Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH2:12]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[CH2:24][C:25](OCC)=[O:26])[CH3:13]>O>[CH2:12]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[CH2:24][C:25]([NH:10][C:9]([NH2:11])=[NH:8])=[O:26])[CH3:13]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1CC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
N-[(2-Ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 4.3 g of potassium tert-butoxide, 3.7 g of guanidinium chloride and 1.9 g of ethyl (2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 60 cm3 of water. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate and is then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. The residue is taken up in water, triturated and filtered. The solid is taken up in methanol and the solvent is then evaporated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. 0.56 g of N-[(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]-guanidine is thus obtained in the form of an off-white solid melting at 223° C. Mass spectrum EI: m/e 260 (M+), m/e 173, m/e 160, m/e 132.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-])=O.[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=O.C(=O)=O>C1COCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:16][CH3:14])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
4-Nitrobenzeneacetic acid (16.6 g, 0.0916 mol) was dissolved in THF (200 mL) and carbonyldiimidazole (CDI, 15.6 g, 0.0963 mol) was added. Carbon dioxide evolution rapidly ensued and the reaction mixture was stirred at RT for 30 min. Gaseous methylamine was then bubbled through the mixture until it was distinctly basic to litmus paper. The THF was removed in vacuo and water (70 mL) was added. The solid material was collected by filtration and placed in a Parr bottle were palladium on carbon (10%, 3 g). A solution of EtOH (200 mL) and 1N HCl (50 mL) was added and the mixture was hydrogenated at 60 psi for 4 h. The reaction was filtered, concentrated in vacuo and the residue made basic with saturated aqueous Na2CO3. The aqueous mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the product (6) (10.0 g, 66.6%) which was pure by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.S(=O)(=O)(O)O.[CH3:32]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:32])=[O:22])=[CH:19][CH:20]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
0.5 g (1.37 mmol) of 4-(3-chloro-anilino)-6-(4-carboxy-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine suspended in 100 ml of methanol is heated under reflux for 24 hours with 0.1 ml of concentrated sulfuric acid. The solution is concentrated and stirred in methanol/diethyl ether. The crystals are filtered off and then suspended in methanol/water. The suspension is adjusted to pH 7-8 with sodium hydrogen carbonate solution and stirred at RT for 30 min. The crystals are filtered off with suction, washed with water, methanol and diethyl ether and dried. The title compound is obtained in the form of colorless crystals, m.p.>300° C.; TLC-Rf =0.6 (toluene/ethyl acetate [3:7]); FAB-MS: (M+H)+ =378.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([N:5]([CH3:18])[S:6]([C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)nc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Yield: 64.4 %

Procedure:
A mixture of 0.97 g (3.9 mmol) of N-tert-butyl-6-chloropyridine-3-sulfonamide, 2.43 mL (39 mmol) of methyl iodide and 5.4 g (39 mmol) of K2CO3 in 40 mL of acetone is refluxed for 12 hours. The reaction medium is filtered at room temperature, and the filtrate is concentrated under reduced pressure. The residue obtained is purified on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 20% EtOAc, to give 0.66 g of N-tert-butyl-6-chloro-N-methylpyridine-3-sulfonamide in the form of a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[CH:14]1([NH:17][C:18]([NH2:20])=[S:19])[CH2:16][CH2:15]1>C(O)C>[CH:14]1([NH:17][C:18]2[S:19][CH:2]=[C:3]([C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[N:20]=2)[CH2:16][CH2:15]1
Reactant: NC(=S)NC1CC1
Reactant: O=C(CBr)c1c[nH]c2ncccc12
Solvent: CCO
Product: c1cnc2[nH]cc(-c3csc(NC4CC4)n3)c2c1
Temperature: 0 °C
Yield: 124.5 %

Procedure:
A mixture of 2-Bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (prepared according to Galvez C. et al, J. Het. Chem. 21, 1984, p421-423) (0.90 g, 3.76 mmol) and cyclopropyl-thiourea (prepared according to Marletta, M. et al, J. Med. Chem. 35, 1992, p1137-1144) (0.46 g, 3.96 mmol) was heated in ethanol (20 mL), at reflux for 4 hours. The reaction mixture was cooled to 0° C. with and ice-water bath, then the solids were filtered and dried to give cyclopropyl-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-amine as a tan solid (1.2 g, 92%). LC/MS MH+ =257.02, LC/MS RT: 1.62 min. 1H NMR (500 MHz, DMSO-d6, ppm) 12.22 (s,1H), 9.20 (bs,1H), 8.42 (d,1H, J=7.82 Hz), 8.36 (dd,1H, J=4.81, 1.22 Hz), 8.00 (s,1H), 7.25 (m,1H), 6.12 (s,1H), 2.77 (t, 1H,J=4.75), 0.86 (m,2H), 0.71 (m,2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[C:6]([OH:12])[C:5]=1[CH2:13][C:14]([CH3:16])=[CH2:15].B(F)(F)F.CCOCC.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[C:6]2[O:12][C:14]([CH3:16])([CH3:15])[CH2:13][C:5]=12)=[O:17]
Reactant: C=C(C)Cc1c(C(=O)OC)cc(O)c(Br)c1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(O)c(Br)c2c1CC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a stirred solution of 4-bromo-3,5-dihydroxy-2-(2-methyl-allyl)-benzoic acid methyl ester (197c) (85 g, 0.28 mol) in CH2Cl2 (1500 mL) was added drop wise BF3.Et2O (180 mL, 1.41 mol) at 0° C. The mixture was stirred at room temperature for 2 hr. After TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete, the reaction mixture was poured into water (1 L). The organic phase was separated and washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated to give a yellow solid. The crude solid was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (37 g, 44% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 5.43 (s, 1H), 3.80 (s, 3H), 3.29 (s, 2H), 1.45 (s, 6H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Pyridin-4-ylboronic acid (500 mg, 4.07 mmol), 1-bromo-4-iodobenzene (1.27 g, 4.47 mmol) and 2M Na2CO3 (6.1 ml, 12.2 mmol) were dissolved in 20 ml DMF and the solution was degassed 3 times. PdCl2(dppf) (149 mg, 0.203 mmol) was added and the mixture was stirred overnight at 80° C. The solution was cooled, poured into 100 ml NaHCO3 (sat.) and extracted 3 times with 20 ml ethyl acetate. The combined organic layers were then washed with 4× water, then dried with Na2SO4. 4-(4-bromophenyl)pyridine was obtained and used without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](O)=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35]([CH2:37][NH2:38])[OH:36].C(N(C(C)C)CC)(C)C>>[N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:30])[NH:38][CH2:37][CH2:35][OH:36])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCO
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(C(=O)NCCO)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and ethanolamine/diisopropylethylamine Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C30H32N4O3
Reaction SMILES: C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH:14]=O.Cl.Cl.[NH2:22][C@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:28][NH:29][C:30]1[NH:31][C:32]2[C:37]([C:38](=[O:40])[CH:39]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14][NH:22][C@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:28][NH:29][C:30]1[NH:31][C:32]2[C:37]([C:38](=[O:40])[CH:39]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: N[C@H]1CCC[C@@H]1CNc1cc(=O)c2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Product: O=c1cc(NC[C@H]2CCC[C@@H]2NCc2ccc(Cl)c(Cl)c2)[nH]c2ccccc12

Procedure:
Title compound was prepared by the procedure described in Example 61d, using sodium acetate (0.020 g, 0.242 mmol), sodium cyanoborohydride (0.012 g, 0.194 mmol), 3,4-dichlorobenzaldehyde (0.017 g, 0.0969 mmol), and 2-[((1R,2S)-2-aminocyclopentylmethyl)amino]-1H-quinolin-4-one dihydrochloride (0.032 g, 0.0969 mmol). δH (CD3OD) 1.25-2.05 (7H, m), 2.73-2.81 (1H, m), 3.10-3.29 (2H, m), 3.61-3.80 (2H, m), 5.56 (1H, s), 7.13-8.00 (7H, m,). MS (AP+) 416 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[O:34]1[CH:38]=[CH:37][C:36]([CH2:39][N:12]2[CH2:13][CH2:14][CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[CH:35]1
Reactant: O=Cc1ccoc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(Cc2ccoc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 3.4 mg of 3-furaldehyde, 0.050 mL of acetic acid, and 0.5 mL of DMF was added 75 mg of MP-Triacetoxyborohydride (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of PS-Isocyanate (Argonaut Technologies, USA) at room temperature, followed by stirring for 2 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl {[1-(3-furylmethyl)-3-phenylpiperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. To 0.5 mL of a methanol solution of the obtained crude product was added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 8.6 mg of (1R)—N-{[1-(3-furylmethyl)-3-phenylpiperidin-4-yl]methyl}-1-(1-naphthyl)ethaneamine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccccc1Cl
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccccc2Cl)n1
Yield: 65.3 %

Procedure:
Following the procedure in Example 161A Step 3, 2-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-amine (1.30 g, 5.22 mmol, 65%). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (d, 1H), 7.48-7.42 (m, 3H), 5.28 (s, 1H), 4.94 (s, 2H), 1.19 (s, 9H); LC-MS (ESI) m/z 250 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17](=[O:36])[NH:18][C:19]3[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:20]=3[O:34][CH3:35])[CH:14]=[CH:13][C:12]=2[CH3:37])[CH:10]=1)=[O:5])C.O[Li].O.CC(O)=O>CO.O>[C:25]([C:23]1[CH:22]=[C:21]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[C:20]([O:34][CH3:35])=[C:19]([NH:18][C:17]([C:15]2[CH:14]=[CH:13][C:12]([CH3:37])=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=2)=[O:36])[CH:24]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cn(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)ccc2C)cn1
Agent: [Li]O
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1c(NC(=O)c2ccc(C)c(-n3cnc(C(=O)O)c3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
1-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-imidazole-4-carboxylic acid ethyl ester (Example 3) (820 mg, 1.55 mmol) was dissolved in 5 mL of cold MeOH and a solution of 130 mg (3.10 mmol) of LiOH-H2O in 3 mL of water was added dropwise. The mixture was allowed to warm to room temperature and was then stirred for 4 h. A 1 N HOAc solution (3.2 mL) was then added and the mixture was diluted with 30 mL of water, and then was extracted with 75 mL of EtOAc. The extract was washed with water and brine, was dried with MgSO4, filtered, and concentrated to provide 631 mg (1.26 mmol, 81%) of 1-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-imidazole-4-carboxylic acid.
Reaction SMILES: [CH:1]1([C:7]2([C:20](=[O:23])[CH2:21][CH3:22])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:24]>C(OCC)(=O)C>[ClH:24].[CH:1]1([C:7]2([C:20](=[O:23])[CH2:21][CH3:22])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)C1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(=O)C1(C2CCCCC2)CCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.4 %

Procedure:
549 mg (1.7 mmol) of tert-butyl 4-cyclohexyl-4-propionylpiperidine-1-carboxylate are dissolved in 2 mL (17 mmol) of 4N hydrogen chloride in ethyl acetate. The reaction mixture is stirred for 6 hours at room temperature. The solvents are evaporated off. The residue is taken up in ether and filtered off. 395 mg of 4-cyclohexyl-4-propionylpiperidine hydrochloride in the form of a white powder are obtained in a yield of 90%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][NH:14][C:15]2[C:16]3[C:21]([N:22]=[C:23]4[C:28]=2[C:27](=[O:29])[CH2:26][CH2:25][CH2:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]2[C:16]3[C:21]([N:22]=[C:23]4[C:28]=2[CH:27]([OH:29])[CH2:26][CH2:25][CH2:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccc(OCc4ccccc4)cc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccc(OCc4ccccc4)cc3)c21
Reaction time: 1 h

Procedure:
To a cooled suspension of 4.75 g of 3,4-dihydro-9-[4-(benzyloxy)benzylamino]acridin-1(2H)-one in 75 ml of tetrahydrofuran was added 6 ml of 1M solution of lithium aluminum hydride in tetrahydofuran. This was stirred for 1 hour.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:17][O:18][CH2:19][CH2:20][O:21][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COCCO
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCOc1ncnc2[nH]ccc12

Procedure:
1.1 A suspension of 1.00 g (6.32 mmol) of 4-chloro-7H-pyrrolo[2,3-d]-pyrimidine and 5.20 g (15.8 mmol) of caesium carbonate in 30 ml of 2-methoxy-ethanol is heated under reflux for 24 hours. The reaction mixture is adsorbed onto kieselguhr and chromatographed on a silica-gel column with dichloromethane/methanol/aqueous ammonia (100:1:1) as eluent, giving 4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine as colourless crystals; m.p. 137-139° C.;
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17]C(=O)OC(C)(C)C)[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>Cl.O1CCOCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C@@H:13]([NH2:17])[C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-n2ccnc2)cc1)C(N)=O
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)[C@H](N)Cc1ccc(-n2ccnc2)cc1
Reaction time: 2 h

Procedure:
A solution of ((R)-tert-butyl 3-(4-(1H-imidazol-1-yl)phenyl)-1-amino-1-oxopropan-2-ylcarbamate (250 mg, 0.757 mmol) in 4M HCl in dioxane (4 mL) and 6N HCl (4 mL) was stirred at room temperature for 30 min. It was then concentrated in vacuo. The residue was dissolved in MeOH (10 mL), MP-carbonate resin (1.00 g, ca. 3 mmol/g, 3.00 mmol) was added. After swirling and standing for 2 h, the resin was filtered off. The filtrate was concentrated in vacuo to give (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-aminopropanamide as free base (100 mg).
Reaction SMILES: F[B-](F)(F)F.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH:14]1[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[N:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl[CH2:33]Cl>>[C:6]([O:10][C:11]([N:13]1[CH:14]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[N:21]=2)[C:15]([O:19][CH3:33])=[N:16][CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1c1nc(-c2cccc(Cl)c2)no1
Agent: F[B-](F)(F)F
Product: COC1=NCCN(C(=O)OC(C)(C)C)C1c1nc(-c2cccc(Cl)c2)no1
Reaction time: 8 h
Yield: 61 %

Procedure:
Trimethyloxoniuim tetrafluoroborate (169.4 mg, 1.15 mmol) was added to 2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.15 mmol) in dichloromethane (3 mL) under argon at room temperature and then stirred overnight. The reaction mixture was directly purified by flash chromatography on basic alumina using 30% ethyl acetate in hexanes to afford the titled compound (284.6 mg, 61%). 1H NMR (CDCl3) δ (ppm): 8.09 (m, 1H), 7.97 (m, 1H), 7.46 (m, 2H), 4.88 (m, 1H), 4.01 (m, 1H), 3.72 (s, 3H), 3.51 (m, 3H), 3.35 (m, 1H), 2.90 (m, 1H), 1.34 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:17].C(N(CC)CC)C.ClC(OCC)=O.[NH2:43][OH:44]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:43][OH:44])=[O:25])=[O:17]
Reactant: O=C(O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
6-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid (396 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (168 mg, 41%) as a brown solid. LC-MS (m/z) 412 (M+1).