Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30]NN>>[CH3:30][N:10]1[CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)=[N:9]1
Reactant: CNN
Reactant: c1ccc2nc(CCc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(CCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting methyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=6.2 Hz, 2 H), 8.06 (t, J=10.4 Hz, 2 H), 7.77 (d, J=7.1 Hz, 1 H), 7.70 (t, J=8.3 Hz, 1 H), 7.57 (s, 1H), 7.50 (t, J=9.1 Hz, 1 H), 7.35 (d, J=8.3 Hz, 2H), 7.24 (m, 3H), 7.20 (d, J=5.0 Hz, 2H), 3.97 (s, 3H), 3.31 (m, 2H), 3.18 (m, 2H); MS: (M+H m/z=391.0).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:26]([F:29])([F:28])[F:27])=[N:19][C:20]([C:21](=[O:25])[NH:22][CH2:23][CH3:24])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:23]([NH:22][C:21]([C:20]1[N:19]=[C:18]([C:26]([F:28])([F:29])[F:27])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:30][C:31]3[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=3[F:39])[CH2:13][C:14]=12)=[O:25])[CH3:24]
Reactant: CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
(R)-[3-(1-Ethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (190 mg, 0.33 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (750 mg, 6.6 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethylamide 42 (120 mg, yield 76.4%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=O)[O:10][C:9]=2[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:10])[N:25]([CH:22]([CH3:24])[CH3:23])[C:9]=2[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)c1oc(=O)c2ccccc2c1-c1ccc(F)cc1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)n1c(C(=O)O)c(-c2ccc(F)cc2)c2ccccc2c1=O
Temperature: 100 °C

Procedure:
A mixture of 4-(4-fluorophenyl)isocoumarin-3-carboxylic acid (59.8 g) and isopropylamine (210 ml) in ethanol (610 ml) was heated in a sealed pressure vessel at 100° C. for 16 hours. The mixture was then evaporated to dryness and the resulting residue was suspended in water (500 ml) and extracted with diethyl ether (100 ml). The layers were separated, and the aqueous layer was acidified to pH1 by treatment with concentrated hydrochloric acid. The precipitate was filtered off, washed with water, and crystallised from aqueous ethanol, to give 4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (51.3 g) in the form of white microcrystals, m.p.128°-130° C. [Elemental analysis: C,65.0; H,5.16; N,3.98; F,5.6; H2O, 6.1%; calculated for C19H16FNO3 :1.3H2O: C,65.4; H,5.38; N,4.02; F,5.45; H2O, 6.7%].
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:12]1([S:18]([CH2:21][C:22]2[C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:26]([OH:35])[C:25]([Br:36])=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:12]1([S:18]([CH2:21][C:22]2[C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[C:26]([O:35][CH2:2][C:3](=[O:4])[NH2:5])[C:25]([Br:36])=[CH:24][CH:23]=2)(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OCC(N)=O
Reaction time: 18 h
Yield: 77.8 %

Procedure:
2-Bromoacetamide (0.12 g) and potassium carbonate (0.28 g) were added to solution of tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 38, 0.34 g) in acetone (10 mL) and the mixture was stirred for 18 hours. The mixture was evaporated to dryness and the residue was suspended in DCM and the insoluble material was removed by filtration. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 50-60% to give tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-carbamoylmethoxybenzoate (0.30 g).
Reaction SMILES: C1(N2C(C(C)C)=C(C=O)C=N2)CC1.N([C:17]1[CH:18]=[C:19]([CH:40]=[CH:41][C:42]=1C)[C:20]([NH:22]C1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=[O:21])=[N+]=[N-]>>[C:20]([NH2:22])(=[O:21])[C:19]1[CH:40]=[CH:41][CH:42]=[CH:17][CH:18]=1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CC(C)c1c(C=O)cnn1C1CC1
Product: NC(=O)c1ccccc1

Procedure:
Example 75 benzamide was prepared from 1-cyclopropyl-5-isopropyl-1H-pyrazole-4-carbaldehyde and 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide in the same manner as Example 39. ESI MS m/z 606 [C31H39N7O4S+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:9]=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C=O)C>[CH3:8][C:5]1[N:4]=[C:3]2[CH:9]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:1][C:2]2=[CH:7][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)c(C=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2nc(C)ccc2o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 233.7 %

Procedure:
To a solution of 3-hydroxy-6-methylpyridine-2-carbaldehyde (4.92 mmol, 35.9 mmol) in DMF (70 mL) were added potassium carbonate (9.93 g, 71.8 mmol) and ethyl bromoacetate (5.97 mL, 53.9 mmol), and the mixture was stirred at 100° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:2) to give the title compound (2.36 g, yield 32%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][C@H:10]1[O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[O:25][CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1CNCC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Benzyl (3R,4R)-4-tert-butoxycarbonylamino-3-methoxy-piperidine-1-carboxylate (2.88 g) is dissolved in ethanol and combined with a spatula tip of Pd/C and hydrogenated under H2 pressure (4 bar). After 18 h the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is used in the next reaction step without any further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:22]([CH3:24])[CH3:23])=[N:5][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)#[CH:2].CC(N=NC(C#N)(C)C)(C#N)C.[I:37]I.CCOC(C)=O>C([SnH](CCCC)CCCC)CCC.CCOCC.CCCCCC>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[CH:7]=[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:5]=[C:4]([CH:22]([CH3:24])[CH3:23])[C:3]=2/[CH:1]=[CH:2]/[I:37])=[CH:10][CH:11]=1
Reactant: C#Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Reactant: II
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/I
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine (1.500 gm, 4.76 mmol) (The preparation of which is described in example 4) and 14 mg of AIBN in tri-n-butylstannyl hydride (BU3SnH) (1.90 ml) was rapidly heated to 120° C. After 4 minutes of heating, the mixture was treated with additional Bu3SnH (0.4 ml) and the temperature of the reaction was raised to 130° C. Approximately 14 mg of AIBN was added to the reaction mixture 0.5, 1.5 and 2.5 hours after heating was initiated. After 4 hours, the mixture was cooled to room temperature, diluted with Et2O (40 ml) and treated with solid I2 (1.92 gm, 7.56 mmol). The dark reaction mixture was stirred for 1.5 hours, then quenched with 10% Na2SO3 in saturated NaHCO3. The layers were shaken and separated. The ethereal layer was washed with brine, dried (Na2SO4), filtered and stripped to yield a yellow oil. Flash chromatography (Merck SiO2, 1% EtOAc in hexane followed by 1.5% EtOAc in hexane afforded (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-6-phenylpyridine as a solid. Recrystallization of the solid from hot hexane gave 1.438 gm (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-6-phenylpyridine. An additional 0.19 gm of compound was obtained from the mother liquor to give a total of 1.628 gm (77%) product. m.p. 111.0°-112.3° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([Cl:15])=[C:8]([C:11]([Cl:14])=[CH:12][N:13]=1)[C:9]#[N:10].[F:16][B-](F)(F)F.[H+]>>[Cl:15][C:7]1[C:6]([F:16])=[N:13][CH:12]=[C:11]([Cl:14])[C:8]=1[C:9]#[N:10]
Reactant: N#Cc1c(Cl)cnc(N)c1Cl
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: N#Cc1c(Cl)cnc(F)c1Cl
Yield: 36.5 %

Procedure:
Sodium nitrite (3.17 g, 46.0 mmol) was added in small portions to a suspension of crude 2-amino-3,5-dichloroisonicotinonitrile (4.32 g) in tetrafluoroboric acid (60 mL, 806 mmol) at −10° C. over 1 h. The resultant mixture was stirred at −10° C. for 1 h, carefully quenched with ice and solid Na2CO3 and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4), concentrated to ˜20 mL in volume, triturated with dichloromethane (30 mL) and filtered. The filtrate was concentrated and purified by silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5 to 30% ethyl acetate in hexanes, to give 3,5-dichloro-2-fluoroisonicotinonitrile (1.60 g, 36% yield for 2 steps). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (1H, s); LC retention time: 2.758 min (analytical HPLC Method A).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([NH:12][NH2:13])=[O:11])=[CH:2]1.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClC(Cl)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([NH:12][NH:13][C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:22])=[O:11])=[CH:2]1
Reactant: NNC(=O)c1c[nH]c2ncccc12
Reactant: S=C=Nc1ccccc1
Solvent: CC(Cl)Cl
Product: O=C(NNC(=S)Nc1ccccc1)c1c[nH]c2ncccc12
Reaction time: 20 h
Yield: 98.6 %

Procedure:
350 mg of (1H-pyrrolo[2,3-b]pyridine-3-carbohydrazide and 261 μl of phenyl isothiocyanate in 10 ml of dichloroethane are stirred at 60° C. for 15 hours in a screw-lid vial. A further 78 μl of phenyl isothiocyanate are added, and the mixture is stirred at the same temperature for 20 hours. After cooling in the refrigerator, the precipitate is filtered off with suction and dried, giving 610 mg of 1-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-phenylthiosemicarbazide as colourless powder; (yield 98.6%); MS-FAB (M+H+)=312.3; Rf (polar method): 1.43 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].Cl[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: Sc1ccccn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1ccc(Sc2ccccn2)cc1
Temperature: 140 °C
Yield: 42.2 %

Procedure:
A mixture of 18.4 g of 2-pyridinethiol, 23.2 g of 4-chlorobenzaldehyde, 40 g of potassium carbonate and 100 ml of hexamethylphosphoramide was heated at a temperature of 140° C. for 4 hours. After cooling, the mixture was filtered and the filtrate was concentrated. The resulting oily substance was dissolved in diethyl ether and the solution was washed successively with an aqueous solution of sodium hydroxide and water, and dried over magnesium sulfate. The solvent was distilled off and the resulting oily substance was distilled under reduced pressure to obtain 15 g (42% yield) of 4-(2-pyridylthio)benzaldehyde as a colorless oil having a boiling point of 136° C./2 mmHg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[C:19]([F:31])[C:20]([S:22]([NH:25][C:26]5[S:30][N:29]=[CH:28][N:27]=5)(=[O:24])=[O:23])=[CH:21][C:16]=4[O:15][C:14]3=[O:32])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:47](O)(=[O:49])[CH3:48].CCN(C(C)C)C(C)C>CO.O.CN1C(=O)CCC1>[S:30]1[C:26]([NH:25][S:22]([C:20]2[C:19]([F:31])=[CH:18][C:17]3[N:13]([CH2:12][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]5[C:10]=4[CH2:11][CH:2]([NH:1][C:47](=[O:49])[CH3:48])[CH2:3][CH2:4]5)[C:14](=[O:32])[O:15][C:16]=3[CH:21]=2)(=[O:24])=[O:23])=[N:27][CH:28]=[N:29]1
Reactant: NC1CCc2cccc(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)c2C1
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Product: CC(=O)NC1CCc2cccc(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)c2C1
Temperature: 25 °C

Procedure:
To a flask was added a single enantiomer (S or R) of 3-((7-amino-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (obtained through chiral separation of racemic 20-4) (15 mg, 0.029 mmol), then anhydrous HOBT (5.15 mg, 0.038 mmol), EDC (7.30 mg, 0.038 mmol), followed by NMP (1 ml), then ACETIC ACID (2.180 μl, 0.038 mmol) then DIPEA (0.025 ml, 0.143 mmol). The reaction mixture was stirred at room temperature (capped but not under N2) & followed by LC/MS for the disappearance of starting amine. The reaction mixture was diluted with MeOH/drops of H2O, was filtered (syringe filter), concentrated to desired volume (blow station) & submitted downstairs for mass guided reverse phase purification (TFA modifier); desired fractions concentrated to yield N-(8-((6-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (22-1, S or R). HRMS [M+H] calculated; 518.0963, observed; 518.0937. 1H NMR (499 MHz, DMSO): presaturation at 3.35 ppm: δ 8.49 (s, 1H); 7.96 (d, J=7.5 Hz, 1H); 7.80 (d, J=5.4 Hz, 1H); 7.29 (d, J=9.6 Hz, 1H); 7.06 (d, J=4.5 Hz, 2H); 6.85-6.81 (m, 1H); 5.02-4.91 (m, 2H); 4.06-3.95 (m, 1H); 3.05-2.99 (m, 1H); 2.86-2.80 (m, 2H); 2.53-2.48 (m, 1H); 1.95-1.85 (m, 1H); 1.82 (s, 3H); 1.68-1.58 (m, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1>CO.[Pt](=O)=O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccnc(-c2ccc(F)cc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(F)cc2)C1
Reaction time: 21 h
Yield: 74 %

Procedure:
Methyl 2-(4-fluorophenyl)isonicotinate hydrochloride (6.4 g, 23.91 mmol) was dissolved in methanol (100 mL) and platinum(IV) oxide (0.271 g, 1.20 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 21 h. The catalyst was filtered off, washed with MeOH and the filtrate evaporated. DCM and satd NaHCO3 were added and the phases separated. The organic layer was washed with brine, passed through a phase separator and evaporated to yield a brown oil. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 0% to 5% of MeOH in DCM (containing 1% Et3N) over 10 CV was used as mobile phase and then isocratically eluted with 5% of MeOH in DCM (containing 1% Et3N). Methyl 2-(4-fluorophenyl)piperidine-4-carboxylate (4.2 g, 74%) was isolated. MS m/z 238 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14]C)=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][CH:6]=2.C1C(=O)N(Br)C(=O)C1.[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1.[OH-].[K+]>C(Cl)(Cl)(Cl)Cl.C(#N)C.CO.O>[CH3:19][S:16]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=1)[C:2]([CH2:1][N:38]1[CH2:43][CH2:42][CH:41]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH2:40][CH2:39]1)=[C:11]2[C:12]([OH:14])=[O:13])(=[O:17])=[O:18]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: COC(=O)c1c(C)c(-c2ccc(C(F)(F)F)cc2)nc2ccc(S(C)(=O)=O)cc12
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-methyl-6-(methylsulfonyl)-2-[4-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.11 g, 2.62 mmol) was added to a flask and azeotroped with benzene to remove any residual water. NBS (0.513 g, 2.88 mmol) and diphenylperoxyanhydride (0.064 g, 0.262 mmol) were added, and the solids were suspended in carbon tetrachloride (42 mL). The solutions was heated to reflux for 24 hrs, cooled to room temperature, and concentrated to a minimal volume to afford a light yellow slurry. The slurry was redissolved in acetonitrile (42.0 mL), and 4-(4-piperidinyl)morpholine (0.669 g. 3.93 mmol) was added. The solution was stirred overnight, then concentrated to dryness. The residue was dissolved in 2N HCl and extracted with CH2Cl2. The phases were separated, and the organic phase was washed with HCl. The combined aqueous extracts were made basic with NaOH (2N) and extracted three times with CH2Cl2. The combined organic extracts were passed over a phase separator and concentrated to afford a yellow residue. The residue was dissolved in methanol (120 ml), water (21 ml) and KOH (1.471 g, 26.2 mmol), and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure to remove MeOH, additional water was added, and the mixture was stirred at room temperature for 1 h. The solid precipitate was collected by filtration to afford the desired product as an off white solid (1.1 g, 68%). MS (m/z) 578.2 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>>[CH2:19]([C:10]1[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][C:6](=[O:22])[N:5]2[CH2:4][CH2:3][CH2:2][N:26]1[CH:25]=[N:24][N:23]=[CH:27]1)[CH:20]=[CH2:21]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCl
Reactant: c1nc[nH]n1
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCn1cnnc1

Procedure:
1-(3-Chloropropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and 1H-1,2,4-triazole were reacted and treated similarly as in Example 71, there was obtained 5,7-diallyl-3,4-dihydro-6-hydroxy-1-[3-(1,2,4-triazol-4-yl)propyl]-2(1H)-quinolinone.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@@H:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)\[CH3:17])=[CH:9][CH:8]=1)C.[OH-].[Na+]>>[Br:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18](/[C:16](/[CH3:17])=[CH:15]/[CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([O:31][CH2:32][CH3:33])[C:4]([OH:34])=[O:3])=[CH:8][CH:9]=3)=[CH:23][CH:22]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (E)-(S)-3-{4-[3-(4′-bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester (example 3) (0.150 g, 0.29 mmol) and sodium hydroxide (1M, 0.45 ml, 0.45 mmol) by a procedure analogous to that described in example 2 yielding 0.180 g (34%) of (E)-(S)-3-{4-[3-(4′-bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[C:39]([NH:46][C@H:47]1[CH2:51][CH2:50][C@@H:49]([C:52](O)=[O:53])[CH2:48]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:52]([C@H:49]2[CH2:50][CH2:51][C@@H:47]([NH:46][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:48]2)=[O:53])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)C1
Yield: 62.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (471 mg, 1.0 mmol), DIEA (Aldrich) (0.20 mL, 1.0 mmol), (−)-(1S, 3R)—N-Boc-aminocyclopentane-3-carboxylic acid (PepTech Corporation) (344 mg, 1.5 mmol), HOAT (Aldrich) (232 mg, 1.70 mmol) and EDC (Aldrich) (544 mg, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (402 mg). MS (ESI, pos. ion) m/z: 647 (M+1); MS (ESI, neg. ion) m/z: 645 (M−1). Calc'd for C32H43ClN4O6S: 647.23.
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][S:16][C:4]=12)=O.[C:17](#[N:21])[CH2:18][C:19]#[N:20].[OH-].[K+]>C(O)C>[C:19]([C:18](=[CH:1][C:3]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][S:16][C:4]=12)[C:17]#[N:21])#[N:20]
Reactant: CCCn1c(=O)c(C=O)c2n(c1=O)CCS2
Reactant: N#CCC#N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(=O)c(C=C(C#N)C#N)c2n(c1=O)CCS2
Temperature: 60 °C
Reaction time: 7 h
Yield: 19.2 %

Procedure:
A solution of 8-formyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione(1 g), malononitrile (0.31 g) and ethanol (20 ml) containing 10% aqueous solution of potassium hydroxide (0.1 ml), were stirred at 60° C. for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform. After washing with water and drying, the organic solution was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystallized from ethyl acetate-isopropyl ether to give pale yellow-red needles (0.23 g, 19%).