Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([N:6]([C:16](=[O:35])[CH:17]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:18](=[O:27])[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:5].[Li+].[OH-]>C1COCC1.O>[CH:21]1([CH2:20][CH2:19][C:18](=[O:27])[CH:17]([CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[C:16]([N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:4]([CH3:5])[C:3]([OH:36])=[O:2])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)C(C)N(Cc1ccc(OC)cc1)C(=O)C(CC1CCCCC1)C(=O)CCC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(C(=O)C(CC2CCCCC2)C(=O)CCC2CCCCC2)C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 8 %

Procedure:
To a solution of methyl esters 59 (200 mg, 4.00 mmol) in THF/H2O (25 mL/4.5 mL) was added LiOH (1 M in H2O, 0.50 mL, 4.4 mmol) at 10° C. dropwise. The reaction mixture was stirred at ambient temperature for 12 h and THF was removed under reduced pressure. The aqueous layer was acidified to pH2 with 1 M HCl and extracted with CH2Cl2 (25 mL×3). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (1:3 EtOAc/hexanes) to give the desired acids 60 (155 mg, 80%) as a white solid. IR (neat) 3199, 1719, 1648, 1612 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J=8.5 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.69 (d, J=17.5 Hz, 1H), 4.54 (q, J=7.0 Hz, 1H), 4.34 (d, J=17.0 Hz, 1H), 3.80 (s, 3H), 3.64 (dd, J=5.5, 8.5 Hz, 2H), 2.49 (dd, J=7.0, 8.5 Hz, 2H), 1.91 (ddd, J=6.0, 8.5, 14.0 Hz, 1H), 0.69-1.70 (m, 28H); LRMS (ESI) Calcd. for C29H43NO5 [M+H] 486, found 486.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9].[OH:18][CH2:19][C@@H:20]([C@H:22]([C@@H:24]([C@@H:26]([CH2:28][OH:29])[OH:27])O)[OH:23])[OH:21].CO[C@H]([C@H]([C@@H]([C@@H](COC)O)OC)OC)C=O.COC[C@@H]([C@H]([C@@H]([C@@H](COC)OC)O)OC)OC>>[CH2:16]([OH:17])[C@H:14]1[O:15][C@H:7]([O:6][C@@H:24]([C@H:22]([OH:23])[C@@H:20]([OH:21])[CH2:19][OH:18])[C@H:26]([OH:27])[CH2:28][OH:29])[C@H:8]([OH:9])[C@@H:10]([OH:11])[C@@H:12]1[OH:13]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: COC[C@@H](O)[C@@H](OC)[C@H](OC)[C@H](C=O)OC
Agent: COC[C@H](OC)[C@@H](OC)[C@H](O)[C@@H](COC)OC
Agent: O=S(=O)(O)O
Product: OC[C@@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO

Procedure:
Sugar components: (a) Acid hydrolysis using 1N sulfuric acid, and subsequent paper and gas-liquid chromatographic analyses confirmed the presence of equimolar D-glucose and D-sorbitol fractions; (b) Complete methylation, hydrolysis and subsequent gas-liquid chromatographic analysis confirmed the presence of equimolar 2,3,4,6-tetra-O-methyl-D-glucose and 1,2,3,5,6-penta-O-methyl-D-sorbitol fractions; (c) The high specific rotation, [α]D20, of +106.5° and the infrared absorption neighboring 840 cm-1 suggest the presence of an α-linkage between the glucose and sorbitol moieties; (d) Paper, gas-liquid and high-pressure liquid chromatographic analyses on the anhydrous crystals of maltitol gave the same single spot or peak at the same position as in the analyses on a commercial authentic maltitol preparation (special grade reagent).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.C[O-].[Na+].CN(C)C=O.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>O.C1(C)C=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=2[C:7]([C:13]2[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=2[F:19])=[N:8][CH2:9][C:10]1=[O:12]
Reactant: O=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2N1
Reactant: COC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CN=C(c2c(F)cccc2F)c2cc(Cl)ccc21
Reaction time: 6 h

Procedure:
A mixture of 0.1 mole of 7-chloro-1,3-dihydro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° C. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl bromoacetate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloride-methanol and the like to obtain 7-chloro-2,3-dihydro-2-oxo-5-(2,6-difluorophenyl)-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.F[C:28](F)(F)[C:29]([OH:31])=[O:30].BrCC(OCC)=O.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>C(O)(C)(C)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([CH2:28][C:29]([OH:31])=[O:30])[C@H:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 50 mg, 0.14 mmol, 1 equiv) in a 1:1 mixture of dichloromethane and trifluoroacetic acid (10 mL) was stirred for 30 minutes, then concentrated. The residue was partitioned between aqueous saturated sodium bicarbonate solution (60 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. A solution of the residue, ethyl bromoacetate (16 μL, 0.14 mmol, 1.0 equiv) and N,N-diisopropylethylamine (29 μL, 0.17 mmol, 1.2 equiv) in DMP (5 mL) was heated at 70° C. for 3 hours. The reaction mixture was partitioned between water (125 mL) and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. A solution of the residue and sodium hydroxide (1N, 280 μL, 0.28 mmol, 2.0 equiv) in tert-butanol (10 mL) was heated at 45° C. for 20 hours. The reaction mixture was then partitioned between water and ethyl ether. The aqueous layer was acidified to pH 4 with aqueous HCl solution, then extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide [(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]acetic acid (28-1) as a colorless oil. LRMS m/z (M+H) 316.3 found, 316.1 required.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:31])[CH2:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.Br[C:33]1[CH:38]=[CH:37][N+:36]([O-:39])=[CH:35][CH:34]=1>O1CCOCC1.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>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:31])[CH2:21][C:22](=[O:23])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:35]3[CH:34]=[CH:33][CH:38]=[CH:37][N+:36]=3[O-:39])[S:17][C:10]=12
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)Nc1ccccc1
Reactant: [O-][n+]1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc[n+]4[O-])sc23)c(F)c1)Nc1ccccc1
Yield: 26.7 %

Procedure:
A solution of 411 (45 mg, 0.08 mmol), 4-bromopyridine N-oxide (250 mg, 1.43 mmol), bistrimethyltin (26 μL, 40 mg, 0.12 mmol) and Pd(PPh3)4 (10 mg, 0.01 mmol) in dioxane (1 mL) was heated to reflux for 4 hrs. The reaction mixture was cooled, concentrated and the residue was purified by flash chromatography using the gradient 5-10% MeOH in DCM as an eluent, to afford 409 (11 mg, 27% yield). 1H NMR δ (400 MHz, CD3OD): 8.71 (d, 1H, J=5.4 Hz), 8.6 (m, 3H), 8.04 (dd, 1H, J=2.4 Hz, J=12.3 Hz), 7.85 (t, 1H, J=8.4 Hz), 7.78 (m, 2H), 7.65 (m, 1H), 7.62 (m, 1H), 7.53 (m, 3H), 7.32 (t, 1H, J=7.4 Hz), 6.81 (d, 1H, J=5.5 Hz), 3.75 (s, 2H). MS (m/z: (M+1) 515.0 (100%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C@@:3]([OH:8])([CH3:7])[C:4](O)=[O:5].N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:44]([O:48][C:49](=[O:68])[NH:50][C:51]1[O:52][CH2:53][C:54]([F:67])([F:66])[C@:55]([C:58]2[CH:63]=[C:62]([NH2:64])[CH:61]=[CH:60][C:59]=2[F:65])([CH3:57])[N:56]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C)C=O.C(#N)C.O.C(O)=O>[C:44]([O:48][C:49](=[O:68])[NH:50][C:51]1[O:52][CH2:53][C:54]([F:67])([F:66])[C@:55]([C:58]2[CH:63]=[C:62]([NH:64][C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:61]=[CH:60][C:59]=2[F:65])([CH3:57])[N:56]=1)([CH3:45])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)C(F)(F)CO1
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(NC(=O)[C@@](C)(O)C(F)(F)F)ccc2F)C(F)(F)CO1
Reaction time: 8 h

Procedure:
A solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (CAS44864-47-3) (20 mg, 0.125 mmol) in N,N-dimethylformamide (1 ml), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU) (66 mg, 0.167 mmol) and diisopropylethylamine (35 mg, 0.267 mmol) was stirred at room temperature for 45 minutes. Thereafter, [(R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester (30 mg, 0.063 mmol) (intermediate XXV-1) was added and stirring continued at room temperature overnight. For the workup, formic acid was added to the incomplete reaction, the mixture was divided in two portions and directly injected on a preparative HPLC column using a gradient of water (+0.1% of formic acid)/acetonitrile=90:10 to 5:95 as the eluent. The {(R)-5,5-difluoro-4-[2-fluoro-5-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-carbamic acid tert-butyl ester was obtained as a colorless, amorphous solid (8 mg, 25% of theory). MS (ISP): m/z=500.2 [M+H]+. b) (R)—N-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide 2,2,2-trifluoroacetate A solution of the {(R)-5,5-difluoro-4-[2-fluoro-5-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl-amino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-carbamic acid tert-butyl ester (8 mg, 0.016 mmol) in 2,2,2-trifluoroacetic acid was stirred at room temperature during 1 hour. Thereafter, the reaction mixture was evaporated at reduced pressure and kept under high vacuum overnight to yield the title compound as yellow oil in quantitative yield. MS (ISP): m/z=400.1 [M+H]+.
Reaction SMILES: O.[BH4-].[Na+].[C:4]([O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]1[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:6])[CH3:5].C(O)(=O)C>CO>[C:4]([O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]1[CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:6])[CH3:5]
Reactant: CCOC(=O)C(=O)c1cc(Br)cn1CCOC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCOC(=O)C(O)c1cc(Br)cn1CCOC(C)=O
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
Methanol (100 ml) containing 2.5 ml water is cooled to -50° C. and 3.07 g of sodium borohydride (81.2 mmole) is added with stirring. After 5 minutes, ethyl 1-(2-acetoxyethyl)-4-bromopyrrole-2-glyoxalate (8.9 g -26.7 mmole) is dissolved in 40 ml methanol and added at a rate such that the reaction temperature does not exceed -40° C. After 1 hour at this temperature, 50% aqueous acetic acid is added until the solution is weakly acidic. The methanol is then removed in vacuo, 100 ml ethyl acetate is added to the residue, and the organic phase is washed well with saturated salt solution and then dried over sodium sulfate. The solvent is removed in vacuo and the residue is immediately crystallized, at low temperature (dry ice-acetone bath), from ether. The ethyl 1-(2-acetoxyethyl)-4-bromopyrrole-2-glycolate thus obtained (6.0 g, 67%) exhibits a m.p. of 59° C. but is unstable and is be stored in an evacuated vessel at -10° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1.[OH-].[K+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:9]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(-c2ccccc2)nc1-c1ccccc1Cl
Yield: 99.5 %

Procedure:
A mixture of 5.70 g of compound E and 2.83 g of potassium hydroxide in 40 cc of ethanol and 0.5 cc of water was heated under reflux for 3 hours. After cooling, the reaction mixture was acidified with 1N HCl, and extracted with chloroform. The extract was dried over magnesium sulfate, and distilled to remove the solvent. Thus, 5.20 g of 4-(2-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid was obtained. Yield: 99.6%.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.S([Cl:27])(C)(=O)=O.S([O-])(=O)(=O)C>C(Cl)Cl.O>[Cl:27][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCN(c2ccccc2)CC1
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: ClCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
The crude 1-(2-hydroxyethyl)-4-phenylpiperazine (~400 g) thus obtained was dissolved in dry CH2Cl2 (3.5 l) containing triethylamine (400 ml; 2.9 mol) and the solution was cooled to ~10. A solution of 250 g (2.18 mol) mesyl chloride in 300 ml CH2Cl2 was added to the stirred mixture over 30 min and then the reaction was allowed to warm up to room temp. It was then stirred at ambient temperature until the in situ conversion of the intermediate mesylate to the chloro compound was completed (16-40 hrs). Water (1 l) was added and the layers separated. The aqueous layer was washed with CH2Cl2 (1×300 ml) and then the combined CH2Cl2 phases were dried (K2CO3) and evaporated. The residue was triturated with hot hexane (1×1 l; 4×200 ml) and the combined extracts were decolorized (charcoal) and then cooled to 0°- 5°. Filtration of the resulting colorless crystals afforded 1-(2-chloroethyl)-4-phenylpiperazine, mp 56°-58°. Concentration of the mother liquor to ~400 ml furnished additional product, mp 55°-57°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[C:6]([CH:9]=1)C=O.C1C=C(Cl)C=C([C:22]([O:24]O)=[O:23])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:22]([O:24][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][CH:12]1[CH2:14][O:13]1)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cc(Br)ccc1OCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=COc1cc(Br)ccc1OCC1CO1

Procedure:
To a solution of 5-bromo-2-(oxiran-2-ylmethoxy)benzaldehyde (12.3 g, 47.7 mmol) in DCM (50 ml) was added m-CPBA (12.8 g, 57.2 mmol). The solution was heated at reflux for 3 h and 30 min and then brought to ambient temperature. Aqueous sodium bicarbonate (saturated) and DCM was added and the phases were separated. The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness to give the crude title compound. Crude yield: 12.3 g. MS m/z (rel. intensity, 70 eV) 272 (M+, 7), 244 (50), 189 (95), 188 (bp), 57 (93).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11](=[O:13])[CH3:12])=[O:3].[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH2:43])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Cl:42])[CH:36]=2)=[CH:31][CH:30]=1>>[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH:43][C:2]([C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11](=[O:13])[CH3:12])=[O:3])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Cl:42])[CH:36]=2)=[CH:31][CH:30]=1
Reactant: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1OC(C)=O
Yield: 90.6 %

Procedure:
2-(S)-[(4-Acetoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (278 mg) was prepared from acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (171 mg, 0.5 mmol) and 2-(S)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (155 mg, 0.5 mmol) following the general procedure M.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:25][CH2:26]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:24])[C:15]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:33]1([C:39]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:25][CH2:26][N:42]3[CH2:41][CH2:40][C:39]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:24])[C:15]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1cc(F)c(F)c(F)c1)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3cc(F)c(F)c(F)c3)C2)CC1

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (1 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.29 g, 1.2 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane and then 6% methanol/dichloromethane to give the title compound: Rf =0.45 (silica gel, 10% methanol in dichloromethane). Exact mass (FAB+): calculated for C37H46Cl2N3O5 calculated 682.2815. Found 682.2799.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][N:16]3[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]3)[CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][N:16]3[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]3)[CH:12]=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cncc(Cn3cc([N+](=O)[O-])cn3)c2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2cncc(Cn3cc(N)cn3)c2)OCCO1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a 0.1M solution of 3-(2-methyl-[1,3]dioxolan-2-yl)-5-(4-nitro-pyrazol-1-ylmethyl)-pyridine (40 mg, 0.14 mmol), iron powder (23 mg, 0.41 mmol) and NH4Cl (37 mg, 0.69 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1N NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a deep red oil. TLC: rf (50:50 hept-EA)=0.1. LC-MS-conditions 02: tR=0.35 min; [M+H]+=261.29.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].[CH3:37][CH:38]([CH:41]([CH3:43])[OH:42])CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:15][CH2:16][C:17]3([O:42][CH:41]([CH3:43])[CH:38]([CH3:37])[O:20]3)[CH2:18][CH2:19]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(O)C(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)C(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
A mixture of 4′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), 2,3-dimethylpropane-1,3-diol (0.56 g), p-toluenesulfonic acid monohydrate (0.036 g) and toluene (30 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 100%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:25])=[O:26])[CH2:20][CH2:19]2)[CH:13]=1
Reactant: O=S(=O)(CC(NO)c1ccc(Cl)c(Cl)c1)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.23 ml) was added directly to formic acid (0.9 ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(6-chloropyrimidin-4-yl)tetrahydropyrazin-1-yl]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]hydroxylamine (0.227 g) in tetrahydrofuran (5 ml). The solution was stirred at room temperature for 18 hours. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was purified by chromatography using a 10 g silica isolute eluting with CH2Cl2-3% Methanol/CH2Cl2 to give N-[2-{[4-(6-chloropyrimidin-4-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.178 g), 98-101° C.