Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([CH3:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N1CCCC1
Agent: [Pd]
Product: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N1CCCC1

Procedure:
The title compound was prepared from (4-methyl-2-nitro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example C36) (3.27 g, 10.2 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a pale brown solid (2.48 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C)C=O>[NH2:26][C:27]1[C:28]([C:29](=[O:30])[NH2:31])=[CH:32][CH:33]=[CH:34][C:35]=1[NH:36][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(methoxycarbonyl)picolinic acid (3.33 g, 18.4 mmol) in a mixture of pyridine (20 mL) and N,N-dimethylformamide (35 mL) was treated with 1,1′-carbonyldiimidazole (3.28 g, 20.2 mmol) at 45° C. for 2 hours. After cooling, 2,3-diaminobenzamide (HCl salt) (4.12 g, 18.4 mmol) was added and the mixture stirred at room temperature overnight. The mixture was concentrated and the residue used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[C@H:10]([CH2:29][CH3:30])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C@H:10]([CH2:29][CH3:30])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H]1C(=O)N(Cc2ccccc2)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(Cc2ccccc2)c2cc(F)ccc2N1C(=O)c1cccc(O)c1
Yield: 74 %

Procedure:
(3R)-1-Benzyl-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-1benzyl-3-ethyl-7-fluoro-4-(3-hydroxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (74%). [α]D25=−279° (c=0.0095G/ML, CHCl3); MS (ESI) m/z 405 ([M+H]+); MS (ESI) m/z 403 ([M−H]−); HRMS: calcd for C24H21FN2O3.0.25H2O, 408.6563; found (ESI+), 405.16003; Anal. Calcd for C24H21FN2O3.0.25H2O: C, 70.49; H, 5.30; N, 6.85. Found: C, 70.42; H, 5.19; N, 6.75.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:52]=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:54][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([CH:52]([OH:53])[CH3:54])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.4 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde 15p (0.71 g, 0.95 mmol) in dry tetrahydrofuran (15 mL) was added dropwise methylmagnesium bromide (0.64 mL, 1.91 mmol, 3M in tetrahydrofuran) under N2 at 0° C. After the addition, the mixture was warmed up to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL). To the mixture was added 20 mL of saturated aqueous sodium chloride and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 15q as colourless oil (104 mg, 14.3%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.45 (s, 1H), 7.40 (s, 2H), 7.38-7.29 (m, 9H), 7.25-7.14 (m, 6H), 7.06 (d, 2H), 6.92 (d, 2H), 4.97 (dd, 2H), 4.81 (d, 2H), 4.29 (d 2H), 4.13-4.07 (m, 3H), 4.06 (s, 3H), 3.84 (d 1H), 3.69 (d, 1H), 3.58 (s, 1H), 1.21 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)CC)(C)C.[F:38][C:39]1([F:44])[CH2:43][CH2:42][NH:41][CH2:40]1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:4]([N:41]2[CH2:42][CH2:43][C:39]([F:44])([F:38])[CH2:40]2)=[O:5])=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:10]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Cl
Reactant: FC1(F)CCNC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-5-[(phenylmethyl)oxy]-4-{[(phenylmethyl)oxy]carbonyl}benzoic acid (may be prepared as described in Description 63; 480 mg, 1.21 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.63 ml, 3.63 mmol), 3,3-difluoropyrrolidine (208 mg, 1.45 mmol), 1-hydroxy-7-azabenzotriazole (198 mg, 1.45 mmol) and EDC (417 mg, 2.18 mmol). The solution was stirred for 18 hours, then water (10 ml) and ethyl acetate (15 ml) were added and the organic layer was separated. The organic layer was washed further with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (2:1-1:1 cyclohexane/ethyl acetate) gave the title compound as a orange solid. 444 mg.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[C:8]([NH2:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([NH:16][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:4]
Reactant: NC(=O)c1ccccc1
Reactant: OC(O)C(Cl)(Cl)Cl
Product: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1

Procedure:
2,2,2-Trichloro-1,1-ethanediol and benzamide were processed as described in Example 37C to provide the desired product.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH2:13][S:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:9][CH2:10][CH:11]1[S:12](=[O:24])[CH2:13][CH2:14][S:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCC1SCCS1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCC1SCCS1=O)c1ccccc1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
2-Benzoyloxymethyl-1,3-dithiolane (example 12) (5.2 g) was dissolved in dry methylene chloride (200 ml) and cooled to 0° C. in an ice bath. Meta-chloroperbenzoic acid (80%, 4.67 g) in methylene chloride (100 ml) was added slowly while under stirring. The mixture was stirred at room temperature for 1 hour and then poured with into saturated aqueous NaHCO3 solution (100 ml). The organic layer was separated, washed first with saturated NaHCO3 solution (2×100 ml), then with water (100 ml), and finally with brine solution (100 ml), dried over MgSO4 and filtered. The filtrate was evaporated in vacuo and the residue purified by chromatography on silica gel using ethyl acetate as eluant to give 4.0 g (74%) of pure product as a mixture cis- and trans-isomers.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:1][CH2:2][C@H:3]2[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
To a stirred solution of tert-butyl (1R,3S)-3-(hydroxymethyl)cyclopentylcarbamate (Step 2, about 4.5 g, 21.12 mmol) in DCM (50 ml), triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0° C. After ten minutes, 4-methylbenzene-1-sulfonyl chloride (about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.45 (s, 9H); 246-2.55 (m, 4H); 2.90-2.91 (m, 1H); 3.95-3.98 (m, 2H); 4.59-4.70 (m, 2H); 5.66-5.77 (m, 2H); 7.34-7.37 (d, J=9 Hz, 2H); 7.77-7.80 (d, J=9 Hz, 2H); ES Mass: 369 [M+1] 370 (100%).
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:9])[O:6][CH2:7][CH3:8])#[N:3].[N:10]#[C:11]N>C1C=CC=CC=1>[C:11]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[CH2:4][C:2]#[N:3])#[N:10]
Reactant: CCOC(=N)CC#N
Reactant: N#CN
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(CC#N)=NC#N
Yield: 100.3 %

Procedure:
A mixture of 44.70 g (0.302 m) of ethyl 2-cyanoacetimidate hydrochloride and 13.29 g of cyanamide in 400 ml of benzene is stirred under nitrogen for fifteen hours. The cyanamide is purified by ether extraction and concentration of the soluble portion in vacuo. After reaction, the precipitated ammonium chloride is filtered. The residue is washed twice with 50 ml benzene portions. The combined organic phases are concentrated in vacuo to give 41.36 g (100%) of a pale yellow crystalline material. The crystallization is exothermic. The product is very clean by tlc and nmr. The crude crystalline material melts at 51°-63° C.
Reaction SMILES: FC(F)(F)C(O)=O.Br[C:9]1[C:10]([NH:16][C:17](=[O:30])[C:18]([CH3:29])([NH:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:19])=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Br:15][C:13]1[N:14]=[C:9]2[N:20]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:18]([CH3:29])([CH3:19])[C:17](=[O:30])[NH:16][C:10]2=[N:11][CH:12]=1
Reactant: CC(C)(NCCC1CCOCC1)C(=O)Nc1ncc(Br)nc1Br
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)Nc2ncc(Br)nc2N1CCC1CCOCC1
Temperature: 110 °C
Yield: 70.4 %

Procedure:
N-(3,5-Dibromopyrazin-2-yl)-2-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)propanamide trifluoroacetate (0.856 g, 1.517 mmol), N,N-diisopropylethylamine (1.321 mL, 7.59 mmol) and 1,4-dioxane (25 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen and the resulting mixture was sealed, stirred vigorously and heated at 110° C. for 2.5 h. The reaction mixture was concentrated under reduced pressure and purified using flash chromatography (5-50% ethyl acetate in hexane) to give the desired product (0.394 g, 1.068 mmol, 70% yield) as a white solid. MS (ESI) m/z 369.4 [M]+, 371.3 [M+2]+.
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:16])[C:12]=2[C:13]([OH:15])=O)=[O:7])[CH2:3]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]3[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][N:28]3[CH:34]=2)[CH:22]=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]3[N:32]=[C:31]([NH:33][C:13]([C:12]4[N:11]([CH3:16])[N:10]=[CH:9][C:8]=4[C:6]([N:4]4[CH2:3][CH:2]([F:1])[CH2:5]4)=[O:7])=[O:15])[CH:30]=[CH:29][N:28]3[CH:34]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)O
Reactant: COc1cccc(-c2cn3ccc(N)nc3n2)c1
Product: COc1cccc(-c2cn3ccc(NC(=O)c4c(C(=O)N5CC(F)C5)cnn4C)nc3n2)c1

Procedure:
The title compound was prepared in analogy to example 82 from 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (100 mg, 440 μmol) and 2-(3-methoxyphenyl)imidazo[1,2-a]pyrimidin-7-amine (106). Yellow solid (142 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:10]1([CH:9]([NH:16][C:24](=[O:25])[CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(CC(N)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccc(CC(NC(=O)C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
2-(4-aminophenyl)-1-phenylethylamine (0.40 g, 1.9 mMol) and diphenylacetic acid (0.40 g, 1.9 mMol) were dissolved in dimethylformamide (DMF) (4 mL) at room temperature. To this was added HOBT (0.26 g, 1.9 mMol), NMM (0.19 g, 1.9 mMol) and EDCl (0.36 g) and the mixture was stirred at room temperature for 18 hours. The DMF was removed under vacuum and the oily residue was taken up in 100 mL ethyl acetate. The ethyl acetate was washed with saturated sodium bicarbonate and with brine, dried over magnesium sulfate, and evaporated to give 0.683 grams of a semi-solid. This was purified on 30 grams of flash-grade silica gel eluting with 100% dichloromethane to give 0.512 grams of the title compound, m.p. 161°-163° C.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].[CH3:37][C:38]([NH2:41])([CH3:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:38]([NH:41][C:8](=[O:10])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=2)=[CH:15][CH:16]=1)([CH3:40])([CH3:39])[CH3:37]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)NC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), 2-methylpropan-2-amine (4.80 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.9) to provide (R/S)-N-tert-butyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide (10 mg, 0.016 mmol, 37.1% yield): LCMS=558.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.36 Hz), 7.53-7.74 (7 H, m), 5.11 (1 H, s), 3.41-3.53 (2 H, m), 2.27-2.41 (2 H, m), 1.30 (9 H, s); HPLC peak RT=9.4 min (Method A).
Reaction SMILES: [F:1][C:2]1[C:3]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:11]=[C:2]([F:1])[C:3]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:4][C:5]1=2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CC1(C)OB(c2cc3c(cc2F)OCCN3)OC1(C)C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCOc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 70 °C
Yield: 74.8 %

Procedure:
A solution of 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.503 g, 1.802 mmol, Ref. WO20100130034) and K2CO3 (0.504 g, 3.65 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, then treated with allyl bromide (0.8 mL, 9.17 mmol). The reaction tube was sealed then heated (70° C.) for 22 h. The reaction was diluted with water (50 mL) and extracted into EtOAc (50 mL). The organic layer was washed with water, brine, and then dried (Na2SO4), filtered, and concentrated. The residue was purified by biotage (4 g SiO2, 5% (3 CV), 5-40% (15 CV), 40% (2 CV), EtOAc in hexanes), affording the desired product (0.430 g, 1.347 mmol, 74.8% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.03 (6, J=5.7 Hz, 1H), 6.51 (d, J=9.9 Hz, 1H), 5.84-5.94 (m, 1H), 5.26-5.31 (m, 1H), 5.24 (m, 1H), 4.25-4.32 (m, 2H), 3.87 (m, 2H), 3.19-3.25 (m, 2H), 1.34 (s, 12H). LCMS (M+H)=319.7.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=4[CH3:23])[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:17][C:16]=4[CH3:23])[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-formyl-2-methylphenyl)-1H-indazole-4-carboxamide (0.15 g, 0.31 mmol) in methanol (5 mL), morpholine (0.081 g, 0.93 mmol) and acetic acid (0.01 g, 0.311 mmol) were added at room temperature and reaction stirred at room temperature for 18 h. Then NaBH3CN (0.023 g, 0.37 mmol) was added and reaction stirred again at room temperature for 18 h. On completion, methanol was removed under reduced pressure and water added to the residue. The aqueous phase was extracted with 10% MeOH/DCM and the combined organic layers dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2-methyl-4-(morpholinomethyl)phenyl)-1H-indazole-4-carboxamide (34% yield). LCMS: 554.30 (M+1)+; HPLC: 95.54% (@ 254 nm) (Rt; 5.595); 1H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1H), 8.52 (t, 1H), 8.38 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.02-7.28 (m, 3H), 5.86 (s, 1H), 5.22-5.26 (m, 1H), 4.34 (d, 2H, J=4.4 Hz), 3.58 (t, 4H), 3.47 (s, 2H), 2.37 (s, 4H), 2.25 (s, 3H), 2.18 (s, 3H), 2.09-2.06 (m, 2H), 2.09 (s, 3H), 1.98-2.03 (m, 2H), 1.86 (m, 2H), 1.66-1.69 (m, 2H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:34]=[C:33]2[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][N:32]2COCC[Si](C)(C)C)=[CH:28][CH:27]=1>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:34]=[C:33]2[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3Cl)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccccc3Cl)ccc12
Yield: 18.9 %

Procedure:
2.9 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 900 mg of N-[6-(2-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 40 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 50 cm3 of ethyl acetate and the organic phase is washed successively with 2×30 cm3 of saturated sodium hydrogen carbonate solution, with 30 cm3 of water and with 30 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 120 mg of N-[6-(2-chlorophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a beige-coloured foam.
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].C(=O)(O)[O-].[Na+].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:16][C:5](=[N:33][NH:32][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1)[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Reactant: NNC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1cccnc1
Yield: 54.7 %

Procedure:
A suspension of 23.6 g (0.089 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 300 ml chloroform was treated with 98 ml 1N aqueous sodium hydoxide. 200 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 13.5 g (0.098 mol) nicotinic acid hydrazide in 500 ml dioxane over night at 50° C. The resulting precipitate was filtered off and dried. A yield of 15.5 g (55%) nicotinic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white solid, MS m/e (%): 319 (M+H+, 100).