Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[CH:32]1([CH2:31][CH2:30][CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: ClCCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCC2CCCCC2)C3)nc1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and (3-chloropropyl)cyclohexane (0.179 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), brine (1×30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 408.3 (M+H)+, HRMS calcd for C25H34N3O2 408.2651 (M+H)+, found 408.2652, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=13.3 min, 100% purity.
Reaction SMILES: [N+](C1C=CC(N)=C(N)C=1)([O-])=O.[CH:12]([C:15]1[NH:16][C:17]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13].[N+](C1NC2C=CC=CC=2N=1)([O-])=O>C(O)(=O)C(C)C.CCOC(C)=O.CO.[Pd]>[CH:12]([C:15]1[NH:16][C:17]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Agent: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=[N+]([O-])c1nc2ccccc2[nH]1
Solvent: CO
Solvent: CC(C)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1nc2ccc(N)cc2[nH]1
Reaction time: 12 h
Yield: 92 %

Procedure:
A solution of 4-nitro-1,2-phenylenediamine (0.9 g, 5.9 mmol) in 5 ml of isobutyric acid was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo to yield a dark brown residue, which was dissolved in 100 ml of EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo, yielding an oil which was characterized as 2-isopropyl-5-nitrobenzimidazole and subjected to a following reaction without further purification. The nitrobenzimidazole and 50 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for 12 h under H2. The reaction mixture was filtered and concentrated in vacuo, yielding 0.95 g (5.4 mmol, 92%) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:5](=[O:6])[CH3:4])[CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:1])[CH3:10]
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 183.9 %

Procedure:
3,5-Dihydroxybenzoic acid (7.2 g, 50 mM) was dissolved in 11 ml of acetic anhydride. To the resulting solution were added 5 drops of sulfuric acid, followed by stirring at room temperature for 20 minutes. Subsequently, 10 g of ice was added and 12 ml of 1N hydrochloric acid was then added. After sonication, a precipitated crystal was recovered by filtration. Washing the crystal with toluene gave 3,5-diacetoxybenzoic acid (10.23 g). The obtained 3,5-diacetoxybenzoic acid (2.38 g, 10 mM) was dissolved in 5 ml of SOCl2 and the solution was heated under reflux at 80° C. for 1 hour. The solvent SOCl2 was distilled off under reduced pressure to yield 3,5-diacetoxybenzoyl chloride (2.44 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[CH3:23]>>[CH3:23][C:17]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: Cc1cccc(Br)c1C
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C)c2C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (99 mg, 0.53 mmol) and 1-bromo-2,3-dimethylbenzene (0.08 mL, 0.59 mmol) according to the general procedure IC to give 22 mg (14%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.42 (EtOAc:hexanes, 2:5); 1HNMR (CDCl3) δ 7.47-7.44 (m, 2H), 7.37-7.34 (m, 1H), 7.19-7.17 (m, 2H), 7.12-7.03 (m, 2H), 3.67 (s, 3H), 2.99-2.94 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz), 2.45 (s, 3H), 2.29 (s, 3H); 13CNMR (CDCl3) δ 173.7, 142.7, 137.8, 132.2, 130.8, 130.5, 129.6, 126.4, 124.0, 122.1, 93.5, 89.2, 35.6, 31.4, 20.3, 17.6; ESI-MS m/z 315.1 (MNa+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Si:20]([C:41]2[CH:46]=[C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:44]([O:51][Si](C)(C)C)=[C:43]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:42]=2)([C:22]2[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([O:32][Si](C)(C)C)=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=2)[OH:21])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[C:37]([C:24]1[CH:23]=[C:22]([Si:20]([C:41]2[CH:42]=[C:43]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:44]([OH:51])=[C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:46]=2)([C:7]2[CH:8]=[C:9]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[OH:21])[CH:27]=[C:26]([C:28]([CH3:31])([CH3:29])[CH3:30])[C:25]=1[OH:32])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1cc([Si](O)(c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc([Si](O)(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
To a stirred solution of 0.40 g (0.45 mmol) of tris-(3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)hydroxysilane in 3 ml of tetrahydrofuran at 0° C. is added dropwise a solution of 0.43 g (1.37 mmol) of tetrabutylammonium fluoride trihydrate in 3 ml of tetrahydrofuran. The reaction mixture is stirred for 5 minutes at 0° C. and to it is added dropwise a solution of 0.19 g of concentrated hydrochloric acid in 1 ml of tetrahydrofuran. The solvent is removed in vacuo and the residue is dissolved in 30 ml of diethylether. The solution is extracted (3×25 ml) with water. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuo to give 0.29 g of a white amorphous solid. The crude product is purified by preparative thin layer chromatography (silica gel, 7:3, heptane:ethyl acetate eluent) followed by crystallization from a heptane/toluene solvent mixture to give 0.14 g (46%) of product as a white solid; mp. 257°-258 ° C.
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[Cl:29][C:30]1[S:34][C:33]([CH2:35][O:36][NH2:37])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[S:34][C:33]([CH2:35][O:36][NH:37][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:32][CH:31]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Reactant: NOCc1ccc(Cl)s1
Product: O=C(NOCc1ccc(Cl)s1)c1ccccc1NCc1ccncc1

Procedure:
Prepared by the same method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(5-chloro-thiophen-2-ylmethyl)-hydroxylamine (see preparation 64).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].N#N.[OH:9][CH2:10][CH2:11][N:12]([CH2:31][CH2:32][OH:33])[C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].[OH-].[K+]>O1CCCC1>[OH:33][CH2:32][CH2:31][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH2:11][CH2:10][OH:9]
Reactant: O=C(CCCCCCCCCCCCCCCO)N(CCO)CCO
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCCCCCN(CCO)CCO
Temperature: 65 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A 500-ml flask equipped with a stirrer and reflux condenser was charged with 3.01 g (79.3 mmol) of LiAlH4 and 200 ml of tetrahydrofuran. While stirring the mixture at room temperature in an N2 atmosphere, 5.00 g (13.9 mmol) of N,N-bis(2-hydroxyethyl)-16-hydroxyhexadecanamide were added, followed by stirring at 65° C. for 18 hours. After cooling the reaction mixture to room temperature, 15 g of 3% aqueous KOH were added, and a salt deposited was separated by filtration. The solvent was then distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 2.98 g (yield: 62%) of the title compound (IId-3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]2[C@@H:18]([CH2:26][NH:27][CH:28]2[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29]2)[CH2:17]1.C(#N)C.[CH:48](I)([CH3:50])[CH3:49]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]2[C@@H:18]([CH2:26][N:27]([CH:48]([CH3:50])[CH3:49])[CH:28]2[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31]2)[CH2:17]1
Reactant: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3cnc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Reactant: CC(C)I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3cnc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C(C)C)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(6-((2,4-dimethoxybenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.06 g, 0.1 mmol) was taken up in acetonitrile (2.6 mL, 50 mmol) and isopropyl iodide (0.098 mL, 0.98 mmol) and triethylamine (0.21 mL, 1.5 mmol) were added. The reaction was heated to 80° C. for 12 hours at which point the reaction appeared to stall. Another 15 equivalents triethylamine and another 15 equivalents isopropyl iodide were added and the reaction continued 8 hours more. Reaction appeared to have stalled again so another 15 equivalents each of isopropyl iodide and triethylamine were added. Upon consumption of the starting material the reaction was concentrated and saturated Na2CO3 (20 mls) and DCM (20 mls) was added. The residue was partitioned between the organic layer and the aqueous layer. The aqueous layer was extracted 3 times with DCM, then the combined organics were dried and purified by FC (DCM/7N NH3 in MeOH 97:3). Product was still contaminated with TEA-H+I—, so to a 30 ml solution of the product in DCM was added 20 mls saturated NaHCO3 and 10 mls 1N NaOH. The mixture was stirred for 15 minutes then the aqueous was extracted with DCM 3 times. The combined organics were dried with MgSO4 and solvent removed to yield pure ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(6-((2,4-dimethoxybenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoate (0.045 g; 70%) as a brown foam/solid with no more amine salts present by NMR. MS (ESI+) for C35H50N6O6 m/z 651.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I>CN(C=O)C.O>[Cl:17][CH2:18][CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: ClCCCI
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (5 g, 26.0 mmol) in DMF (100 ml), cooled to 0° C. was added sodium hydride (3.12 g, 78 mmol). The mixture was stirred until bubbling had ceased, then 1-chloro-3-iodopropane (8.23 ml, 78 mmol) was added. The reaction was kept in an ice bath and allowed to warm to room temperature slowly, then stirred overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organics were then washed with a 1:1 mixture of brine and water (3×), then brine (1×). The organic phase was dried, filtered and concentrated then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.22 g, 19.43 mmol, 74.7% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[C:6]([OH:8])=O)[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:41][CH2:42][C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[C:6]([NH:48][CH2:47][C:46]1[CH:49]=[CH:50][C:43]([C:42]#[N:41])=[CH:44][CH:45]=1)=[O:8])[CH3:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(=O)C(OCC)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(OCC)C(=O)NCc1ccc(C#N)cc1
Reaction time: 24 h
Yield: 78.5 %

Procedure:
A solution under N2 of (RS)-2-ethoxy-malonic acid monoethyl ester (666 mg, 1.0) in THF (37 ml) was prepared. BOP (2.17 g), 4-aminomethyl-benzonitrile hydrochloride (555 mg) and N-ethyldiisopropylamine (733 mg) were added at 0° C. The ice bath was removed and the reaction was let to stir 24 h. THF was evaporated and the mixture was diluted with EtOAc. This organic phase was washed with a sat. aq. NaHCO3 sol. and with brine. The aqueous phases were extracted with one more portion of EtOAc and dried over MgSO4. The solvent was evaporated. The crude product was purified by flash chromatography. (heptane/EtOAc 3:1 to 2:1). 750 mg (68%) of (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid ethyl ester were isolated as a yellow oil. MS 308.4 (100, [M+NH4]+), 291.1 (88, [M+H]+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[N:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:17]([C:33]([NH2:35])=[O:34])=[C:15]3[NH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[O:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18]2[C:17]([C:33]([NH2:35])=[O:34])=[C:15]3[NH:16][C:10]4[CH2:9][NH:8][CH2:13][CH2:12][C:11]=4[N:14]3[N:19]=2)=[CH:25][CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CN(Cc1ccccc1)CC3
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CNCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 6-benzyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide (640 mg, 0.00138 mol) and 10% w/w Pd/C (700 mg) in 60 mL of MeOH was stirred at RT under 1 atm of H2 overnight. TLC and LCMS analysis showed starting material was consumed. The reaction was filtered, filtrate was concentrated to get 397 mg (77%) of 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide. 1H NMR (400 MHz, CD3OD-d4) δ 7.65-7.55 (m, 2H), 7.43-7.33 (m, 2H), 7.18-7.12 (m, 1H), 7.11-6.99 (m, 4H), 4.18 (s, 2H), 3.44 (t, J=5.8 Hz, 2H), 3.01 (t, J=5.8 Hz, 2H). MS (ESI) m/e [M+1]+ 373.9.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][C@@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:18]=1)=[O:11].[S:39]1[CH:43]=[C:42]([CH:44]=O)[N:41]=[CH:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C.[B-]C#N.[Na+]>CO.ClCCCl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][C@H:9]([NH:8][CH2:44][C:42]2[N:41]=[CH:40][S:39][CH:43]=2)[C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:25]([CH3:29])([CH3:30])[C:26]([OH:28])=[O:27])[CH:16]=[C:17]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[CH:18]=2)=[O:11])=[CH:37][CH:36]=1
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)[C@@H](N)Cc2ccc(Cl)cc2)cc(-c2ccncc2)c1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)(C(=O)O)c1cc(NC(=O)[C@H](Cc2ccc(Cl)cc2)NCc2cscn2)cc(-c2ccncc2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a 100 ml flask were added (S)-2-(3-(2-amino-3-(4-chlorophenyl)propanamido)-5-(pyridin-4-yl)phenyl)-2-methylpropanoic acid TFA salt 63.1.C (200 mg, 0.36 mmole), thiazole-4-carbaldehyde (33 mg, 0.21 mmole), sodium triacetoxyborohydride (154 mg, 0.73 mmole), 20 ml of DCE, 1 ml MeOH and DIEA (95 μl, 0.54 mmole). The reaction was stirred at 70° C. for 2 hours at which time sodium cyanotrihydroborate (46 mg, 0.73 mmole) was added and stirred at 70° C. for an additional 1 hour. The reaction mixture was then partitioned between CH2Cl2 and water and the solvent was removed from the organic layer by rotary evaporation. The crude product was purified by reverse phase preparative HPLC to give (S)-2-(3-(3-(4-chlorophenyl)-2-(thiazol-4-ylmethylamino)propanamido)-5-(pyridin-4-yl)phenyl)-2-methylpropanoic acid TFA salt 63.1 as an off white solid (72.5 mg, 60% yield). LCMS ESI (pos.) m/e: 535.2 (M+1): 1H NMR (500 MHz, MeOH) δ ppm 9.14 (d, J=1.96 Hz, 1H), 8.79-8.91 (m, 2H), 8.14-8.25 (m, 2H), 7.99 (t, J=1.71 Hz, 1H), 7.82 (d, J=1.96 Hz, 1H), 7.69 (t, J=1.59 Hz, 1H), 7.52 (t, J=1.71 Hz, 1H), 7.35 (m, 2H), 7.27 (m, 2H), 4.43-4.63 (m, 2H), 4.28 (dd, J=9.29, 5.87 Hz, 1H), 3.45 (dd, J=13.45, 5.62 Hz, 1H), 3.24 (dd, J=13.33, 9.41 Hz, 1H), 1.65 (d, J=6.85 Hz, 6H).
Reaction SMILES: BrC1C=CC=CN=1.C([C:12]1[O:13][C:14]2[C:20](C(C)C)=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)CC#C>>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[CH:12]1
Reactant: C#CCCc1nc2cccc(C(C)C)c2o1
Agent: Brc1ccccn1
Product: c1ccc2ocnc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (41 mg, 0.26 mmol) and 2-(but-3-ynyl)-7-isopropyl-benzo[d]oxazole (55 mg, 0.26 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 4.2 mg (14 μmol, 6%) of 7-isopropyl-2-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a red oil.
Reaction SMILES: FC(F)(F)C1C=CC(OCC2C=CC(SC3C=CC(OCC(O)=O)=C(C)C=3)=CC=2)=CC=1.C([O:34][C:35](=[O:66])[CH2:36][O:37][C:38]1[CH:43]=[C:42]([CH3:44])[C:41]([S:45][C:46]2[CH:51]=[CH:50][C:49]([CH2:52][O:53][C:54]3[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=3)=[CH:48][C:47]=2[Cl:64])=[CH:40][C:39]=1[CH3:65])C>>[Cl:64][C:47]1[CH:48]=[C:49]([CH2:52][O:53][C:54]2[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=2)[CH:50]=[CH:51][C:46]=1[S:45][C:41]1[C:42]([CH3:44])=[CH:43][C:38]([O:37][CH2:36][C:35]([OH:66])=[O:34])=[C:39]([CH3:65])[CH:40]=1
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)cc1C
Agent: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O
Product: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)c(C)cc1OCC(=O)O

Procedure:
The title compound was prepared according to the method described for preparing compound 7, using compound 24.3 as the starting material. MS APSI m/e: 495 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 12.97 (1H, brs); 7.66 (2H, d, J=8.8 Hz); 7.59 (1H, d, J=1.5 Hz); 7.35 (1H, s); 7.28 (1H, dd, J=1.4, 8.0 Hz); 7.17 (2H, d, J=8.8 Hz); 6.97 (1H, s); 6.49 (1H, d, J=8.0 Hz); 5.12 (2H, s); 4.78 (2H, s); 2.24 (3H, s); 2.17 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@:14]([OH:19])([CH2:16][O:17][CH3:18])[CH2:13][C@H:12]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH2:30]>>[OH:19][C@@:14]1([CH2:16][O:17][CH3:18])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([C:20](=[O:22])[NH:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)[CH2:13]1
Reactant: NOC1CCCCO1
Reactant: COC[C@@]1(O)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Product: COC[C@@]1(O)C[C@@H](C(=O)NOC2CCCCO2)N(C(=O)OCc2ccccc2)C1
Yield: 59 %

Procedure:
(2S,4R)-Benzyl 4-hydroxy-4-(methoxymethyl)-2-(tetrahydro-2H-pyran-2-yloxycarbamoyl)pyrrolidine-1-carboxylate is prepared from (2S,4R)-1-(benzyloxycarbonyl)-4-hydroxy-4-(methoxymethyl)pyrrolidine-2-carboxylic acid and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine following Method G (yield=59%). 1H NMR (300 MHz, CHCl3) δ 7.57-7.18 (m, 5H), 5.33-5.07 (m, 2H), 4.64-4.45 (m, 1H), 4.09-3.21 (m, 7H), 2.44-1.98 (m, 3H); ESI(+) calcd. for C15H18NO6 (308.11). Found 308.0
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:10][CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:7]2[CH2:8][CH2:9][CH2:10][C:5]3([C:1](=[O:11])[NH:2][CH2:3][CH2:4]3)[CH2:6]2)=[N:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C1NCCC12CCCNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1NCCC12CCCN(c1ccc(C(F)(F)F)cn1)C2

Procedure:
A mixture of 2,7-diazaspiro[4.5]decan-1-one (50.0 mg, 0.000324 mol), 2-chloro-5-(trifluoromethyl)pyridine (71 mg, 0.00039 mol) and N,N-diisopropylethylamine (0.17 mL, 0.00097 mol) in N-methylpyrrolidinone (2 mL, 0.02 mol) was irradiated with microwaves at 180° C. for 20 min. The product was purified by prep-HPLC. LC-MS: 300.2 (M+H)+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:18]([OH:20])=O.Cl.[NH:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:18]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:20]
Reactant: O=C1CCNCC1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 60.2 %

Procedure:
CDI (9 g) added to a solution of 3-methoxy-4-nitrobenzoic acid (10 g) stirring in THF (200 ml) at RT. After 1 hour, 4-piperidone hydrochloride (6.9 g) and triethylamine (7.8 ml) were added and the mixture stirred overnight. The mixture was diluted with ethyl acetate, washed with 2N HCl (100 ml) then saturated NaHCO3 solution (200 ml) then saturated brine (200 ml). The organic layer was dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography (silica, mixtures of MeOH in dichloromethane) to give the product as a yellow solid (8.5 g; MS: APCI+(M+H) 279).