Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccc(Cl)cc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 5-chloro-2-(bromoacetamido)benzoic acid from Example 41 (10 g, 0.03 mol), aniline (8 g, 7.8 mL, 250 mol %) and DMF (60 mL) was heated at 100-110° C. for 4 h. The reaction mixture was poured into ice-water (200 mL) and the resulting solid product was solubilized by adding 5% KOH (40 mL). The mixture was extracted with CH2Cl2 (3×100 mL) and the aqueous layer was acidified with 5% HBr to pH=3 and extracted with EtOAc (3×200 mL). The EtOAc washings were dried (Na2SO4), filtered and concentrated to afford, after drying under vacuum, 7.8 g (75%) of the title compound as a white solid, mp 210-212° C.; 1H NMR (DMSO-d6) δ 13.99 (s, 1H, NH), 11.96 (s, 1H, COOH), 8.75 (d, 1H, J=8), 7.87 (d, 1H, J=2.8), 7.68 (d, 1H, J=2.4), 7.65 (d, 1H, J=2.8), 7.10 (t, 2H, J=7.6), 6.61 (m, 4H), 3.84 (s, 2H); 13C NMR (DMSO-d6) δ 171.08, 167.81, 148.05, 139.36, 133.81, 130.25, 128.97, 126.20, 121.25, 117.77, 117.14, 112.45, 48.90; MS (EI, m/z) 304 (M+)
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([CH3:31])([CH3:30])[CH2:5][C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[S:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=2.C1COCC1.[Li+].[OH-].Cl>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=3)[C:14]([S:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[C:6]2[CH2:5][C:4]([CH3:31])([CH3:30])[C:3]([OH:32])=[O:2])=[CH:24][CH:25]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
The compound from Step A was hydrolysed using 325 mL of THF, 600 mL of MeOH and 325 mL of 1.0M LiOH. The solution was heated to 80° C. for 3 h. The solution was acidified with 1N HCl and extracted with 3×200 mL of EtOAc. The organic phase was washed with 0ater (2×150 mL) and dried over MgSO4. The solution was evaporated to dryness to provide the title compound. m.p. 190°-191° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][C:17]3[CH2:23][CH2:22][CH2:21][C:18]=3[CH:19]=2)[NH:14][C@@H:13]([CH3:24])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[CH2:36]([O:35][C:33]([N:14]1[C:15]2[C:20](=[CH:19][C:18]3[CH2:21][CH2:22][CH2:23][C:17]=3[CH:16]=2)[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH2:12][C@@H:13]1[CH3:24])=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc3c(cc2N1)CCC3
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc3c(cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C)CCC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of cis-(2-methyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[g]quinolin-4-yl)-carbamic acid benzyl ester (Example 1A) (2.0 g, 4.9 mmol) in anhydrous dichloromethane (50 mL) was added pyridine (1.0 mL). The mixture was cooled to 0° C., and ethyl chloroformate (1.0 mL) was slowly added. The reaction was stirred at 0° C. for 30 min, then at room temperature for 4 h. The reaction mixture was washed twice with 25 mL of 2N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 15% ethyl acetate/hexanes as eluent afforded the title product (500 mg). 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.2 (t, 3H), 4.2 (m, 2H), 5.2 (s, 2H), 7.0 (s, 1H), 7.3 (s, 1H), 7.4 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)=[CH2:13])[CH2:11][O:10]1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.[Na]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:16][CH:15]=1)=[CH2:13])[CH2:11][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: c1nc[nH]n1
Reactant: C=C(c1ccc(-n2cncn2)cc1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(c1ccc(-n2cncn2)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 89 %

Procedure:
By the method of Preparation 20(v), 2-(2,4-difluorophenyl)-2-[1-{4-(1,2,4-triazol-1-yl)phenyl}ethenyl]oxirane (570 mg, 1.75 mmol) was treated with sodium 1,2,4-triazole in DMF (10 ml) at 70° C. for 8 hours, to give 2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)-3-[4-(1,2,4-triazol-1-yl)phenyl]-3-buten-2-ol (620 mg, 89%), as a solid, which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: Cl[C:2](=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>N1C=CC=CC=1>[Cl:19][C:16]1[CH:15]=[C:11]2[C:10](=[CH:18][CH:17]=1)[NH:9][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:14][C:12]2=[O:13]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=O)c1cc(Cl)ccc1N
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(=O)c2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl chlorooxoacetate (2.0 mL) was added to a solution of 2-amino-5-chlorobenzamide (2.50 g) in pyridine (15 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resultant residue was dissolved in acetic acid (50 mL). Acetic anhydride (5.0 mL) was added to the solution, and the mixture was heated under reflux for 16 hours. The solvent was distilled away under reduced pressure, and ethanol was added to the residue. Crystals precipitated were collected by filtration and washed, to thereby give the title compound (2.71 g).
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]([CH:14]=[C:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[OH-].[Li+]>C1COCC1.O>[CH2:19]([O:18][C:16](=[O:17])/[C:15](=[CH:14]\[C:12]1[O:13][C:9]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1)/[C:21]([OH:23])=[O:22])[CH3:20]
Reactant: CCCCCCC#Cc1ccc(C=C(C(=O)OCC)C(=O)OCC)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC#Cc1ccc(/C=C(/C(=O)O)C(=O)OCC)o1
Temperature: 70 °C

Procedure:
Diethyl 2-[5-(1-octynyl)-2-furanylmethylene]propan-1,3-dioate (1.04 g, 3 mmole from Example 10) was added to a solution of lithium hydroxide monohydrate (0.13 g, 1 eq) in THF/water (1:1, 15 ml) and the mixture was heated to 70° C. for 3 hr. The resulting clear solution was acidified and then extracted into diethyl ether (2×50 ml). The etheral solution was dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as a yellow solid which was recrystallised from hexane 0.65 g (68%), mp 89°-90° C., νmax (mull), 2600(broad), 2220, 1740, 1695, 1615, 1555, 1270, 1235, 1215 cm-1 ; δ(CDCl3), 0.89(3H, distorted t), 1.43(3H, t, J=7.5 Hz), 1.45(8H, m), 2.42 (2H, t, J=6.5 Hz), 4.40(2H, q, J=7.5 Hz), 6.54(1H, d, J=3.0 Hz), 6.86(1H, d, J=3.0 Hz), 7.57(1H, s), 11.5(1H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27]>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Product: CCS(=O)(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method the same as for Preparation 6 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 0.57 mmol) and ethanesulphonylchloride (54 μl, 0.57 mmol) as starting materials. The reaction was carried out at 0° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:16]>CN(C)C=O>[Br:1][C:2]1[C:11]([O:12][CH3:16])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Oc1c(Br)ccc2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(Br)ccc2cccnc12
Reaction time: 0.05 h
Yield: 99.8 %

Procedure:
In an oven dried round bottom flask under nitrogen, a solution of 7-bromoquinolin-8-ol (1 g, 4.46 mmol) in N,N-dimethylformamide (20 mL) at room temperature was treated with sodium hydride (60% dispersion in mineral oil, 0.268 g, 6.69 mmol) to give a bright yellow mixture and was stirred for 3 min. Iodomethane (0.307 mL, 4.91 mmol) was then added by syringe and the reaction was stirred for 30 min. The reaction was quenched carefully with water (50 mL) and diluted with ethyl acetate (100 mL). The layers were separated and the organic layer was dried over magnesium sulfate and concentrated in vacuo to give a liquid, which solidified to a white solid (1.06 g, quantitative yield) on standing overnight. MS(ES)+ m/e 237.8, 239.7 [M+H]+.
Reaction SMILES: [CH:1]1([S:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CC(C)=O>[CH:1]1([S:7][CH2:8][S:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(SCSC2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Oc1ccc(SCSC2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
In 300 g of acetone was dissolved 26 g of the cyclohexylthio(4-hydroxyphenylthio)methane crude product in Synthesis Example 10. To this were added 21 g (0.15 mol) of potassium carbonate and 13 g (0.11 mol) of methanesulfonylchloride. While heating in an oil bath at 70° C., the solution was ripened for 4 hours. At the end of ripening, the inorganic salt was filtered and washed with 50 g of acetone. The filtrate and wash liquid combined was concentrated, and the residue was dissolved in 300 g of dichloromethane and washed with 50 g of water. The organic layer was concentrated in vacuum again, obtaining 30 g of an oily product, which was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]1[C:3]([NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])([C:4]([OH:6])=O)[CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:51]1[CH:55]=[C:54]([C:56]2([NH2:59])[CH2:58][CH2:57]2)[N:53]=[CH:52]1>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C:3]1([C:4](=[O:6])[NH:59][C:56]2([C:54]3[N:53]=[CH:52][O:51][CH:55]=3)[CH2:58][CH2:57]2)[CH2:2][CH2:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: NC1(c2cocn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)NC2(c3cocn3)CC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
To a round bottom flask was added Z-1-aminocyclopropane-1-carboxylic acid (150 mg, 0.638 mmol) in DMF (10 ml), followed by the addition of Hunig's base (207 mg, 1.6 mmol) and HATU (270 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 15 min, followed by the addition of 1-Oxazol-4-yl-cyclopropylamine (200 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC to afford 70 mg of [1-(1-oxazol-4-yl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid benzyl ester, m/z 343 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH:15]([CH3:17])[CH3:16]>C1COCC1>[CH3:14][CH:15]([CH3:17])[CH2:16][CH:10]([C:7]1[CH:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=1)[C:11]#[N:12]
Reactant: CC(C)CBr
Reactant: Cc1ccc(CC#N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)CC(C)C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a cooled (0° C.) slurry of NaH (60% dispersion in oil, 2.74 g, 68.5 mmol) in THF (120 mL) was added a solution of (6-methylpyridin-3-yl)-acetonitrile (8.23 g, 62.3 mmol) in THF (60 mL). The mixture was stirred at room temperature for 3 h and then warmed to 40° C. for 1 h. The resulting reddish brown slurry was cooled to −20° C. and a solution of 1-bromo-2-methylpropane (8.53 g, 62.3 mmol) in THF (30 mL) was added dropwise and then stirred for 18 h at room temperature. The reaction was quenched with water and extracted with AcOEt. The organic extracts were combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15% EtOAc in hexane) to give 7.52 g (64% yield) of 4-methyl-2-(6-methylpyridin-3-yl)-pentanenitrile as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.00 (dd, J=6.64, 4.30 Hz, 6 H), 1.53-1.70 (m, 1 El), 1.71-1.99 (m, 2 H), 2.57 (s, 3 H), 3.81 (dd, J=9.57, 6.45 Hz, 1 H), 7.19 (d, J=7.82 Hz, 1 H), 7.59 (dd, J=7.82, 2.34 Hz, 1 H), 8.43 (d, J=2.34 Hz, 1 H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][CH:12]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>C(O)C>[N:20]([CH2:3][CH:2]([OH:1])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: c1cc(CN2CCCCC2)cc(OCCC2CO2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCC(O)CCOc1cccc(CN2CCCCC2)c1
Yield: 53 %

Procedure:
A solution of 1-[[3-[2-oxiranylethoxy]phenyl]methyl]piperidine (17 g), sodium azide (5.1 g) and ammonium chloride (2.73 g) in 25% aqueous ethanol (200 ml) was refluxed for 6 h and concentrated to ca. 130 ml. The concentrate was diluted with water (50 ml), saturated with potassium carbonate and extracted with isopropanol. The extract was dried and evaporated to given an oil (20 g) which was chromatographed on silica using dichloromethane:ethanol:ammonia (200:8:1) to give the title compound (10.5 g) as a colourless oil.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:26])[C@H:12]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[NH:13]C(OC(C)(C)C)=O)C.C([O:30][C:31](=[O:42])[C:32](=O)[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C>>[C:31]([CH:32]([NH:13][C@H:12]([C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[CH2:5][C:4]([OH:27])=[O:3])=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([OH:30])=[O:42]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CCOC(=O)C[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Product: NCCCC[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1CC(=O)O

Procedure:
The product of Step A above is condensed with 2-oxo-4-phenylbutyric acid ethyl ester by the procedure of Example 1, Step E. The diastereomers are separated by silica gel chromatography. The individual diastereomers are converted into the corresponding diacids by saponification as in Example 2 and the -BOC group is removed in hydrogen chloride in ethyl acetate by the procedure of Example 1, Step D. The resulting hydrochloride salt is converted to the free base by absorbing on a strong acid ion exchange resin (Dowex 50W; H+ cycle) and eluting with 3% pyridine in water. Freeze drying affords the desired product, and the S,S,S and R,S,S, diastereomers are separated using reverse phase HPLC.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[OH:12])=[CH:5][CH:4]=1
Reactant: O=C1CCc2ccc(C(F)(F)F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC1CCc2ccc(C(F)(F)F)cc21
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of 6-(trifluoromethyl)indan-1-one (2.20 g, 11 mmol) in THF (30 mL) was added sodium borohydride (0.50 g, 13 mmol). After being stirred for 30 min, methanol (10 mL) was added slowly. Stirring was continued for 2 hrs. The reaction was quenched by addition of an aqueous ammonium chloride solution. The two layers were separated and the water layer was extracted by ether. The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. Column chromatography on silica (10-15% EtOAC in hexane) gave the title compound (1.52 g, 68%) as an oil. MS calculated for C10H9F3O: (M+H)+203; found 185.0 (M−H2O+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18].[C:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH3:25]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([N:30]2[CH2:31][CH2:32][N:27]([C:24](=[O:26])[CH3:25])[CH2:28][CH2:29]2)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Reactant: CC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1N1CCN(C(C)=O)CC1
Temperature: 147 °C
Yield: 34.8 %

Procedure:
(R)-N-[2-Chloro-3-fluoro-4-(ethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 15; 2.0 g) was added to a solution of 1-acetylpiperazine (2.0 g, 3 eq) in anhydrous NMP (3 ml) under argon and the mixture was stirred and heated to 147° C. for 24 hours. The reaction mixture was cooled and partitioned between a saturated aqueous solution of ammonium chloride (80 ml) and ether (4×200 ml). The combined ether extracts were washed with brine (200 ml), dried and concentrated to give a gum. The residue was purified by chromatography on a Mega Bond Elut column (50 g) eluting with 0-4% MeOH/DCM to give the title compound (0.895 g) as a white foam. NMR: 1.14 (t, 3H), 1.61 (s, 3H), 2.05 (s, 3H), 2.75-2.82 (m, 1H), 2.94 (brm, 2H), 3.25-3.44 (m, 3H), 3.49-3.56 (q, 2H), 3.85 (d, 1H), 4.39 (d, 1H), 7.94 (d, 1H), 8.07 (brs, 1H), 8.26 (d, 1H), 9.94 (brs, 1H); m/z: 484.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:12]([OH:14])=O)=[N:6][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH:52]([N:55]1[CH2:60][CH2:59][CH:58]([NH2:61])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]>CN(C=O)C>[CH:52]([N:55]1[CH2:60][CH2:59][CH:58]([NH:61][C:12]([C:7]2[NH:8][C:9]3[C:10](=[O:11])[N:2]([CH3:1])[C:3](=[O:16])[N:4]([CH3:15])[C:5]=3[N:6]=2)=[O:14])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]
Reactant: CC(C)N1CCC(N)CC1
Reactant: Cn1c(=O)c2[nH]c(C(=O)O)nc2n(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.45 mmol) 1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid were dissolved in 5 mL DMF. Subsequently 227 μl (1.35 mmol) DIPEA and 186.5 mg (0.495 mmol) HATU were added. After 1 h 105.6 mg (0.495 mmol) 1-isopropyl-piperidine-4-ylamine-dihydrochloride and 227 μl (1.35 mmol) DIPEA were added and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as its formiate.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 5% MeOH in CH2Cl2 (1L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 153.5 mg (55%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:5]1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:41](=[O:43])[CH3:42])[CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[O:21])[CH2:5]1
Reactant: CON=C1C[C@@H](c2nc(C3CCNCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C1C[C@@H](c2nc(C3CCN(C(C)=O)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime (Example 12) was dissolved in dry DCM at 0° C. in presence of 1.5 equivalent of triethyl amine and treated with 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. It was then dried with magnesium sulfate and solvent removal afforded a residue which was purified by flash-chromatography using cyclohexane/ethylacetate (1/1) as eluent to give (3EZ,5S)-5-[3-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers in 95% yield (100% purity by HPLC).