Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@H:27]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: Cc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4)n4ccnc(N)c34)cc2)n1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3nccc(C)n3)cc2)c2c(N)nccn12
Yield: 27.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-methylpyrimidin-2-yl)benzamide (intermediate 29) and acryloylchloride, to afford the title compound (4.5 mg, 27.4%). Data: UPLC(C) Rt: 1.79 min; m/z 483.3 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.[CH:31](=[O:33])[CH3:32]>>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([CH:31]([OH:33])[CH3:32])[CH:13]=[N:12][C:11]=1[NH:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC=O
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(C(C)O)cc2OCc2ccccc2)n1
Yield: 58.9 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1) (0.350 g, 0.930 mmol), MeLi (0.727 mL, 1.16 mmol), butyllithium (0.465 mL, 1.16 mmol), and acetaldehyde (0.0410 g, 0.930 mmol) were reacted according to the method of Example 7 to provide 1-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)ethanol (0.187 g, 58.8%). Mass spectrum (apci) m/z=342.1 (M+H).
Reaction SMILES: N#N.C([O:5][C:6](=O)[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[F:21])C.CC(C[AlH]CC(C)C)C.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.O>[F:21][C@H:9]1[C@@H:8]([CH2:7][CH2:6][OH:5])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1F
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](CCO)[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate (348 mg, 1.20 mmol) in dry THF (9 mL) was added DIBAL-H (2.41 mL of a 1M solution in toluene, 2.41 mmol). The reaction mixture was stirred at rt for 2 h. DIBAL-H (0.60 mL of a 1M solution in toluene, 0.60 mmol) was added again and the reaction mixture further stirred at rt for 1 h before being cooled to 0° C. Water (0.15 mL) was added followed by aq. 2N NaOH (0.30 mL). The mixture was stirred for 20 min, filtered through celite, washed with EA and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 7:3→1:1) to give the title compound as a colorless oil. LC-MS-conditions 08: tR=0.69 min; [M-CH3+H]+=233.35.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[C:3]=1[F:16].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[C:3]=1[F:16]
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)c(F)c3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3c(F)c(Cl)ccc3n2CCc2ccc(C(F)(F)F)nc2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-9-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[N+](C1C=CC=CC=1O)([O-])=O.[CH3:24][O:25][C:26]([C:28](=[CH2:30])[CH3:29])=O.[OH-].[Na+]>O.CO>[CH3:24][O:25][CH2:26][C:28]1[CH:29]=[N:6][C:7]2[C:12]([CH:30]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13]
Reactant: C=C(C)C(=O)OC
Reactant: Nc1ccccc1O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1ccccc1O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1cnc2c(O)cccc2c1
Temperature: 70 °C

Procedure:
A solution of methanol and sulfuric acid (10.0 g, 0.1 mol) is heated to 65° C., treated with o-aminophenol (4.36 g, 0.04 mol) and o-nitrophenol (2.78 g, 0.02 mol), heated to 70° C., treated with methoxymethacrolein (6.0 g, 0.06 mol) over 40 minutes at 85° to 90° C. and diluted with water. The aqueous mixture is adjusted to about pH 2 with 50% sodium hydroxide solution and filtered. The filtrate is adjusted to about pH 7 with 50% sodium hydroxide solution and extracted with chloroform. The combined organic extracts are concentrated in vacuo to give the title product as a solid which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1.[CH:15]([NH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:15]([N:18]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)c1ccc(CBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-bromomethyl-2-methoxybenzoate (2.59 g), diisopropylamine (3.92 ml), potassium carbonate (1.38 g) and dimethylformamide (30 ml) was stirred at 80° C. for 2 hours, to which was added water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in THF-EtOH (1:1, 30 ml), to which was added 1 N sodium hydroxide solution (15 ml) and the solution was stirred at 80° C. for 20 minutes. To the solution was added water and the solution was washed with ether, made acidic with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in THF and insoluble materials were filtered off. The filtrate was concentrated and crystallized with isopropylether to give the title compound (0.3 g).
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22](O)[N:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)[Cl:31]>P(Cl)(Cl)(Cl)=O>[Cl:31][C:22]1[N:17]2[N:16]=[C:15]([CH2:14][O:13][C:10](=[O:12])[CH3:11])[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=1
Reactant: CC(=O)OCc1cc(O)n2nc(COC(C)=O)nc2n1
Reactant: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCc1cc(Cl)n2nc(COC(C)=O)nc2n1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 28 ml of N,N-dimethylaniline, and 30.5 g of 2,5-bis(acetoxy- methyl)-7-hydroxy-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50° C. for 1.5 hours. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, the mixture was condensed. This was applied to a silica gel column chromatography (eluent: chloroform) and fractions containing the title compound were condensed to obtain 14 g of the title compound as an oily product.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[N:14])[CH:8]=2)[O:3]1.C=O.N1CCCC[CH2:19]1>C(O)C>[CH3:1][C:2]1([CH3:15])[C:11](=[CH2:19])[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[N:14])[CH:8]=2)[O:3]1
Reactant: CC1(C)CC(=O)c2cc(C#N)ccc2O1
Reactant: C1CCNCC1
Agent: C=O
Solvent: CCO
Product: C=C1C(=O)c2cc(C#N)ccc2OC1(C)C

Procedure:
A solution of 24 g of the chromanone, 12 g of paraformaldehyde and 24 ml of piperidine in 300 ml of ethanol is heated at 70° for 3 hours and evaporated. The residue is taken up in dichloromethane/petroleum ether 1:1, the mixture is filtered through silica gel and evaporated, and 2,2-dimethyl-3-methylene-6-cyano-4-chromanone is obtained as an unstable oil.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[C:11](=[O:21])[CH:12]=[C:13]([CH3:20])[O:14]2.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[Cl:22][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[C:11](=[O:21])[CH:12]=[C:13]([CH3:20])[O:14]2
Reactant: Cl
Reactant: Cc1cc(=O)c2c(N)ccc(C)c2o1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1cc(=O)c2c(Cl)ccc(C)c2o1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
0.42 g (3.9 mmol) of copper(II) chloride and 0.45 g (3.96 mmol) of tert-butyl nitrite are introduced into 20 ml of acetonitrile and heated to 65° C. 0.5 g (2.63 mmol) of 5-amino-2,8-dimethyl-4H-chromen-4-one in 10 ml of acetonitrile are slowly added dropwise to this suspension. The reaction mixture is stirred at 65° C. for 10 min and then allowed to cool to room temperature, and subsequently 5 ml of concentrated hydrochloric acid are added. After extraction with diethyl ether, the combined organic phases are washed with water and dried over sodium sulfate. After removal of the solvent in vacuo, the remaining crude product is purified by preparative HPLC. 0.27 g (50% of theory) of the title compound is obtained.
Reaction SMILES: [CH:1]1([C:6]2[CH:37]=[CH:36][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:16]5=[C:15]([CH:32]5[CH2:35][CH2:34][CH2:33]5)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:38]([F:41])([F:40])[F:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.NC(CS)C(O)=O>C(O)(C(F)(F)F)=O>[CH:32]1([C:15]2[C:14]3[CH:13]=[C:12]([O:11][CH2:10][C:9]4[CH:36]=[CH:37][C:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[C:7]([C:38]([F:41])([F:40])[F:39])[CH:8]=4)[CH:20]=[CH:19][C:18]=3[N:17]3[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]=23)[CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(C1CCC1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCn2c1c(C1CCC1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
tert-Butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclobutyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (17.2 mg, 0.031 mmol) was added to a solution of 2-amino-3-mercaptopropanoic acid (3.76 mg, 0.031 mmol) in TFA (1 mL) and were stirred at 23° C. for 15 min in a 20 mL sealed scintillation vial. After 15 min, the reaction mixture was poured into about 4 mL of ice water. The product precipitated and was collected by vacuum filtration. The solid was washed with n-hexane (3×5 mL) and dried (vacuum oven) to give the title compound as an off-white solid (6.7 mg). LCMS m/z=512.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.72 (m, 4H), 1.80-1.91 (m, 3H), 1.93-2.04 (m, 3H), 2.17-2.36 (m, 5H), 2.39-2.48 (m, 1H), 2.63 (dd, J=15.98, 3.98 Hz, 1H), 2.69-2.78 (m, 1H), 3.19-3.28 (m, 1H), 3.57-3.69 (m, 2H), 3.90-4.02 (m, 2H), 5.16 (s, 2H), 6.76 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.62 (d, J=8.09 Hz, 1H), 7.67-7.76 (m, 2H), 12.26 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([O:55][C:56]2[CH:63]=[CH:62][C:59]([C:60]#[N:61])=[CH:58][C:57]=2[CH:64]2[CH2:66][CH2:65]2)=[N:53][CH:54]=1>CN(C)C=O>[C:60]([C:59]1[CH:62]=[CH:63][C:56]([O:55][C:52]2[N:53]=[CH:54][C:49]([NH:48][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:50][CH:51]=2)=[C:57]([CH:64]2[CH2:65][CH2:66]2)[CH:58]=1)#[N:61]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1ccc(Oc2ccc(N)cn2)c(C2CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)cc2C2CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (121.4 mg, 0.60 mmol) was dissolved in N,N-Dimethylformamide (1 mL). N,N-Diisopropylethylamine (0.126 mL, 0.72 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (227.2 mg, 0.60 mmol) were added. The reaction mixture was stirred at r.t. for 30 min. 4-[(5-amino-2-pyridinyl)oxy]-3-cyclopropylbenzonitrile (Intermediate 145, 100 mg) was dissolved in 1.0 mL of DMF and the obtained solution was added to the reaction mixture. The reaction mixture was stirred and heated at 60° C. for 2 h. After cooling down to r.t., the reaction mixture was evaporated under vacuum and the crude obtained was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 100:0 to 50:50 Cyclohexane/EtOAc, then plateau at 50:50) affording 133 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[N:9]=[CH:8]2)[OH:4].[OH-].[K+].I[CH2:34][C:35]([NH2:37])=[O:36]>CN(C=O)C>[F:30][C:2]([F:1])([F:29])[C:3]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH2:34][C:35]([NH2:37])=[O:36])[CH:21]=1)([OH:4])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[N:9]=[CH:8]2
Reactant: OC(c1ccc2c(cnn2-c2cccnc2)c1)(c1c[nH]c2ccccc12)C(F)(F)F
Reactant: NC(=O)CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)Cn1cc(C(O)(c2ccc3c(cnn3-c3cccnc3)c2)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a chilled (0° C.) solution of 45 mg (0.11 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-(1-pyridin-3-yl-1H-indazol-5-yl)ethanol in 5 mL of DMF was added 13 mg (0.17 mmol) of powder KOH followed by 31 mg (0.17 mmol) of iodoacetamide. The mixture was stirred over night at room temperature, poured onto ice water and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, adsorbed on to silica gel and purified by Combiflash chromatography using EtOAc/hexanes (0-80% gradient, product eluted at 40% EtOAc) to provide a colorless film. The material from the column was crystallized from EtOAc-hexanes to afford 20 mg (39%) of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4][NH:3][CH2:2]1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:18]([O:17][C:15]([CH:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4]1)=[O:16])[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C1CNCCc2c1[nH]c1ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(c2ccccc2)CCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.9 %

Procedure:
The mixture of ethyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (520 mg, 2 mmol), cupric acetate (728 mg, 4 mmol), phenyl boronic acid (490 mg, 4 mol) and pyridine (0.35 mL, 4 mmol) in dry DCM (20 mL) was stirred at ambient temperature for 3 days. The mixture was filtered though a pad of celite. The filtrate was concentrated in vacuo and then purified by chromatography on silica gel eluting with EtOAc-Hexane (7:93) to give the title compound (53 mg); 1H-NMR (CDCl3): δ 8.66 (1H, s), 7.42 (1H, d), 7.26-7.18 (4h, m), 7.10-7.00 (2H, m), 7.69 (2H, m), 6.67 (1H, t), 5.22 (1H, m), 4.40-4.18 (3H, m), 4.04-4.01 (1H, m), 3.98-3.88 (1H, m), 3.58-3.52 (1H, m), 3.22-3.15 (1H, m), 3.08-3.02 (1H, m), 1.27 (3H, t); MS (ES): 335 (MH+).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].Cl.CO[C:10](=[NH:12])[NH2:11]>>[O:5]=[C:4]([CH2:3][N:1]([C:10](=[NH:11])[NH2:12])[CH3:2])[OH:6]
Reactant: COC(=N)N
Reactant: CNCC(=O)O
Agent: Cl
Product: CN(CC(=O)O)C(=N)N

Procedure:
The reaction of sarcosine with O-methylisourea hydrochloride, described by E. Schutte in Hoppe-Seylers Z. Physiol. Chemie 279 (1943) 52-59, affords creatine in a yield of only 21%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=3[O:26][CH3:27])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:29][C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[C:6]=2[CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH2:60][CH2:61][O:62][C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=4[CH3:69])[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=3[O:26][CH3:27])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:29][C:30]([N:32]3[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]3)=[O:31])[C:6]=2[CH:39]=1
Reactant: COc1cc(NC(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Reactant: Cc1ccccc1OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N(CCOc2ccccc2C)C(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-(2-methoxy-4-trifluoroacetylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in dry tetrahydrofuran (20 ml) are added triphenylphosphine (0.54 g) and o-(2-hydroxyethoxy)toluene (0.29 g) at room temperature. To the mixture is added dropwise a solution of diethyl azodicarboxylate (0.32 ml) in dry tetrahydrofuran (5 ml), and the mixture is stirred at room temperature for 16 hours. To the mixture is added water, and the mixture is extracted with diethyl ether. The ether layer is dried, evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1→30:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[2-methoxy-4-{N-[2-(2-methylphenoxy)ethyl]-N-trifluoroacetylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.46 g) as colorless amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:14](=[O:21])[N:13]([CH2:22][C:23](=[O:37])[NH:24][C:25]3[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=3[CH:34]([CH3:36])[CH3:35])[C:12]2=[O:38])=[CH:7][CH:6]=1)C>CO.S(=O)(=O)(O)O>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:14](=[O:21])[N:13]([CH2:22][C:23](=[O:37])[NH:24][C:25]3[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=3[CH:34]([CH3:35])[CH3:36])[C:12]2=[O:38])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N2C(=O)N(CC(=O)Nc3c(C(C)C)cccc3C(C)C)C(=O)C23CCCCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(N2C(=O)N(CC(=O)Nc3c(C(C)C)cccc3C(C)C)C(=O)C23CCCCC3)cc1

Procedure:
33 mg of 4-{3-[(2,6-diisopropylphenylcarbamoyl)-methyl]-2,4-dioxo-1,3-diazaspiro[4.5]dec-1-yl}benzoic acid ethyl ester are dissolved in 10 ml of methanol, 1 drop of concentrated sulfuric acid is added and the solution is refluxed for 18 hours. The mixture is stirred at reflux for 72 hours. The solvent is evaporated off. The residue is dissolved in DCM, heptane is added until slight cloudiness appears, and the solution is stirred at room temperature under nitrogen for 16 hours. The product 4-{3-[(2,6-diisopropylphenylcarbamoyl)methyl]-2,4-dioxo-1,3-diaza-spiro[4.5]dec-1-yl}benzoic acid methyl ester is obtained in the form of fine white needles.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].C(=O)(O)[O-].[Na+].[N:21]([CH2:24][C:25]([O:27]CC)=[O:26])=[C:22]=[O:23].Cl>O>[N+:9]([NH:8][C:7](=[NH:12])[NH:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH:1][C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:13]1=[O:15])([O-:11])=[O:10]
Reactant: CCOC(=O)CN=C=O
Reactant: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N=C(NCCC[C@@H]1NC(=O)N(CC(=O)O)C1=O)N[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
11 g (0.05 mol) of H-Arg(NO2)-OH are dissolved with 4.3 g (0.05 mol) of sodium bicarbonate in 200 ml of water under reflux. At 70° C., 7.1 g (0.055 mol) of ethyl isocyanato-acetate are added dropwise. The mixture is stirred at 70° C. for 1 hour, left to cool and stirred at room temperature overnight, 50 ml of concentrated hydrochloric acid are added, the mixture is concentrated, 20 ml of 50% concentrated hydrochloric acid are added, the mixture is heated under reflux for 1 hour and substantially concentrated, and the precipitated product is filtered off with suction.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([N:25]2[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]2)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:25]3[CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:28]3)=[O:24])[N:19]=2)[CH2:7][C:6]([OH:33])=[O:5])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.3 %

Procedure:
A solution of methyl 1-[(5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazol-3-yl)carbonyl]-3-azetidinecarboxylate (Preparation 42) (225 mg, 0.48 mmol) in dichloromethane (8 ml) was treated with trifluoroacetic acid (4 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×2). The residue was dissolved in ethyl acetate and washed sequentially with a saturated aqueous solution of sodium citrate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:10].[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]12>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[C:13]3[CH2:17][CH2:18][CH2:19][CH2:20][C:12]=3[C:11]2=[O:16])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Yield: 34.8 %

Procedure:
2-Chloro-4-fluoro-5-aminophenol (6.6 g) and 2,4,5,6-tetrahydrophthalic anhydride (6 g) are dissolved in acetic acid (20 ml) and refluxed for 2 hours. The resultant mixture is allowed to cool to room temperature and poured into ice-water, followed by extraction with ether. The ether extract is washed with a saturated sodium hydrogen carbonate solution and water in order, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by silica gel-chromatography to give 4.0 g of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 151° C.