Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS.C(=O)([O-])[O-].[K+].[K+].ClC1C(Cl)=CC(C(OC)=O)=C(C)C=1C1CCON=1.Cl[C:28]1[C:29]([CH3:44])=[C:30]([C:39]2[CH2:43][CH2:42][O:41][N:40]=2)[C:31]([CH3:38])=[C:32]([CH:37]=1)[C:33]([O:35][CH3:36])=[S:34]>CN(C=O)C>[O:41]1[CH2:42][CH2:43][C:39]([C:30]2[C:31]([CH3:38])=[C:32]([CH:37]=[CH:28][C:29]=2[CH3:44])[C:33]([O:35][CH3:36])=[S:34])=[N:40]1
Reactant: COC(=S)c1cc(Cl)c(C)c(C2=NOCC2)c1C
Agent: COC(=O)c1cc(Cl)c(Cl)c(C2=NOCC2)c1C
Agent: CS
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=S)c1ccc(C)c(C2=NOCC2)c1C
Temperature: 25 °C

Procedure:
10 ml of degassed DMF was placed in a colorless, transparent glass container, and 420 mg of methyl mercaptan was blown in to dissolve. Then 600 mg of potassium carbonate and 500 mg of methyl 4,5-dichloro-3-(2-isoxazolin-3-yl)-2-methylbenzoate were added one by one. The resulting solution was stirred with a Teflon magnetic stirrer at room temperature with light shielded under the nitrogen atmosphere. After stirring it for an hour, it was confirmed by NMR that methyl 5-chloro-3-(2-isoxazolin-3-yl)-2-methyl-4-methylthiobenzoate was a major product. Succeedingly, the reaction system was stirred at 40° C. for 2 hours, while irradiating with white fluorescent light. The reaction solution was poured into ice-water, and extracted with ether-chloroform (5:1) and then with ether. The organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (elution with n-hexane/ethyl acetate=95/5) to give 424 mg of the title compound as white crystals. Melting point: 109-111° C.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[C:10]([C:14]1[CH:15]=[C:16]([NH2:31])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1.O>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:31][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH:15]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(N3CCOCC3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(N3CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
2,2,2-Trichloroethylchloroformate (175 mg, 0.82 mmol) was added dropwise to a solution of Intermediate 23d (190 mg, 0.63 mmol) and DIPEA (244 mg, 1.89 mmol) in THF (10 mL), and the mixture stirred at RT for 1.5 h. The mixture was diluted with water and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (140 mg, 46%). LCMS (Method 4): Rt 3.94, m/z 475 [MH+].
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH3:15][C@H:16]([CH2:20][CH2:21][CH:22]=[C:23](C)[CH3:24])[CH2:17]CO.O(C)[Na].O>C1CCCCC1.CCOCC>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH2:13][C@H:23]([CH3:24])[CH2:22][CH2:21][CH:20]=[C:16]([CH3:17])[CH3:15])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)=CCC[C@@H](C)CCO
Reactant: CCOC(=O)C(=O)C1CCC(C)CC1
Agent: CO[Na]
Solvent: O
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(C)=CCC[C@@H](C)CCOC(=O)C(=O)C1CCC(C)CC1
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of ethyl 2-(4-methylcyclohexyl)-2-oxoacetate (5.0 g, 25 mmol), of (R)-3,7-dimethyl-6-octenol (4.74 g, 30 mmol) and NaOCH3 (0.5 ml, 30% in methanol) in cyclohexane (50 ml) was heated with a water separator under reflux for 2 days. After cooling to room temperature, ether was added and the organic phase washed with a saturated solution of NaCl, dried (Na2SO4), filtered and concentrated. Column chromatography (SiO2, heptane/ether 7:3 and heptane/ether 95:5) gave 1.16 g (15%) of the pure product a colorless oil as a mixture of cis/trans isomers (ca. 1:3).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 85 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D44) (630 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (560 mg) and tripotassium phosphate (1237 mg) in N,N-dimethylformamide (DMF) (5 mL) and water (1.25 mL) stirred under nitrogen was added Pd(Ph3P)4 (225 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was concentrated and purified by column chromatography to give 5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D54) (670 mg) as a colorless oil. MS (ES): C23H23N3O2S requires 405. found 406.2 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][CH:4]([NH:6]S(C)(=O)=O)[CH2:3]1.[CH3:12][O:13][C:14](=[O:27])[C:15]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](F)=[CH:17][C:16]=1[CH3:26].C(N=C(N(C)C)N(C)C)(C)(C)C>CN1C(=O)CCC1>[CH3:12][O:13][C:14](=[O:27])[C:15]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[C:18]([NH:6][CH:4]2[CH2:3][C:2]([F:1])([F:11])[CH2:5]2)=[CH:17][C:16]=1[CH3:26]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Reactant: CS(=O)(=O)NC1CC(F)(F)C1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(NC2CC(F)(F)C2)cc1C
Temperature: 150 °C
Reaction time: 6 h
Yield: 17.5 %

Procedure:
0.70 g of N-(3,3-Difluoro-cyclobutyl)-methanesulfonamide, 0.93 g of 4-fluoro-5-methanesulfonyl-2-methyl-benzoic acid methyl ester, and 1.5 ml of N″-tert-butyl-N,N,N′,N′-tetramethyl-guanidine were dissolved using 10 ml NMP (anhydrous) and stirred for 6 h at 150° C. The reaction mixture was cooled to ambient temperature and 200 ml of EE added. This solution was washed three times using 20 ml of a saturated aqueous NaHSO4-solution each time. Thereafter, the organic layer was washed three times using 30 ml of a saturated aqueous Na2CO3-solution each time. The organic layer was dried over MgSO4 and the solvent removed in vacuo. Chromatography on silica gel using DIP yielded 220 mg of a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.Cl[CH:17]([CH3:19])[CH3:18].ClC1N=CC2C(C(=O)C)=CN(C3CCCC3)C=2N=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:17]([CH3:19])[CH3:18])=[CH:9][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1
Reactant: CC(C)Cl
Reactant: Clc1ncc2ccn(C3CCCC3)c2n1
Agent: CC(=O)c1cn(C2CCCC2)c2nc(Cl)ncc12
Product: CC(C)c1cn(C2CCCC2)c2nc(Cl)ncc12

Procedure:
2-Chloro-7-cyclopentyl-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidine is prepared from 2-chloro-7-(cyclopentyl)-7H-pyrrolo[2,3-d]pyrimidine and 2-chloropropane using a method similar to that for the preparation of 1-(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone given in Example 325.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[C:29]2[NH:36]N>>[F:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[C:29]2[N:36]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccnc2ccc(F)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccc(F)cc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=462.3 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27]O)[CH:24]=[CH:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][O:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:19])[CH:14]=1
Reactant: OCc1cccc(Cl)c1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4cccc(Cl)c4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (3-chlorophenyl)methanol (56 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (36 mg).
Reaction SMILES: C[CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][C:35]=4[F:63])[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[OH:64])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:64][C@@H:14]1[CH2:15][C@H:16]2[C@:21]([CH3:22])([CH2:20][CH2:19][C@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]3[CH:39]=[CH:38][C:37]([C@H:40]4[CH2:57][C@@:55]5([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]5([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]5[C:41]4=[C:42]4[C:47]([CH2:48][CH2:49]5)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]4)=[CH:36][C:35]=3[F:63])[CH3:33])[CH2:17]2)[C@@H:23]2[C@@H:13]1[C@H:12]1[C@:26]([CH3:27])([C@@H:25]([OH:28])[CH2:24]2)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:2][C:3]([OH:5])=[O:4])[CH2:10][CH2:11]1
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)c(F)c3)C[C@@]21C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]45)c(F)c3)C[C@@]21C
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
The compound of Example 3D (360 mg, 0.408 mmol) was dissolved in 6 ml of THF and CH3OH (1:1). Then 2.5 ml of LiOH solution (1M, aqueous) was added at 0° C. The resulting mixture was stirred for 5 hour at ambient temperature. The organic solvent was removed in vacuo, and enough water was added to make one phase. The solution was acidified with acetic acid to precipitate a light yellow solid, which was extracted with EtOAc (3 times). The combined organic layer was washed with brine and dried over Na2SO4 Concentration in vacuo gave the title compound (350 mg, 98% yield). 1H NMR (300 MHz, CDCl3) δ 6.83–6.74 (m, 3 H), 5.78 (s, 1 H), 4.34 (d, J=7.2 Hz, 1 H), 3.98 (m, 1 H), 3.84 (m, 1 H), 3.52–3.33 (m, 5H), 2.92 (s, 3H), 2.80–1.10 (m, 44H), 1.89 (s, 3H), 0.99 (d, J=6.0 Hz, 3 H), 0.89 (s, 3 H), 0.69 (s, 3 H), 0.55 (s, 3 H); MS (ESI) m/e 868 (M+H)+, 866 (M−H)—.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(=O)C>[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 69.9 %

Procedure:
In 100.4 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 27.7 g (0.1 mole) of L-phenylalanine methyl ester sulfate was added at 10°-15° C. Successively 11.1 g (0.105 mole) of sodium carbonate was added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. Thereafter 75.3 g of water was added and cooled to 0°-5° C. Precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 29.9 g (69.9% yield on L-phenylalanine methyl ester sulfate).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:4].[OH-].[Na+].OS([O-])(=O)=O.[K+].CCOC(C)=O>C1COCC1.CCO>[C:33]([O:32][C:30]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C(=O)O
Yield: 103.5 %

Procedure:
A solution of 14.7 g (29.2 mmol) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was dissolved in 660 ml THF/EtOH (1:1) and treated at RT with 58.4 ml (58.4 mmol) aqueous 1 N NaOH. After 2 h the reaction was poured into aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl solution and dried over Na2SO4 to give 14.8 g (quantitativ) of (2S,4R)-4-Tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. MS: 488 (M-H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:33])[C:30]([OH:32])=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][O:59][C:60]1[CH:67]=[C:66]([O:68][CH3:69])[CH:65]=[CH:64][C:61]=1[CH2:62][NH2:63].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:33])[C:30]([NH:63][CH2:62][C:61]3[CH:64]=[CH:65][C:66]([O:68][CH3:69])=[CH:67][C:60]=3[O:59][CH3:58])=[O:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(O)C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)N1C(=O)[C@@](C)(CC(O)C(=O)NCc2ccc(OC)cc2OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.1 h

Procedure:
To a solution of 43 mg (0.09 mmol) of 3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanoic acid (Example 81, Step B) in DMF (5 mL) was added 67 mg (0.18 mmol) of HATU, 58.5 mg (0.35 mmol) of 2,4-dimethoxybenzylamine and 36 μL (0.26 mmol) of triethylamine. The resulting yellow solution was stirred at room temperature for 1.1 h, and then was partitioned between saturated aqueous sodium bicarbonate and EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound (mixture of alcohol epimers) was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([OH:16])[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].I[CH2:20]C>CN(C=O)C.CCOC(C)=O>[CH3:20][O:16][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[C:10]2[C:5]=1[NH:4][N:3]=[C:2]2[CH3:1]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c2[nH]nc(C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a 0° C. solution of ethyl 3-methyl-7-hydroxy-1H-indazole-5-carboxylate (0.84 g, 3.8 mmol) in DMF (25 mL) was added 60% oil dispersion of NaH (152 mg, 3.81 mmol). After stirring for 1 hour at 0° C., a solution of iodoethane (595 mg, 0.31 mL, 3.81 mmol) in DMF (3 mL) was added. The mixture was kept at 0° C. for several hours before allowing the mixture to warm to room temperature while stirring overnight. Dilute with EtOAc, wash with saturated aqueous NaHCO3, water, saturated aqueous NaCl and the organic extract was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (80 g column, 0-30% EtOAc/hexanes gradient) to provide ethyl 7-methoxy-3-methyl-1H-indazole-5-carboxylate (516 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[CH3:30][Mg]Br>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:10])[CH3:30])=[C:4]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[N:3]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(Cl)c2C=O)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(Cl)c2C(C)O)cc1

Procedure:
Procedure as above with 2-Amino-4-chloro-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde (0.20 g; 0.48 mmol) and 3.0 M methyl magnesium bromide (3 eq; 0.5 ml). Product obtained as a colourless glass (0.159 g; 0.37 mmol; 77%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:29])([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH3:29]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=409.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(2-aminoethyl)morpholine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a light yellow rigid foam: 1H NMR (CDCl3) δ 10.41 (1H, m), 8.57 (1H, s), 7.15 (2H, dd, J=8.5, 6 Hz), 7.03 (3H, m), 4.92 (2H, s), 4.12 (2H, s), 3.99 (4H, m), 3.89 (2H, q, J=6 Hz), 3.72 (2H, m), 3.50 (2H, m), 3.46 (2H, m), 3.35 (2H, t, J=6 Hz), 2.93 (2H, br), 1.70 (2H, m), 1.61 (2H, m), 1.53 (2H, m); HRMS calcd for C29H34FN5O5+H+: 552.2622. Found: 552.2618 .
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH2:26])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([C:34]2[S:35][C:36]([CH:39]=O)=[CH:37][N:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH:26][CH2:39][C:36]4[S:35][C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[N:38][CH:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=Cc1cnc(-c2ccccc2)s1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NCc4cnc(-c5ccccc5)s4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 21, Step 5, using the following starting materials: 1-[4′-(5-amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-thiazole-5-carbaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=Cc1cc(OC)ccc1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cc(OC)ccc1F
Reaction time: 15 h
Yield: 92 %

Procedure:
To a solution of ethyl 3-(2-fluoro-5-methoxyphenyl)acrylate (224 mg) in ethanol (50 mL) was added 10% palladium-activated carbon (24 mg), and the mixture was stirred for 15 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (208 mg) as a colorless oil. This compound was used for the next step without further purification.