(-c3ccc(O)cc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3ccc(O)cc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 1 h

Procedure:
m-Chloroperoxybenzoic acid (134 mg, 0.5022 mmol, 0.8 eq) was added at 0° C. to a stirred solution of 86a) (280 mg, 0.6278 mmol, 1.0 eq) in dichloromethane/DMF (10:1; 22 mL) and the solution was stirred for 1 h at this temperature. The reaction mixture was then diluted with dichloromethane (20 mL), washed with saturated sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvents were removed under vacuum and the residue was purified by preparative TLC using ethyl acetate as eluent. White solid. Yield: 65 mg (21% of theory)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=1[CH3:25]>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=3[CH3:25])=[CH:8][C:7]1=2
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
Prepared according to Procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 5-bromo-4-methyl-2-thiophenecarbonitrile. Off-white solid: mp 195-200° C. 1H-NMR (DMSO-d6) δ10.2 (s, 1H), 8.32 (s, 1H), 7.41-7.44 (m, 2H), 7.01 (d, 1H, J=8.8 Hz), 2.28 (s, 3H), 1.64 (s, 6H); MS (APCI) m/z 299 [M+H]+. Anal. Calc. For C16H14N2O2S; C, 64,41; H, 4.75; N, 8.89. Found: C, 64.64; H, 4.62; N, 9.39.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C@H:4]1[CH3:23].[C:24]([N:31]([CH3:37])[C@H:32]([C:34](O)=[O:35])[CH3:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[CH3:37][N:31]([C@@H:32]([CH3:33])[C:34]([NH:2][C@H:3]1[C@H:4]([CH3:23])[N:5]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[NH:8][C:9]1=[O:10])=[O:35])[C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29]
Reactant: C[C@H]1[C@H](N)C(=O)Nc2ccccc2N1C(=O)C1CCOCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a room temperature solution of (3S,4S)-3-amino-4-methyl-5-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one hydrochloride (173 mg, 509 μmol) in N,N-dimethylformamide (2 ml) was added Boc-N-methyl-L-alanine (114 mg, 560 μmol), N,N-diisopropylethylamine (440 μl, 2.55 mmol), and HBTU (212 mg, 560 μmol). The reaction was stirred at room temperature for 2 h. After this time, the reaction was diluted with ethyl acetate (20 mL), washed with a saturated aqueous sodium bicarbonate solution (20 mL) and the aqueous layer was then extracted with ethyl acetate (3×10 mL) and the combined organics were washed with a saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and the filterate concentrated in vacuo. The crude material was purified using an Initelliflash 280 system (4 g silica gel column Varian brand, 20-90% ethyl acetatehexanes) to afford tert-butyl methyl((S)-1-((2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (238 mg, 96%): LC-MS m/z 487 [M−H]−.
Reaction SMILES: [OH2:1].S(=O)(=O)(O)[OH:3].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#N)=[CH:13][CH:14]=2)[CH:9]=[N:8]1>C(O)(=O)C>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:3])=[O:1])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: O=S(=O)(O)O
Reactant: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]ncc2c1
Temperature: 100 °C
Yield: 88 %

Procedure:
Water (20 ml) and concentrated sulfuric acid (20 ml) were added to a solution of 1H-indazole-5-carbonitrile (3.00 g, 20.1 mmol) in acetic acid (20 ml) at room temperature, and the resulting mixture was heated at 100° C. for 3 hours. Then, the reaction solution was poured onto ice and the solid precipitated was collected by filtration and dried under reduced pressure to obtain 1H-indazole-5-carboxylic acid (2.88 g, 88%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[C:14]([CH3:32])[N:13]=1>C1COCC1.CCOC(C)=O>[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([CH2:24][OH:25])=[CH:22][C:21]=2[O:30][CH3:31])=[C:14]([CH3:32])[N:13]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1Cl
Temperature: 25 °C

Procedure:
A solution of diisobutylaluminium hydride (1M in hexanes, 5.44 mL) was added over 10 min to a suspension of the product from example 21 step (iii) (0.5 g) in THF (10 mL) at 0° C. The mixture was allowed to warm to rt and stirred for Ih. EtOAc (10 mL) was added cautiously and then the reaction mixture was added to ice/water (100 mL). The mixture was stirred for 30 min and then diluted with EtOAc (50 mL). The organic phase was separated and the aqueous was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to afford the subtitle compound, 0.39 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C2C=C3C4([C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[NH:35]C4=O)COC3=CC=2ON=1.Br.BrCC1C=CC=CN=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:37][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:35]=1)[C:10]3=[O:18]
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: Br
Agent: BrCc1ccccn1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6-methoxy-1′-(pyridin-2-ylmethyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one was obtained (67%) as a colorless solid: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.63 (dd, J=7.8, 7.8 Hz, 1H), 7.32-7.09 (m, 3H), 7.0 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.65 (d, J=7.8 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.36 (dd, J=7.8, 2.1 Hz, 1H), 5.18 (d, J=15.9 Hz, 1H), 4.98 (d, J=15.9 Hz, 1H), 5.00 (d, J=8.7 Hz, 1H), 4.72 (d, J=8.7 Hz, 1H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 162.1, 161.5, 155.5, 149.4, 142.1, 137.0, 132.3, 128.7, 123.7, 123.6, 123.4, 122.7, 121.5, 120.8, 109.4, 107.5, 96.5, 80.4, 57.6, 55.5, 46.0; MS (ES+) m/z 359.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH:7]([NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:29])[C:15]=2[C:14]([NH2:30])=[CH:13][CH:12]=1)([CH3:9])[CH3:8].C(N(CC)CC)C.CO>CN1CCCC1=O>[CH:7]([NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:29])[C:15]=2[C:14]([NH:30][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:13][CH:12]=1)([CH3:9])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Nc1ccc(N)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)Nc1ccc(NC(C)C)c2c1C(=O)c1c(cccc1[N+](=O)[O-])C2=O

Procedure:
5 ml of chloroformic acid ethyl ester are added dropwise to 10 g of 1-isopropylamino-4-amino-5-nitroanthraquinone in 50 ml of N-methylpyrrolidone at room temperature. 4 ml of triethylamine are then added dropwise and the mixture is stirred further, finally for a short time at 30°-40° C, until only small amounts of starting material remain detectable. After working up with methanol, 1-isopropylamino-4-ethoxycarbonylamino-5-nitroanthraquinone is obtained.
Reaction SMILES: C(OC([C@H:8]1[NH:13][C:12]([CH3:18])([C:14]([NH:16][NH2:17])=[O:15])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20])=O)(C)(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=O)[CH:25]=[CH:26][CH:27]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.CC[N:44](CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]2[O:15][C:14]([C@@:12]3([CH3:18])[NH:13][C:8](=[NH:44])[N:9]([CH3:20])[C:10](=[O:19])[CH2:11]3)=[N:16][N:17]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CN1C(=O)CC(C)(C(=O)NN)N[C@@H]1C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Reactant: O=C=Nc1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CN1C(=N)N[C@](C)(c2nnc(Nc3cccc(Cl)c3)o2)CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide (CY1, R6=Me, 0.030 g, 0.10 mmol) in DCM (0.25 mL) was added 3-chlorophenylisocyanate (0.015 mL, 0.20 mmol, 2 eq). The mixture was stirred at RT for 3 h and volatiles were then removed in vacuo. The residue was treated with TsCl (0.020 g, 0.10 mmol, 1 eq), Et3N (0.083 mL, 0.60 mmol, 6 eq), and DMAP (0.002 g, 0.016 mmol, 0.16 eq) in DCM (0.25 mL) at RT for 16 h. The mixture was diluted with DCM (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was treated with 30% TFA/DCM (1 mL) at RT for 1 h. The mixture was concentrated in vacuo and the residue was purified on reverse phase HPLC (B) to give 0.006 g (10%) of (S)-6-(5-(3-chlorophenylamino)-1,3,4-oxadiazol-2-yl)-2-imino-3,6-dimethyl-tetrahydropyrimidin-4(1H)-one (DA1; R6=Me). 1HNMR (CD3OD, 300 MHz): 7.78 (t, 1H), 7.47 (m, 2H), 7.17 (dt, 1H), 3.53 (m, 2H), 3.36 (s, 3H), 1.78 (s, 3H). MS (ESI): MH+=335.3, HPLC (A) Rt=5.710 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][CH3:13])=[O:11].[C:14](CC(O)=O)#[N:15].C(O[C:24](=[O:26])[CH3:25])(=O)C>>[NH2:15][C:14]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10](=[O:11])[N:12]([CH3:13])[C:24](=[O:26])[CH:25]=1
Reactant: N#CCC(=O)O
Reactant: CNC(=O)Nc1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Product: Cn1c(=O)cc(N)n(-c2ccc(Cl)cc2Cl)c1=O
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 54 %

Procedure:
A solution of N-(2,4-dichlorophenyl)-N′-methyl-urea (12.0 g, 54.8 mmol) in acetic anhydride (100 mL) was treated with cyanoacetic acid (5.6 g, 65.8 mmol). The reaction mixture was heated at 85° C. for 2.5 h. Additional cyanoacetic acid (0.90 g, 11.0 mmol) was added and the reaction mixture was stirred for 45 min. A third portion of cyanoacetic acid (0.45 g, 5.5 mmol) was added and the reaction mixture was stirred for 30 min. Excess acetic anhydride was distilled off under reduced pressure at a temperature not higher than 70° C. The residue was treated with 20% aqueous sodium hydroxide (95 mL) in portions. During the addition a spontaneous increase in temperature (65–70° C.) occurred. The reaction mixture was heated at 60° C. for 1 h during which time the product precipitated. The reaction mixture was then cooled to 0° C. The precipitate was collected on a Buchner funnel, washed with cold water, and dried at 55° C. under vacuum. The crude product was triturated in hot toluene (stirred for 1 h at 110° C.), and the solid was immediately collected on a Buchner funnel then dried under vacuum to afford a pale yellow solid (8.46 g, 54% yield): mp 249–251° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.89 (d, J=1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 2H), 6.44 (s br, 1H), 4.79 (s, 1H), 3.09 (s, 3H); LRMS (APCI) m/e 286.0 [(M+H)+, calcd for C11H10N3O2Cl2 286.0].
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[N:26]=[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]2[CH:37]=1)C.[S:38]([O-:42])([O-])(=[O:40])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:38]([C:17]1[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=[CH:15][C:16]=1[C:25]1[N:26]=[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][N:28]2[CH:37]=1)(=[O:42])=[O:40])[CH3:11]
Reactant: CCSc1cc(C(F)(F)F)ccc1-c1cn2cc(C(F)(F)F)ccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1cn2cc(C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
436 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 236 mg of 2-(2-ethylsulfanyl-4-trifluoromethylphenyl)-6-trifluoromethyl-imidazo[1,2-a]pyridine and 5 ml of chloroform under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 122 mg of 2-(2-ethylsulfonyl-4-trifluoromethylphenyl)-6-trifluoromethyl-imidazo[1,2-a]pyridine (hereinafter, referred to as Compound of Present Invention 7).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:18]([C:10]1[CH:9]=[C:8]2[C:17]3=[C:16]4[C:5](=[CH:4][CH:3]=[C:2]([C:26]5[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=5)[C:15]4=[CH:14][CH:13]=[C:12]3[CH:11]=1)[CH:6]=[CH:7]2)([CH3:21])([CH3:19])[CH3:20]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1cc2ccc3ccc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
Then, a mixed solution of 106.9 g of 1-bromo-7-t-butylpyrene, 54.5 g of 4-chlorophenylboronic acid, 0.223 g of bis(triphenylphosphine)dichloropalladium, 350 ml of an aqueous 2M sodium carbonate solution and 1586 ml of 1,2-dimethoxyethane was heated and stirred for about 5 hours under a nitrogen stream and under refluxing. After the mixture was cooled to room temperature, 640 ml of water was added, and this was extracted with 1170 ml of toluene. The organic layer was washed with 640 ml of water two times, dried with magnesium sulfate, and evaporated, 270 ml of toluene and 1350 ml of methanol were added, and the mixture was stirred for about 2 hours, and filtered. After the resultant was vacuum dried, 105.16 g of 7-t-butyl-1-(4-chlorophenyl)pyrene was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=S)[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:20][NH2:21]>CO>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]([NH:20][NH2:21])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C1CN=C(c2ccccc2)c2ccccc2N1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC1=Nc2ccccc2C(c2ccccc2)=NC1

Procedure:
A stirred mixture of 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-thione (7.45 g., 0.03 mole) in methanol (300 ml.) was allowed to react with hydrazine hydrate (6.0 g., 0.12 mole) to give 5-phenyl-3H-1,4-benzodiazepin-2-yl hydrazine as an oil. A solution of thio material in tetrahydrofuran (75 ml.) was cooled in an ice bath and treated with a solution of chloroacetyl chloride (3.39 g., 0.03 mole) in tetrahydrofuran (25 ml.) to give 6.43 g. of chloroacetic acid, 2-(5-phenyl-3H-1,4-benzodiazepin-2-yl) hydrazide (A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])C)[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.F[C:33]1[CH:38]=CC(C2C=NC(N3CCN(S(CC4(C(O)=O)CCCCC4)(=O)=O)CC3)=NC=2)=C[CH:34]=1>>[OH:28][NH:27][C:25]([C:24]1([CH2:23][S:20]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][N:12]=3)[CH2:15][CH2:16]2)(=[O:21])=[O:22])[CH2:38][CH2:33][CH2:34][CH2:31][CH2:29]1)=[O:26]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Yield: 18 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 1-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}cyclohexanecarboxylic acid (0.241 g), to yield the title compound as a white solid (0.045 g, 18%).