Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:31][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:29][NH:30][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:11])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: Cc1ccc(F)cc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 5-fluoro-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=431.2, tR (minutes, Method D)=0.79
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:21]([C:31]1[CH:32]=[N:33][C:34]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)=[N:35][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][C:40]3[CH:39]=[CH:38][C:37]([C:34]4[N:33]=[CH:32][C:31]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:36][N:35]=4)=[CH:42][CH:41]=3)=[O:19])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCC1Cc2ccc(C(=O)O)cc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc4c(c3)CC(CCCCCCCC)C4)cc2)nc1
Reaction time: 5 h
Yield: 59.8 %

Procedure:
1.00 g (3.64 mM) of 2-octylindan-5-carboxylic acid and 1.13 g (3.62 mM) of 5-decyl-2-(4-hydroxyphenyl)pyrimidine were dissolved in 30 ml of dichloromethane. To the solution, 0.74 g (3.59 mM) of N,N'-dicyclohexylcarbodiimide (DCC) and 0.05 g of 4-pyrrolidinopyridine were added, followed by stirring for 5 hours. The resultant N,N'-dicyclohexylurea was recovered by filtration, washed with dichloromethane, and added to the filtrate. The resultant dichloromethane solution was subjected to distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 1.23 g of 4-(5-decylpyrimidine-2-yl)phenyl 2-octylindan-5-carboxylate (Yield: 60.3%). ##STR131##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(CCC(=O)O)C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate (Preparation 20; 90 mg; 0.186 mmol) in ethanol (2 ml) and THF (2 ml) at room temperature was added 2N sodium hydroxide (0.186 ml; 0.372 mmol), and the resulting mixture was stirred at room temperature for ca. 2.5 h. Removal of most of the solvents, dilution with ca. 1 ml of water, followed by addition of acetic acid (ca. 300 μl) gave a precipitate. The mixture was extracted with dichloromethane to give, after removal of the solvent and trituration with diethyl ether, the title compound as a white solid (40 mg).
Reaction SMILES: C(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)(=O)/C=C/C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH-:31].[Na+]>CCOCC.O>[CH2:14]([O:13][C:9]1[CH:8]=[C:7]([CH:7]([CH3:12])[CH2:8][CH2:9][OH:31])[CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C/C=C/C(=O)Oc1cccc(OCc2ccccc2)c1
Reactant: [OH-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(CCO)c1cccc(OCc2ccccc2)c1

Procedure:
A solution of ethyl 3-(3-benzyloxyphenyl crotonate (17.7 g., 60 mM) in ether (250 ml.) is added to a mixture of lithium aluminum hydride (3.42 g., 90 mM) and ether (250 ml.). Aluminum chloride (0.18 g., 1.35 mM) is added and the mixture refluxed for 12 hours and then cooled. Water (3.4 ml.), sodium hydroxide (3.4 ml. of 6 N) and water (10 ml.) are then added successively to the reaction mixture. The inorganic salts which precipitate are filtered off and the filtrate is then concentrated in vacuo to give the desired alcohol as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:29])=[C:8]([C:30]([O:32]CC)=[CH2:31])[C:7]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>ClCCl.C(OCC)C.C([O-])(O)=O.[Na+]>[C:30]([C:8]1[C:7](=[O:35])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:19][N:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:29])(=[O:32])[CH3:31]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.490 g, 1.03 mmol) was dissolved in dichloromethane (5 mL). 2 N HCl in diethyl ether (3 mL) was added and the resulting mixture was stirred at room temperature for 4 hours. Then, additional 2 N HCl in diethyl ether (2 mL) was added and the mixture was stirred for an additional 12 hours. The reaction mixture was diluted with dichloromethane and aqueous NaHCO3. The layers were separated and the organic layer was dried over MgSO4, filtered, and the solvent evaporated to give a yellow solid. The solid was recrystallized from a mixture of hexanes, ethyl acetate and dichloromethane to give 6-acetyl-8-cyclopentyl-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.280 g, 60.7%). MS (APCI); M++1: Calc'd, 449.2, Found 449.2. 1H NMR δ (400 MHz, DMSO-d6) 8.79 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.31 (dd, J=2.9, 9.0 Hz, 1H), 5.86 (m, 1H), 3.88 (m, 4H), 3.15 (m, 4H), 2.54 (s, 3H), 2.36 (s, 3H), 2.32 (m, 2H), 2.05 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:36][CH:37]([CH3:39])[CH3:38]>C(Cl)(Cl)Cl>[CH3:36][CH:37]([CH3:39])[CH2:38][O:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)CBr
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(=N\OCC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
Ethyl (Z)-2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate hydrochloride (1 g) was alkylated with 1-bromo-2-methylpropane (0.48 ml) as described in Example 5a to give the title compound (0.8 g), νmax (CHCl3) 3400, 2960, 1725, 1520 and 1025 cm-1 m; δH (CDCl3) 1.09 (6H, d, J 7 Hz), 1.30 (3H, t), 1.90 (1H, m), 3.95 (2H, d, J 7 Hz), 4.30 (2H, q), 6.42 (1H, s), 6.93 (1H, br.s), 7.22 (15H, m). [Mass spectrum: +ve ion (3NOBA) MH+ (514)].
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+]=[N-].[Na+].N(CC1CC2C=CC=C(C3C=CC(F)=CC=3)C=2O1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pt]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH2:29])[CH2:17][C:16]=3[CH:18]=[CH:19][CH:20]=2)=[CH:23][CH:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4)c3O2)cc1
Agent: [Pt]
Agent: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(F)cc3)c2O1
Agent: [Na+]
Product: NCC1Cc2cccc(-c3ccc(Cl)cc3)c2O1
Yield: 78.9 %

Procedure:
Treatment of (±)-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.2 g, 2.89 mmol) with sodium azide (0.752 g, 11.57 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.082 g, 5 wt. %) generally according to the procedure described for Example 1 provided 0.592 g (69%) of (±)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 212-214° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 65.10; N, 4.73. Found: C, 59.99; H, 5.00; N, 4.47.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][SH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl>CN(C=O)C.O>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCBr
Reactant: SCCOCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCSCCOCCc1ccccc1
Yield: 72.3 %

Procedure:
A solution of 2-[2-phenylethoxy]ethane thiol (2.13 g) in dry DMF (10 ml) was added dropwise to a cooled (0°) stirred suspension of sodium hydride (0.60 g, 80% in oil) in DMF (50 ml). The mixture was stirred at 0° for 90 min. A solution of 3-bromopropanoic acid (3.15 g) in dry DMF (10 ml) was then added dropwise and the reaction was stirred at room temperature for 16 hours. Water (250 ml) was added and the whole was acidified to pH 2/3 with concentrated hydrochloric acid. The aqueous solution was extracted several times with ether and the combined ethereal layers were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. This yielded the crude acid which was purified by flash chromatography over silica using 6:1 dichloromethane:ether (1 drop acetic acid/100 ml of eluant) to give the subtitled compound (2.15 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH2:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([S:28][C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(NCc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (57 mg, 0.319 mmol) was reacted with the product from Example 44c (102 mg, 0.319 mmol) for 72 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (169 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.74 (s, 3H) 4.30 (s, 2H) 6.15 (d, J=6.99 Hz, 1H) 6.52 (d, J=8.46 Hz, 1H) 6.56-7.39 (m, 11H) 7.75 (d, J=8.46 Hz, 1H) 8.28 (d, J=7.36 Hz, 1H) 9.50 (br s, 1H) 10.85 (br s, 1H) 14.25 (br s, 1H); MS (ESI+) m/z 465 (M+H−TFA)+; (ESI−) m/z 463 (M−H−TFA)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CN(C)CCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60.0 mg, 0.309 mmol), β-dimethylaminoethyl chloride hydrochloride (49.0 mg, 0.340 mmol) and cesium carbonate (0.302 g, 0.928 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature, quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, then filtered and concentrated under reduced pressure to give the desired product (60 mg, 88%). LCMS calculated for C13H25BN3O2 (M+H)+: m/z=266.2. Found: 266.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[CH:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:29])[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:29][C@:21]4([CH2:20][N:19]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2ccc(Cl)nc2s1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 50.6 %

Procedure:
A mixture of dimethyl 5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (100 mg, 0.35 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (79 mg, 0.35 mmol) and cesium carbonate (225 mg, 0.69 mmol) in DMF (1.7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and the solids collected by filtration. The crude solids were purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform) to afford (R)—N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′ bicyclo[2.2.2]octan]-2-amine (62 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (br. s., 1 H) 7.93 (d, J=8.53 Hz, 1 H) 7.45 (d, J=8.28 Hz, 1 H) 3.92 (d, J=10.29 Hz, 1 H) 3.67 (d, J=10.29 Hz, 1 H) 3.00-3.14 (m, 2 H) 2.77-2.93 (m, 2 H) 2.69 (t, J=7.65 Hz, 2 H) 2.12 (br. s., 1 H) 1.95 (br. s., 1 H) 1.43-1.72 (m, 3 H). MS (LC/MS) R.T.=1.10; [M+H]+=350.10.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][S:4][C:3]=1/[CH:7]=[CH:8]\[C:9]1[CH2:30][S:29][C@@H:12]2[C@H:13]([NH:16][C:17](/[C:19](/[C:23]3[N:27]=[C:26]([NH2:28])[S:25][CH:24]=3)=[N:20]\[O:21][CH3:22])=[O:18])[C:14](=[O:15])[N:11]2[C:10]=1[C:31]([O-:33])=[O:32].[Na+].C(=O)(O)[O-].[Na+].[C:40]([O:46][CH2:47]I)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].C(OC(C)C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.CN(C=O)C>[CH3:1][C:2]1[N:6]=[CH:5][S:4][C:3]=1/[CH:7]=[CH:8]\[C:9]1[CH2:30][S:29][C@@H:12]2[C@H:13]([NH:16][C:17](/[C:19](/[C:23]3[N:27]=[C:26]([NH2:28])[S:25][CH:24]=3)=[N:20]\[O:21][CH3:22])=[O:18])[C:14](=[O:15])[N:11]2[C:10]=1[C:31]([O:33][CH2:47][O:46][C:40]([C:41]([CH3:44])([CH3:43])[CH3:42])=[O:45])=[O:32]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C\c3scnc3C)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(/C=C\c3scnc3C)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 97 %

Procedure:
To DMF (80 ml), Cefditoren Sodium (10 gm) was added at 30° C. and stirred to get a clear solution. To the clear solution, solid sodium bicarbonate (1.6 gm), and tetra butyl ammonium hydrogen sulphate were added. The reaction mass was cooled to −20° C. and iodomethyl pivalate (9.76 gm) was charged and stirred for 60 minutes. The reaction mass was poured into isopropyl ether (100 ml). To this reaction mixture DM Water (100 ml) was added. The solid obtained was stirred at 5° C., filtered, washed with water and IPE, and finally dried to get the title compound. Purity(HPLC): 97-99% Yield: 8.5 gm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[C:40]#[N:41])=[CH:4][C:5](=[O:32])[N:6]([CH:8]([CH3:31])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22](C(OC(C)(C)C)=O)[NH:21][C:20](=[O:30])[CH:19]=3)=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[C:40]#[N:41])=[CH:4][C:5](=[O:32])[N:6]([CH:8]([CH3:31])[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[NH:22][NH:21][C:20](=[O:30])[CH:19]=3)=[CH:16][CH:17]=2)=[O:10])[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(-c2cc(=O)[nH][nH]2)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
17.8 mg (purity 78%, 0.02 mmol) of tert-butyl 5-[4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate (racemate) (Example 12.2A) were reacted with TFA according to General Method 2. Yield: 6 mg (55% of theory)
Reaction SMILES: [CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:21])[N:4]1[CH3:22])[CH3:2].[OH-].[K+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CS(C)=O.C(OCC)(=O)C>[CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:21])[N:4]1[CH3:22])[CH3:2]
Reactant: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Product of Step 9 (1 g) was dissolved in dimethylsulfoxide (60 mL). To this, powdered potassium hydroxide (1 g) and tertiarybutyl bromoacetate (2.5 mL) was added. The reaction mixture was stirred under argon for 3 hr at 25° C. The reaction mixture was diluted with ethyl acetate (800 mL) and was extracted with water (twice at 200 mL each) and saturated sodium chloride in water (200 mL). The organic layer was dried on magnesium sulfate, was filtered, and was concentrated under vacuum. Crude product was loaded on a SNAP cartridge containing 100 g silica gel and eluted with a gradient of chloroform and methanol using the BIOTAGE® AB ISOLERA™ flash chromatography system. Fractions containing product were pooled and evaporated to obtain product of Step 10 as a red oil (0.26 g). 1H NMR (CDCl3): 1.3 δ (—CH—CH3 of isopropyl), 1.5 δ (—(CH3)3 of tertiarybutyl) 2.1 δ (3H, ═CH—CH3 of ethylidene) 2.9 δ (3H, —N—(CH3)), 2.8, 3.1, 3.5 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 4.4 δ (1H, ═CH—CH3 of ethylidene), 4.5 (2H, —O—CH2-C(O)—) 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=408 (M+H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([O:10][C:11]1[C:16]([C:17]2[NH:18][C:19](=[O:33])[C:20]3[C:21](=[C:23]([CH2:31][CH3:32])[N:24]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[N:25]=3)[N:22]=2)=[CH:15][C:14]([C:34]#[CH:35])=[CH:13][N:12]=1)[CH2:7][CH2:8][CH3:9]>CC(C)=O.CO.S([O-])([O-])(=O)=O.[Hg+2]>[C:34]([C:14]1[CH:15]=[C:16]([C:17]2[NH:18][C:19](=[O:33])[C:20]3[C:21](=[C:23]([CH2:31][CH3:32])[N:24]([CH2:26][CH2:27][N:28]([CH3:29])[CH3:30])[N:25]=3)[N:22]=2)[C:11]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])=[N:12][CH:13]=1)(=[O:2])[CH3:35]
Reactant: C#Cc1cnc(OCCCC)c(-c2nc3c(CC)n(CCN(C)C)nc3c(=O)[nH]2)c1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: CC(C)=O
Solvent: CO
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1

Procedure:
1 N Sulfuric acid (1 mL) was added to a stirred solution of 5-(2-butoxy-5-ethynyl-3-pyridinyl)-2-[2-(dimethylamino)ethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 46) (280 mg, 0.69 mmol) in acetone (8 mL) at room temperature. Mercury sulfate (40 mg, 0.14 mmol) was added and the mixture heated at reflux for 5 h. The reaction mixture was cooled, diluted with methanol (10 mL), filtered and the filtrate washed with further methanol. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (100 mL). The aqueous was washed with a further 100 mL of ethyl acetate and the combined organics dried (MgSO4) and concentrated. Purification by flash column chromatography (elution with 95% dichloromethane/methanol) gave the product as a cream coloured solid (140 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2cccnc2Cl)CCCC1
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
2-(2-Chloropyridin-3-yl)acetonitrile (0.280 g, 1.835 mmol) was dissolved in dry tetrahydrofuran (1.5 mL) under nitrogen and cooled in an ice bath. 1,4-Dibromobutane (0.220 ml, 1.842 mmol) was added followed by dropwise addition of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 4.5 ml, 4.50 mmol). The mixture was stirred for 20 minutes then quenched by addition of saturated ammonium chloride (10 mL). Water (100 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 1-(2-chloropyridin-3-yl)cyclopentanecarbonitrile (0.252 g, 1.219 mmol, 66.4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[O:16][C:17](Br)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC(O)=O.CC(O)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[O:16][C:17]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(OC)cc3)o2)c1
Temperature: 70 °C
Yield: 92.8 %

Procedure:
To a previously degassed mixture of (3-[(5-bromo-furan-2-carbonyl)-amino]-phenyl)-acetic acid ethyl ester (11) (0.4 g), 4-methoxyphenylboronic acid (0.19 g), potassium carbonate (0.39 g) and tetra-n-butylammonium bromide (0.37 g) in water (2 ml) was added palladium II acetate (circa 10 mg). The mixture was heated to 70° C. for an hour, cooled and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulphate and evaporated in vacuo. (3-[(5-(4-Methoxy-phenyl)-furan-2-carbonyl)-amino]-phenyl)-acetic acid ethyl ester (0.4 g) was obtained following silica gel column chromatography of the residue in 2:1 ethyl acetate:petroleum ether.