Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([NH2:12])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH3:26])[CH:22]=2)[N:17]=[C:16]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:15]=1.O>CN(C=O)C>[CH2:25]([O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[N:15]=[C:14]2[O:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[C:3]([NH2:12])=[O:11])[CH3:26]
Reactant: CCOc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: NC(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2nc(-c3cccnc3)nc(Oc3ccccc3C(N)=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.3 %

Procedure:
(The method G8 is representative of method G6, G7, G9, G10 and G11. These six methods can be implemented in a similar way except for substitution of the appropriate base, solvent and temperature) To a 2.5 dram reaction vial was first added sodium hydride 60% (0.028 g, 0.700 mmol) and salicylamide (0.072 g, 0.525 mmol) in DMF (2 mL). The mixture was allowed to stir at room temperature for 1 h. Then, 4-chloro-6-ethoxy-2-(pyridin-3-yl)quinazoline (0.100 g, 0.350 mmol) was added to the mixture, and the reaction was allowed to proceed at room temperature overnight. LC-MS analysis of the crude mixture showed about 85% of product formed and 10% remaining starting material. Water (30 mL) was added to the mixture, and the product was extracted with chloroform (3×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified via ISCO (silica gel, 97.5:2.5 CH2Cl2/MeOH; 12 g column) to afford 13.9 mg of the desired product as a white solid (10.3%) LCMS m/z=387 (M+1) (Method C) (retention time=2.05 min). 1H NMR (300 MHz, DMSO) δ 11.47 (s, 2H), 9.39 (s, 1H), 8.66 (d, J=2.8 Hz, 1H), 8.56-8.47 (m, 1H), 8.01-7.90 (m, 2H), 7.69-7.55 (m, 2H), 7.55-7.40 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.23 (q, J=6.9 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:13]=[O:14])[CH:8]=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])C.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1.II.O1CCOC[CH2:29]1>>[CH:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:8]=[C:9](/[CH:10]=[CH:24]/[C:23](=[O:25])[C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)[CH:12]=1)[CH:13]=[O:14])([CH2:3][CH3:29])[CH3:4]
Reactant: CC(C)(C)c1cc(C=O)cc(C=O)c1O
Reactant: C1COCCO1
Reactant: CC(=O)c1ccc(C)cc1
Agent: II
Product: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc(C=O)c1O
Temperature: 90 °C

Procedure:
A solution of 5-tert-butyl-4-hydroxyisophthalaldehyde of formula I (0.50 g, 3.05 mmol) and p-methyl acetophenone (0.41 g, 3.05 mmol) in dioxane (25 mL) was treated with iodine (0.78 g, 0.31 mmol). The solution was heated at 90° C. for 5.0 h. Most of the excess reagent was evaporated under reduced pressure, and the residue was treated with aq. Na2S2O3 solution (5%, 40 mL) and the product was extracted 3-fold with CHCl3 (50 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 4% ethyl acetate in hexane, which upon concentration provides (E)-3-tort-butyl-2-hydroxy-5-(3-oxo-3-p-tolylprop-1-enyl)benzaldehyde (General Formula III).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])[CH3:2].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:8][C:7](=[O:9])[CH:6]([O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[CH2:1][CH3:2])[CH2:10][CH3:11])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CCc1ccccc1OC(CC)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCc1ccccc1OC(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 121.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 416 mg of (2RS)-2-(2-ethylphenoxy)butyric acid and 551 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 900 mg of the title compound as a colorless foam.
Reaction SMILES: [C:1]1([CH:7]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C@@H:8]([NH:49][C:50](=[O:67])[C@H:51]([CH2:63][CH:64]([CH3:66])[CH3:65])[NH:52][C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])[CH:9]=[CH:10][S:11]([CH:14]=[CH:15][C@H:16]([NH:30][C:31](=[O:48])[C@H:32]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(OO)(C)(C)C.C1(C(C2C=CC=CC=2)[C@H](NC(=O)[C@H](CC(C)C)NC(OCC2C=CC=CC=2)=O)C=CS(C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(OCC2C=CC=CC=2)=O)C(C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[C:18]1([CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:16]([NH:30][C:31](=[O:48])[C@H:32]([CH2:44][CH:45]([CH3:46])[CH3:47])[NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[CH:15][CH2:14][S:11]([CH2:10][CH:9]=[C:8]([NH:49][C:50](=[O:67])[C@H:51]([CH2:63][CH:64]([CH3:66])[CH3:65])[NH:52][C:53]([O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[O:54])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)(=[O:12])=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C=CS(=O)(=O)C=C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OO
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(=CCS(=O)(=O)CC=C(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 15 %

Procedure:
Cbz-Leu-D-Phe-VS-Ph was treated with butyllithium and tert-butylhydroperoxide in freshly distilled THF as described with Cbz-Leu-Phe-VS-Ph above to give Cbz-Leu-Phe-AS-Ph (Isomer B) as a white powder, yield 15%. 1H-NMR (CDCl3) δ 0.8-0.9 (2d, 6H, 2×Leu-CH3), 1.4-1.6 (m, 2H, Leu-CH2), 2.06 (m, 1H, Leu-CH), 3.8 (s, 2H, CH2-Phe), 3.9 (d, 2H, CH2—SO2), 4.1 (m, 1H, α-H), 4.8 (t, 1H, CH═), 4.9-5.0 (b, 1H, NH), 5.1 (m, 2H, Cbz), 7.1-7.4 (m, 10H, 2×Ph), 7.5-7.7 (m, 5H, SO2-Ph); 8.4 (b, 1H, NH). MS (ESI) m/z 535 (M+1, 100%). Anal. calcd. for C30H34N2O5S: C, 67.39; H, 6.56; N, 5.43. Found: C, 67.12; H, 6.61; N, 5.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[O:10][C:9]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][C:7]=2[CH:17]=1.Cl>>[CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:17]=1
Reactant: COc1cc2cc(C3CCNCC3)oc2cc1OC
Agent: Cl
Product: COc1cc2cc(-c3ccncc3)oc2cc1OC

Procedure:
Likewise analogously to Example 2, there is obtained, by hydrogenation of 12.5 g of 4-(5,6-dimethoxy-2-benzofuranyl)-pyridine, 4-(5,6-dimethoxy-2-benzofuranyl)-piperidine, M.P. 95-98, and its hydrochloride, M.P. 227°-229°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[CH:23]=O)([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:23])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reaction time: 6 h

Procedure:
2-(4-Benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (9.00 g, 26.3 mmol) in ethanol (250 mL) is treated with 5% Pd/C (1.25 g) and hydrogen (60 psi, rt, overnight). Additional 5% Pd/C (1.25 g) is added, and the reaction is continued for 6 h at 40° C. The mixture is filtered and concentrated to a tan oil (6.25 g). This oil contained 9 mol % of 2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (400 MHz, CDCl) δ 1.26 (t, 3H, J=7.3 Hz), 1.51 (s, 6H), 2.14 (s, 3H), 4.24 (q, 2H, J=7.3 Hz), 5.68 (brs, 1H), 6.47 (dd, 1H, J=3.4, 8.8 Hz), 6.59 (d, 1H, J=8.3 Hz), 6.60 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16]([I:17])[C:11]=3[O:10][CH:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([C:23]4[N:22]([CH3:21])[C:30]5[C:25]([CH:24]=4)=[CH:26][CH:27]=[CH:28][CH:29]=5)=[O:32])=[C:3]([O:19][CH3:20])[CH:4]=3)=[CH:9][O:10][C:11]=2[C:16]([I:17])=[CH:15][N:14]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-7-iodofuro[3,2-c]pyridin-4-amine (2.53 g, 6.65 mmol) in pyridine (30 mL) was cooled to 0° C. and 1-methyl-1H-2-indolecarbonyl chloride (2.57 g, 13.3 mmol) was added. The mixture was stirred for 15 minutes at 0° C. and then allowed to rise to ambient temperature over an 18 hour time period. The solvent was removed in vacuo and the residue was dissolved in water (50 mL) and brought to pH 12 with 0.1 N aqueous sodium hydroxide, at which point a precipitate formed. The suspension was extracted with dichloromethane (4×25 mL) and the combined organic layers were washed with brine (25 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (3.21 g, 89%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 8.04 (t, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.30–7.37 (m, 2H), 7.25 (d, 1H), 7.11–7.18 (m, 2H), 5.75–5.83 (bs, 2H), 4.04 (s, 3H), 3.93 (s, 3H); RP-HPLC (Conditions d) Rt 8.73 min.; MS: MH+ 539.
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.F[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[I:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=2)[CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:7][CH:8]=1
Reactant: CC(C)CC(N)c1ccc(I)cc1
Reactant: COC(=O)c1ccc(F)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC(CC(C)C)c2ccc(I)cc2)nc1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
1-(4-Iodophenyl)-3-methylbutan-1-amine hydrochloride (1.14 g, 3.49 mmol), methyl 6-fluoronicotinate (0.568 g, 3.66 mmol), and potassium carbonate (1.45 g, 10.5 mmol) were combined in N,N-dimethylformamide (11.6 mL) and heated to 100° C. for 3.5 hours. The reaction was then cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate/heptane) provided methyl 6-(1-(4-iodophenyl)-3-methylbutylamino)nicotinate (0.772 g, 52%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.69 (d, J=1.8 Hz, 1H), 7.89 (dd, J=8.8, 2.3 Hz, 1H), 7.60-7.64 (m, 2H), 7.04-7.08 (m, 2H), 6.16 (d, J=8.4 Hz, 1H), 5.49 (d, J=6.4 Hz, 1H), 4.62-4.69 (m, 1H), 3.82 (s, 3H), 1.54-1.76 (m, 3H), 0.90-0.97 (m, 6H). MS (M+1): 425.2.
Reaction SMILES: Cl.Cl.[Cl:3]C1C=C([CH:10]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:11][C:12]2([OH:22])[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][CH2:14][CH2:13]2)C=CC=1.Cl.Cl.[Cl:32][C:33]1[CH:34]=[C:35](C(C2(O)C3C(CCCC3)CCC2)CN2CCNCC2)[CH:36]=[CH:37][CH:38]=1>>[ClH:3].[ClH:32].[Cl:32][C:33]1[CH:38]=[C:37]([CH:11]([C:12]2([OH:22])[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][CH2:14][CH2:13]2)[CH2:10][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH:36]=[CH:35][CH:34]=1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCC2CCCCC21
Reactant: CN1CCN(C(CC2(O)CCCC3CCCCC32)c2cccc(Cl)c2)CC1
Agent: Cl
Product: CN1CCN(CC(c2cccc(Cl)c2)C2(O)CCCC3CCCCC32)CC1

Procedure:
In an analogous manner to Example 24 1-[1-(3-chlorophenyl-2-(4-methylpiperazin-1-yl)ethyl]decahydronaphthalen-1-ol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]decahydronaphthalen-1-ol (see Example 72). MS (ES) m/z 391.3; RMS: calcd for C23H35ClN2O+H, 391.25161; found (ESI, [M+H]+), 391.2528.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21]2)=[O:19])[C:13]([O:15]C)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:25]2)=[O:19])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of (R)-methyl 3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoate (2.44 g, 5 mmol) in THF (50 mL) was added a solution of lithium hydroxide (420 mg, 10 mmol) in water (15 mL) at room temperature. After 1 h, most of the THF was removed and neutralized with 1.0 M hydrogen chloride to give (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoic acid as a white solid in 95% yield. 1H-NMR (CD3OD) δ 7.97 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.60 (s, 1H), 7.51-7.48 (m, 2H), 7.33 (d, J=8 Hz, 1H), 7.27-7.24 (m, 1H), 7.12 (s, 1H), 4.61-4.58 (m, 1H), 4.14-4.08 (m, 2H), 3.76-3.73 (m, 2H), 3.13-2.84 (m, 4H), 2.54 (s, 3H), 1.90-1.84 (m, 4H), 1.48-1.34 (m, 2H); MS (ESI) 474 (M+H) ; Rf=1.89.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>C(O)C>[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccccc1COCC(=O)c1ccccc1
Yield: 58.8 %

Procedure:
102 g (0.75 mol) of 2-hydroxyacetophenone and 102 g (0.75 mol) of potassium carbonate in 500 ml of absolute ethanol are initially taken. 139 g (0.75 mol) of 2-methylbenzyl bromide are added dropwise and the mixture is refluxed for 10 h. The mixture is cooled and filtered under suction, after which the filtrate is evaporated down. The crude product is recrystallized from diethyl ether. 106 g (59%) of product are obtained as crystals (mp.=53°-55° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.CN(C)C=O>[CH3:9][CH:2]([CH3:1])[CH2:3][C:4](=[O:8])[C:5]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC(=O)C(=O)N1CCCC1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Add oxalychloride (5.3 mL, 60.24 mmol, 1.6 eq.) slowly to the solution of 4-methyl-2-oxovaleric acid (4.90 g, 37.65 mmol, 1.0 eq.) in dichloromethane (50 mL) at 0° C. under nitrogen. Add Dimethylforamide (2 drops) last. Stir the reaction mixture overnight. Concentrate in vacuo. Add dichloromethane (100 mL). Add this solution to the solution of pyrrolidine (6.90 g, 97.02 mmol, 2.6 eq.) in dichloromethane (50 mL) at 0° C. slowly under nitrogen. Stir the reaction mixture for 1 hour at room temperature after addition. Wash with HCl (1 N) until the aqueous layer is acidic, then with aqueous saturated sodium chloride (2×20 mL) and water (2×30 mL). Dry the organic phase over MgSO4 and filter the drying reagent off. Concentrate in vacuo. Purify by column chromatography (0%→5% ethyl acetae in dichloromethane) to afford product (4.60 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]([NH:20][NH2:21])=O)=[CH:4][CH:3]=1.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=N)[NH2:30].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[NH:30][C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)=[N:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)c1ccccn1
Reactant: NNC(=O)Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3ccccn3c2Cc2nnc(-c3ccccn3)[nH]2)cc1
Temperature: 120 °C

Procedure:
A mixture of 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetohydrazide (0.55 mmol, 1.0 eq) in DMF (1-2 ml) and picolinimidamide hydrochloride (1.5 eq) was heated at 120° C. for 3 h. The mixture was cooled to rt, treated with sat. NaHCO3 (5 ml), extracted with CH2Cl2 (10 ml). The organic solution was dried with Na2SO4, evaporated under vacuum. The crude product was purified by HPLC. M/e+ 387 for C21H16ClN6 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ 9.11 (d, J=1.4 Hz, 1H), 8.56 (d, J=3.7 Hz, 1H), 8.36 (d, J=6.2 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.70 (dt, J=8.4, 2.9 Hz, 2H), 7.36 (m, 2H), 6.99 (m, 2H), 4.64 (s, 2H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][S:6](=[O:13])(=[O:12])[NH:7][C:8]([CH3:11])([CH3:10])[CH3:9])C.[OH-].[Na+].Cl>CCO.O>[C:8]([NH:7][S:6]([CH2:5][C:4]([OH:14])=[O:3])(=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOC(=O)CS(=O)(=O)NC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)CC(=O)O
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of ethyl-2-(N-tert-butylsulfamoyl)acetate (4 g, 17.9 mmol.) in 65 mL of EtOH and 13 mL of H2O at 0° C. was slowly added NaOH (3.6 g, 89.5 mmol.). The reaction was allowed to room temperature and stirred overnight. TLC analysis showed the reaction complete. The mixture was acidified to pH=5 with aq. HCl (1M). The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated to afford crude 2-(N-tert-butylsulfamoyl)acetic acid (2.4 g, 69%), which was used directly without purification.
Reaction SMILES: [ClH:1].[C:2]1([CH:12]([NH:14][CH2:15][CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)O)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O.CN(C=O)C.CC(OC)(C)C>C1(C)C=CC=CC=1>[ClH:31].[Cl:1][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH2:16][CH2:15][NH:14][CH:12]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(NCC[C@@H](O)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(NCC[C@@H](Cl)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IXa) (20.0 g, 48.796 mmol) is suspended in toluene (140 ml) at 40° C. and phosphoryl chloride (4.3 g, 28.044 mmol) is added drop-wise over 10 minutes. The reaction mixture is stirred two hours at 60° C., then DMF (1.0 g) is added at 40° C., followed by additional phosphoryl chloride (3.2 g, 20.870 mmol). The mixture is stirred at 40° C. overnight and then MTBE (40 ml) is added. Volatiles are removed by repeatedly distilling off under vacuum and restoring MTBE. After that a 1:1 vol/vol toluene/MTBE solution is received, which is heated up to 70° C. and allowed to cool down slowly to 15°-20° C. the so-obtained precipitate is aged at room temperature overnight, then filtered and washed with a 1:1 vol/vol toluene/MTBE mixture (3×12 ml). (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X) is obtained as a white powder after exsiccation at 55° C. under vacuum (6.0 g, 14.008 mmol, yield: 28.7%).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9](=[O:10])[NH:8][CH:7]=[CH:6][N:5]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:3])[CH3:2].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>ClCCCl>[CH:1]([C@@H:4]1[C:9](=[O:10])[NH:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1C(=O)NC=CN1C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)[C@@H]1C(=O)NCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a stirring solution of (R)-benzyl 2-isopropyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate (400 g, 1.46 mol) in DCE (2 L) was added Et3SiH (424 g, 3.65 mol) and TFA (665 g, 5.8 mol) at rt. The reaction was stirred under reflux for 36 h. After cooling to rt, the solution was concentrated to remove the solvent. The residue was diluted with EtOAc (2 L), and added slowly into stirring cooled sat. aq. NaHCO3 (2 L) to make sure that the pH>8. The mixture was extracted with EtOAc (2×2.5 L). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give (R)-benzyl 2-isopropyl-3-oxopiperazine-1-carboxylate (402 g, yield 99.75%), which was used for next step without further purification. LC-MS m/z 276.9 [M+H]+. 1H NMR (DMSO-d6 400 MHz): δ 7.93 (s, 1H), 7.39-7.31 (m, 5H), 5.09 (s, 2H), 4.06-4.01 (m, 1H), 3.99-3.92 (m, 1H), 3.23-3.14 (m, 3H), 2.20-2.12 (m, 1H), 0.96-0.94 (m, 3H), 0.85 (d, J=6.0 Hz, 3H).