Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:31](=[O:32])[N:5]2[C:6]([C:15]([O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[C:7](/C=C/C#CC)[CH2:8][S:9][C@H:4]12.[C:33]([CH2:36][O:37]/[N:38]=[C:39](/[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[S:46][CH:47]=1)\[C:40]([OH:42])=O)(=[O:35])[NH2:34].O.ON1[C:74]2[CH:75]=C[CH:77]=[CH:78][C:73]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(N(CC)CC)C>[C:33]([CH2:36][O:37]/[N:38]=[C:39](/[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[S:46][CH:47]=1)\[C:40]([NH:2][C@@H:3]1[C:31](=[O:32])[N:5]2[C:6]([C:15]([O:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])=[CH:7][CH:8](/[CH:75]=[CH:74]/[C:73]#[C:78][CH3:77])[S:9][C@H:4]12)=[O:42])(=[O:35])[NH2:34]
Reactant: On1nnc2ccccc21
Reactant: NC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC#C/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#C/C=C/C1C=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(N)=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2S1
Reaction time: 3 h
Yield: 54.1 %

Procedure:
A stirred solution of diphenylmethyl(6R,7R)-7-amino-3-[(E)-pent-1-en-3-ynyl]ceph-3-em-4-carboxylate, hydrochloride (432 mg) in tetrahydrofuran (10 ml) was treated with triethylamine (125 μl). (Z)-2-(Carbamoylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (441 mg), 1-hydroxybenzotriazole hydrate (162 mg) and N,N'-dicyclohexylcarbodiimide (248 mg) were added in that order. After 3 h, the precipitated N,N'-dicyclohexylurea was filtered off, the filtrate evaporated and the residue purified by column chromatography (60 g silica gel). Elution with ethyl acetate:dichloromethane (1:3) gave the title compound as a foam (441 mg); νmax (CHBr3) 3500, 3398 (NH2 +NH), 2215 (C≡C), 1786 (β-lactam), 1722 (CO2R), 1682, 1528 cm-1 (CONH); τ(CDCl3) 4.24 (CH=CH--C≡C), 5.33 (OCH2CONH2), 6.48, 6.60 (2-CH2), 8.02 (C≡CCH 3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([CH3:12])[C:3]=1[Cl:13].[Cu](C#N)[C:15]#[N:16].O>CN(C=O)C>[Cl:13][C:3]1[C:4]([CH3:12])=[C:5]([CH2:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: N#C[Cu]C#N
Reactant: Cc1c(CC(N)=O)ccc(Br)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CC(N)=O)ccc(C#N)c1Cl
Temperature: 150 °C
Yield: 67 %

Procedure:
A suspension of bromide 4B (2.70 g, 10.3 mmol) and copper cyanide (0.92 g, 10.3 mmol) in DMF (30 mL) was heated to 150° C. for 4 h. The suspension was cooled, poured into water with stirring, and the solid was filtered and dried to give 1.44 g (67%) of the desired nitrile. 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 2.29 (s, 3H), 7.72 (d, J=8.8, 1H), 7.75 (d, J=8.2, 1H), 9.73 (s, 1H); 13C NMR (DMSO-d6) δ 15.3, 23.5, 107.7, 116.5, 123.0, 130.1, 131.5, 135.7, 142.3, 168.8; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.23 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.13 min retention time (95%); MS (ES) m/z 209 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH:3]([O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1)[C:4]([O:6]CC1C=CC=CC=1)=[O:5].C(O)(=O)C.[H][H]>[C].[Pd].C(O)C>[CH3:1][C:2]([CH3:26])([CH3:25])[CH:3]([O:14][C:15]1[N:16]=[C:17]([O:23][CH3:24])[N:18]=[C:19]([O:21][CH3:22])[N:20]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: COc1nc(OC)nc(OC(C(=O)OCc2ccccc2)C(C)(C)C)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(OC)nc(OC(C(=O)O)C(C)(C)C)n1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
4.5 g of benzyl 3,3-dimethyl-2-(4,6-dimethoxy-S-triazin-2-yl)oxybutyrate and 0.5 g (10%) of palladium carbon wetted with 2 ml of acetic acid were added to 100 ml of ethanol. 257 ml of hydrogen was added thereto at room temperature under stirring. The reaction solution was subjected to filtration, and the filtrate was extracted twice with 200 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.1 g of the desired product.
Reaction SMILES: O=[C:2]1[N:13]2[C:14]3[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=[C:3]1[C:15](OCC)=O.CO[CH2:22][N:23](CC1C=CC=CC=1)C[Si](C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:44]>>[ClH:44].[ClH:44].[CH:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][CH2:12][N:13]3[C:14]=2[C:5]=1[C@@H:4]1[CH2:22][NH:23][CH2:15][C@@H:3]1[CH2:2]3
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: ClCCl
Reactant: CCOC(=O)c1cc2cccc3c2n(c1=O)CCC3
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1cc2c3c(c1)[C@@H]1CNC[C@@H]1CN3CCC2
Temperature: 40 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a solution of ethyl 5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylate (25.0 g, 97 mmol) in 400 mL of methylene chloride was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (46.1 g, 194 mmol) and trifluoroacetic acid (2.22 g, 19 mmol). The reaction mixture was stirred at 40° C. for 24 h. The reaction mixture was allowed to cool and was washed with sat'd aq. NaHCO3 and brine, dried (K2CO3) and concentrated in vacuo. The residue was purified by recrystallization from 4:1 hexane/ethyl acetate to afford 36.6 g (96%) of the title compound of Part B as an off white solid. 1H NMR (CDCl3) δ: 7.37-7.20 (m, 5H), 7.05-7.00 (m, 1H), 6.97-6.88 (m, 2H), 4.28-4.19 (m, 1H), 4.12-4.01 (m, 2H), 3.80-3.68 (m, 4H), 3.57 (ABq, 2H, JAB=10.2 Hz), 3.17 (app t, 1H, J=8.8 Hz), 2.85-2.77 (m, 2H), 2.49 (app t, 1H, J=9.5 Hz), 2.05-1.95 (m, 2H), 1.09 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]([OH:16])=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:22]=[O:23].O>C1COCC1>[OH:23][CH2:22][C:12]1([C:14]([OH:16])=[O:15])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: C=O
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(CO)c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
9-fluorene carboxylic acid (4.98 g, 23.7 mmol) and anhydrous THF (300 ml) were introduced into a flame-dried reaction vessel in which the atmosphere had been replaced by nitrogen, the reaction solution was cooled to −78° C., and n-butyl lithium (41.0 ml of 1.6M hexane solution, 71.0 mmol) was added. After stirring the reaction solution at −78° C. for 30 minutes, paraformaldehyde (2.30 g, 75.0 mmol) dissolved in anhydrous THF (100 ml) was added at −78° C., and stirred at room temperature for 13 hours. Distilled water was added, the solution was extracted with ether, and the pH of the aqueous layer was adjusted to 2 using 1N hydrochloric acid. It was then extracted again with chloroform, and the organic layer was dried by anhydrous magnesium sulfate. The low-boiling fraction was distilled under reduced pressure with the rotary evaporator, and 4.21 g of crude product was thus obtained. The methylene chloride-insoluble fraction of this crude product was collected, and the target compound (4.60 g, 19.3 mmol, 80.5%) was thus obtained. 1H-NMR (500 MHz, CDCl3) d: 7.78 (d, J=7.5, 2H), 7.67 (d, J=7.5, 2H), 7.46 (dd, J=7.0, 2H), 7.54 (dd, J=8.0, 2H), 4.02(s, 4H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[CH2:14]([O:16][C:17](=[O:26])[C:18]([C:24]#[N:25])=[C:19](OCC)[CH3:20])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[C:19]([CH3:20])=[N:3][N:2]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[C:24]=1[NH2:25])=[O:26])[CH3:15]
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cc(C(=O)O)ccc2C)c1N
Temperature: 65 °C
Yield: 87.9 %

Procedure:
To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 353 mg, 1.74 mmol, 1.0 eq) in 15 mL of ethanol were added 2-cyano-3-ethoxy-but-2-enoic acid ethyl ester (prepared as described by Xia et al., J. Med. Chem., 1997, 40, 4372) (319 mg, 1.746 mmol, 1.0 eq) and triethylamine (242 μL, 1.74 mmol, 1.0 eq) and the mixture was heated at 65° C. overnight. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel (loaded with CH2Cl2, and packed and eluted with gradient from 6/4 hexanes/EtOAc to elute byproducts followed by 8/2 EtOAc/hexanes and 8/2 EtOAc/MeOH to elute product) to provide the product as a brown solid (464 mg, 68%). HPLC (4 minute 10-95 gradient) tR 1.97 min; MS m/z 304.1 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](S(CC)(=O)=O)=[C:16]([C:25]#[N:26])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1.Br[C:28]1C=CC(CCCC(O)=O)=C(C)C=1.NC1C=C(C=CC=1)C#N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:25]#[N:26])[CH:15]=2)=[O:12])=[C:6]([CH3:28])[CH:7]=1
Reactant: Cc1cc(Br)ccc1CCCC(=O)O
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Agent: N#Cc1cccc(N)c1
Product: Cc1cc(Br)ccc1CCCC(=O)Nc1cccc(C#N)c1
Yield: 76 %

Procedure:
Using a procedure analogous to that used to prepare 6C, 55B (216 mg, 0.84 mmol) was reacted with 3-aminobenzonitrile to afford 55C (228 mg, 76%) as a solid. MS (ESI) m/z 358.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[SiH:11]([CH3:13])[CH3:12])[CH:2]=[CH2:3].[C:14]([Li])(C)([CH3:16])[CH3:15].BrCCC[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.[NH4+].[Cl-]>C1COCC1>[CH2:16]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH2:3][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:5]([SiH:11]([CH3:13])[CH3:12])[CH:6]=1)[CH:14]=[CH2:15]
Reactant: [Li]C(C)(C)C
Reactant: C=CCc1ccc(Br)cc1[SiH](C)C
Reactant: BrCCCOC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1ccc(CCCOC2CCCCO2)c([SiH](C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 1-allyldimethylsilyl-4-bromobenzene (1 Scheme 1, 1.3 g, 5 mmol) in dry THF (10 mL) at −78° C. was added t-butyllithium (3.0 mL, 1.7 M solution in pentane, 5.1 mmol) over a period of 5 min. After 30 min stirring at −78° C., 2-(3-bromopropoxy)tetrahydro-2H-pyran (850 μL, 5 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred further for 16 h. Concentrated NH4Cl (1 mL) was added to the solution, and the reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL) and brine (5 mL), and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:20 ethyl acetate/hexanes) to afford a colorless oil (621 mg, 39%). 1H NMR (300 MHz, CDCl3) δ 0.33 (s, 6 H), 1.52-1.94 (8H), 1.99 (m, 2 H), 2.77 (m, 2 H), 3.40-3.57 (m, 2 H), 3.78-3.96 (m, 2 H), 4.64 (m, 1 H), 4.88 (s, 1 H), 4.93 (d, J=8.7 Hz, 1 H), 5.82 (m, 1 H), 7.26 (d, J=7.8 Hz, 2 H), 7.49 (d, J=7.8 Hz, 2 H), 13C NMR (75 MHz, CDCl3) −3.1, 19.9, 24.1, 25.8, 31.1, 31.5, 32.8, 62.6, 67.1, 99.1, 113.6, 128.3, 134.0, 135.0, 135.7, 143.2; HRMS (EI) calcd for C19H30O2Si 318.2015, found 318.2009.
Reaction SMILES: [C:1]1([CH:7]([C:15]([OH:17])=[O:16])[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH3:19].[H-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[C:1]1([CH:7]([C:15]([OH:17])=[O:16])[N:8]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: O=C(O)C(NC(=O)C(F)(F)F)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)C(F)(F)F)C(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A mixture of 2-phenyl-N-(trifluoroacetyl)-glycine (2.5 g, 0.01 mol) and iodomethane (11.35 g, 0.08 mol) in tetrahydrofuran is treated portionwise with a 60% dispersion of sodium hydride in mineral oil (1.2 g, 0.03 mol NaH), stirred at ambient temperatures for 1 hour, heated at reflux temperature for 17 hours, cooled to room temperature, diluted with ethyl acetate followed by 1 mL of water and concentrated in vacuo to a wet yellow solid residue. The residue is dispersed in a mixture of ether and water. The ether layer is washed with a sodium bicarbonate solution. The aqueous phases are combined, acidified with 10% HCl and extracted with ethyl acetate. The ethyl acetate extract is washed sequentially with water, sodium thiosulfate and saturated sodium chloride solution, dried over MgSO4 and concentrated in vacuo to give a pale yellow solid which is recrystallized for methylcyclohexane to give the title compound as white crystals, 0.5 g, (19.1% yield), mp 124°-126° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC1(C)CC(CO)CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (1 g, 6.93 mmol) in DCM (5 mL) and pyridine (5 mL, 61.8 mmol) was added para-toluenesulfonyl chloride (1.586 g, 8.32 mmol) and DMAP (0.042 g, 0.347 mmol). The mixture was stirred for 18 hr at ambient temperature. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with water and DCM. The separated organic layer was washed with 0.2N aqueous HCl (1×), 1N aqueous HCl (2×), brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/hexane=0/100 to 50/50; 25 min] providing (R/S)-(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield: 2.05 g. LCMS (m/z): 299.1 [M+H]+; Retention time=0.96 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([N:25]3CCOC[CH2:26]3)=[N:23][CH:24]=2)O1.[CH3:32][O:33]C1C=CC2N=C(C3C=NC(N)=NC=3)SC=2C=1>CCCCCCC.CCOC(C)=O>[CH3:32][O:33][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][CH3:26])=[N:23][CH:24]=3)=[N:6][C:5]=2[CH:7]=1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Reactant: Brc1nc2ccccc2s1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1

Procedure:
2-Bromo-1,3-benzothiazole (100 mg, 0.47 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (163 mg, 0.56 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine. Flash chromatography (Heptane/EtOAc 1:1) furnished the title compound (73 mg) as an off-white solid. 1H NMR δ 8.81 (d, 1 H) 8.18 (dd, 1 H) 8.10 (d, 1H) 7.98 (d, 1 H) 7.54-7.48 (m, 1 H) 7.44-7.38 (m, 1 H) 7.00 (d, 1 H) 3.74-3.70 (m, 4 H) 3.65-3.60 (m, 4 H); MS m/z (M+H) 298.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[C:25]=1[F:33].C(=O)([O-])[O-].[NH4+:39].[NH4+].O.C(OCC)(=O)C>CS(C)=O>[NH2:39][C:26]1[C:25]([F:33])=[C:24]([CH:29]=[CH:28][C:27]=1[C:30]#[N:31])[C:23]([NH:22][C:3]1[C:4]([C:18]([F:20])([F:21])[F:19])=[CH:5][C:6]([C:8]([F:17])([C:13]([F:15])([F:14])[F:16])[C:9]([F:10])([F:12])[F:11])=[CH:7][C:2]=1[Br:1])=[O:34]
Reactant: N#Cc1ccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c(F)c1F
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c(F)c1N
Temperature: 100 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To a solution of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-4-cyano-2,3-difluorobenzamide in 5 ml of DMSO was added 49.0 mg of ammonium carbonate, followed by stirring 100° C. for 5 hours. To the reaction liquid were added water and ethyl acetate, and the organic layer was washed with water, and then and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=8:1→4:1) to prepare 0.30 g (yield 51%) of a target compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[N:28](COCC[Si](C)(C)C)[CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14](O)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Cl.[F:40][C:41]([F:46])([F:45])[C@@H:42]([NH2:44])[CH3:43]>>[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:44][C@@H:42]([CH3:43])[C:41]([F:46])([F:45])[F:40])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: C[C@H](N)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ccnc21
Agent: Cl
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1)C(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 34, Step 3 starting from 5-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylic acid and (2S)-1,1,1-trifluoropropan-2-amine hydrochloride. LCMS (M+H)+: m/z=496.1. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (br, 1H), 8.99 (s, 1H), 8.83 (d, J=9.3 Hz, 1H), 8.69 (d, J=1.4 Hz, 1H), 8.47 (s, 1H), 8.32 (d, J=5.6 Hz, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.67 (dd, J=3.3, 2.6 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 7.09 (dd, J=3.4, 1.7 Hz), 4.83 (d, J=10.0 Hz, 2H), 4.80 (m, 1H), 4.57 (d, J=9.6 Hz, 2H), 3.78 (s, 2H), 1.36 (d, J=7.2 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[C:16]1([CH:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH:22]([NH:24][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]=2[C:4]#[N:5])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(N)c1ccccc1
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Product: CC(Nc1cccc(-c2ccccc2)c1C#N)c1ccccc1
Temperature: 120 °C

Procedure:
The product of example 1a above, 2-fluoro-6-phenylbenzonitrile, (0.118 g, 0.6 mmol), and (+/−)-1-(phenyl)ethylamine (0.5 mL) were combined in a sealed tube that had been flushed with argon. The tube was heated in an oil bath to 120° C. for 18 hours. The reaction was not complete at this time, so the reaction was heated at 150° C. for an additional 48 hours. Flash chromatography on silica gel eluted with 0-3% ethyl acetate in hexane gave the title product. ES (+) MS m/e=299 (MH+)
Reaction SMILES: [C:1](N)(=O)C1C=CC=CC=1.[CH3:10][C:11]1[C:16]([C:17]([NH2:19])=[O:18])=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=[C:13]([S:29][CH3:30])[N:12]=1.[CH3:31][N:32]([CH:34]=O)[CH3:33]>>[CH3:31][N:32]([CH3:34])/[CH:33]=[CH:10]/[C:11]1[N:12]=[C:13]([S:29][CH3:30])[N:14]=[C:15]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=3)[CH:1]=[N:19][C:17](=[O:18])[C:16]=12
Reactant: CSc1ccc(Nc2nc(SC)nc(C)c2C(N)=O)cc1
Reactant: CN(C)C=O
Reactant: NC(=O)c1ccccc1
Product: CSc1ccc(-n2cnc(=O)c3c(/C=C/N(C)C)nc(SC)nc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of 4-methyl-2-(methylthio)-6-{[4-(methylthio)phenyl]amino}-5-pyrimidinecarboxamide benzamide (0.50 g, 1.57 mmol) in DMF (20 ml) was added dimethylormamide-dimethylacetal (0.56 g, 4.7 mmol), and the reaction mixture was stirred at 85° for 1.5 h. It was cooled to room temperature and DMF was removed under vacuum. The residue was chromatographed (silica gel, eluting with hexane to ethyl acetate gradient followed by 10% methanol in methylene chloride) to yield the product (0.43 g, 72% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>CC(CC)=O>[Br:1][C:2]1[C:7]([O:8][CH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: C[C@@H](CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C[C@@H](CO)COc1cccnc1Br
Temperature: 100 °C
Yield: 80 %

Procedure:
2-bromo-3-pyridinol (230 mg) and potassium carbonate (216 mg) was dissolved in methylethylketone (10 ml) and reacted for 30 minutes. Then, (S)-3-bromo-2-methyl-1-propanol (0.21 ml) was added to the solution and refluxed for 3 hours at 100° C. Potassium carbonate was filtered out and separated by flash chromatography under a silica gel phase (ethyl acetate:normal hexane=1:1). As a result, (S)-3-(2-bromopyridine-3-yloxy)-2-methyl-1-propanol (260 mg, yield: 80%) was obtained.
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.CN(C)C=O.[S:45]1[CH:49]=[CH:48][N:47]=[C:46]1[NH:50][S:51]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([NH2:60])[CH:55]=1)(=[O:53])=[O:52]>CO>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:60][C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([S:51]([NH:50][C:46]4[S:45][CH:49]=[CH:48][N:47]=4)(=[O:53])=[O:52])[CH:55]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: CCN(CC)CC
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: Nc1cccc(S(=O)(=O)Nc2nccs2)c1
Solvent: CO
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)Nc2cccc(S(=O)(=O)Nc3nccs3)c2)(C2CCCCC2)N=Cc2ccccc21

Procedure:
The title compound was prepared from 5-cyclohexyl- 1,3-dihydro-1-methyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.3 g, 0.69 mmol), triethylamine (96 μl, 0.69 mmol), dimethylformamide (6 ml) and 1-(thiazol-2-ylaminosulphonyl)-3aminobenzene (0.19 g, 0.76 mmol) using the procedure described in Example 11, Step 4. The product (125 mg, 33% ) was afforded as a cream solid after trituration with methanol. mp 230° C. (dec.). 1H NMR (360 MHz, D6 -DMSO) δ 0.84-0.96 (1H, m), 1.08-1.65 (7H, m), 1.71-1.81 (1H, m), 1.86-1.94 (1H, m), 2.88-2.96 (1H, m), 3.32 (3H, s), 5.06 (1H, d, J=8.2 Hz), 6.80 (1H, d, J=4.6 Hz), 7.22 (1H, d, J=4.6 Hz), 7.28-7.42 (5H, m), 7.55 (1H, d, J=7.4 Hz), 7.64 (1H, dd, J=7.1 and 7.0 Hz), 7.75 (1H, d, J=7.9 Hz), 7.98 (1H, s), 9.30 (1H, s), 12.63 (1H, brs).