Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH:15]([NH2:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:42][CH2:43][C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][CH2:43][C:44]([NH:20][C@H:15]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:22][CH2:23][N:24]2[C@H:29]3[CH2:30][CH2:31][C@@H:25]2[CH2:26][CH:27]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:28]3)[CH2:9][CH2:10]1)=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:45]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(N)C(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)CCl)C(C)(C)C)CC1

Procedure:
2-chloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl)-}-piperidinyl)carbonyl]-2,2-dimethylpropyl}carbamate (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Chloro-acetyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-N-(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide (0.038 g, 66%) as an oil. ES-LCMS m/z 636 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@@H:19]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[CH3:20])[C:13]=1[N+:25]([O-])=O.Cl[Sn]Cl.O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:9])[CH3:10])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@@H:19]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[CH3:20])[C:13]=1[NH2:25]
Reactant: C[C@@H](Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CCC1
Agent: Cl[Sn]Cl
Solvent: O
Product: C[C@@H](Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1N)C1CCC1
Yield: 99.9 %

Procedure:
(R)-[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-ethyl)-amine (326 mg, 0.83 mmol) and SnCl2.H2O (472 mg, 2.5 mmol) were treated substantially as described in Part D of Example 74a to yield 301 mg of crude (R)-4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N2-(1-cyclobutyl-ethyl)-pyridine-2,3-diamine: MS (EI) m/z 363.24 [(M+H)+, 100].
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][N:5]([CH2:7]Cl)[CH:6]=1.[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][N:5]([CH2:7][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24])[CH:6]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)C(F)(F)c1nn(CCl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)c(C(F)(F)C(F)(F)F)n1
Yield: 74.6 %

Procedure:
6.84 g of 4-bromo-1-(chloromethyl)-3-(pentafluoroethyl)-1H-pyrazole and 3.54 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 60 ml of N,N-dimethylformamide. 6.08 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.15 g of [(4-bromo-3-(pentafluoroethyl)-1H-pyrazole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (37), hereinafter) shown by below formula.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:19])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].C(O)(C(F)(F)F)=O>CC(O)=O>[OH:19][C:6]1[C:7](=[O:8])[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COc1ccc(CNC(=O)C(=O)NCC(OC)OC)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2ccnc(O)c2=O)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of N1-(2,2-dimethoxyethyl)-N2-(4-methoxybenzyl)oxalamide (7.5 g, 25.3 mmol) and TFA (2.340 mL, 30.4 mmol) in AcOH (160 mL) was stirred at 135° C. in a seal tube for 1.5 hours. After cooling to RT and removal of the volatiles under vacuum, ethyl ether (150 ml) and sat. aq. NaHCO3 solution (150 ml) were added. The resulting precipitate was collected by filtration, washed with H2O (50 ml) and ether (50 ml) prior to drying under high vacuum to yield 3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (5.30 g, 21.68 mmol, 86% yield) as brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (1H, br. s.), 7.18 (2H, d), 6.81 (2H, d), 6.46 (1H, d, J=5.77 Hz), 6.23 (1H, br. s.), 4.74 (2H, s), 3.24 (1H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:2]=1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cccnc2)n1
Yield: 1.07 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid (0.285 g, 1.381 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.3 g, 1.151 mmol). The product was purified by triturated using DCM. Yield 1.065%. 1H-NMR (400 MHz; CDCl3): δ 1.31 (d, 3H), 4.34 (dd, 1H), 4.48 (dd, 1H), 4.60-470 (m, 1H), 6.63 (d, 1H), 7.37 (dd, 1H), 7.50-7.54 (m, 2H), 7.80 (dd, 1H), 7.88 (d, 1H), 7.98 (d, 1H), 8.13-8.18 (m, 2H), 8.73 (dd, 1H), 9.16 (d, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([N+:19]([O-:21])=[O:20])=[CH:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2)#[N:7].[OH2:26]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([N+:19]([O-:21])=[O:20])=[CH:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2)(=[O:26])[NH2:7]
Reactant: O
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: NC(=O)N1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 ml of concentrated sulphuric acid are added dropwise to a suspension of 4.0 g (0.015 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine in 40 ml of acetic acid and the mixture is stirred for a further 15 hours at room temperature. 100 ml of water are gradually added to the clear solution, the precipitated material is taken up in chloroform, and the chloroform layer is washed with water and evaporated to dryness. After recrystallisation of the residue from isopropanol, pure 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine is obtained; melting point 208°-212°, yield 2.2 g, 52.4% of the theoretical yield. The analytical and spectroscopic data agree with the given structure.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:2].[CH:15]1(Br)[CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([S:3][CH2:1][CH3:2])[CH:12]=3)[C:8]([C:13]#[N:14])=[CH:9]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CCSc1ccc2c(C#N)c[nH]c2c1
Reactant: BrC1CCC1
Solvent: CN(C)C=O
Product: CCSc1ccc2c(C#N)cn(C3CCC3)c2c1
Temperature: 85 °C
Yield: 95.8 %

Procedure:
A mixture of 6-ethylsulfanyl-1H-indole-3-carbonitrile (2.13 g, 10.5 mmol) Cs2CO3 (6.9 g, 21 mmol), cyclobutyl bromide (1.78 g, 13.2 mmol) and DMF (20 mL) was heated to 85° C. overnight and, after cooling, partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc/hexane 5% to 30%) to provide 1-cyclobutyl-6-ethylsulfanyl-1H-indole-3-carbonitrile (2.58 g, 96%) as a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][Br:17])[CH2:12][CH2:11][CH:10]([CH2:13]CC)[O:9]2)=[CH:4][CH:3]=1.Cl[C:19]1C=CC(C(CCC(O)(C)C)=C)=CC=1.BrBr.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:16][Br:17])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:19])[O:9]2)=[CH:6][CH:7]=1
Reactant: C=C(CCC(C)(C)O)c1ccc(Cl)cc1
Reactant: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Agent: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CCC(CBr)(c2ccc(Cl)cc2)O1

Procedure:
By the cyclisation procedure described for the preparation of 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran (see Example 1), 2-(4-chlorophenyl)-5-hydroxy-5-methylhex-1-ene (5.3 g), bromine (3.8 g), and pyridine (1.9 g), in dichloromethane (60 ml), gave 2-(4-chlorophenyl)-2-bromomethyl-5,5-dimethyltetrahydrofuran (7.6 g) as a red oil, 1H nmr (CDCl3): δ1.2 (3H, singlet) and 1.4 (3H, singlet), 2×CH3, 3.5 (2H, singlet, CH2Br).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.C[O-].[Na+].[Br:16][C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20]([NH:26][C:27](=O)[O:28]CC)=[C:19]([F:32])[CH:18]=1>CN(C=O)C>[Br:16][C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:27]2=[O:28])=[C:19]([F:32])[CH:18]=1
Reactant: CCOC(=O)Nc1cc(OCC)c(Br)cc1F
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (3.42 g) was dissolved in DMF (19 ml). To this solution, a suspension of sodium methoxide (1.10 g) in DMF was added dropwise at 5° C., and the mixture was stirred at 5° C. for 30 minutes. Then, a DNF solution of ethyl N-(4-bromo-5-ethoxy-2-fluorophenyl)-carbamate was added dropwise thereto, and the mixture was stirred at 130° C. for 4 hours. After the reaction, DMF was distilled off under reduced pressure. Then, the residue was acidified by adding diluted hydrochloric acid thereto. This was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:3 v/v) to obtain the objective 3-(4-bromo-5-ethoxy-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (3.63 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:2]1.C(OCC)(=O)C.[ClH:22]>>[ClH:22].[ClH:22].[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][NH2:8])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC1CCCOC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC1CCCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(tetrahydro-2H-pyran-3-yl)hydrazinecarboxylate (3.65 g) was dissolved in 4N hydrogen chloride-ethyl acetate solution (85 mL) under ice-cooling, and the solution was stirred overnight, at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (2.40 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:30][CH:31]=O)[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:30][CH2:31][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:13](=[O:18])[CH2:14]2)[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]
Reactant: COc1cc(CC=O)ccc1[N+](=O)[O-]
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Product: COc1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(=O)C2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and (3-Methoxy-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 429 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 81.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.042 g, 0.085 mmol) obtained in step 2 and ethanesulfonamide (0.045 g, 0.42 mmol), the title compound (0.041 g, 82%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([CH:29]2[NH:34][C:33](=[O:35])[C@:32]([CH2:37][CH2:38][CH2:39][OH:40])([CH3:36])[O:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:34]1[C@H:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:30][O:31][C@@:32]([CH2:37][CH2:38][CH2:39][OH:40])([CH3:36])[C:33]1=[O:35])=[O:4]
Reactant: C[C@]1(CCCO)OCC(C2CCCCC2)NC1=O
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@](C)(CCCO)OC[C@H]1C1CCCCC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
To a 10 mL vial was added trans-cyclohexane diamine (13.4 mg, 0.12 mmol, 1.0 equiv), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (70.8 mg, 0.24 mmol, 2.0 equiv), K2CO3 (32.5 mg, 0.24 mmol, 2.0 equiv), CuI (22 mg, 0.12 mmol, 1.0 equiv), (R)-5-cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-morpholin-3-one (30 mg, 0.12 mmol, 1.0 equiv) and 1,4-dioxane (0.4 mL). The mixture was flushed with N2 and stirred at 120° C. for 18 hours. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, EtOAc/heptane 80% to give product 15 mg (yield 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])[S:15][C:8]=23)=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:39])[CH2:35][C:36](O)=[O:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.CC#N>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:36](=[O:37])[CH2:35][C:34]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])=[O:39])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[S:15][C:8]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: Nc1ccc(Oc2ccnc3cc(N4CCCC4=O)sc23)c(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(N4CCCC4=O)sc23)c(F)c1
Reaction time: 6 h
Yield: 18.1 %

Procedure:
A solution of the amino lactam 285 (80.7 mg, 0.243 mmol), 3-(2-methoxyphenylamino)-3-oxopropanoic acid 27 (76.1 mg, 0.365 mmol), EDC (70 mg, 0.365 mmol) and HOBt (56 mg, 0.365 mmol) in DMF (2.4 mL) was stirred overnight at room temperature. More 27 (76.1 mg, 0.365 mmol) and EDC (70 mg, 0.365 mmol) were added and the mixture was stirred 6 h more. The mixture was diluted with EtOAc, extracted with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was crystallized from MeCN affording title compound 284 (24 mg, 0.044 mmol, 18% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.73 (s, 1H), 9.63 (s, 1H), 8.64 (d, J=6.5 Hz, 1H), 8.06 (dd, J=10 Hz, J=1.5 Hz, 1H), 7.92 (dd, J=13.1 Hz, J=2.3 Hz, 1H), 7.59-7.48 (m, 2H), 7.12-7.05 (m, 3H), 6.94-6.90 (m, 2H), 4.07 (dd, J=7.0 Hz, J=7.4 Hz, 2H), 3.86 (s, 3H), 3.67 (s, 2H), 2.69 (dd, J=7.8 Hz, J=8.2 Hz, 2H), 2.24 (m, 2H). MS (m/z): (M+1) 535.1 (100%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[C:23]([O:25][CH3:26])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+]>CO>[C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][C@@H:11]2[C:23]([O:25][CH3:26])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 50 °C
Yield: 33.4 %

Procedure:
A solution of 258A (4.50 g, 12.4 mmol) in methanol (124 mL) at room temperature was treated with 25% NaOMe in methanol (8.04 mL). This reaction mixture was heated to 50° C. for 3.0 hours, cooled to room temperature, and then concentrated in vacuo. The oily residue was dissolved in dichloromethane (200 mL), and washed with 20% NH4Cl (2×75 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 to 25% EtOAc/hexanes) on silica gel to give 1.50 g (yield: 30%) of Compound 260A as an oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>>[CH:4]([C:3]1[CH:6]=[C:7]([C:12]([CH3:13])=[CH:11][C:10]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:9][CH:2]=1)=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: C/C=C/C(=O)OCC
Product: CCOC(=O)C=C(C)c1cccc(C=O)c1

Procedure:
Coupling of 3 bromobenzaldehyde with ethyl crotonate following the method used in Example 26 gave ethyl 3-(3-formylphenyl)but-2-enoate as a light yellow oil Yield (0.547, 23%): 1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 7.99 (t, J=1.6 Hz, 1H), 7.87 (dt, J=7.6, 1.3 Hz, 1H), 7.74 (m, 1H), 7.56 (t, J=7.6 Hz, 1H), 6.19 (q, J=1.2 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 2.61 (d, J=1.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)=[O:6].Cl[C:24]1C=CC=CC=1O>>[CH3:24][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)=[O:6]
Reactant: Oc1ccccc1Cl
Reactant: CC(=O)Oc1ccc(C(=O)c2cccc(C(=O)O)c2)cc1Cl
Product: CC(=O)Oc1ccc(C(=O)c2cccc(C(=O)O)c2)cc1C

Procedure:
The 3-chloro-4-acetoxy-3'-carboxybenzophenone may be obtained by similar reactions using o-chlorophenol in place of o-cresol.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[CH3:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[S:3][C:4]=4[CH:10]=3)=[O:16])[CH2:25][CH2:24]2)=[CH:29][CH:30]=1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)sc4c3)CC2)cc1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-oxalamic acid (Example 61b) and 4-(4-methyl-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 221-222° C. (diethylether)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:16].[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:3]1[CH:4]=[C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:22]1[N:23]([CH3:24])[C:19]([C:17]#[N:18])=[CH:20][CH:21]=1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(c1ccc(Br)c(F)c1)N1CCCC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)N2CCCC2)cc1F
Reaction time: 16 h
Yield: 31 %

Procedure:
According to general procedure B, 1-[(4-bromo-3-fluorophenyl)sulfonyl]pyrrolidine (182 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 5-[2-fluoro-4-(pyrrolidin-1-ylsulfonyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile (61 mg, 31%) was provided after purification. HRMS: calcd for C16H16FN3O2S+H+, 334.10200; found (ESI, [M+H]+), 334.1035. HPLC purity 100.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19](OCC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([CH2:19][OH:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate (2.26 g, 6.23 mmol) in anhydrous tetrahydrofuran (60.0 mL) was added lithium aluminium hydride (0.35 g, 9.33 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 4 h, then quenched with 10% aqueous hydrochloric acid solution (3 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was triturated with ether to the title compound: mp 164-166° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.30 (dd, J=8.7, 8.7 Hz, 2H), 7.15 (dd, J=8.7, 8.7 Hz, 2H), 4.96 (s, 2H), 4.57 (s, 2H), 2.22 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.7, 160.5, 150.2 (d, 3JC-F=12 Hz), 143.2, 132.8 (d, 3JC-F=11 Hz), 132.5, 130.7, 130.4 (d, 3JC-F=33 Hz), 116.9 (d, 3JC-F=86 Hz), 55.3, 48.1, 15.1; MS (ES+) m/z 321.2 (M+1).