Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C@H:22]1[CH2:26][N:25]([C:6](=[O:8])[CH2:5][CH2:4][C:3](=[O:2])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: Cl
Product: O=C(CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1ccccc1
Yield: 39.7 %

Procedure:
Proceeding as in Example 1, but substituting 4-oxo-4-phenylbutanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 124, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxo-4-phenylbutanoyl)pyrrolidine-2-carboxamide (13.1 mg, 39.7%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.87 (s, 1H), 7.94-7.99 (m, 2H), 7.60-7.605 (m, 2H), 7.50-7.56 (m, 3H), 7.30-7.34 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.46 (m, 1H), 3.73 (m, 1H), 3.28 (m, 4H), 3.13 (m, 1H), 2.66 (m, 3H), 1.93 (m, 2H). MS (EI) for C34H31FN2O4. found 551.6 (MH+).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(O)=O.[OH:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:16]=1.[S:26]([NH:36][C@H:37]([C:39](Cl)=[O:40])[CH3:38])([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>O1CCCC1>[S:26]([NH:36][C@H:37]([C:39]([O:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:16]=1)=[O:40])[CH3:38])([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:27])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Reactant: Oc1c[nH]c(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Oc2c[nH]c(-c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of anhydrous tetrahydrofuran (THF, 450 mL), pyridine (43.8 mL; 0.542 mol; 1.2 eq) and trifluoroacetic acid (85.0 mL; 1.10 mol; 2.4 eq), maintained at 0° C. under an inert gas atmosphere, was treated in one portion with 3-hydroxy-5-phenylpyrrole (3) (71.5 g; 0.45 mol; 1.0 eq) followed immediately by the dropwise addition, over 5-10 minutes of a solution of freshly prepared N-tosyl-L-alaninyl chloride (141.0 g; 0.54 mol; 1.2 eq) in anhydrous THF (450 mL). The resulting mixture was stirred for 15 minutes at 0° C. The reaction was then quenched by addition of a solution of 1.0M aqueous citric acid (315 mL) and EtOAc (1.35 L). After brief mixing the phases were separated and the organic layer washed with a solution of aqueous NaCl (360 mL; 0.18 g NaCl per mL of water). The organic layer was next extracted twice with a solution of 5% aqueous NaHCO3 (1.35 L each), and then washed with another portion of aqueous NaCl (360 mL; 0.18 g NaCl per mL of water). The reddish brown organic layer was stirred at ambient temperature for 15 minutes with MgSO4 (101 g) and Darco-G60 (143 g), then filtered through Celite and evaporated to dryness in vacuo from a 37° bath to give (4) as a pinkish-white solid. The crude product was ground to a powder and dissolved in warm (50° C.) THF (250 mL), stirred vigorously and diluted with n-hexane (250 mL). The stirring was continued for 1 hour at ambient temperature as the product crystallized. The solid was filtered, washed with toluene (about 1.0 L) until the filtrate was colorless, then dried in vacuo overnight to yield the title compound (112 g; 65%) as a white powder with mp=154.5°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:12]=O)[CH:10]=O)=[CH:5][CH:4]=1.[NH2:14][NH2:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:12]=[N:14][NH:15][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C=O)C=O)cc1
Reactant: NN
Solvent: CCO
Product: COc1ccc(-c2cn[nH]c2)cc1
Temperature: 0 °C

Procedure:
The (4-methoxyphenyl)malonaldehyde (1.5 g, 8.42 mmol) was dissolved in ethanol (10 mL), followed by addition of hydrazine (540 mg g, 16.8 mmol). The pale yellow solution was heated in a microwave sealed tube at 110° C. overnight. Large amount of white crystalline solid formed. The reaction mixture was cooled to 0° C. The white solid was collected by filtration and was washed with 5 mL of ice-cold ethanol to give the desired product, which was further dried under high vacuum pump.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[CH3:18][O-:19].[Na+].CO>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([O:19][CH3:18])=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2nc(OC)ncc2I)cn1
Temperature: 140 °C
Yield: 90.6 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), sodium methoxide (0.5 M solution in methanol, 0.043 mL, 0.749 mmol) and methanol (1 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 15 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-2-methoxy-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (162 mg, 0.452 mmol, 91% yield). 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H); 8.26 (d, J=2.05 Hz, 1H); 7.83 (dd, J=8.84, 2.56 Hz, 1H); 6.87 (s, 1H); 6.78 (d, J=8.77 Hz, 1H); 3.94 (s, 3H); 3.89 (s, 3H). m/z (ESI, +ve ion) 359.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[CH:14]([O:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21])([CH3:16])[CH3:15]>>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:18]=3[O:17][CH:14]([CH3:16])[CH3:15])=[O:21])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc2c(c1)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(N(C)C)cc2C1

Procedure:
Prepared in analogy to example 1.1 from dimethyl-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-amine (CA [138276-84-3]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[N:13]=[C:12]2S)[CH:5]=1.[N+]([O-])(O)=O.N([O-])=O.[Na+].[OH-].[Na+]>O.CC(O)=O>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][C:6]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12]1
Reactant: COC(=O)c1ccc(C)c(-n2cc(-c3cccnc3)nc2S)c1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-n1cnc(-c2cccnc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a suspension of 85 mg (0.261 mmol) of 3-(2-mercapto-4-pyridin-3-yl-imidazol-1-yl)-4-methyl-benzoic acid methyl ester in 1.8 mL of water was added 0.68 mL of concentrated HNO3 and 2 mg of NaNO2. After 2 h, the mixture was cooled to 0° C. and 4N NaOH was added until the pH reached about 10. The mixture was stirred for 30 min then HOAc was added until the pH reached about 6. The resulting precipitate was filtered, washed with water and dried to provide 16 mg (0.057 mmol; 22%) of 4-methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzoic acid.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:6][C:7]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:8]=1[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])[CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:48]CCCl>C(Cl)(Cl)(Cl)Cl>[Cl:48][CH2:2][C@@H:3]([NH:6][C:7]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:8]=1[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])[CH2:4][CH3:5]
Reactant: CC[C@@H](CO)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2
Reactant: ClCCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@@H](CCl)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2

Procedure:
To a solution of (S)-2-[1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (127 mg) in 1,2-dichloroethane (4 mL) and carbontetrachloride (2 mL) was added triphenylphosphine (215 mg), and the mixture was stirred for an hour under reflux. The solvent was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give (S)-2-[1-(chloromethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (71 mg) as a solid substance.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1CCOCC1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (500 mg) in dry N,N-dimethylformamide (8 ml) at room temperature and under nitrogen was added potassium carbonate (1.17 g) in one go. The reaction was stirred at 60° C. for 1.5 hours and then cooled to room temperature. 4-(bromomethyl)tetrahydro-2H-pyran (0.3 ml) was added in one go and the reaction heated at 50° C. overnight. The reaction was diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic layer was separated and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford the title compound as a yellow viscous oil (315 mg, 90% clean).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15]CC)=[O:14])[CH2:11][CH2:10][C@@H:9]1[C:18]([O:20]CC)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(C(NNCCC(NCC2C=CC=CC=2)=O)=O)CC1>Cl>[CH2:1]([N:8]1[C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][C@@H:12]1[C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](C(=O)OCC)N1Cc1ccccc1
Agent: Cl
Agent: O=C(CCNNC(=O)C1CCCCC1)NCc1ccccc1
Product: O=C(O)[C@H]1CC[C@@H](C(=O)O)N1Cc1ccccc1

Procedure:
The first step in the preparation of this compound was to prepare diethyl cis-N-benzylpyrrolidine-2,5-dicarboxylate from diethyl meso-α,α'-dibromoadipate (see Example 1) as described by G. Cignarella and G. Nathansohn in J. Org. Chem., 26, p 1500, 1961. Diethyl cis-N-benzylpyrrolidine-2,5-dicarboxylate (103.5 g, 0.340 mole) was then heated in 1 liter concentrated hydrochloric acid at 100° C for 2 hours. Upon cooling, a crystalline solid precipitated. It was isolated by filtration, triturated with acetone-diethyl ether, and recrystallized from ethanol-water to give 41.3 g (49%) of partially hydrated product, melting point 254°-258° C. An infrared spectrum analysis gave λmax.Nujol = 2.95 μ (O--H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:13]#[CH:14]>>[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:3])[CH2:17][CH2:16]1)[C:13]#[CH:14]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Product: C#CCC1CCN(C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
4-(chloro)phenyl chloroformate (5.00 g, 26.2 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (5.50 g, 20.1 mmol) according to general procedure 1. Yield=4.83 g, 86%. m/z MH+=278.13. HPLC rt=13.0 min.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])O[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].[CH2:15]1[C@@H:18](C(O)=O)[NH:17][CH2:16]1>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[C:7]2[C:8](=[O:13])[N:17]3[CH2:18][CH2:15][C@H:16]3[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: O=c1[nH]c2ccc(F)c(F)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)c(F)c2C(=O)N2CC[C@@H]12
Yield: 68.3 %

Procedure:
A solution of 19.6 g (98.4 mmol) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione and 9.95 g (98.4 mmol) of L-azetidine-2-carboxylic acid in 125 ml of dimethylformamide and 25 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 16 g (68%) of (S)-5,6-difluoro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione as colourless needles of m.p. >250°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][C:12]([C:15]([CH3:17])=[CH2:16])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:25]([O:24][C:22]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:13][N:14]=1)=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: C=C(C)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C(=O)OC)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(C(C)C)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.1 %

Procedure:
A solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-(prop-1-en-2-yl)pyrazine-2-carboxylate (323 mg, 0.82 mmol) in MeOH (4 ml) was charged under an argon atmosphere at r.t. with Pd/C 10% (30 mg, 0.28 mmol). The reaction mixture was stirred at r.t. under a hydrogen atmosphere for 15 h, filtrated and the solvent was removed to yield the product as yellow viscous oil (302 mg, 92%) which was used without any purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH3-]C#N.[Na+]>>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2c(c1)CCN2
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one (Step 5, synthesis of Example 86) (0.24 g, 0.60 mmol) in ACOH (5 mL) was added NaCNBH3 (0.06 g, 1.0 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc, and the precipitate was collected by filtration. Trituration with CH2Cl2 afforded 3-Chloro-4-(2,4-difluorobenzyl-oxy)-1-(2,3-dihydro-1H-indol-5-ylmethyl)-1H-pyridin-2-one as a white solid (0.2 g, 81%): mp 137-139° C.; 1H NMR (300 MHz, CDCl3) δ 7.51 (app q, J=9 Hz, 1H), 7.21 (d, J=6 Hz, 1H), 7.11 (s, 1H), 6.99-6.80 (m, 3H), 6.57 (d, J=9 Hz, 1H), 6.08 (d, J=9 Hz, 1H), 5.18 (s, 2H), 5.02 (s, 2H), 3.83 (br s, 1H), 3.55 (t, J=9 Hz, 2H), 2.99 (t, J=9 Hz, 2H). ES HRMS m/z 403.1022 (M+H C21H18ClF2N2O2 requires 403.1019).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].CS[C:24]1[NH:25][CH:26]=[C:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35](=[O:38])[NH:36][CH:37]=2)[C:28](=[O:30])[N:29]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:24]3[NH:25][CH:26]=[C:27]([CH2:31][C:32]4[CH:33]=[N:34][C:35](=[O:38])[NH:36][CH:37]=4)[C:28](=[O:30])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2cnc(=O)[nH]c2)c[nH]1
Solvent: c1ccncc1
Product: O=c1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c[nH]1
Temperature: 150 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.380 mmol, 1.00 eq) and 2-methylsulfanyl-5-(2-oxo-1,2-dihydro-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.240 mmol, 0.63 eq) were dissolved in dry pyridine (300 μL) and stirred at 150° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-10% in 25CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]ethylamino}-5-(2-oxo-1,2-dihydro-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.041 mmol, yield: 11%, HPLC-MS/UV:[M+H]+=518.047; rt: 10.97 mins; purity: 85%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.80 (t, J=6.50, 2H), 3.19-3.22 (m, 2H), 3.41-3.52 (m, 2H), 5.39 (br.s., 1H), 6.33-6.64 (m, 1H), 6.99-7.10 (m, 2H), 7.22 (dd, J=9.24, J=3.42, 1H), 7.26-7.32 (m, 2H), 7.38-7.43 (m, 1H), 7.58-7.72 (m, 2H), 8.11 (br.s., 1H), 10.93 (br.s., 1H)
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([C:7]([N:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]([C@@H:29]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[N-:43]=[N+:44]=[N-:45].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[C:31]1([C@H:29]([N:21]([CH2:20][C@@H:11]2[C@@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:13][N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([C:1]4[NH:45][N:44]=[N:43][N:2]=4)=[CH:42][CH:41]=3)[CH2:10]2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:30])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(-c3nnn[nH]3)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 87.7 %

Procedure:
A 1.5 ml DMF solution of 72 mg of tert-butyl {[(3R,4S)-1-(4-cyanobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was mixed with 153 mg of sodium azide and 304 mg of triethylamine hydrochloride and stirred at 120° C. for 2Hours. By post-treating and purifying this in the standard method, 68 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]({(3R,4S)-4-phenyl-1-[4-(1H-tetrazol-5-yl)benzoyl]pyrrolidin-3-yl}methyl)carbamate was obtained as a yellow amorphous substance. EN: 601
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[C:13]([N+:25]([O-])=O)[C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:4].N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:25][C:13]1[C:14](=[O:24])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:8]1[CH2:7][CH2:6][C@@H:5]2[CH:3]([CH2:2][OH:1])[CH3:4]
Reactant: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
A solution of 20-hydroxymethyl-4-nitropregn-4-en-3-one (2.01 g, 5.35 mM) in absolute ethanol (28 mL) is treated sequentially with Lindlar's catalyst (5% Pd on CaCO3 with 5.2% Pb, 0.81 g) and with quinoline (37 μl) and kept under hydrogen at between 40-55 p.s.i. for 24 hours. The mixture is then filtered through celite, and the filtrate is concentrated to a yellow solid which is purified by short path chromatography to give 4-amino-20-hydroxymethylpregn-4-en-3-one, m.p. 180-185° C. (aqueous isopropanol).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH3:22][O:23][C:24](=[O:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH3:34])=[CH:29][C:28]=1[CH3:35].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CS(C)=O.CCOCC>[CH3:22][O:23][C:24](=[O:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:2][C:3]2[C:4]([CH:19]3[CH2:21][CH2:20]3)=[N:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)=[N:7][CH:8]=2)[CH3:34])=[CH:29][C:28]=1[CH3:35]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CNc1ccc(OCC(=O)OC)c(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)COc1ccc(N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
To a solution of 400 mg (1.28 mmol) 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) and 268 mg (1.28 mmol) of (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester (example 5F]) in 8 ml of DMSO was added 194 mg (1.41 mmol) potasium carbonate and 192 mg (1.28 mmol) sodium iodide. The reaction mixture was stirred for 20 min at RT. It was then taken up in ether and washed with aqueous 10% KHSO4-solution (10%) and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:3, to give 403 mg of pure (4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid methyl ester.