Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:38][CH:37]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC1CC1(NC(=O)C1CC(O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 72.2 %

Procedure:
Compound 132 (6.13 g, 16.6 mmol), 4-nitrobenzoic acid (4.17 g, 25 mmol) and PPh3 (6.55 g, 25 mmol) was dissolved in THF (130 ml). The solution was cooled to ˜0° and diisopropyl azidocarboxylate (5.1 g, 25 mmol) was added slowly. The cooling was then removed and the mixture was left over-night at ambient condition. Aqueous sodium hydrogen carbonate (60 ml) was added and the mixture was extracted with dichloromethane. Purification by flash chromatography (pentane-ether, 2:1→pentane-ether, 1:2→2% methanol in ether) gave pure title compound (6.2 g, 72%).
Reaction SMILES: O1CCOCC1.[ClH:7].[OH:8][CH:9]1[CH2:13][O:12][CH2:11][CH:10]1[NH:14][NH:15]C(OC(C)(C)C)=O>CO>[ClH:7].[NH:14]([CH:10]1[CH2:11][O:12][CH2:13][CH:9]1[OH:8])[NH2:15]
Reactant: CC(C)(C)OC(=O)NNC1COCC1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NNC1COCC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4 M hydrogen chloride-1,4-dioxane solution (50 mL) was added to a solution of t-butyl 2-((3RS,4SR)-4-hydroxytetrahydrofuran-3-yl)hydrazinecarboxylate (5.78 g) in methanol (30 mL) under ice-cooling, and the mixture was then warmed to room temperature and stirred overnight. The reaction mixture was concentrated to give the title compound (5 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:33]=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Ic1ccccc1-c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccccc4-c4ccccc4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-iodo-1,1′-biphenyl and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 528.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16](OCC)=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.O.[NH2:22][NH2:23].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:16]([NH:22][NH2:23])=[O:17])=[N:4][C:5]([C:12]([F:14])([F:15])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate (Int. G1)(455 mg, 1.501 mmol) in MeOH (10 ml) was treated with hydrazine monohydrate (0.147 ml, 3.00 mmol) and stirred at RT overnight. The reaction mixture was diluted with water (50 ml) and the pH was adjusted to pH4-5 using 1M HCl. A yellow precipitate formed which was filtered under vacuum, washed with water and air dried to afford the title compound which was used without further purification;
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([C:25]2[N:26]=[CH:27][N:28]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:38])=[CH:32][CH:31]=3)[CH:29]=2)(C(OC)=O)[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C>Cl.O>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([C:25]2[N:26]=[CH:27][N:28]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:38])=[CH:32][CH:31]=3)[CH:29]=2)[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc(NC(=O)Nc3ccccc3)cc2)cn1
Agent: Cl
Solvent: O
Product: Nc1ccc(CC(C(=O)O)c2cn(-c3ccc(NC(=O)Nc4ccccc4)cc3)cn2)cn1
Reaction time: 1.5 h
Yield: 57.3 %

Procedure:
47 mg (75 μmol) of the compound from example 12g were heated in 4 ml of 50% concentrated hydrochloric acid to 100° C. After 1.5 h, the mixture was diluted with water, and the reaction mixture was freeze-dried. Preparative HPLC of the residue afforded 19 mg of the title compound as bistrifluoroacetate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:17][O:16][C:5]2=[C:6]([F:15])[CH:7]=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][CH:30]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:15][C:6]1[CH:7]=[C:8]2[C:13](=[C:4]3[CH2:3][CH:2]([NH:1][CH2:30][CH2:29][CH2:28][C:22]4[C:21]5[C:25](=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=5)[NH:24][CH:23]=4)[CH2:17][O:16][C:5]=13)[C:12](=[O:14])[NH:11][CH2:10][CH2:9]2
Reactant: NC1COc2c(F)cc3c(c2C1)C(=O)NCC3
Reactant: O=CCCc1c[nH]c2ccc(F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCc2cc(F)c3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9-amino-6-fluoro-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one (49) (110 mg, 0.47 mmol) in anhydrous methanol (7 ml) was added 3-(5-fluoro-1H-indol-3-yl) propanal (2) (89 mg, 0.47 mmol), acetic acid (0.060 ml), and NaBH3CN (59 mg, 0.930 mmol). Resulting reaction mixture was stirred at room temperature for 3 hr. The solvent was removed in vacuo and the residue was re-dissolved in CH2Cl2 (120 ml). The solution was washed with 1 N NaOH and H2O, saturated. NaCl. The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The crude compound was purified on silica gel eluting with 80% EtOAc/Hexane to yield the title compound. MS (ES) m/z 410.2.
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]2=[O:19])=[CH:6][CH:5]=1.IC.[CH3:22]COC(C)=O>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C:12]([CH3:22])([C:15]([O:17][CH3:18])=[O:16])[C:11]2=[O:19])=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C1CCN(c2ccc(F)cc2)C1=O
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(C)CCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
LiH (13.8 mg, 1.737 mmol) was added to the solution of methyl 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylate (0.206 g, 0.868 mmol) in DMF (5 mL) at 0° C. After 30 minutes stirring, iodomethane (0.16 mL, 2.61 mmol) was added to the reaction mixture at 0° C., and then the reaction was warmed to room temperature. The reaction mixture was stirred for 17 hours and heated at 40° C. for 3 hours. After cooling to room temperature, the mixture was treated with EtOAc, quenched with ice water, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to give the crude material that was purified by silica gel flash column chromatography (19:1=CH2Cl2:EtOAc) to afford 0.149 g (68%) of the desired product. LRMS (ESI pos) m/e 252.1 (M+1). 1H-NMR (400 MHz, CDCl3) δ 7.61 (m, 2H), 7.07 (m, 2H), 3.94 (m, 1H), 3.78 (m, 1H), 3.75 (s, 3H), 2.68 (m, 1H), 2.06 (m, 1H), 1.55 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −117.6.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCCCN
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxypropan-1-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (quin, J=6.63 Hz, 2 H) 2.44 (s, 3 H) 3.25 (s, 3 H) 3.34 (q, J=6.65 Hz, 2 H) 3.40 (t, J=6.19 Hz, 2 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1H) 7.78 (d, J=6.82 Hz, 1 H) 8.18 (br. s., 1 H) 8.41 (d, J=6.06 Hz, 2 H) 8.71 (t, J=5.31 Hz, 1H) 8.83-9.01 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 392.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[CH3:10][CH:4]([CH2:3][CH2:2][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(C)CCBr
Solvent: c1ccccc1
Product: CCOC(=O)C(C)CCN1CCCCC1
Temperature: 60 °C

Procedure:
10.5 g. (0.05 mole) of ethyl γ-bromo-α-methylbutyrate is combined with 17.0 g. (0.20 mole) of piperidine and 100 ml. of benzene, stirred for 16 hours at room temperature and heated at 60° C. for 4 hours. The reaction mixture is cooled and the colorless solid which appeared is removed by filtration. The mother liquor is concentrated to give ethyl α-methyl-γ-piperidinobutyrate as a mobile yellow liquid which distills (b.p. 78° at 0.25 mm.) as 6.7 g. (63%) of colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([CH3:14])[CH3:13]>CN(C)C=O>[CH:12]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:14])[CH3:13]
Reactant: CC(C)Br
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 250 mg, 2.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.5 mL) and a 60% dispersion of sodium hydride in mineral oil (97 mg, 2.43 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and 2-bromo-propane (324 mg, 2.64 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to give an oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 1-isopropyl-3-nitro-1H-pyrazole (146 mg, 43%) as a white waxy solid: H1-NMR (400 MHz, CDCl3) δ 1.58 (6H, d, J=6.8 Hz), 4.59 (1H, septet, J=6.4 Hz), 6.88 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=2.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.ClC(Cl)C.[C:24](Cl)(=[O:26])[CH3:25].[Cl-].[Cl-].[Cl-].[Al+3].Cl>O>[C:24]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:15]=[C:14]2[C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=1[CH2:13]2)(=[O:26])[CH3:25]
Reactant: COC(=O)c1ccc2c(c1)Cc1cc(C)ccc1O2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)Cc1cc(C)cc(C(C)=O)c1O2

Procedure:
A mixture of 130 g. of methyl 7-methylxanthene-2-carboxylate in 200 ml. of dichloroethane is cooled to -5°C and to the cooled solution are added 4.95 ml. of acetyl chloride and then 17.0 g. of aluminum trichloride. The resultant solution is stirred at room temperature for 1.75 hours. After this time, the solution is poured into a mixture of 300 g. of ice, 700 ml. of water and 20 ml. of concentrated hydrochloric acid. The mixture is then extracted with three 500 ml. portions of methylene chloride. The combined extracts are washed with 10% aqueous potassium hydroxide solution and the washed solution evaporated to give methyl 5-acetyl-7-methylxanthene-2-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Br:29])[CH:28]=1)[CH2:24]Br>>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Br:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: BrCc1cc(Br)cc(Br)c1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(Br)cc(Br)c2)c(=O)[nH]c1=O
Yield: 67.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (356 mg, yield: 67.9%).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[CH3:28][NH:29][C@@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>ClC(Cl)C.O1CCCC1>[OH:36][C@@H:33]1[CH2:34][CH2:35][C@H:30]([N:29]([CH3:28])[C:8]([NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)=[O:27])[CH2:31][CH2:32]1
Reactant: CN[C@H]1CC[C@@H](O)CC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N(C)[C@H]3CC[C@@H](O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with cis-4-Methylamino-cyclohexanol in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][O:27][C@H:28]([CH3:37])[C:29](N3CCOCC3)=[O:30])=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C[O:41]CC1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1[N:3]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][O:27][C@H:28]([CH3:37])[C:29]([OH:41])=[O:30])=[CH:24][CH:25]=2)[C:4]2[C:9]([C:10]=1[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)c2c(C)n(-c3ccc(CO[C@H](C)C(=O)N4CCOCC4)cc3)c3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)c2c(C)n(-c3ccc(CO[C@H](C)C(=O)O)cc3)c3ccccc23)cc1

Procedure:
The compound of Example 89-1 (33 mg, 0.06 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N aqueous lithium hydroxide solution (1 ml), followed by stirring under reflux for 10 hours. The mixture was diluted with water and washed with ethyl ether. The aqueous layer was adjusted to around pH 4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (quant.).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=O)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:24]3[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]3)=[O:15])[N:10]=[C:9]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:8]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1

Procedure:
The title compound was prepared as in Example 7, except [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (3.40 g, 10.93 mmol) and tert-butyl piperidin-4-ylcarbamate (2.36 g, 12.02 mmol) were used. The title compound was isolated as an off-white solid, 3.8 g, 90%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.53 (d, 2 H), 7.66 (d, 2 H), 7.30 (t, 2 H), 7.14 (t, 2 H), 6.51 (s, 1 H), 5.16 (q, 2 H), 4.09 (d, 1 H), 3.94 (s, 2 H), 3.78 (d, 1 H), 3.07 (t, 1 H), 2.68-2.83 (m, 2 H), 1.63-1.79 (m, 2 H), 1.13-1.28 (m, 1 H), 0.99-1.12 (m, 1 H); m/z (APCI+) for C22H24N5OF 394.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: Oc1cccc(F)c1
Reactant: O=C(O)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cccc(F)c1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
3-Fluorophenol (8.9 g, 79.5 mmol) and 3-bromopropionic acid (12.24 g, 80.0 mmol) were placed in a flask. A solution of NaOH (6.7 g, 167 mmol) in 20 mL water was added slowly to the flask. The reaction mixture was heated to reflux for two hours and then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, and solvent was evaporated under reduced pressure to give 4.57 g (25 mmol, 31.4%) of 3-(3-fluoro-phenoxy)-propionic acid. MS: 185 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Li+].[CH2:18]([C@H:20]1[O:22][CH2:21]1)[Cl:19]>C(OCC)(=O)C>[Cl:19][CH2:18][C@@H:20]([OH:22])[CH2:21][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and lithium bromide (1.7 g, 20 mmol) were added to 100 mL ethyl acetate and stirred for 30 minutes. (S)-epichlorohydrin (21 g, 0.23 mol) was then added. The reaction went on at room temperature (32° C.) for 2 hours. Filtered, and the solvent was evaporated to provide 53 g of colorless oil with 90% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:22][CH2:23][OH:24]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][OH:24])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Yield: 165.3 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (5 g, 25 mmol) is dissolved in 100 ml of ethanol. After addition of sodium carbonate (10.6 g, 100 mmol), 2-bromo-ethanol (3.55 ml, 50 mmol) is added dropwise. The reaction mixture is refluxed for 16 h and then evaporated. The residue is dissolved in 100 ml of dichloromethane and filtrated. The residue is washed with DCM. The combined filtrates are evaporated, which afforded 10.1 g of a yellow oil, which is further purified by flash chromatography (silicagel, DCM/methanol/conc. ammonia 90:9:1).
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC(C)(C)C1CCC(NC2CCCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cyclohexyl-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=[CH:37]2)=[NH:33]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:31]=[C:32]([C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=[CH:37]4)[N:33]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C(=N)NO)ccc21
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(ccn4C(=O)OC(C)(C)C)c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
Prepared using General Procedure 2. A flask containing 3-cyano-4-isopropoxybenzoic acid (135 mg, 0.66 mmol), HOBt (130 mg, 0.85 mmol) and EDC (164 mg, 0.85 mmol) in DMF (2.5 mL) was stirred for 1.5 h at room temperature under an atmosphere of N2. A solution of crude tert-butyl 5-(N-hydroxycarbamimidoyl)-1H-indole-1-carboxylate INT-66 (199 mg, 0.72 mmol) in DMF (2.5 mL) was added to the mixture. After 1 h at room temperature, the mixture was heated to 75° C. and stirred overnight. The reaction mixture was diluted with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated. The resulting crude material was chromatographed (EtOAc/hexanes) to provide 174 mg (59%) of tert-butyl 5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-1-carboxylate INT-67 as a white solid. LCMS-ESI (m/z) calculated for C25H24N4O4: 444.5; found 445.1 [M+H]+, tR=3.67 min (Method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][N:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][N:29]=2)[CH2:26][CH2:27]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)nc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(F)c4)C3)CC2)nc1
Yield: 24.2 %

Procedure:
The title compound (D159) (22.4 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (60 mg, 0.186 mmol) and methyl 6-(1-aminocyclopropyl)nicotinate hydrochloride (D12) (28.5 mg, 0.186 mmol).