Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[Cl:16].[H-].[Na+].CC1C=CC(S(O[CH2:30][C:31]2([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:30][C:31]2([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:5]=[CH:4][C:3]=1[Cl:16]
Reactant: COC1(COS(=O)(=O)c2ccc(C)cc2)CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1(CN(C(=O)OC(C)(C)C)c2ccc(Cl)c(Br)n2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 6-bromo-5-chloropyridin-2-ylcarbamate (140 mg, 0.455 mmol) in DMF (2 ml) under nitrogen was added NaH (60%, 30 mg, 0.774 mmol). The resulting mixture was stirred at ambient temperature for one hour. A solution of (4-methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (intermediate O, 164 mg, 0.546 mmol) in DMF (1.5 ml) was then added to the preceding mixture. The resulting mixture was then stirred overnight at about 85° C. The stirred mixture was diluted with 30 ml of ethyl acetate, washed with water (20 ml×3) and dried. After concentration the resulting residue was purified by silica gel chromatography using a 12 g column, eluting with 5-20% ethyl acetate in hexane to yield the desired compound “P” as a viscous oil (92 mg), which solidified upon standing overnight. LCMS (m/z): 437.0 [M+H]+; Retention time=1.158 min.
Reaction SMILES: C([O:8][C:9]1[C:14]2[C:15]([CH3:45])=[C:16]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:41]([O:43][CH3:44])=[O:42])[CH:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)=[O:19])[O:17][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:46][CH3:47])C1C=CC=CC=1.C1COCC1>CO.[Pd]>[CH2:46]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([NH:36][C@H:37]([C:41]([O:43][CH3:44])=[O:42])[CH:38]([CH3:40])[CH3:39])(=[O:34])=[O:35])=[CH:31][CH:32]=4)=[CH:25][CH:26]=3)=[O:19])=[C:15]([CH3:45])[C:14]=2[C:9]=1[OH:8])[CH3:47]
Reactant: CCc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c2c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c2c1O
Reaction time: 4 h
Yield: 129.9 %

Procedure:
To 0.1 g (0.15 mmol) of methyl N-{[4′-({[4-(benzyloxy)-5-ethyl-3-methyl-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valinate from Example 89, dissolved in 20 mL of methanol and 10 mL of THF was added 0.2 g of 10% palladium on active carbon and the mixture was hydrogenated in a Parr hydrogenator at 40 psi for 4 hours. The reaction mixture was then filtered through celite and the celite pad was washed with with methanol. The filtrate was concentrated in vacuo to provide 0.11 g of methyl N-[(4′-{[(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate. Yield ˜100%, m.p. 75-80° C. MS: 565.2 (M+H)+.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH2:26]O)=[CH:20][C:19]=1[CH3:28].[C:29]([O:33][C:34]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:35])([CH3:32])([CH3:31])[CH3:30].C(P(CCCC)CCCC)CCC>ClCCl>[C:40]([O:39][C:37]([N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:26][CH2:25][C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([Br:17])=[C:19]([CH3:28])[CH:20]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: Cc1cc(CCO)cc(C)c1Br
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Product: Cc1cc(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of di-tert.-butyl azodicarboxylate (2.85 g) in dichloromethane (10 mL) is added dropwise over 15 minutes to a solution of 2-(4-bromo-3,5-dimethylphenyl)ethanol (950 mg), di-tert.butyl-iminodicarboxylate (3.75 g) and tributylphosphine (4.4 mL) in dichloromethane (40 mL) at −10° C. The resulting solution is stirred for 2 hours while warming to room temperature and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 1.19 g; LC (method 8): tR=1.06 min; Mass spectrum (ESI+): m/z=451 [M+Na]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:32]([F:42])[CH:31]=3)[O:27][N:26]=2)=[CH:21][CH:20]=1>CN(C)C=O>[F:42][C:32]1[CH:31]=[C:30]([C:28]2[O:27][N:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])=[CH:20][CH:21]=3)[N:29]=2)[CH:35]=[CH:34][C:33]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OCCNCCO
Reactant: Fc1cc(-c2nc(-c3ccc(CCl)cc3)no2)ccc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCCN(CCO)Cc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Temperature: 90 °C

Procedure:
Diisopropylethylamine (23.5 mL, 0.136 mol) and diethanolamine (14.2 g, 0.135 mol) are added to a stirred solution of 3-(4-chloromethylphenyl)-5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole (33 g, 0.090 mol) in N,N-dimethyl-formamide (200 mL). The reaction mixture is heated at 90° C. for 2.5 hrs, the solvent is removed under reduced pressure and the residue is treated with demineralized water (200 mL) to get a solid which is filtered and washed with n-hexane (150 mL) and diethyl ether (100 mL) to furnish 2-[{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}(2-hydroxyethyl)amino]ethanol.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[CH:10]=[C:11](N)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[O:21]1CCCC1.C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[CH3:1][NH:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[CH2:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: CNC(=O)c1cccnc1C=C(N)c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(=O)c1cccnc1CC(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
22 g. (76.5 mmol.) of 2-(4'-chloro-β-aminostyryl)nicotinic acid N-methylamide (Compound XIX) were dissolved in 80 ml. of tetrahydrofuran and 40 ml. of ethanol and a mixture of 40 ml. of acetic acid and 40 ml. of water was added. The reaction mixture was stirred at 40° C. for 4 hours. The reaction mixture was then made basic to pH 9 with sodium hydroxide solution and extracted with diethyl ether, ethyl acetate and methylene chloride. The three organic extracts were combined, treated with charcoal, dried over anhydrous magnesium sulfate and concentrated at reduced pressure to obtain a yellow solid which was recrystallized from ethanol to obtain the product as a yellow green solid, m.p. 162°-163° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:42]3[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-hydroxypiperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H41Cl2N4O3 [(M+H)+] 623.255, observed 623.2551.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.Cl>C(O)(=O)C>[F:21][C:19]1[C:18]([F:22])=[CH:17][C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:23])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine (8 g) in 17.5% strength aqueous hydrochloric acid solution (80 cc) and acetic acid (80 cc) is heated with stirring to a temperature in the region of 100° C. for 1 hour and a half. After cooling to approximately 20° C., the solid is drained and washed with water (6×100 cc). After 1 recrystallization in dimethylformamide (160 cc), 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3 -carboxylic acid (6.44 g) is obtained in the form of a yellow solid, decomposing at 360° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[CH:9]1[C:15]([NH2:16])=[N:14][C:12](=[O:13])[N:11]([C@@H:17]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C:18]2([F:26])[F:25])[CH:10]=1.Cl>>[CH2:5]([O:4][C:2]([NH:16][C:15]1[CH:9]=[CH:10][N:11]([C@H:17]2[C:18]([F:26])([F:25])[C@H:19]([OH:24])[C@@H:20]([CH2:22][OH:23])[O:21]2)[C:12](=[O:13])[N:14]=1)=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CCCCOC(=O)Cl
Agent: Cl
Product: CCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 91 %

Procedure:
Using Method A and butyl chloroformate, gemcitabine hydrochloride was converted to 15 (white solid, 91% yield): 1H NMR (200 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.23-8.27 (d, 1H), 7.11-7.15 (d, 1H), 6.37 (s, 1H), 6.16-6.23 (t, 1H), 5.33 (s, 1H), 4.12-4.18 (t, 2H), 3.65-3.95 (m, 4H), 1.44-1.66 (m, 2H), 1.33-1.40 (m, 2H), 0.93-0.97 (t, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].O>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=1
Reactant: CC(C)(O)CN
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1cc(Cl)nn2c(I)cnc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 1.20 g (3.35 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c in 24 mL N,N-dimethylformamide were added 895 mg 1-amino-2-methylpropan-2-ol and the mixture was stirred at 40° C. overnight. Water was added and the mixture was extracted with dichloromethane and methanol. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 798 mg (65%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11](OC)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2ncn(CC3CCN(CC)CC3)c2n1
Yield: 94.4 %

Procedure:
2-(Butyloxy)-9-[(1-ethyl-4-piperidinyl)methyl]-8-(methyloxy)-9H-purin-6-amine (37 mg, 0.102 mmol) was dissolved in methanol (5 ml) and 4M hydrogen chloride in 1,4-dioxane (0.638 ml, 2.55 mmol) and stirred at rt for 5 hours. The solvent was removed in vacuo to give a white solid. The sample was dissolved in methanol and loaded onto an aminopropyl SPE (2 g), eluting with methanol. The solvent was removed to give the title compound as a white solid (32 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[C:30](=[O:31])[C:29]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([NH2:32])[CH:27]=5)[NH:22][C:21]=4[C:20]([CH3:34])([CH3:33])[C:19]=3[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[C:30](=[O:31])[C:29]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([NH:32][S:36]([CH3:39])(=[O:38])=[O:37])[CH:27]=5)[NH:22][C:21]=4[C:20]([CH3:34])([CH3:33])[C:19]=3[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4ccc(N)cc4c2C3=O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4ccc(NS(C)(=O)=O)cc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the pyridine (2 ml) solution of 4-(2-amino-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl oxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound P6, 50 mg, 0.105 mmol), mesyl chloride (9 μl, 1.2 eq.) was added and stirred at room temperature for 30 min. Upon the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the title compound as an unpurified product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2([CH3:44])[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[O:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:44][C:31]1([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:45])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2(C)CCN(C(=O)OC(C)(C)C)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NC2(C)CCNCC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 2.5 h

Procedure:
To a stirred solution of racemic tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-4-methylpiperidine-1-carboxylate (27.0 mg, 0.0407 mmol, example 386) in dichloromethane (3 mL) was added TRIFLUOROACETIC ACID (4.44 g, 3 mL) and the reaction mixture was stirred at 0˜5 C for 2.5 hrs. The solvent was removed in vacuum and residue was dissolved in CH2Cl2 (80 mL), washed with sat Na2CO3 (15 mL), water (2×15 mL) and evaporated to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methyl-piperidin-4-yl)-amide as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 563. found: 563.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1(O)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[OH-].[Na+]>>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH:13]=1
Reactant: CN1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CC=C(c2cccc(C(F)(F)F)c2F)CC1
Yield: 52.6 %

Procedure:
A solution of 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methylpiperidin-4-ol (1.2 g, 4.33 mmol) in polyphosphoric acid (4 ml) was heated at 100° C. for 2 h. The mixture was poured on to ice and was basified with an aqueous sodium hydroxide solution (15%). The mixture was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.59 g). MS m/z (rel. intensity, 70 eV) 259 (M+, bp), 258 (66), 147 (74), 146 (27), 96 (52).
Reaction SMILES: C([O:8][C:9]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.O1CCCC1>CO.[C].[Pd]>[OH:8][C:9]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)OB(c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)OC1(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OB(c2ccc(C(=O)O)c(O)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
To a solution of benzyl 2-benzyloxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.243 g) in methanol (6 mL)/tetrahydrofuran (6 mL) was added 10% palladium-carbon (0.05 g) at room temperature under an atmosphere of argon. The mixture was stirred at room temperature for 3 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford the title compound (0.146 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])C(=O)[NH:6]2.OO.Cl.C(O)(=[O:19])C>[OH-].[Na+]>[NH2:6][C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[C:3]=1[C:4]([OH:13])=[O:19]
Reactant: Cc1cc(C)c2c(c1)NC(=O)C2=O
Reactant: CC(=O)O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Cc1cc(C)c(C(=O)O)c(N)c1
Temperature: 25 °C

Procedure:
To a heated (70° C. bath temperature) deep red solution of 4,6-dimethyl-1H-indole-2,3-dione (1.00 g, 5.71 mmol) in 33% aqueous sodium hydroxide (35 mL) was added 35% hydrogen peroxide (3.33 g, 34.3 mmol) over a period of 5 minutes. The reaction mixture was heated for another 15 min, then cooled to room temperature, and ice was added. The pH was adjusted to approximately 8 with concentrated HCl at 0° C. and acidified further to pH approximately 6 with glacial acetic acid. The solid precipitated was filtered, washed well with cold water, and dried under vacuum at 40° C. overnight to obtain 2-amino-4,6-dimethyl-benzoic acid as a pale brown solid. Yield: 0.35 g (37%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[C:14]([NH:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:12]=[CH:11][N:10]=1>>[CH3:17][CH:16]([NH:15][C:14]1[C:9]([N:1]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=[CH:2]2)=[N:10][CH:11]=[CH:12][N:13]=1)[CH3:18]
Reactant: C1CNCCNC1
Reactant: CC(C)Nc1nccnc1Cl
Product: CC(C)Nc1nccnc1N1C=CC=NC=C1

Procedure:
Following the general procedure of PREPARATION 24 and making non-critical variations but starting with homopiperazine (2.46 g) and 2-chloro-3-(1-methylethyl)aminopyrazine (PREPARATION 23), the title compound is obtained, NMR (300 MHz, CDCl3) 7.56, 7.34, 4.75, 4.04, 3.28-3.18, 3.00-2.94, 1.79, and 1.15 δ.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH2:33][CH3:34])/[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]>C(O)C>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH2:33][CH3:34])/[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CCC)C(=O)OCC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CCC)C(=O)O)cc2)c1
Temperature: 50 °C
Yield: 74 %

Procedure:
176 mg (4.4 mmol) of sodium hydroxide are added to a solution of 192 mg (0.44 mmol) of ethyl 2-[1-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]pentanoate in 8 mL of ethanol. The reaction mixture is heated at 50° C. for 15 hours. The reaction medium is evaporated to dryness, taken up in water, acidified with 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the solid obtained is purified by chromatography on a column of silica eluted with a 50/50 heptane/ethyl acetate mixture. The solvents are evaporated off and the oil obtained is crystallized from ethyl ether, filtered and dried. 133 mg (74%) of 2-[1-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]pentanoic acid are obtained in the form of a white powder with a melting point of 118-119° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=1.BrCCC=C>O1CCCC1>[CH2:13]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: [Li]CCCC
Agent: C=CCCBr
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C(=O)O)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (100 ml of 2.5M solution in hexane, 0.25 mol) was added to a stirred solution of diisopropylamine (35 ml, 0.25 mol) in dry tetrahydrofuran (250 ml) at -78° C. under a nitrogen atmosphere. The solution was allowed to warm up to -5° C., stirred for 30 minutes, cooled back to -78° C., and treated with p-toluic acid (17.0 g, 0.125 mol) in portions over 2 hours. The resulting mixture was allowed to warm up to -5° C. and stirred for 30 minutes. The resulting black solution was again cooled to -78° C. and treated dropwise with a solution of 4-bromobutene (17 ml, 0.166 mol) in dry tetrahydrofuran (100 ml) over 1 hour. The resulting yellow solution was allowed to warm up to room temperature and stirred for an additional 12 hours. The solvent was evaporated off under reduced pressure and the residue was treated with hydrochloric acid (500 ml of 5M) and extracted with dichloromethane (3×300 ml). The combined extracts were washed with water (2×250 ml), brine (250 ml) and dried over sodium sulfate. The solvent was evaporated off under reduced pressure to give crude 4-(4-pentenyl)benzoic acid as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][S:32]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH:15]([NH:17][C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:16]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:34])=[O:33]
Reactant: O=C(NC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a solution of 3-hydroxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (360 mg, 0.863 mmol) (obtained as described in Reference Example 75(2)) in methylene chloride (18 ml) were added methanesulfonyl chloride (200 μl, 2.59 mmol) and triethylamine (363 μl, 2.59 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride→methylene chloride:methanol (95:5) as the eluant to afford 3-methanesulfonyloxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (390 mg, yield 91%) as a pale yellow solid.