Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].O=[C:16]([CH:20]=[N:21][OH:22])[CH:17]=[N:18][OH:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:16]([CH:20]=[N:21][OH:22])[CH:17]=[N:18][OH:19]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(C=NO)C=NO
Solvent: CCO
Product: ON=CC(C=NO)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 2,6-dichloro-4-trifluoromethylphenylhydrazine (34 g), 2-oxopropanedial 1,3-dioxime (17 g) and ethanol (300 ml) was heated under reflux for 31/2 hours. The solvent was evaporated under reduced pressure and the residue triturated with light petroleum (bp 40°-60°) and filtered to give 2-oxopropanedial 2-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 1,3-dioxime.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([O:16]C3CCCCO3)[CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][N:26]([CH2:29][CH2:30][C@@:31]([CH3:46])([S:42]([CH3:45])(=[O:44])=[O:43])[C:32]([NH:34][O:35]C2CCCCO2)=[O:33])[C:25](=[O:47])[CH:24]=1.ONC(=O)[C@](C)(S(C)(=O)=O)CCN1C=CC(C2C=CC(OC[C@H]3CC[C@@H](O)CC3)=CC=2)=CC1=O>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][N:26]([CH2:29][CH2:30][C@@:31]([CH3:46])([S:42]([CH3:45])(=[O:43])=[O:44])[C:32]([NH:34][OH:35])=[O:33])[C:25](=[O:47])[CH:24]=1
Reactant: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](O)CC3)cc2F)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
The title (0.16 g, 62.6%) compound was prepared from (2R)-4-[4-(2-fluoro-4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.35 g, 0.516 mmol) by a procedure analogous to that described for (2R)—N-hydroxy-4-[4-{4-[(cis-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanamide, Example 8, Step F. LCMS m/z 511.7 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.25 (m, 4H) 1.57 (s, 3H) 1.60-1.75 (m, 1H) 1.83 (br. s., 4H) 2.08-2.24 (m, 1H) 2.35-2.48 (m, 1H) 3.11 (s, 3H) 3.28-3.44 (m, 1H) 3.65-3.80 (m, 1H) 3.84 (d, J=6.64 Hz, 2H) 4.01-4.22 (m, 1H) 6.47 (dt, J=7.18, 1.88 Hz, 1H) 6.53 (s, 1H) 6.87 (dd, J=8.79, 2.54 Hz, 1H) 6.94 (dd, J=13.38, 2.44 Hz, 1H) 7.51 (t, J=8.98 Hz, 1H) 7.71 (d, J=7.23 Hz, 1H) 9.24 (br. s., 1H) 11.15 (s, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:23][C:24](=[O:31])[C@@H:25]([NH:30][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH:33]([CH3:35])[CH3:34])=[CH:37][CH:38]=1)(=[O:44])=[O:43])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(C(C)C)cc1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
Using a procedure similar to that described in Example 36, the product from Example AI ([S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.20 g, 0.45 mmol) and 4-isopropylphenylsulfonyl chloride (0.10 g, 0.45 mmol) were coupled to give the title compound as a white solid (0.20 g, 71%), mp=147-148° C.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24](/[N:28]=[CH:29]\[NH:30]O)[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]2[N:30]=[CH:29][N:28]=[C:24]2[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ON/C=N\c1cc(OCc2ccccc2)ccn1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: c1ccc(COc2ccn3ncnc3c2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Trifluoroacetic anhydride (2.62 mL, 18.9 mmol) was added dropwise to a solution of (Z)-N′-(4-(benzyloxy)pyridin-2-yl)-N-hydroxyformamidine (4.37 g, 17.9 mmol) in THF (180 mL), and the mixture was cooled to 0° C. The ice bath was then removed and the reaction was stirred for 12 hours. The reaction was concentrated to about 15-25 mL, then poured into 400 mL of iced 1 M NaOH. The mixture was stirred for 1 hour. The resulting white solids were collected by filtration, washed with hexanes, and dried under high vacuum for 1 hour to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[H-].[Na+].Br.Br[CH2:21][C:22]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[O:23]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:21][C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Cc1ccc(C(=O)CBr)cn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CN2c3nc(Cl)cc(=O)n3CC[C@H]2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g (3.94 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one is added to a suspension of 394.27 mg (9.86 mmol) of sodium hydride in 40 mL of DMF. The reaction mixture is placed under magnetic stirring at room temperature for 15 minutes. A solution of 1.16 g (3.94 mmol) of 2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide in 10 mL of DMF is added dropwise to the reaction medium at 0° C. The reaction is stirred at room temperature overnight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 480 mg of (8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:13]([NH:15][C:16]([NH2:18])=[NH:17])#N>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[NH:10][C:5]=2[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: N#CNC(=N)N
Product: N=C(N)Nc1nc2ccc(C(F)(F)F)cc2[nH]1

Procedure:
4-Trifluoromethyl -o- phenylenediamine (25.46g) and cyanoguanidine (12.40g) were reacted together in a manner analogous to that of Example 2 to yield 5-Trifluoromethyl-2-guanidinobenzimidazole is a red gummy solid which when dissolved in 5N hydrochloroic acid and evaporated to dryness yielded the dihydrochloride (25.01g) as a brown solid, m.p. 206°-209°C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>CN1C(=O)CCC1.ClCCl>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:13]=[CH:12][N:11]=2)[N:8]=1)[C:30](=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC(=O)Cl
Reactant: CNc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: C=CC(=O)N(C)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N4-(6-(methylamino)pyridine-2-yl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (0.07 g, 0.18 mmol) in NMP (1 mL) was added acryloyl chloride (0.032 g, 0.36 mmol) at 0° C. and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane (2 mL), was washed with NaHCO3 (1 mL), water (1 mL), and brine (1 mL). The dichloromethane solution was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give N-methyl-N-(6-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyridin-2-yl)acrylamide (I-78) as a yellow solid. 1H NMR (DMSO-d6) δ ppm: 3.22 (s, 3H), 5.60 (dd, J=2.56 & 9.76 Hz, 1H), 6.12-6.16 (m, 2H), 6.79 (d, J=7.56 Hz, 1H), 6.96 (d, J=8.64 Hz, 5H), 7.09 (t, J=7.32 Hz, 1H), 7.23 (s, 1H), 7.33-7.37 (m, 4H), 7.45 (d, J=8.2 Hz, 2H), 7.32 (t, J=7.8 Hz, 1H), 8.24 (s, 1H); LCMS: m/e 439.3 (M+1).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C(Cl)CCl.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][C:25](O)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:25](=[O:26])[CH2:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[Cl:15])[CH3:2]
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)Cc1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ethanol (8.72 mL, 150 mmol), DMAP (304 mg, 2 mmol), EDC (9.56 g, 50 mmol), and triethylamine (6.91 mL, 50 mmol) were added under cooling (ice) to a solution of (2-chloro-4-methoxy-phenyl)-acetic acid (10.00 g, 50 mmol, [CAS Reg. No. 91367-09-8]) in CH2Cl2 (200 mL). The reaction mixture was stirred at r.t. overnight, then diluted (CH2Cl2), and washed (1N HCl). The organic layer was dried (Na2SO4), and the solvent was evaporated. Purification of the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-70:30) gave the title compound (7.27 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.18 (1H, d), 6.94 (1H, d), 6.79 (1H, dd), 4.17 (2H, q), 3.79 (3H, s), 3.69 (2H, s), 1.26 (3H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: O=c1cnccn1-c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2ccncc2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 520 mg 1-(4-Nitro-phenyl)-1H-pyrazin-2-one in 26 mL ethyl acetate and 1.3 mL ethanol, 2.7 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 6 h. Then, after cooling to RT the mixture was stirred for 16 h. The precipitated product was collected by filtration and was pure enough for the next reaction step. Yield: 450 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([N:34]=[C:35]=[S:36])[CH2:32][CH3:33]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:35]([NH:34][CH2:31][CH2:32][CH3:33])=[S:36])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: CCCN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCNC(=S)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 32.5 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 652 mg (2 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.2 ml (1.8 mmol) of n-propyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. The crude product obtained after purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) was crystallized from ethyl acetate. 155 mg (33%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[C@@H:24]2[CH2:29][OH:30])[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3N(C4CC4)N=N[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)[C@@H]2COC(=O)C(F)(F)F)C2N=NNC=2N=1)(C)(C)C.Br[CH2:65][C:66]1C(C)=N[O:68][N:67]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[C@@H:24]2[CH2:29][OH:30])[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:66]([CH3:65])=[N:67][O:68][N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CC[C@H](O)[C@@H]2CO)c2nn(Cc3nnnn3C3CC3)nc2n1
Reactant: Cc1nonc1CBr
Agent: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)[C@@H]2COC(=O)C(F)(F)F)c2nn[nH]c2n1
Product: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)[C@@H]3CO)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (2S,3S)-1-[5-tert-Butyl-2-(1-cyclopropyl-1H-tetrazol-5-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol (example 97), the title compound was prepared from Trifluoro-acetic acid (2S,3S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-2-(2,2,2-trifluoro-acetoxymethyl)-pyrrolidin-3-yl ester and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as white solid. MS (m/e): 389.3 (MH+).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[C:9]12([NH2:19])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2>ClCCl>[C:9]12([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C1COCC(=O)O1
Solvent: ClCCl
Product: O=C(O)COCC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 3.67 h

Procedure:
In a similar operation, a solution of 11.56 g (0.100 mole) of diglycolic anhydride in 1 liter of dichloromethane was added with stirring to a solution of 15.11 grams (0.100 mole) of 1-adamantanamine in 700 milliliters of dichloromethane during about 24 minutes at about 15° to 25° C., whereupon a reaction took place with the formation of heterogeneous milky white mixture. The mixture was stirred for 3.67 hours at temperatures of about 23°-25° C. to complete the reaction with the formation of the desired product in the reaction mixture. The mixture was then concentrated on a rotary evaporator to recover 32.7 grams of a white solid which after recrystallization from 1:1 isopropanol-water mixture yielded the desired [2-(1-adamantylamino)-2-oxoethoxy]acetic acid as white plates, m.p. 181°-183° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[O:38][CH:37]=[N:36][CH:35]=3)[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[O:38][CH:37]=[N:36][CH:35]=3)[CH2:24][C:23]2=[O:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3cnco3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3cnco3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(1,3-oxazol-5-yl)phenyl]piperidin-3-ol (3.36 g, 6 mmol) obtained in Step 1 in 20 ml of dimethyl sulfoxide (DMSO), was added 2.7 ml of triethylamine (19 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (3.04 g, 19 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.67 g of the titled compound.
Reaction SMILES: C([N:8]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])C1C=CC=CC=1.CO.C(O)C>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 100 %

Procedure:
tert-Butyl 4-(trifluoromethyl)phenylsulfonylcarbamate was prepared by a method analogous to the method disclosed in Tet. Lett. 2004, 45, 8483-8487. tert-Butyl benzyl(4-(trifluoromethyl)phenylsulfonyl)carbamate (Intermediate 86, 520 mg) was hydrogenated (1 atm H2) over 20 wt % Pd(OH)2 (52 mg) in 1:1:1 methanol:ethanol:ethyl acetate (8 ml) for 16 hours. The reaction was filtered over celite and concentrated to yield the title compound (407 mg). MS M−H 324.3
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](Cl)=[O:8])(=[O:3])[CH3:2].[OH:10][C@@H:11]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13]>>[C:1]([S:4][CH2:5][CH2:6][C:7](=[O:8])[O:10][C@@H:11]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(O)[C@@H](O)COCc1ccccc1
Reactant: CC(=O)SCCC(=O)Cl
Product: CC(=O)SCCC(=O)O[C@@H](COCc1ccccc1)C(=O)O
Yield: 50.1 %

Procedure:
3-(Acetylthio)propanoyl chloride (0.26 g, 1.56 mmol) and (S)-2-hydroxy-3-(phenylmethoxy)propanoic acid (0.3 g, 1.53 mmol) were heated at 60° for 1 h. The cooled reaction mixture was purified by chromatography on silica with dichloromethane/acetic acid mixtures as eluant to give the sub-title acid (0.25 g).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:29])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:29])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: COc1cccc(C(=O)c2ccc(O)cc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C(=O)c2ccc(OCCCOc3ccc(C[C@H](OC)C(=O)O)cc3)cc2)c1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with (4-Hydroxy-phenyl)-(3-methoxy-phenyl)-methanone from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H28O7 [M+H]+: 465.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[N:15]([C:23](=[O:33])[C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C@@H:14]([CH3:34])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH2:35]([O:37][C:38](=[O:74])[CH2:39]CCOC1C=CC(C(N2C3C(=CC=CC=3)[C@H](N(C3C=CC(Cl)=CC=3)C(=O)CC)C[C@@H]2C)=O)=CC=1)[CH3:36].BrCCCC(OCC)=O>>[CH2:35]([O:37][C:38](=[O:74])[CH2:39][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][C@H:14]([CH3:34])[N:15]2[C:23](=[O:33])[C:24]2[CH:25]=[CH:26][C:27]([N:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:36]
Reactant: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2cc(O)ccc21
Agent: CCOC(=O)CCCBr
Product: CCOC(=O)COc1ccc2c(c1)N(C(=O)c1ccc(N(C)C)cc1)[C@@H](C)C[C@H]2N(C(C)=O)c1ccc(Cl)cc1

Procedure:
(±)-Cis-[4-[acetyl-(4-chloro-phenyl)-amino]-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-7-yloxy]-acetic acid ethyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-dimethylamino-benzoyl)-7-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide, following the alkylation conditions described for the synthesis of (±)-cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester, substituting ethyl bromoacetate for ethyl 4-bromobutyrate.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([NH:14][C:15]([C:17]2[C:21]([CH3:22])=[C:20](/[CH:23]=[C:24]3\[C:25](=[O:34])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[NH:19][C:18]=2[CH3:35])=[O:16])[CH2:9]1)C1C=CC=CC=1.CN(C=O)C>C(O)(=O)C.[Pd].CO>[OH:13][CH:11]1[CH2:12][NH:8][CH2:9][CH:10]1[NH:14][C:15]([C:17]1[C:21]([CH3:22])=[C:20](/[CH:23]=[C:24]2\[C:25](=[O:34])[NH:26][C:27]3[C:32]\2=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[NH:19][C:18]=1[CH3:35])=[O:16]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CN(Cc2ccccc2)CC1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CNCC1O
Yield: 78.5 %

Procedure:
A mixture of Example 26 (283.7 mg, 0.59 mmol), 10% Pd/C (282 mg) and acetic acid (3 drops) in 30 mL of [DMF:MeOH=1:1] was stirred at r.t. under H2 atmosphere. After the reaction was complete as detected by LC/MS, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was triturated with ethanol to provide 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-pyrrolidin-3-yl)-amide (178 mg, 67%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[CH2:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[Cl:15]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[Cl:15]
Reactant: C=Cc1nc(C(=O)OC)c(Cl)c(N)c1F
Agent: [Pd]
Solvent: CCO
Product: CCc1nc(C(=O)OC)c(Cl)c(N)c1F
Yield: 76.9 %

Procedure:
A solution of methyl 4-amino-3-chloro-5-fluoro-6-vinylpyridine-2-carboxylate (3.00 g, 13.0 mmol) and 10% Pd/C (0.30 g) in ethanol (200 mL) was stirred under an atmosphere of hydrogen at 20 psi using a Parr apparatus for 1 hour. The mixture was filtered through celite, concentrated and the residue purified by column chromatography (50% ethyl acetate in hexane) to provide methyl 4-amino-3-chloro-6-ethyl-5-fluoropyridine-2-carboxylate (2.35 g, 10.0 mmol), mp 109-110° C.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2.[I-:18].[Na+]>CC(C)=O>[I:18]/[CH:2]=[CH:3]/[C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2
Reactant: O=C(/C=C/Cl)CCCCC1CCC2CCC1C2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)CCCCC1CCC2CCC1C2
Yield: 84.4 %

Procedure:
A solution of 3.2 g (13 mmol) of 1-chloro-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one and 7.5 g (50 mmol) of sodium iodide in 25 ml of dry acetone (distilled from potassium carbonate) was refluxed for 18 hr under nitrogen. The solvent was removed in vacuo, and the residue was taken up in 50 ml of water and then extracted three times with 30 ml portions of ether. The combined ether extracts were washed with aqueous sodium thiosulfate, dried (MgSO4) and evaporated in vacuo to yield 3.8 g (88%) of 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one.