Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:35])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].Br[CH:37]([CH3:42])[C:38]([O:40]C)=[O:39]>>[CH:27]1([NH:26][C:24]([C:23]2[CH:30]=[C:31]([F:34])[C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][CH2:42][CH2:37][C:38]([OH:40])=[O:39])([CH3:12])[CH3:13])[C:16]3=[O:35])[CH:22]=2)=[O:25])[CH2:28][CH2:29]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN)c1=O
Reactant: COC(=O)C(C)Br
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCNCCC(=O)O)c1=O

Procedure:
of the title compound was prepared from 3-(3-(2-(2-(2-aminoethoxy)phenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 311) and methyl bromopropanoate using a similar method to that described for Example 312.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[CH:6]=[C:5]2C(O)=O)[CH2:3][CH2:2]1.[BH4-].[Na+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(=O)c2cc(F)c(F)cc2n1C1CC1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCN(C2CC2)c2cc(F)c(F)cc21
Yield: 71.3 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline carboxylic acid(20 g) and sodium borohydride(11.5 g) were reacted in the same method as described in Preparation 1-A to give the yellow above-indicated compound(12 g).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)C1C=CC=CC=1.C(O)C>[C].[Pd].O>[ClH:1].[C:17]([O:16][CH2:15][CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCC1CN(Cc2ccccc2)CCO1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(OCC1CNCCO1)c1ccccc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
10% Palladium-carbon (40 g) and 4-benzyl-2-benzoyloxymethylmorpholine hydrochloride (202 g) are added to a mixture of ethanol (600 ml) and water (200 ml), and the mixture is stirred under hydrogen pressure of 10 kg/cm2 at 40° C. for 5 hours. Palladium-carbon is filtered off, and the solvent is distilled off under reduced pressure. To the residue is added ethanol, and the mixture is distilled under reduced pressure. This procedure is repeated three times. The resulting crystals are washed with ether and recrystallized from chloroform-ethanol to give the title compound (91 g) as colorless crystals.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:11]([O:13]C)=O)=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1.O.[NH2:16][NH2:17]>CO>[NH2:2][C:3]1[S:4][C:5]([C:11]([NH:16][NH2:17])=[O:13])=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1
Reactant: COC(=O)c1sc(N)nc1C1CC1
Reactant: NN
Agent: Br
Solvent: CO
Solvent: O
Product: NNC(=O)c1sc(N)nc1C1CC1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
Methyl 2-amino-4-cyclopropyl-1,3-thiazole-5-carboxylate hydrobromide (1.78 g) was dissolved in methanol (4.0 ml), hydrazine monohydrate (2.0 ml) was added thereto, followed by stirring at 55° C. for 3 days. After cooling to room temperature, an insoluble substance was filtered, the mother solution was mixed with basic silica gel and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel chromatography (chloroform:methanol) to obtain, as a dark brown solid, 2-amino-4-cyclopropyl-1,3-thiazole-5-carbohydrazide (224 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2OC)[N:3]=1.[NH2:30][C:31]1[C:36]2[C:37](=[O:41])[N:38]([CH3:40])[CH2:39][C:35]=2[CH:34]=[CH:33][N+:32]=1[O-:42]>>[CH3:40][N:38]1[CH2:39][C:35]2[CH:34]=[CH:33][N+:32]([O-:42])=[C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=4)[N:3]=3)[C:36]=2[C:37]1=[O:41]
Reactant: CN1Cc2cc[n+]([O-])c(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c4c(cc[n+]3[O-])CN(C)C4=O)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (204 mg, 0.381 mmol) and 4-amino-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 5-oxide (Compound 310A, 68.3 mg, 0.381 mmol). The reaction mixture was concentrated under reduced pressure to yield a dark yellow oil which was purified by silica gel chromatography on the combi-flash Rf system using DCM/MeOH (100:0→90:10). The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (38.4 mg, 17%). 1H NMR (DMSO-d6, 400 MHz): δ=8.99 (br. s., 1H), 8.47-8.55 (m, 3H), 7.47 (d, J=6.57 Hz, 1H), 7.24 (d, J=7.58 Hz, 1H), 6.85 (s, 1H), 6.56 (d, J=8.08 Hz, 1H), 4.45 (s, 2H), 3.90-3.99 (m, 4H), 3.70 (s, 3H), 3.12-3.21 (m, 2H), 2.86-2.89 (m, 3H), 1.17 (t, J=7.07 Hz, 6H). MS (ES+): m/z 597.10 [MH+] (TOF, polar).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([N:17]1[CH2:63][CH2:62][CH2:61][C@H:18]1[C:19]([N:21]1[CH2:60][CH2:59][CH2:58][C@H:22]1[C:23]([NH:25][C@H:26]([C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])=[O:53])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:51])[NH:32][S:33]([C:36]1[C:49]([CH3:50])=[C:47]([CH3:48])[C:46]2[O:45][C:42]([CH3:44])([CH3:43])[CH2:41][CH2:40][C:39]=2[C:37]=1[CH3:38])(=[O:35])=[O:34])=[O:24])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:64]([C:76]([O:78][CH2:79][CH:80]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[C:86]2[C:81]1=[CH:82][CH:83]=[CH:84][CH:85]=2)=[O:77])[C@H:65]([C:73](O)=[O:74])[C@@H:66]([CH3:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:64]([C:76]([O:78][CH2:79][CH:80]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[C:86]2[C:81]1=[CH:82][CH:83]=[CH:84][CH:85]=2)=[O:77])[C@H:65]([C:73]([NH:1][C@H:2]([C:15]([N:17]1[CH2:63][CH2:62][CH2:61][C@H:18]1[C:19]([N:21]1[CH2:60][CH2:59][CH2:58][C@H:22]1[C:23]([NH:25][C@H:26]([C:52]([C:54]([CH3:55])([CH3:57])[CH3:56])=[O:53])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:51])[NH:32][S:33]([C:36]1[C:49]([CH3:50])=[C:47]([CH3:48])[C:46]2[O:45][C:42]([CH3:43])([CH3:44])[CH2:41][CH2:40][C:39]=2[C:37]=1[CH3:38])(=[O:35])=[O:34])=[O:24])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[O:74])[C@@H:66]([CH3:72])[O:67][C:68]([CH3:70])([CH3:71])[CH3:69]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)[C@@H](C)OC(C)(C)C)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
H-Lys(Boc)-Pro-Pro-Arg(Pmc)-t-Bu (3.55 g, 3.86 m mmol) was added to a solution of the activated acid prepared from Fmoc-Thr(t-Bu)-OH (1.6 g, 4 mmol) and HATU (1.9 g, 5 mmol) and DIEA (1.29 g, 10 mmol) in dry CH2Cl2 (25 ml) and stirred for 20 h at RT.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH:11]=1>>[C:1]1([C:7]#[C:8][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: IC1=CCCc2ccccc21
Product: C(#Cc1ccccc1)C1=CCCc2ccccc21

Procedure:
The modified procedure was used to convert phenylacetylene and 1,2-dihydro-4-iodonaphthalene to the title product in 24 hours. Purification by flash chromatography (20% CH2Cl2 in hexanes) gave the analytically pure product as a light yellow oil (360 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=7.58, 1H), 7.52 (m, 2H), 7.31 (m, 3H), 7.25 (m, 1H), 7.18 (t, 1H), 7.13 (d, J=7.33, 1H), 6.54 (t, 1H), 2.80 (t, 2H), 2.42, (m, 2H). 13C NMR (100 MHz, CDCl3) δ 135.49, 135.05, 132.64, 131.54, 128.29, 128.07, 127.66, 127.39, 126.62, 125.05, 123.43, 121.72, 90.28, 87.29, 27.14, 23.69. Anal. Calc'd. for C18H14: C, 93.87; H, 6.13; Found C, 93.79; H, 6.36.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1.Cl.[N:16]1([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=3)[CH2:20][CH2:21]2)=[N:23]1
Reactant: CC(=O)Nc1ccc(CCCl)cc1C
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: Cl
Product: CC(=O)Nc1ccc(CCN2CCN(c3n[nH]c4ccccc34)CC2)cc1C
Yield: 11 %

Procedure:
Starting with N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-acetamide (0.194 g, 0.915 mmol) and 3-piperazin-1-yl-1H-indazole hydrochloride (0.328 g, 1.372 mmol), and following the procedure outlined in Example 501, N-(4-{2-[4-(1H-indazol-3-yl)-piperazin-1-yl]-ethyl}-2-methyl-phenyl)-acetamide was obtained as its hydrochloride salt (0.038 g, 0.101 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(S)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(SCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-chloro-3-nitrothiophenol (0.4 g) and benzyl bromide (0.3 mL) in N,N-dimethylformamide (6 mL) was added potassium carbonate (0.44 g), and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane −n-hexane/ethyl acetate=9/1) to give 1-benzylthio-4-chloro -3-nitrobenzene (0.54 g). This material was dissolved in methanol (5 mL)-tetrahydrofuran (5 mL). To the solution were added nickel (II) bromide (21 mg) and sodium borohydride (0.22 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH2:29][CH:26]2[CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NCC1CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC3CC3)c2c1N

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and cyclopropylmethanamine as a pale-yellow solid (80%). 1H NMR (400 MHz, DMSO-d6) δ 0.12-0.13 (m, 2H), 0.29-0.31 (m, 2H), 0.90 (m, 1H), 1.27 (s, 6H), 1.33 (t, J=8.0 Hz, 3H), 2.56 (s, 3H), 2.97 (t, J=8.0 Hz, 2H), 4.14 (s, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.91 (t, J=4.0 Hz, 1H), 8.11 (s, 2H). MS 400 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]1=[O:20].C([Li])CCC.Br[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C1COCC1>[Si:33]([O:32][CH2:31][CH2:30][CH:5]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]1=[O:20])[C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[CH:3]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: O=C1N(Cc2cccc(F)c2)c2ccccc2C12CCCCC2
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
1′-(3-fluorobenzyl)spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (0.61 g, 1.97 mmol) was dissolved in THF and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 0.87 mL, 2.2 mmol) was added dropwise and the mixture was warmed to 0° C. (2-Bromoethoxy)-tert-butyldimethylsilane (0.65 mL, 3 mmol) was added and the mixture was allowed to warm to 25° C. The mixture was stirred for 16 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-10% ethyl acetate in hexane) to afford 0.86 g (92%) 1′-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-fluorophenyl)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[CH:14]1([C:19](Cl)=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+].Cl>C(Cl)Cl.O>[CH:14]1([C:19]2[NH:6][C:4](=[O:5])[NH:3][N:2]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCCC1
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]nc(C2CCCC2)[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a suspension of semicarbazide hydrochloride (5.00 g, 44.8 mmol) in DCM (100 mL) was added triethylamine (10.00 g, 99 mmol) and the mixture was stirred at −10° C. for 30 min. Cyclopentane carbonylchloride (5.00 g, 37.7 mmol) was added at the same temp and the mixture was allowed to warm to RT over night. The solvent from the reaction mixture was completely removed and the residue stirred in MeCN (200 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was treated with sodium hydroxide (7.00 g, 175 mmol) and water (20 mL). The resulting reaction mixture was heated at 100° C. for 3 h. The reaction mixture was cooled and acidified with conc. HCl. The solids were collected, washed and dried to provide 3-cyclopentyl-1H-1,2,4-triazol-5(4H)-one (2.24 g, 38.8% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 11.03 (s, 1H), 2.80 (m, 1H), 1.86 (m, 2H), 1.58 (m, 6H); MS (ESI) m/z: 154.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][C:10]([O:12]C)=[O:11])[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Li+].[OH-]>C1COCC1>[CH3:1][C:2]1([CH2:9][C:10]([OH:12])=[O:11])[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: COC(=O)CC1(C)SC(=O)NC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(CC(=O)O)SC(=O)NC1=O
Reaction time: 5 h
Yield: 92.2 %

Procedure:
To a solution of Compound 1e (0.18 g, 0.86 mmol) in THF (8 mL) was added 1 M LiOH (2.6 mL, 2.6 mmol) at rt. After 5 h, the organic solvent was evaporated under reduced pressure and the resultant aqueous layer was diluted with water and acidified by the addition of 1 N HCl solution to pH ˜2. The solution was extracted with EtOAc (2×) and the combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford Compound 1a (150 mg, 92%) as a white solid. LCMS=0.67 min using analytical method (B), 189.9 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.15-2.89 (m, 2H), 1.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:20][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Chlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[F:9][C:8]([F:11])([F:10])[CH2:7][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1C
Product: FC(F)(F)CNc1ccccc1

Procedure:
2.5 g (10.7 mmol) 2,2,2-trifluoroethyl trifluoromethanesulphonate were added to 2.0 g (21.5 mmol) aniline in 50 mL xylene and the mixture was refluxed for 2 days. After cooling, the mixture was filtered, washed with DIPE and the filtrate was evaporated down i.vac. The residue was purified by flash chromatography. The product fractions were combined and evaporated down i.vac.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>O1CCOCC1>[C:12]([O:11][C:9]([N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH2:6][CH:5]2[CH2:1]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc1
Temperature: 75 °C
Yield: 75.6 %

Procedure:
To a solution of tert-butyl hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylate (1.11 g, 5.23 mmol) in dioxane were added ethyl 6-chloronicotinate (1.28 g, 6.9 mmol) and DIPEA (2 ml, 11.6 mmol). The mixture was heated at 75° C. for 3 days. The mixture was then poured into EtOAc (100 ml) and washed with saturated ammonium chloride (50 ml), water (50 ml) and brine (50 ml). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (5% MeOH-DCM) to yield the title compound (1.429 g, 75%). m/z 362.25 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 8.32 (1H, dd, J=0.6, 2.1 Hz), 8.03 (1H, dd, J=2.4, 9.0 Hz), 6.32 (1H, d, J=8.7 Hz), 4.34 (2H, q, J=6.9 Hz), 3.24-3.85 (8H, m), 3.03 (2H, m), 1.47 (9H, s), 1.38 (3H, t, J=7.2 Hz).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17](=[O:35])[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=2)[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:21]=1)#[N:9].[OH-].[Na+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17](=[O:35])[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][S:39]([CH3:38])(=[O:41])=[O:40])[CH:29]=2)[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:21]=1)#[N:9]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(N)c2)c1=O
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Reaction time: 0.17 h

Procedure:
Triethylamine (0.2 ml) was added to a solution of 31 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-aminophenyl)-1,2-dihydropyridin-2-one in 2 ml of tetrahydrofuran, 0.1 ml of methanesulfonic acid chloride was dropped thereinto with ice cooling and the mixture was stirred for 10 minutes. To this were added 2 ml of 2N sodium hydroxide, the mixture was stirred at room temperature for 5 minutes and partitioned to ethyl acetate-water, the organic layer was washed with water, dried and concentrated and the residue was purified by a silica gel column chromatography (ethyl acetate-hexane system) to give 38 mg of the title compound as a pale yellow amorphous substance.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([OH:11])=[N:5][C:6]([F:10])=[C:7]([Cl:9])[CH:8]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([Cl:9])=[C:6]([F:10])[N:5]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Oc1nc(F)c(Cl)cc1Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)COc1nc(F)c(Cl)cc1Cl

Procedure:
A solution was prepared by dissolving 6.9 grams (0.3 mole) of sodium metal in 700 milliliters of 95 percent ethanol. To this solution was added with stirring 54.5 grams (0.3 mole) of 3,5-dichloro-6-fluoro-2-pyridinol. Thereafter 58.5 grams (0.35 mole) of ethyl bromoacetate was added and the mixture refluxed for 5 hours. At the completion of the reaction, the ethanol was distilled off and the residue poured into water. The solid which precipitated was filtered off and taken up in hexane and dried with activated carbon and anhydrous sodium sulfate. The mixture was filtered and the hexane removed and the ethyl-(3,5-dichloro-6-fluoro-2-pyridyloxy) acetate product was recovered by distillation. The product was a white waxy solid which boiled at 135°-170° C. (M.P. 63.5°-64° C.)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[F:59][C:60]([F:70])([F:69])[O:61][C:62]1[CH:67]=[CH:66][C:65](Br)=[CH:64][CH:63]=1>C1(C)C=CC=CC=1>[F:59][C:60]([F:69])([F:70])[O:61][C:62]1[CH:67]=[CH:66][C:65]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:64][CH:63]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Temperature: 110 °C

Procedure:
Piperazine (0.588 g, 6.84 mmol), Pd(II)acetate (0.027 g, 0.123 mmol), sodium t-butoxide (0.837 g, 10.06 mmol) and BINAP (0.154 g, 0.286 mmol) were stirred at room temperature in 10 mL dry toluene for 15 min. 4-trifluoromethoxy bromo benzene (1.5 g, 6.22 mmol) in 10 mL dry toluene was added into the reaction mixture. Then the reaction mixture was refluxed at 110° C. for 20 hrs. The reaction mixture was filtered through a celite bed, washed with toluene, concentrated, ethyl acetate added and then extracted with 1.5 (N) aqueous HCl solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate and concentrated to afford the product.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.O=S(Cl)[Cl:18]>CN(C=O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:18])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1
Yield: 100 %

Procedure:
(1,1′-biphenyl)-4-carboxylic acid (20 g, 100.9 mmol) was refluxed for one night in 100 ml of SOCl2 in the presence of a few drops of DMF. Thionyl chloride was removed at ordinary pressure and the residue was triturated in Et2O and filtered. Yield 100% of (1,1′-biphenyl)-4-carbonyl chloride (21.9 g), white crystalline solid. m.p. 116-119° C. 1H-NMR(CHCl3) 7.41-7.73 (7H, m), 8.18 (2H, d, J=8.3 Hz). 13C-NMR(CHCl3) 128.0, 128.1, 129.5, 129.7, 132.4, 132.6, 139.6, 148.7, 168.6