Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([N:24]([CH3:26])C)=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN(C)[CH:38]=[O:39]>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:24][CH3:26])=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=3)[C:13]([CH:38]=[O:39])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc(-n2ccc3cc(N(C)C)c(C(F)(F)F)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-n2cc(C=O)c3cc(NC)c(C(F)(F)F)cc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(5-dimethylamino-6-trifluoromethylindol-1-yl)benzoic acid ethyl ester (0.054 g) in N,N-dimethylformamide (2 mL) was added phosphoryl chloride (0.026 g) under ice cooling, and this mixture was stirred at room temperature for 16 hours. To this mixture was added 2 mol/L aqueous sodium hydroxide solution (5 mL), and this resulting mixture was stirred at 50° C. for 30 minutes. After cooling to ambient temperature, 1 mol/L hydrochloric acid (10 mL) was added to this mixture, and the precipitated solid was collected by filtration. This solid was washed with water and n-hexane, dried under reduced pressure at 50° C. to give the title compound (0.026 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:31])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:32].CCN(C(C)C)C(C)C.C(Cl)Cl.[CH3:45][C@H:46]1[CH2:48][O:47]1>CO>[Cl:31][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:45][C@@H:46]([OH:47])[CH3:48])[C@H:3]([OH:32])[CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]2=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]2[N:18]=1
Reactant: C[C@H]1CO1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC[C@H](C)O)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a solution of 2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 375B) (50 mg, 0.110 mmol) and DIPEA (0.031 mL, 0.221 mmol) in MeOH (0.5 mL)/DCM (0.5 ml) was added (S)-2-methyloxirane (64.1 mg, 1.104 mmol). The reaction was stirred for 16 hours. The solvents were removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 10-55% B over 25 minutes, then a 8-minute hold at 100% B; Flow: 20 mL/min Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(((S)-2-hydroxypropyl)amino)piperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (14.5 mg,).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.O1CCCC1.[H-].[Na+].C1(C)C=CC(S(O[CH:28]([CH3:40])[CH2:29][CH:30]([CH3:39])[CH2:31][CH2:32][CH2:33][C:34]([O:37][CH3:38])([CH3:36])[CH3:35])(=O)=O)=CC=1>CN(C)P(=O)(N(C)C)N(C)C>[CH3:38][O:37][C:34]([CH3:35])([CH3:36])[CH2:33][CH2:32][CH2:31][CH:30]([CH3:39])[CH2:29][CH:28]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1)[CH3:40]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: COC(C)(C)CCCC(C)CC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(C)(C)CCCC(C)CC(C)Oc1ccc2c(c1)OCC2
Temperature: 25 °C

Procedure:
A solution of 2.7 g. of 6-hydroxy-2,3-dihydrobenzofuran in 10 ml. of absolute tetrahydrofuran is allowed to drop at 0° C. and while stirring into a suspension, cooled in ice, of 0.5 g. of sodium hydride in 5 ml. of absolute tetrahydrofuran. The mixture is stirred for 2 hours (during which time it is allowed to warm up to room temperature), again cooled to 0° C. and added dropwise to a solution of 7.13 g. of 7-methoxy-1,3,7-trimethyloctyl p-toluenesulfonate in 10 ml. of absolute tetrahydrofuran. The mixture is then diluted with 4 ml. of absolute hexamethylphosphoric acid triamide and stirred for 20 hours at room temperature. The mixture is then poured onto ice-water, extracted three times with diethyl ether, the ether extracts are washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (19:1 parts by volume) there is obtained pure 2,3-dihydro-6-[(7-methoxy-1,3,7-trimethyloctyl)-oxy]-benzofuran which is distilled in a bulb-tube at 145° C./0.03 mmHg; nD20 = 1.5046.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:3]1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[CH3:1][C@@H:2]1[N:7]([S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:3]1
Reactant: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 67 was prepared as described in general Method F. (S)-1-(3-methylpiperazin-1-yl)-4-phenylphthalazine (JK-8) (150 mg, 0.493 mmol) was dissolved in DMF (3 mL) and N,N-diisopropylethylamine (0.400 mL). Benzenesulfonyl chloride (104 mg, 0.591 mmol) was added and the reaction stirred at rt for 18 hours. The reaction was taken up in ethyl acetate (75 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a brown oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave 67 as an off-white solid. MS (M+H)+=445.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH2:22][CH3:23])[CH2:12][C:13](OC(C)(C)C)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]2[CH2:12][C:13](=[O:14])[N:21]([CH2:22][CH3:23])[CH2:20]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCNC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Temperature: 65 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-(ethylamino)butanoate (5.66 g, 16.8 mmol), HCl (4M in dioxane, 40 mL) and MeOH (100 mL) was stirred at 65° C. for 2 h. After cooling, the reaction was concentrated. To the residue, K2CO3 (325 mesh, 6.6 g, 47.5 mmol) and MeOH (150 mL) were added and the reaction was stirred at 65° C. for 1 h. Solvent was removed and the residue was partitioned between EtOAc and H2O. The organic layer was dried over MgSO4 and concentrated to give the product as a white solid (2.4 g, 54%). LC-MS (ES) m/e 264.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14]=[C:13]([CH3:18])[C:11]3=2)[NH:6][CH:5]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14]=[C:13]([CH3:18])[C:11]3=2)[N:6]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:5]=1
Reactant: CC1=NCCOc2ccc3[nH]cc(Cl)c3c21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Yield: 21.1 %

Procedure:
Sodium hydride (60% in mineral oil, 38 mg, 0.95 mmol) was added to 10-chloro-1-methyl-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole (Intermediate 40, 45 mg, 0.19 mmol) and benzensulfonyl chloride (74 μl, 0.58 mmol) in DMF (3 ml). The reaction mixture was stirred at room temperature for 10 minutes before water was added dropwise. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (15 mg) as a red solid. MS m/z 375 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[N+:30]([O-])=O)=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH:30][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:20][CH:21]=1)[CH3:14]
Reactant: CCOc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CCOc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (250 mg, 1.56 mmol) was reacted with the product from Example 54a (259 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (241 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.31 (t, J=6.99 Hz, 3H) 2.34 (s, 3H) 2.76 (s, 3H) 3.97 (q, J=6.99 Hz, 2H) 6.26 (d, J=7.35 Hz, 1H) 6.83 (d, J=8.82 Hz, 2H) 7.11 (d, J=7.72 Hz, 1H) 7.24 (d, J=8.82 Hz, 2H) 7.27 (s, 1H) 7.30 (s, 1H) 7.80 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.82 Hz, 1H) 11.01 (s, 1H) 14.38 (s, 1H); MS (ESI+) m/z 402 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([NH:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(C(F)(F)F)cc2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile and 4-trifluoromethylbenzylamine in DME. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[C:10]2=[O:20])=[CH:5][CH:4]=1.[C:23]([Mg]Br)([CH3:25])=[CH2:24].Cl[Ce](Cl)Cl>>[OH:19][C:16]1([C:23]([CH3:25])=[CH2:24])[CH2:15][CH2:14][C:11]2([C:10](=[O:20])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=3)[CH2:13][CH2:12]2)[CH2:18][CH2:17]1
Reactant: O=C1CCC2(CC1)CCN(c1ccc(C(F)(F)F)cc1)C2=O
Reactant: C=C(C)[Mg]Br
Agent: Cl[Ce](Cl)Cl
Product: C=C(C)C1(O)CCC2(CCN(c3ccc(C(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 55 from 2-(4-trifluoromethyl-phenyl)-2-aza-spiro[4.5]decane-1,8-dione (product of example 208, step 2) by reaction with isopropenylmagnesium bromide (0.5 M in THF), but without use of anhydrous cerous(III)-chloride in the reaction, as a light yellow solid. MS (m/e): 353 [M F].
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=S)[N:15]3[CH:18]([CH3:24])[C:19](OCC)=[O:20])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.O.[NH2:27][NH2:28]>CCO>[CH3:7][C:4]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14]4[N:15]3[CH:18]([CH3:24])[C:19](=[O:20])[NH:27][N:28]=4)=[CH:10][CH:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)CCc2ccc(-n3c(C)ccc3C)cc21
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)n1-c1ccc2c(c1)N1C(=NNC(=O)C1C)CC2
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of ethyl 2-(7-(2,5-dimethyl-1H-pyrrol-1-yl)-2-thioxo-3,4-dihydroquinolin-1(2H)-yl)propanoate (0.2 g, 0.561 mmol) in EtOH (10 mL) was added hydrazine hydrate (6 mL) and the solution was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. Water (10 mL) was added to the residue and the mixture was extracted with EtOAc (2×30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 30-50% EtOAc in petroleum ether) to give 9-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-5,6-dihydro-1H-[1,2,4]-triazino[4,3-a]quinolin-2(3H)-one (0.14 g, 81%). 1H NMR (CDCl3, 400 MHz): δ 8.04 (brs, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.73 (s, 1H), 5.89 (s, 2H), 4.56 (q, J=6.8 Hz, 1H), 2.93 (m, 2H), 2.63 (m, 2H), 2.05 (s, 6H), 1.42 (d, J=6.8 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[O:9])=[CH:6][N:5]=[C:4]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])=[CH:6][N:5]=[C:4]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cnc(-n2cccn2)nc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1cnc(-n2cccn2)nc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl N-{[4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidin-5-yl]carbonyl}glycinate (140 mg, 0.44 mmol, prepared in similar fashion to that of the preceding examples) was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction was stirred at rt for 4 h, concentrated and partially dissolved in EtOAc and hexane was added to precipitate the desired compound. The product was isolated affording the title compound. HPLC/MS: 264.0 (M+1); Rt=0.65 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:51][C:52]1[N:60]=[CH:59][CH:58]=[C:57]([CH3:61])[C:53]=1[C:54](O)=[O:55].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:51][C:52]1[N:60]=[CH:59][CH:58]=[C:57]([CH3:61])[C:53]=1[C:54]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5])=[O:55]
Reactant: Cc1ccnc(Cl)c1C(=O)O
Reactant: CCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-ethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (58.0 mg, 0.15 mmol), EDCI (30.9 mg, 0.16 mmol) and HOBT (21.8 mg, 0.16 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (27.5 mg, 0.16 mmol) followed by DIPEA (30.6 μL, 0.18 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by preparative TLC (91:8:1, CH2Cl2/MeOH/NH4OH) afforded 2-chloro-N-((R)-3-{4-[(4-ethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide as a white foam (49.2 mg, 61%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=5 Hz), 1.25 (s, 1H), 1.35 (t, 4H, J=5 Hz), 1.58 (m, 1H), 1.84 (m, 4H), 2.15 (m, 1H), 2.35 (s, 6H), 2.54 (m, 1H), 2.86 (m, 3H), 3.31 (m, 2H), 3.78 (m, 1H), 3.93 (m, 4H), 6.66 (dd, 4H, J=9 Hz, 24 Hz), 7.00 (dd, 2H, J=6 Hz, 18 Hz), 8.01 (d, 1H, J=6 Hz), 8.35 (m, 2H). ES-MS m/z 550 (M+H). Anal. Calcd. For C31H40ClN5O2: C, 67.68; H, 7.33; Cl, 6.44; N, 12.73.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3C)oc2C)c1)C(=O)O
Yield: 43 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-5-methyl-2-o-tolyl-oxazole, the title compound was obtained in 43% yield as a pale brown solid. MS: (M+H)+ 419.3.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[N:4]=[CH:5][C:6]=1[Br:7].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[N:3]([CH3:8])[N:4]=[CH:5][C:6]=1[Br:7])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1ncc(Br)c1N
Product: CC(=O)Nc1c(Br)cnn1C

Procedure:
3-acetamido-4-bromo-2-methylpyrazole (92°-94° C.) was prepared by acetylation of 3-amino-4-bromo-2-methylpyrazole in acetic anhydride.
Reaction SMILES: [N:1]1([CH:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11](O)=[O:12])C2C=CC=CC=2N=N1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=1[C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O.CN1CCOCC1>C1COCC1.C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]2[NH:31][C:11](=[O:12])[CH:10]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:1]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:33]=2[CH:34]=1
Reactant: COc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)OCc1ccccc1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)acetic acid (0.446 g, 1.965 mmol) in 5 mL of dry THF was cooled to 0° C. and then treated with oxalyl chloride (0.171 mL, 1.34 mmol). The mixture was stirred for 30 min at 0° C. A mixture of Intermediate 7A (0.235 g, 1.034 mmol) and NMM (0.237 mL, 2.59 mmol) in DCM (3 mL) was added to the above mixture. The resulting mixture was stirred at room temperature for 2 h and then filtered. The filtrate was treated with 2M methanolic ammonia (10 mL) and stirred at room temperature for 12 hrs. The mixture was then evaporated to dryness and the residue was treated with AcOH (5 mL) and stirred for 2 hrs at room temperature. The reaction mixture was then concentrated and purified by flash column chromatography to provide Intermediate 7B as a white solid: 70 mg (16.29%). HPLC: RT=1.908 min (ACN/H2O with TFA, UPLC R BEH C18, 1.7 μm, 2.1×50 mm, gradient=4 min, Flow=1.8 mL/min; Mobile Phase A: 0.1% TFA in water; Mobile Phase B: Acetonitrile; wavelength=220 nm); MS(ES): m/z=416 [M+H]+; 1H NMR (CDCl3) δ 8.681 (brs, 1H), 7.565-7.583 (d, J=7.2 Hz, 1H), 7.30-7.50 (m, 7H), 7.097 (brs, 2H), 6.80 (brs, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.34 (d, J=7.2 Hz, 1H), 5.17 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:14][C@H:9]2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[O:14][C@H:9]2[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1O[C@@H]1c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1O[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl (2R,3R)-3-(4-fluorophenyl)-2,3-epoxypropionate (206 mg, 1.05 mmol) dissolved in 5 ml of methanol was cooled by an ice bath, and a solution of lithium hydroxide (30 mg, 1.26 mmol) dissolved in water (3 ml) was added to the above solution. After the mixture was stirred at room temperature for 1.5 hours, the reaction mixture was concentrated. While cooling by an ice bath, a 5% citric acid aqueous solution was added to the residue obtained, and the mixture was extracted with chloroform. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was removed to obtain (2R,3R)-3-(4-fluorophenyl)-2,3-epoxypropionic acid (which was unstable so that it could not be isolated nor purified).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37](=[N:39]O)[NH2:38])[CH:33]=[CH:34][C:35]=1[F:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[N:39]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:38]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccc(F)c(Cl)c1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccc(F)c(Cl)c3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 41 mg (0.22 mmol, 1.1 eq.) of 3-chloro-4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 51 mg (46% of theory)
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:24][C:23]2=[O:38]>>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH:25]2[CH2:24][CH:23]([OH:38])[C:22]3[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=3)[O:26]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(C2CC(=O)c3cc(O)ccc3O2)cc1
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: COc1ccc(C2CC(O)c3cc(O)ccc3O2)cc1

Procedure:
2-(4-Methoxyphenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 6-hydroxy-2-(4-methoxyphenyl)chroman-4-one. 1H NMR (300 MHz, d6-DMSO) δ: 8.78 (s, 1H), 7.35 (d, 2H, J 8.7 Hz), 6.94 (d, 2H, J 8.7 Hz), 6.88 (d, 1H, J 2.5 Hz), 6.56 (d, 1H, J 8.7 Hz), 6.52 (dd, 1H, J 8.7, 2.5 Hz), 5.37 (br s, 1H), 5.04 (d, 1H, J 10.9 Hz), 4.83-4.89 (m, 1H), 3.76 (s, 3H), 2.18-2.25 (m, 1H), 1.85-1.97 (m, 1H).