Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].O1CC[CH2:39][CH2:38]1.C([Mg]Br)C.Cl>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]([OH:18])[CH2:38][CH3:39])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: C1CCOC1
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -73 °C
Yield: 30.6 %

Procedure:
To a cooled (-73° C.), stirred solution of 1.559 g. of benzhydryl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate and 20 ml. of dry tetrahydrofuran was added 3.13 ml. of 2.88 M. ethyl magnesium bromide. After the reaction mixture was allowed to stir for four minutes at -73° C., 10 ml. of 1N.HCl was added and the solution allowed to warm to 0° C. The reaction mixture was transferred to a separatory funnel with the aid of cold ethyl acetate and cold 1N.HCl. The organic layer was separated and washed twice with cold 1N.HCl and twice with brine and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided a product residue which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 0.140 g. of the starting 3-formyl-2-cephem ester and 0.507 g. (30.6 percent) of the title product as a mixture of diasteromers:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Temperature: 130 °C
Yield: 100 %

Procedure:
To a solution of 6-(trifluoromethyl)-3-pyridinol (2 g, 12.26 mmol) and 4-fluorobenzaldehyde (1.315 ml, 12.26 mmol) in DMF (50 mL), was added K2CO3 (2.54 g, 18.39 mmol). The mixture was heated at 130° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (3.28 g, 12.26 mmol, 100% yield) as a brown oil. LCMS: rt=3.16 min, [M+H+]=268
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH:8]=[C:9]([Br:17])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:5][CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:16])[C:14]3[C:6]([C:7]=2[CH:8]=1)=[CH:5][CH:4]=[C:3]([CH2:2][O:20][C:18](=[O:21])[CH3:19])[CH:15]=3
Reactant: O=C1c2cc(CBr)ccc2-c2cc(Br)ccc21
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
7-Bromomethyl-3-bromo-9-fluorenone (1.7 g) was suspended in DMF (25 ml). To this suspension was added potassium acetate (576 mg). The reaction mixture was stirred at 100° C. for one hour. It was then diluted with ethyl acetate, washed four times with water, twice with brine, dried and evaporated. The residue was chromatographed on silica gel using 2% ethyl acetate/methylene chloride and gave the desired product (1.18 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]([C:18]([NH:20][C@H:21]([C@H:29]([OH:48])[C@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16].N=[C:50]=[NH:51]>>[NH:51]1[C:50]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C@@H:29]([OH:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:44])[CH3:45])[NH:42][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: N=C=N
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cc2ccccc2[nH]1)C(C)C

Procedure:
Indole-2-carboxylic acid was coupled to the resultant compound of Example 319 using the carbodiimide coupling procedure of Example 55 to provide the desired compound.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>>[CH3:3][C:2]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:19]2[CH2:20][O:21]2)=[CH:14][CH:15]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: ClCC1CO1
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Product: CC(C)(c1ccccc1)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-(1-methyl-1-phenyl-ethyl)-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:11][CH:10]=2)([O:3]CC)=[O:2].Cl>C(O)C.[OH-].[Na+].O>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:1]([OH:3])=[O:2]
Reactant: CCOC(=O)c1cnc2ccc(C3CCCCC3)cc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2ccc(C3CCCCC3)cc2c1O

Procedure:
A solution of 11 g of 3-carboethoxy-4-hydroxy- 6-cyclohexyl-quinoline in 300 ml of ethanol and 50 ml of 10 N sodium hydroxide solution is heated for 3 hours on a water bath. It is then diluted with 200 ml of water and the clear solution is acidified with concentrated hydrochloric acid, whereupon a solid precipitate results. This is filtered off and recrystallised from ethanol or dimethylformamide, and gives 4-hydroxy-6-cyclohexyl-quinoline-3-carboxylic acid in the form of pale yellow crystals of melting point 263°-265°C.
Reaction SMILES: [CH2:1]1[C:13]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH2:3][CH2:2]1.[H][H]>CO.O=[Pt]=O>[CH2:1]1[C@@H:13]2[C@H:4]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: c1ccc2nc3c(cc2c1)CCC3
Agent: O=[Pt]=O
Solvent: CO
Product: c1ccc2c(c1)C[C@@H]1CCC[C@H]1N2

Procedure:
The title compound was prepared by catalytic hydrogenation of 2,3-dihydro-1H-cyclopenta[b]quinoline (0.5 g, 2.43 mmol) in the presence of PtO2 and hydrogen (45 psi) in methanol (50 ml) to give the cis and trans isomers. Separation by flash chromatography (10–30% ethyl acetate/petroleum ether) gave the title compounds as light yellow solids (75%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Methyl 3-amino-2-fluorobenzoate hydrochloride (7.77 g, 0.037 mol) was suspended in methylene chloride (100 ml), and pyridine (6.94 g, 0.085 mol) was added dropwise thereto. Benzoyl chloride (5.78 g, 0.041 mol) was added dropwise to this reaction mixture under cooling, and the mixture was agitated overnight at room temperature. After completion of the reaction, the reaction mixture was washed sequentially with a 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and the reaction mixture was dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and then the filtrate was concentrated under reduced pressure. The concentration residue was recrystallized from ethyl acetate, as a result of which 8.79 g (yield: 85%) of the indicated compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH:25]4OCCC[O:26]4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH:25]=[O:26])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCCO4)CC3)CC2)CC1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC=O)CC3)CC2)CC1

Procedure:
To 140 g (333 mmol) of trans-4-(trans-4-(trans-4-(2-(1,3-dioxane-2-yl)ethyl)cyclohexyl)cyclohexyl)cyclohexane carboxylic acid methyl ester dissolved in 1.5 liters of toluene were added 153 g (3330 mmol) of formic acid and the mixture was heated under reflux for one hour. The reaction solution was washed three times with 500 ml of an aqueous saturated sodium carbonate and then with 750 ml of water, and dried over anhydorus magnesium sulfate. Distilling off the solvent under reduced pressure gave 90.0 g of crude trans-4-(trans-4-(trans-4-(2-formylethyl)cyclohexyl)-cyclohexyl)cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4C(=O)C5C(=CC=CC=5)C4=O)[N:17]=[C:13]3[N:12]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[C:11]([CH3:39])=[C:10]2[C:40]#[N:41])=[C:5]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:4]=1)#[N:2].O.NN.Cl>C(O)C>[NH2:18][C:16]1[N:17]=[C:13]2[N:12]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)[C:11]([CH3:39])=[C:10]([C:40]#[N:41])[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[S:42]([CH3:45])(=[O:44])=[O:43])[N:14]2[N:15]=1
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 85 °C

Procedure:
In a pressure-proof glass tube, (rac)-7-[4-cyano-2-(methylsulfonyl)phenyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (10 mg, 16 μmol) was initially charged in abs. ethanol (3 ml). Hydrazine hydrate (1.3 μl, 27 μmol, 1.7 eq.) was added, and the mixture was heated at 85° C. for 1 h. The reaction mixture was concentrated under reduced pressure, the residue was taken up in DMF (1 ml), 1 N hydrochloric acid (32 μl, 2 eq.) was added and the product was purified by preparative HPLC (Reprosil C18 column, 10 μm, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (7.9 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][CH3:6].[S:11](N)(N)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:6][N:5]1[CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[NH:1][S:11]1(=[O:13])=[O:12]
Reactant: NS(N)(=O)=O
Reactant: CNCc1ccccc1N
Solvent: c1ccncc1
Product: CN1Cc2ccccc2NS1(=O)=O

Procedure:
2-Amino-N-methyl-benzylamine (3.7 g;27mmol) and sulfamide (5.2 g: 54 mmol) were dissolved in pyridine (40 ml). Mixture was refluxed for 3 hours, then the solvent was removed in vacuo, and water (50 ml) was added. Reaction mixture was extracted with ethyl acetate. Extract was dried over magnesium sulfate and solvent was evaporated off. Crude product was recrystallized from chloroform-hexane, to give the product, (4.4 g).
Reaction SMILES: [CH3:1][P:2]([C:5]1[N:6]=[C:7]([O:12][CH3:13])[C:8](N)=[N:9][CH:10]=1)([CH3:4])=[O:3].Cl[C:15]1[N:20]=[C:19]([Cl:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:21][C:19]1[C:18]([C:22]([F:24])([F:23])[F:25])=[CH:17][N:16]=[C:15]([C:8]2[C:7]([O:12][CH3:13])=[N:6][C:5]([P:2]([CH3:4])([CH3:1])=[O:3])=[CH:10][N:9]=2)[N:20]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1nc(P(C)(C)=O)cnc1N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in Example 33: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, is allowed to stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature and filtered to obtain a white solid. The white solid is washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid is dried under vacuum to yield 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:22]([C:30]1[CH:31]=[C:32]([CH2:36][C:37](O)=[O:38])[CH:33]=[CH:34][CH:35]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([C:30]1[CH:31]=[C:32]([CH2:36][C:37]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=3)=[O:9])[CH:3]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(=O)c4ccccc4)c3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 2-(3-benzoylphenyl)acetic acid to afford the title compound in 86% yield, 31 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:37])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@@H]1CC(NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of (1R,2S,SR)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate (460 mg, 1.0 mol) (from Example 12b, Step 6 above) in CH2Cl2 was treated with a solution of 37% aq formaldehyde (1 ml) and NaBH(OAc)3 (436 mg, 2.0 mol) and stirred at room temperature overnight. The solution was diluted with CH2Cl2 (50 ml) and washed with 1 N NaOH, water, brine, concentrated in vacuo and the residue chromatographed (1:9:90 NH4OH:MeOH:CH2Cl2) to give 330 mg (70%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)-cyclohexanecarboxylate. MS found: (M+H)+=460.49
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:36]=[CH:35][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])=[O:25])=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2]>C1COCC1.CO.O.[OH-].[Li+]>[C:1]([C:3]([C:6]1[CH:36]=[CH:35][C:9]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[S:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])=[O:25])=[N:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc2)s1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-(5-(4-(4-(2-cyanopropan-2-yl)benzamido)phenyl)thiazole-2-carboxamido)-3-methylbutanoate (Example 85, 65 mg) in THF (1 ml), methanol (1 ml) and 1M lithium hydroxide monohydrate (0.51 ml) was added and reaction mixture was stirred overnight at RT. Organic solvent was concentrated and added water, dilute HCl was added under stirring to pH acidic. The reaction mixture was filtered, to obtain the title compound. Yield: 22 mg (35%). 1HNMR (DMSO-d6, 300 MHz): δ 13.0 (bs, 1H), 10.49 (s, 1H), 8.4 (s, 1H), 8.37 (d, 1H), 8.04 (d, 2H), 7.93 (d, 2H), 7.81 (d, 2H), 7.71 (d, 2H), 4.31 (m, 1H), 2.25 (m, 1H), 1.74 (s, 6H), 0.97 (m, 6H); MS (ES+) m/z 491.2 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([C:52]([F:55])([F:54])[F:53])=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40](O)=[O:41]>>[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([C:52]([F:55])([F:53])[F:54])=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:41]
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5nnnc5C(F)(F)F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 51.1 using 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoic acid to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[N:8][CH:9]=1.SC[C@H]([C@@H](CS)O)O.ClC1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH3:37])=[O:35])[C:29]=1[F:38].[OH-].[Na+]>CO>[F:38][C:29]1[C:30]([C:34]([O:36][CH3:37])=[O:35])=[N:31][CH:32]=[CH:33][C:17]=1[S:16][C:13]1[S:12][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[CH:9][N:8]=2)=[N:15][CH:14]=1
Reactant: COC(=O)c1nccc(Cl)c1F
Reactant: COCc1ccc(Nc2ncc(SC#N)s2)nc1
Agent: O[C@H](CS)[C@H](O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1ccc(Nc2ncc(Sc3ccnc(C(=O)OC)c3F)s2)nc1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
A suspension of N-(5-(methoxymethyl)pyridin-2-yl)-5-thiocyanatothiazol-2-amine (0.109 g, 0.392 mmol) in methanol (15 mL) was bubbled with argon for 10 minutes and then treated with dithiothreitol (0.079 g, 0.510 mmol). The reaction was stirred at 23° C. for 10 minutes, then methyl 4-chloro-3-fluoropicolinate (0.0743 g, 0.392 mmol) was added, followed by aq. NaOH (1N, 0.43 mL, 0.431 mmol). The resulting brown solution was stirred for 45 minutes, then concentrated to about one quarter of the volume, diluted in water (15 mL) and neutralized with aq. sat. ammonium chloride. The precipitate was filtered to give the crude title material (0.062 g, 39%) as a solid which was used as such in the next reaction. HPLC ret. time (Condition A): 1.625 min. LC/MS (M+H)+: 407.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:17])([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:5]([F:7])[F:6].[CH3:18][C:19]([CH3:21])=[O:20]>O>[F:3][C:4]([F:17])([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:16][C:9](=[O:1])[CH:10]=[CH:11][C:12]2[CH:15]=[CH:21][C:19]([O:20][C:4]([F:3])([F:17])[CH:5]([F:6])[F:7])=[CH:18][CH:13]=2)=[CH:11][CH:10]=1)[CH:5]([F:7])[F:6]
Reactant: O=Cc1ccc(OC(F)(F)C(F)F)cc1
Reactant: CC(C)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(C=Cc1ccc(OC(F)(F)C(F)F)cc1)C=Cc1ccc(OC(F)(F)C(F)F)cc1
Yield: 25 %

Procedure:
Aqueous sodium hydroxide (28.1 ml; 10%) is added dropwise, rapidly, to a stirred mixture of p-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (11 ml; 0.069 mole), acetone (2.4 ml; 0.33 mole), absolute alcohol (135 ml) and water (14 ml). The reaction mixture exotherms to 30° C. The reaction mixture is then cooled, the precipitated material is filtered, washed and dried to afford 3.8 g (25%) of title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH2:18][CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:16]2[CH2:17][CH2:18][O:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)OC1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CCOC2)CC1

Procedure:
To tetrahydro-furan-3-ol (1.0 g, 11.4 mmol) in anhydrous dichloromethane (15 mL) with triethylamine (2.37 mL, 17.03 mmol), was added methane sulfonyl chloride (12.5 mmol) at 0° C. The reaction mixture was stirred at RT for 3.5 hours, diluted with dichloromethane (50 mL) and washed with water. The organic phase was dried (MgSO4) and evaporated in-vacuo to give methanesulfonic acid tetrahydro-furan-3-yl ester as light orange oil (1.68 g, 89%). A mixture of piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5.38 mmol), methanesulfonic acid tetrahydrofuran-3-yl ester (1.07 g, 6.45 mmol) and K2CO3 (2.96 g, 21.5 mmol) was stirred in anhydrous acetonitrile (50 mL) under reflux conditions for 12 hours. The reaction mixture was cooled and poured onto water and extracted with dichloromethane to give after silica chromatography, 4-(tetrahydro-furan-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, as a colourless oil (0.57 g, 41%).