Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([OH:22])[CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:24].O1CCOCC1.Cl.Cl.Cl.CC1CCN(CCN2CCC(N)CC2)CC1>>[ClH:24].[ClH:24].[ClH:24].[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([OH:22])[CH2:17]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2CCC[C@@H](O)C2)CC1
Agent: CC1CCN(CCN2CCC(N)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CCN2CCC[C@@H](O)C2)CC1

Procedure:
It is prepared by BOC-cleavage of tert-butyl ester 13 (1.7 g, 5.19 mmol) with 4M−HCl in dioxane (10.4 ml, 41.52 mmol) as described for amine 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([C:8](=[O:20])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=1.S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:21][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[CH:9][C:8]2=[O:20]
Reactant: COc1ccc(C(=O)CC(=O)c2cc(Br)ccc2O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)c3cc(Br)ccc3o2)cc1

Procedure:
A mixed solution consisting of compound 14 (2.67 g, 7.65 mmol), concentrated sulfuric acid (0.78 ml), and acetic acid (40 ml) was heated to reflux for 1 hour. The temperature of the resultant was returned to room temperature, and ice pieces were then added to the reaction solution. The precipitated crystal was collected by filtration, so as to obtain a product of interest, 6-bromo-4′-methoxyflavone (compound 15). Yield: 2.01 g (yield constant: 79.4%) 1H NMR (300 MHz, CDCl3) δ8.35 (s, 1H), 7.87 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 1H), 7.45 (d, J=9.3 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.75 (s, 1H), 3.90 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:25](O)=[O:26])=[O:22])[NH:18][C:15]2=[CH:16][N:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[C:25](=[O:26])[C@@H:24]([NH:23][C:21]([C:19]1[NH:18][C:15]2=[CH:16][N:17]=[C:12]([Cl:11])[CH:13]=[C:14]2[CH:20]=1)=[O:22])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)(=[O:9])[NH2:10]
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NC(=O)C1CCCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)C1CCCCN1C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of piperidine-2-carboxylic acid amide hydrochloride (Preparation 80, 24 mg, 0.17 mmol) in DMF (3 mL) was added 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 230, 52 mg, 0.14 mmol), followed by HATU (65.6 mg, 0.17 mmol) and DIPEA (63 μL, 0.36 mmol), and the reaction stirred at rt for 16 h. Solvent was removed in vacuo, purification via preparative HPLC gave the title compound as an off-white powder. m/z (ES+)=472.31 [M+H]+; RT=3.19 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:42])([CH3:41])[CH3:43])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:6][CH2:7]1)[CH3:50]
Reactant: CCOC(=O)CBr
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCOC(=O)CNC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 146, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with ethyl bromoacetate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3076.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][CH3:26])[CH2:21][CH2:20]2)=[O:18])[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[CH3:26][O:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH2:16][O:15][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH3:27])=[CH:10][CH:11]=3)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)c1cc(OCC(=O)N2CCC(OC)CC2)c2ccc(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC1CCN(C(=O)COc2cc(C(=O)O)nc3cc(C)ccc23)CC1
Reaction time: 2 h

Procedure:
To a solution of 980 mg 4-[2-(4-Methoxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid methyl ester in 10 ml THF were added 2.5 ml aqueous NaOH (1 M) at 0° C. After 2 h the mixture was brought to pH 4 by using Amberlite IR-120 ion exchange resin. The reaction mixture was filtered and concentrated and the crude product obtained used in the next step without further purification. Yield: 800 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[ClH:15]>CCO.[Pd]>[ClH:15].[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14]
Reactant: N#CCc1ccc(C(F)(F)F)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCc1ccc(C(F)(F)F)cc1F
Yield: 78 %

Procedure:
2-Fluoro-4-trifluoromethyl-phenyl acetonitrile (2 g, 9.85 mmol) is hydrogenated with H2 in a balloon, 10% Pd/C (522 mg, 5 mol %) in 95% EtOH (50 mL) containing concentrated hydrochloric acid (1.64 mL) at room temperature for 15 hours. The mixture is filtered and filtrate is concentrated to a solid that is washed with diethyl ether to obtain 2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamine hydrochloride (1.88 g, 78%) as a solid. LC/MS: 208 (M+H). This compound (1.8 g, 8.7 mmol) is dissolved in EtOH (25 mL) and treated with 4,6-dichloro-2-methoxy-pyrimidine [1.3 g, 7.25 mmol, Intermediate (4)] and sodium bicarbonate (1.52 g, 18.13 mmol). The mixture is heated to reflux for 5 hours. Solid is filtered and EtOH is removed in vacuo. The residue is washed with small amount of DCM to obtain (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine (2.59 g, 76%) as a solid. LC/MS: 350 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[N:9]=[C:8]([OH:16])[CH:7]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.OC1N=CC=CC=1C([O-])=O>CN(C=O)C>[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[N:9]=[C:8]([O:16][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[CH:7]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)OC(=O)c1cc(O)nc(OC(C)C)c1
Agent: O=C([O-])[O-]
Agent: O=C([O-])c1cccnc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(Oc2ccc(C#N)cc2)nc(OC(C)C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
2-Hydroxy-6-isopropoxy-isonicotinic acid isopropyl ester (0.5 g, 2.09 mmol) and 0.577 g (4.18 mmol) potassium carbonate was dissolved in 5 ml of dry DMF. 0.25 g (2.09 mmol) of 4-fluorobenzonitrile, dissolved in 5 ml of DMF, was added to the stirred solution of hydroxynicotinate over a period of 15 min and then the contents of the reaction flask were stirred overnight at 100° C. Reaction mixture was concentrated and the residue was dissolved in 100 ml of ethylacetate and washed with water. Ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 0.3 g of required product which was used for the next step without further purification. 1H NMR (CDCl3): δ 1.2 (6H, d), 1.35 (6H, d), 4.8 (1H, m), 5.25 (1H, m), 7.2 (3H, m), 7.7 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:31](=[O:33])[CH3:32])[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCCC2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)C2CCCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclopentylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:32])[NH:20][C:21]([CH3:31])=[CH:22][C:23]=2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C(O)C.C(N(CC)CC)C>[Pd].C1COCC1>[CH3:13][CH:11]([N:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:32])[NH:20][C:21]([CH3:31])=[CH:22][C:23]=3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:12]
Reactant: Cc1cc(Cc2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2cccc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 6 h

Procedure:
To a dried 50 mL round bottom flask was placed 10% Pd/C (0.020 g, 9.63 mol), followed by degassing with N2. Added about 5 mL EtOH and then added 6-bromo-1-(1-methylethyl)-N-{[6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}-1H-indazole-4-carboxamide (0.095 g, 0.193 mmol) and ethanol (5 mL) and THF (1 mL). Next added in triethylamine (0.081 mL, 0.578 mmol) via syringe. The mixture was stirred under atmosphere of hydrogen (balloon) for 6 h. The mixture was purged with nitrogen and then diluted with DCM (10 mL) and a small amount of celite, After stirring for 10 min, the contents were then filtered through analytical grade celite and washed with 10% MeOH/DCM, EtOH, and then DCM. The filtrate was concentrated in vacuo and dried under hi vacuum overnight. The crude product was purified by silica gel chromatography (eluent: 5-50% gradient of 10% methanol in dichloromethane and dichloromethane). The final product was concentrated from MTBE and dried in vacuum oven at 45° C. for 18 h. The title compound was collected as a white solid (0.75 g, 92% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.57 Hz, 6H) 2.10 (s, 3H) 3.98 (s, 2H) 4.43 (d, J=5.05 Hz, 2H) 5.03 (quin, J=6.63 Hz, 1H) 5.81 (s, 1H) 7.15-7.31 (m, 5H) 7.39 (t, J=7.71 Hz, 1H) 7.52 (d, J=6.82 Hz, 1H) 7.85 (d, J=8.34 Hz, 1H) 8.34 (s, 1H) 8.50 (t, J=5.05 Hz, 1H) 11.61 (s, 1H); MS (ES) [M+H]+ 415.0.
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.[CH3:27][C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:34][C:28]1([CH3:27])[CH2:33][CH2:32][N:31]([C@H:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[O:4])[CH2:30][CH2:29]1
Reactant: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Reactant: CC1(O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(C)(O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
To a solution of (S)-1-phenylethyl 2-bromo-2-phenylacetate (0.464 g, 1.45 mmol) in THF (8 mL) was added triethylamine (0.61 mL, 4.35 mmol), followed by tetrabutylammonium iodide (0.215 g, 0.58 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-methyl-4-hydroxypiperidine (0.251 g, 2.18 mmol) in THF (2 mL) was added. The mixture was stirred for 1 hour at room temperature and then it was heated at 55-60° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was then diluted with ethyl acetate (30 mL), washed (H2O×2, brine), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (0-60% ethyl acetate-hexane) to provide first the (S,R)-isomer of the title compound (0.306 g, 60%) as a white solid and then the corresponding (S,S)-isomer (0.120 g, 23%), also as a white solid. (S,R)-isomer: 1H NMR (CD3OD) δ 7.51-7.45 (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, J=6.6 Hz, 1H), 4.05 (s, 1H), 2.56-2.45 (m, 2H), 2.41-2.29 (m, 2H), 1.71-1.49 (m, 4H), 1.38 (d, J=6.6 Hz, 3H), 1.18 (s, 3H). LCMS: Anal. Calcd. for C22H27NO3: 353. found: 354 (M+H)+. (S,S)-isomer: 1H NMR (CD3OD) δ 7.41-7.30 (m, 5H), 7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, J=6.6 Hz, 1H), 4.06 (s, 1H), 2.70-2.60 (m, 1H), 2.51 (dt, J=6.6, 3.3 Hz, 1H), 2.44-2.31 (m, 2H), 1.75-1.65 (m, 1H), 1.65-1.54 (m, 3H), 1.50 (d, J=6.8 Hz, 3H), 1.20 (s, 3H). LCMS: Anal. Calcd. for C22H27NO3: 353. found: 354 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH:6]=2)[CH2:3][CH2:2]1.[NH:22]1[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:28]4\[NH:22][C:23](=[O:24])[NH:25][C:26]\4=[O:27])=[C:9]3[N:8]=[C:7]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(NC(=O)C3CC3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(NC(=O)C4CC4)nc23)N1
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide (74 mg, 0.26 mmol) in 1.0 mL ethanol was added hydantoin (26 mg, 0.26 mmol) and piperidine (24 ul). The reaction was heated at 80° C. for two hours. The reaction mixture was cooled to room temperature, concentrated and diluted with MeOH. The product was purified by prep HPLC to yield 14 mg (20% yield) (Z)—N-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide. LCMS (M+1=368)
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(O)(=O)C1C=CC=CC=1.[Mn]([O-])(=O)(=O)=O.[K+].S(Cl)([Cl:29])=O>S(=O)(=O)(O)O.CN(C)C=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([Cl:29])=[O:9])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc(C=O)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)Cl)cc1

Procedure:
p-isopropylbenzaldehyde is oxidized to the corresponding benzoic acid by using potassium permanganate in sulfuric acid as the oxidizing agent at low temperature. The acid is converted to the acid chloride using thionyl chloride with a trace of dimethylformamide as a catalyst to give p-isopropylbenzoyl chloride.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].CCOCC>C1COCC1.[Cl-].[Na+].O>[CH2:34]([CH:29]([CH:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:10]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:11])[C:30]([O:32][CH3:33])=[O:31])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)C(Br)Cc1ccccc1
Reactant: O=C(COCc1ccccc1)N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(Cc1ccccc1)C(OCc1ccccc1)C(=O)N1CCOCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C@H:9]([NH:28]C(OCC1C=CC=CC=1)=O)[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C@H:9]([NH2:28])[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC[C@H](N)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 83.2 %

Procedure:
7 g of (S)-4-Benzyloxycarbonylamino-5-oxo-5-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-pentanoic acid tert-butyl ester were dissolved in 120 ml of EtOH and 70 mg of Pd/C 10% was added. Hydrogenation under 3 bar of hydrogen was continued until full conversion of the reaction was obtained. After filtration of the catalyst all volatiles were evaporated under reduced pressure to give 4.4 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[C:6]([F:13])[C:5]=1[F:14])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[C:17]=1[F:24].C(=O)([O-])[O-].[Na+].[Na+].Cl>[Pd].CC(O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[C:17]=2[F:24])=[C:6]([F:13])[C:5]=1[F:14])[CH3:2]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: Oc1ccc(Br)c(F)c1F
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCOc1ccc(-c2ccc(O)c(F)c2F)c(F)c1F
Temperature: 25 °C
Yield: 56 %

Procedure:
In a reactor under nitrogen atmosphere, 20.0 g of compound (a2), 17.2 g of 4-bromo-2,3-difluorophenol (a3), 30.6 g of sodium carbonate, 0.54 g of palladium on carbon catalyst (Pd/C) were dissolved in 120 mL of 2-propanol (IPA), followed by stirring by refluxing for 10 hours. The reaction mixture was cooled to room temperature, and injected into a mixture of 500 ml of 1N hydrochloric acid and 300 ml of toluene which were cooled into 0° C. The mixture was allowed to separate into organic layer and aqueous layer and the organic layer was extracted. The resulting organic layer was washed with saturated chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to provide the residue. The resulting residue was purified by recrystallization from heptan, and dried to provide 13.2 g of 4′-ethoxy-2,3,2′,3′-tetrafluorobiphenyl-4-ol (a4) as a white solid.
Reaction SMILES: [NH:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1O)C(C)=O.[C:20](=[O:23])([O-])[O-].[K+].[K+].[C:26](=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:23][CH2:20][CH3:26]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1c(O)ccc2cc(S(=O)(=O)O)ccc12
Agent: [K+]
Agent: [Na+]
Product: CCOc1ccc2cc(S(=O)(=O)O)ccc2c1N
Temperature: 120 °C
Yield: 190.3 %

Procedure:
6.42 kg (62% pure=4 kg of 100% pure) of 1-acetamino-2-hydroxy-naphthalene-6-sulphonic acid, prepared according to Example 4, 0.98 kg of potassium carbonate and 0.75 kg of sodium carbonate are introduced into a 150 l autoclave. After flushing the autoclave with nitrogen, 22 kg (28 l) of ethanol are added to the mixture. The autoclave is closed and heated to 120° C., whilst stirring thoroughly. 7 kg (6.5 l) of 2 N potassium hydroxide solution and 2.75 kg (about 3 l) of ethyl chloride are now pumped into the autoclave in the course of 1 to 2 hours. The entire reaction mixture is stirred for a further 5 hours at 120° C. After cooling the reaction mixture to room temperature, the autoclave is let down and flushed twice with nitrogen. The contents of the autoclave are then introduced into a 250 ml V4A steel kettle. The autoclave is rinsed out with 5 kg of 80% pure ethanol and the rinsing solution is likewise introduced into the steel kettle. The mixture in the steel kettle is heated to the boiling point, about 20 kg of alcohol being distilled off. 13 kg of water are then allowed to run slowly into the boiling solution and the mixture is distilled until no further alcohol passes over. After adding 4.3 kg of 50% strength sodium hydroxide solution, the mixture is stirred at 100° C. for 4 hours. The mixture is then cooled to 20° C. and the product which has precipitated is filtered off and washed with 25 kg of sodium chloride solution. After drying, 3.6 kg of 1-amino-2-ethoxy-naphthalene-6-sulphonic acid (content: 84.2% pure, corresponding to 3.03 kg of 100% pure=80% of theory, relative to 1-acetamino-2-hydroxy-naphthalene-6-sulphonic acid, or 61.6% of theory, relative to 2-hydroxy-naphthalene-6-sulphonic acid) are obtained.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:8]2)[O:4][N:3]=1.[NH:30]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]1>C(O)C>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:11]2[CH2:12][CH:7]([C:5]3[O:4][N:3]=[C:2]([N:30]4[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]4)[N:6]=3)[CH2:8][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:10]2)=[CH:14][CH:15]=1)[CH3:20]
Reactant: O[C@@H]1CCNC1
Reactant: CCc1ccc(C2CC(c3nc(Cl)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Solvent: CCO
Product: CCc1ccc(C2CC(c3nc(N4CC[C@@H](O)C4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.191 mmol) of the oxadiazole from Example 25A in 1.20 ml of ethanol were added 333 mg (3.82 mmol) of (3R)-pyrrolidin-3-ol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure, dichloromethane was added and the mixture was washed with water. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 64.8 mg (70% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:14](=O)C1C=CC=CC=1.CI>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCO
Solvent: CI
Product: CNCCc1ccc(OC)c(OC)c1
Yield: 74.3 %

Procedure:
3,4-Dimethoxybenzeneethanamine (100 g) was mixed with benzaldehyde (59 g), and rotoevaporated to give an oil. Methyl iodide (69 ml) was then added and the mixture was heated for 48 h at 40° and then boiled with 80% ethanol (500 ml) for 3 h. After half of the ethanol had evaporated, the solution was treated with ether (1 liter) to give a solid that was filtered, washed with ether, treated with dilute sodium hydroxide and extracted with ether to give the title compound (80 g) as an oil that was distilled under reduced pressure, b.p. 0.1 mm; 92°-95°.