Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25](=[O:27])[CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1.[Na]>CN(C=O)C.CO>[CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH:25]([OH:27])[CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(COCc2ncnn2C)c1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(O)c1ccc2c(c1)ncn2-c1cccc(COCc2ncnn2C)c1
Yield: 46 %

Procedure:
To a solution of compound 21d (4.9 g, 13.9 mmol) in a mixture of DMF (90 ml) and methanol (10 ml) was added sodium boronhydride (0.53 g, 13.9 mmol). The resultant mixture was stirred at 60° C. for 1 hour. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and eluted through silica gel with a mixture of ethyl acetate and methanol (9:1 v/v). The pure fractions were concentrated and compound 23 was precipitated as the hydro chloride upon addition of etheral hydrogen chloride to the concentrate. Yield: 46%. LC-ESI-HRMS of [M+H]+ shows 364.1764 Da. Calc. 364.177325 Da, dev. −2.5 ppm
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: NCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A commercially available solution of 2-phenylethylamine (2 ml, 15.8 mmol) in pyridine (5 ml) is added with acetic anhydride (2 eq., 3 ml) and the solution is stirred at room temperature for 12 hours. The solvent is evaporated off under reduced pressure and the residue is taken up with water (40 ml) and the aqueous phase is extracted with EtOAc (4×25 ml). The organic extracts are pooled, anhydrified over Na2SO4 and evaporated under reduced pressure. The residue is crystallised from petroleum ether to give compound 28 as white solid (2.56 g, quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Li+].CC([N-]C(C)C)C.CN(OC)[C:21]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)=[O:22].[Cl-].[NH4+].C>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[C:6]([C:7]#[N:8])[C:5]([F:10])=[C:4]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH:3]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)cc(C#N)c2F)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 111.3 %

Procedure:
A solution of 5-bromo-2-fluorobenzonitrile (7.34 g, 36.7 mmols) in dry THF (90 mL) was cooled to −78° C. under a nitrogen atmosphere. A 2M solution of LDA in THF (21.48 mL, 43.0 mmols) was added during 15 mins and the mixture was stirred at −78° C. for 2 h giving a deep blue solution. 1,1-dimethylethyl 4{[methyl(methyloxy)amino]carbonyl}-1-piperidinecarboxylate (12.5 g, 45.9 mmols) in dry THF (45 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 16 hrs (overnight). Saturated aqueous ammonium chloride (200 mL) was added followed by ethyl acetate (200 mL). The mixture was treated with charcoal to decolorize, filtered and the organic phase separated. The organic layer was washed with saturated aqueous ammonium chloride and dried over MgSO4. Evaporation of the solvent afforded a green solid (16.8 g). The solid was purified by flash chromatography (Dry loaded onto silica, gradient elution with pentane/ethyl acetate 9:1 v/v to 3:2 v/v) to give the title compound (1.35 g) as a green gum (9%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:40](O)=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2].Cl.C[O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([C:40](=[O:41])[NH:51][CH2:50][CH2:49][C:48]([OH:52])=[O:47])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2]
Reactant: COC(=O)CCN
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)NCCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 21 h
Yield: 85.3 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in N,N-dimethylformamide (2 ml), and thereto are added triethylamine (53 μl), 3-aminopropionic acid methyl ester hydrochloride (67 mg), 1-hydroxybenzotriazole hydrate (65 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92 mg) under ice-cooling. The mixture is stirred for 21 hours. The reaction solution is concentrated under reduced pressure, then the residue is partitioned by adding a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer is concentrated under reduced pressure. The resulting residue is dissolved in methanol (2 ml), and thereto is added 5N aqueous NaOH solution (1 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added 6N HCl (0.85 ml), and then the mixture is extracted with ethyl acetate and the organic layer is concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→19: 1) to give (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(2-carboxyethyl)carbamoyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (190 mg). MS (m/z): 699 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:10][C:7]2[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([F:11])[C:4]=2[CH:5]=[O:6])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=Cc1c(O)ccc(Cl)c1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)c(F)c2C=O)CC1
Yield: 106.1 %

Procedure:
In a manner similar to the method described in example 4a, 3-chloro-2-fluoro-6-hydroxy-benzaldehyde (2.07 g, 11.8 mmol) reacted with 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (3.51 g, 9.88 mmol, ASTATECH) and K2CO3 in N,N-dimethylformamide to give 4-(4-chloro-3-fluoro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil (Yield 3.75 g, 84%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[C:10](Cl)(=[O:12])[CH3:11]>C(Cl)Cl>[C:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: CCc1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-ethylphenol (3.38 g, 27.67 mmol) in DCM (50 mL) in an ice bath was added TEA (7.2 mL, 55.34 mmol), followed by the dropwise addition of acetyl chloride (2.2 mL, 30.44 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with water (40 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl-].[C:22]1([CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](Cl)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:32])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
To 3.03 g of methyl 4-aminobenzoate and 3.12 g of N,N-diisopropylethylamine in 75 ml of methylene to chloride is added 5.54 g of 2-(phenylmethyl)benzoyl chloride and the reactants stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2 SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 5.04 g of the desired product as a crystalline solid, m.p. 138°-139° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[C:18]([CH3:19])=[CH:17][C:10]([O:11][C@@H:12]2[CH2:15][C@H:14]([NH2:16])[CH2:13]2)=[CH:9][C:8]=1[CH3:20].C(N(CC)CC)C>ClCCl>[Br:6][C:7]1[C:18]([CH3:19])=[CH:17][C:10]([O:11][C@@H:12]2[CH2:15][C@H:14]([NH:16][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13]2)=[CH:9][C:8]=1[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(O[C@H]2C[C@@H](N)C2)cc(C)c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O[C@H]2C[C@@H](NS(C)(=O)=O)C2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.16 mL), cis-3-(4-Bromo-3,5-dimethylphenoxy)cyclobutanamine (300 mg) and triethylamine (0.3 mL) are stirred at 0° C. in dry dichloromethane (25 mL). After 10 min, the reaction mixture is warmed to ambient temperature. After stirring for 3 hours, the mixture is diluted with dichloromethane, washed with 10% aqueous solution of KHSO4, then with 10% aqueous solution of K2CO3. The organic phase was passed through a phase separator and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→50:50) to give the title compound. Yield: 200 mg.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]#[N:8])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:7][NH2:8])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cccc(-c2ccccc2)c1C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)Nc1cccc(-c2ccccc2)c1CN
Temperature: 25 °C

Procedure:
The product of example 2a above, 2-isopropylamino-6-phenylbenzonitrile, (0.095 g, 0.4 mmol) was dissolved in dry tetrahydrofuran (20 mL) and stirred under argon at room temperature. Lithium aluminum hydride (0.160 g, 4 mmol) was added and the mixture heated to reflux under argon for 16 hours. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added followed by the addition of a freshly prepared saturated solution of anhydrous sodium sulfate. The solvent was evaporated and the residue triturated with ethyl acetate, filtered and evaporated. Flash chromatography on silica gel eluted with 0-3% methanol in methylene chloride followed by recrystallization from ethyl acetate/hexane gave the title compound as a white crystalline solid. ES (+) MS m/e=241 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][O:14][NH:15][CH3:16].Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:15]([O:14][CH3:13])[CH3:16])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a stirred solution of 2-(4-fluorophenyl)acetic acid (15 g, 97.32 mmol, 1.00 equiv) in CH2Cl2 (300 mL) was added methoxy(methyl)amine hydrochloride (11.1 g, 113.79 mmol, 1.20 equiv), 4-dimethylaminopyridine (12 g, 98.22 mmol, 1.00 equiv), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (28.2 g, 147.10 mmol, 1.50 equiv), and DIEA (37.5 g, 290.14 mmol, 3.00 equiv). The resulting solution was stirred at room temperature for 16 h and then diluted with EtOAc (150 mL). The organics were washed with aqueous 1N HCl (2×150 mL) and brine (2×150 mL). It was then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel, eluting with EtOAc/petroleum ether (1:3)). This resulted in 18 g (88%) of the title compound as yellow oil. 1H-NMR (400 MHz, CDCl3): δ ppm 7.29-7.25 (m, 211), 7.03-6.99 (m, 2H), 3.75 (s, 2H), 3.65 (s, 3H), 3.21 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][Br:14].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]([Br:15])[Br:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: BrCc1ccc2ccccc2c1CBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1c(C(Br)Br)ccc2ccccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
In 150 ml of carbon tetrachloride, 20 g (64 mmole) of 1,2-bis(bromomethyl)naphthalene and 23 g (130 mmole) of N-bromosuccinimide were suspended. To the obtained suspension, 1.1 g (6.7 mmole) of 2,2′-azobis(isobutyronitrile) was added and the mixture was vigorously stirred at 100° C. for 2 hours. After the reaction was completed, the reaction mixture was filtered and the residue was washed with 150 ml of dichloromethane. The filtrate and the washing were combined. The combined solution was treated by the column chromatography (silica gel/dichloromethane) without additional treatments and 16 g (the yield: 64%) of a white solid of 1-(bromomethyl)-2-(dibromomethyl)naphthalene was obtained.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH3:30][C:31]1[O:35][N:34]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]=1[C:42](Cl)=[O:43]>>[CH3:30][C:31]1[O:35][N:34]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]=1[C:42]([O:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=2)[CH2:10][CH2:11]1)=[O:43]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Product: Cc1onc(-c2ccccc2)c1C(=O)OC(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 580.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:36]=[C:37]([O:39][CH2:40][C:41]4[N:42]=[C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[S:44][CH:45]=4)[CH:38]=3)[CH2:17][N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:19]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:36]=[C:37]([O:39][CH2:40][C:41]4[N:42]=[C:43]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[S:44][CH:45]=4)[CH:38]=3)[CH2:17][N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:19]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCc3csc(-c4ccccc4)n3)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2cc(OCc3csc(-c4ccccc4)n3)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
After a mixture of ethyl 3-[1-[3,5-bis(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (498 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[3,5-bis(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (378 mg, yield: 79%). This was recrystallized from ethyl acetate-hexane. Melting point: 78–79° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][C:16](O)=[O:17])[N:10]3[N:19]=[CH:20][C:21]([C:22]4[CH:23]=[N:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[C:9]3[N:8]=2)[CH2:3][CH2:2]1.[NH4+].[OH-]>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:12]3[C:16](=[O:17])[CH2:15][CH2:14][NH:13][C:11]=3[N:10]3[N:19]=[CH:20][C:21]([C:22]4[CH:23]=[N:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[C:9]3[N:8]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)CCNc1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: [NH4+]
Agent: [OH-]
Product: O=C1CCNc2c1c(N1CCOCC1)nc1c(-c3cnc4ccccc4c3)cnn21
Temperature: 125 °C

Procedure:
A mixture of 3-(5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)propanoic acid (19.8 mg, 0.047 mmoL) and PPA was heated at 125° C. for 2 h. The reaction was cooled to 0° C. and the PH was adjusted to 8 by the addition of NH4OH. Extraction with 20% iPrOH/CH2Cl2 (×3), concentration of dried organic layer and purification by prep-LC afforded 5-morpholino-3-(quinolin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one. LCMS tR=2.79 Min (10 min run, UV254nm). Mass calculated for, M+ 400.1, observed LC/MS m/z 401.1 (M+H).
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][C:16]([NH:19][CH2:20][C@@H:21]([C:23]1[CH:24]=[C:25]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=1)[OH:22])([CH3:18])[CH3:17])[CH:9]=[CH:8]2)#[N:4]>C(O)C>[C:33]1([S:30]([NH:29][C:25]2[CH:24]=[C:23]([C@@H:21]([OH:22])[CH2:20][NH:19][C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3]([NH:1][OH:2])=[NH:4])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)[CH:28]=[CH:27][CH:26]=2)(=[O:32])=[O:31])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NO
Reactant: CC(C)(CCn1ccc2cc(C#N)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Solvent: CCO
Product: CC(C)(CCn1ccc2cc(C(=N)NO)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1

Procedure:
Hydroxylamine (600 μl) is added to a solution of N-(3-{(R)-2-[3-(5-cyano-indol-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-phenyl)-benzenesulphonamide (Example 1) (170 mg, 0.34 mmol) in 5 ml of ethanol. The reaction mixture is refluxed for 5 hours. Then the solvent is eliminated in vacuo.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[N:15]([C:16](=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[N:27][N:26]=[N:25]4)=[CH:20][CH:19]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[CH:13]12[N:15]([C:16](=[O:29])[CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH:28]=[N:27][N:26]=[N:25]4)=[CH:22][CH:23]=3)[CH:10]([CH2:11][CH2:12]1)[CH2:9][NH:8][CH2:14]2
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1C2CCC1CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Benzyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (580 mg, 1.49 mmol) was dissolved in ethanol (20 mL), concentrated HCl solution was added (37%, 2.0 mL, 24.4 mmol), followed by palladium on carbon (200 mg). The mixture was degassed and stirred under hydrogen gas at room temperature overnight. The reaction mixture was filtered through a Celite® plug and the filtrate was concentrated. The product was partitioned between DCM and saturated sodium bicarbonate solution, then the organic layer was dried over MgSO4. Purification by MPLC eluting with 10% methanol in DCM afforded the title compound. LC/MS: [(M+1)]+=299.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C1CCC(N=C=NC2CCCCC2)CC1.CN1CCOCC1>ClCCl>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Yield: 62 %

Procedure:
A solution of β-alanine ethyl ester hydrochloride salt (5) (3.07 g; 0.02 mmol), N-(tertbutoxycarbonyl)glycine (3.5 g; 0.02 mmol), DCCI (4.12 g; 0.02 mmol) and 4-methylmorpholine (2.2 ml) in dichloromethane (60 ml) was stirred overnight under argon atmosphere at ambient temperature. After filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (96/4) to give ethyl 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (6).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.[OH-].[Na+].Cl>CCO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CCOC(=O)COc1ccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ncc(-c2ccc(OCC(=O)O)cc2)cc1-c1nc2ccccc2s1

Procedure:
To a suspension of ethyl 4-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenoxyacetate (132 mg, 0.330 mmol) in EtOH (2.0 mL) was added 3M aqueous NaOH (0.50 mL, 1.5 mmol). Then, the mixture was acidified to pH=2 with 1M aq. HCl. Vacuum filtration afforded the title compound as a yellow solid. MS (ES+): m/z=506.88 (100) [MH+]. HPLC: tR=3.14 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:6]2.[Br:17]N1C(=O)CCC1=O>C(#N)C>[Br:17][C:14]1[N:13]=[CH:12][C:11]([N:5]2[CH2:6][CH:7]3[N:2]([CH3:1])[CH:3]([CH2:10][CH2:9][CH2:8]3)[CH2:4]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1C2CCCC1CN(c1cccnc1)C2
Solvent: CC#N
Product: CN1C2CCCC1CN(c1ccc(Br)nc1)C2
Temperature: 0 °C

Procedure:
A mixture of 9-methyl-3-pyridin-3-yl-3,9-diaza-bicyclo[3.3.1]nonane (1.38, 6.2 mmol) and acetonitrile (40 ml) was cooled to 0° C. N-bromo-succinimide (1.1 g, 6.2 mmol) in acetonitrile (20 ml) was added during 2 h. The mixture was stirred over night at room-temperature. The mixture was evaporated. Aqueous sodium hydroxide (20 ml, 1 M) was added followed by extraction with dichloromethane (3×10 ml). The product was purified by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (9:1:1%). Yield 900 mg (49%). LC-ESI-HRMS of [M+H]+ shows 296.0757 Da. Calc. 296.076235 Da, dev. −1.8 ppm.