Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reactant: OCc1ccccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(OCc3ccccn3)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
A solution of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.39 mmol, Description 3) and 2-pyridinylmethanol (43 mg, 0.39 mmol) in dichloromethane (3 ml), was treated with triphenylphosphine (103 mg, 0.39 mmol) and then diisopropyl azodicarboxylate (77 ul, 0.39 mmol). The resulting solution was stirred at room temperature, under an atmosphere of argon, for 16 hours. The solution was then partitioned between water and dichloromethane and the organic solution was dried (MgSO4) and evaporated under reduced pressure to yield the crude product. The crude product was purified using MDAP. The resulting solution was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic solution was dried (MgSO4) and evaporated under reduced pressure to obtain the title compound as a white solid (70 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[O:34][CH:33]([CH2:35]Br)[CH2:32][C:31]=2[CH:37]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1([OH:13])[CH2:8][CH2:9][N:10]([CH2:35][CH:33]2[CH2:32][C:31]3[CH:37]=[C:27]([O:26][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:28]=[CH:29][C:30]=3[O:34]2)[CH2:11][CH2:12]1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: OC1(Cc2cccc(C(F)(F)F)c2)CCNCC1
Product: OC1(Cc2cccc(C(F)(F)F)c2)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=498.6 (M+H+) was prepared from 4-(3-trifluoromethyl-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]=[N+:13]=[N-:14].O>C(O)C>[NH2:3][C:2]1[N:12]([CH2:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[Cl:8])[N:13]=[N:14][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1ccccc1Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccccc2Cl)c1N

Procedure:
23 g (1 mol) of sodium are dissolved in 1 litre of ethyl alcohol and 101 g (1.2 mol) of cyanoacetamide are added thereto. 167.5 g (1 mol) of o-chlorobenzyl azide are added to this suspension at 40°-45° and the whole is heated for 2 hours under reflux. After cooling to 30°, 1000 ml of water are added, the precipitated product is filtered off with suction and then washed several times with warm water. After recrystallisation from dioxan and toluene, 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained in the form of colourless crystals having a melting point of 206°-207°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[C:16]3[N:15]=[C:14](Cl)[CH:13]=2)[CH:6]=1)[CH3:2].[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[C:16]3[N:15]=[C:14]([NH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([NH2:36])[CH:30]=3)[CH:13]=2)[CH:6]=1)[CH3:2]
Reactant: Nc1cccc(N)c1
Reactant: CCOC(=O)c1cccc(Nc2cc(Cl)nc3c(CCCCC#N)cnn23)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cccc(Nc2cc(Nc3cccc(N)c3)nc3c(CCCCC#N)cnn23)c1
Temperature: 160 °C
Yield: 123.9 %

Procedure:
A mixture of compound (14a) (0.63 g. 1.6 mmol) and benzene-1,3-diamine (69 mg, 0.636 mmol) in 2 mL of NMP was heated at 160° C. overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aq NaHCO3 and brine and dried over anhydrous Na2 SO4. HPLC purification provided 3-[5-(3-amino-phenylamino)-3-(4-cyano-butyl)-pyrazolo[1,5-a]pyrimidin-7-ylamino]-benzoic acid ethyl ester (15a) (0.37 g. 50%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[C:27]([NH2:30])(=[O:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:30][C:27](=[O:29])[CH3:28])=[N:7][CH:6]=2)=[N:9]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)nc2)c2c1-c1ccsc1C2
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sccc2-3)cn1
Temperature: 100 °C
Yield: 71 %

Procedure:
A mixture of the corresponding intermediate 6-(6-Bromo-pyridin-3-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), acetamide (0.15 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give N-{5-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-pyridin-2-yl}-acetamide as brown solid in 71% yield.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
This compound was prepared by method C using compound 12a and 1-bromo-4-fluorobenzene. HRMS (ESI+): m/z=343.1258 [M+H]
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>ClCCl>[CH2:39]([O:38][C:36](=[O:37])[NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OCc3ccccc3)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl), phenyl)-3-methoxybenzamide (50 mg, 136 μmol) and triethylamine (0.038 mL, 0.27 mmol) in dichloromethane was added benzyl chloroformate (26 mg, 150 μmol), dropwise at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane (3×20 mL) and dried over anhydrous MgSO4. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography. (EtOAc/Hexane=50-90%). {2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]ethyl}-carbamic acid benzyl ester was obtained as white solid in 37% yield. LCMS m/z (%)=501 (M+H, 100) 1H NMR (400 MHz, CDCl3) δ ppm 3.5 (q, J=5.4 Hz, 2 H), 3.7 (s, 3H), 3.9 (s, 3 H), 4.0 (t, J=5.1 Hz, 2 H), 4.9 (t, J=5.8 Hz, 1 H), 5.1 (s, 2 H), 6.3 (d, J=2.0 Hz, 1 H), 7.0 (d, J=8.6 Hz, 1 H), 7.1 (m, 1 H), 7.3 (m, 5 H), 7.4 (m, 1 H), 7.5 (m, 2 H), 7.7 (dd, J=8.8, 2.8 Hz, 1 H), 7.8 (s, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:30]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[N:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O1CCOCC1>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:35][C:32]3[CH:33]=[CH:34][NH:30][N:31]=3)[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: O=Cc1cc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccc(C2CCN(Cc3cc[nH]n3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.9 %

Procedure:
tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) and 1H-pyrazole-3-carbaldehyde (50.7 mg, 0.53 mmol) were stirred at ambient temperature in dichloromethane (5 ml) for 1 hour. Sodium triacetoxyborohydride (150 mg, 0.71 mmol) was added and the mixture stirred at ambient temperature for 48 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give a foam. This was dissolved in 1,4-dioxane (2 ml), a 4M solution of hydrogen chloride in 1,4-dioxane (2 ml) was added and the solution stiffed at ambient temperature for 48 hours. The product was filtered and washed with diethyl ether and air-dried. The resulting solid was dissolved in water, basified with 2N sodium hydroxide and the resulting solid filtered, washed with water and dried under vacuum to give the title compound (61 mg, 44%). NMR Spectrum: 1H NMR (DMSO d6) δ 1.71 (m, 4H), 2.07 (m, 2H), 2.56 (m, 1H), 2.95 (m, 2H), 3.53 (s, 2H), 4.86 (s, 2H), 6.16 (s, 1H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (t, 1H), 7.18 (d, 1H), 7.37 (d, 2H), 7.64 (m, 1H), 7.91 (d, 2H), 9.55 (s, 1H), 12.59 (m, 1H); Mass Spectrum: M+H+ 376.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)([CH3:4])([CH3:3])[CH3:2].C([N:30]=[C:31]=[S:32])(=O)C1C=CC=CC=1>CC(C)=O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:31]([NH2:30])=[S:32])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1-n1cccn1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc(NC(N)=S)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of the compound (1.0 g) obtained in Example 2b and acetone (30 ml), benzoyl isothiocyanate (0.52 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated at reduced pressure. Methanol (50 ml) and potassium carbonate (0.53 g) were added to the resulting residue. The reaction mixture was stirred at room temperature for 80 minutes and then concentrated at reduced pressure. Water was added to the resulting residue and extraction with ethyl acetate was conducted. The organic layer was washed with brine, dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=3:1) to give the titled compound quantitatively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=O)=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.[N:27]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N.CO>CN(C=O)C.CCOC(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:27])=[O:19])=[CH:5][CH:6]=1
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: NC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Yield: 56.2 %

Procedure:
At −20° C. stir a solution of 3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid (1.26 g, 3.0 mmol) in DMF (12 mL) and add BOP (1.32 g, 3.0 mmol) and then diisopropylethylamine (0.8 mL, 4.5 mmol). Stir the reaction for 0.25 h and add a solution of 7M NH3 in MeOH (0.43 mL, 3.0 mmol). Allow the reaction to stir at room temperature overnight and add EtOAc. Wash the organic solution with aqueous NaHCO3, brine and dry over MgSO4. Filter and concentrate the filtrate under vacuum to obtain a solid. Recrystallize the solid from EtOAc to obtain 0.425 g of the title compound as a yellow solid: MS 253(M+H); m.p. 230° C. (decomposition); TLC (silica gel, dichloromethane/MeOH/NH4OH, 8:2:0.1 v/v), Rf=0.39.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(C#N)cc4)cc3c2C1
Yield: 46.7 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.9 mg (0.101 mMol) 4-cyanobenzoic acid, 6.7 mg (47%) of the title compound were recovered as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl.[NH2:37][CH2:38][C:39]([NH:41][C@@H:42]([C:46]([O:48]C(C)(C)C)=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[O:16])[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:37][CH2:38][C:39]([NH:41][C@@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])=[O:33])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](NC(=O)CN)C(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@@H](C(=O)O)C(C)C)cc2)cc1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of [4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.0153 g, 0.031 mmol), tert-butyl glycyl-D-valinate hydrochloride (0.0099 g, 0.037 mmol) and N-methylmorpholine (0.010 ml, 0.091 mmol) in DCM (2 ml) was stirred at room temperature. TBTU (0.016 g, 0.050 mmol) was added and the mixture was stirred for 3.5 h. Trifluoroacetic acid (0.5 ml) was added and after 3.5 h the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a Kromasil C8-column using a gradient of 5-100% MeCN in 0.15% trifluoroacetic acid buffer as eluent. The solvent was removed under reduced pressure and 0.015 g (74%) of the title product was obtained. M/z 652.20.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14]Br.Cl>CN(C)C=O.O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: COC(CBr)OC
Reactant: Oc1cccc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1cccc(Br)c1)OC
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a suspension of 60% sodium hydride. (60 g) in N,N-dimethylformamide (1.4 l) was added dropwise 3-bromophenol (260 g) under ice-cooling. After stirring for 10 minutes, to the solution was added dropwise bromoacetaldehyde dimethyl acetal (318 g) and the mixture was heated with stirring for 3 hours at 90° C. After cooling, water was added to the resulting solution and acidified with 1 M hydrochloric acid and then extracted with ether (3 l). The organic layer was washed with successive water, saturated aqueous sodium bicarbonate solution and saturated aqueous NaCl solution. After drying over anhydrous sodium sulfate, ether was removed in vacuo and the residue was purified by silica gel column chromatography to give 363.3 g of the objective compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH:23]=O)[CH:16]=[C:17]([F:20])[C:18]=1[CH3:19]>>[F:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH:23]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[C:17]([F:20])[C:18]=1[CH3:19]
Reactant: Cc1c(F)cc(CCC=O)cc1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(C)c(F)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (296.9 mg; 1.120 mmol) and 3-(3,5-difluoro-4-methyl-phenyl)-propionaldehyde (206.7 mg; 1.120 mmol) afforded 8-[2-(3,5-difluoro-4-methyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH2:12])=[CH:7]2.C(N(CC)CC)C.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH:12][C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:7]2
Reactant: Nc1cnc2c(Cl)ccnc2c1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cnc2c(Cl)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A round bottom flask under nitrogen was charged with 8-chloro-1,5-naphthyridin-3-amine (41 mg, 0.23 mmol), triethylamine (64 μl, 0.46 mmol), and dichloromethane (1 mL). To this was added 2-methoxyacetyl chloride (42 μl, 0.46 mmol) dropwise via syringe and reaction allowed to stir overnight at room temperature. Next day reaction mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Layers separated and organic layer dried over sodium sulfate to afford yellow oil. This was purified by ISCO silica gel chromatography (2-5% MeOH/DCM) to afford N-(8-chloro-1,5-naphthyridin-3-yl)-2-methoxyacetamide (43 mg, 75% yield) as light yellow solid. MS[M+H]=251.9. Calc'd for C11H10ClN3O2=251.7.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH:3]1[CH2:6][CH:5]([C:7]([O:9]C)=[O:8])[CH2:4]1.[ClH:12]>O1CCOCC1>[ClH:12].[CH3:1][N:2]([CH3:11])[CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4]1
Reactant: COC(=O)C1CC(N(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C1CC(C(=O)O)C1
Temperature: 70 °C
Yield: 100.8 %

Procedure:
A solution of methyl 3-(dimethylamino)cyclobutanecarboxylate (0.596 g, 3.79 mmol) in dioxane (5 mL) was treated with HCl (6N, 10 mL, 60 mmol) and heated at 70° C. overnight. The organics were removed under reduced pressure and the aqueous residue was treated with MeCN, frozen and lyophilized to afford 3-(dimethylamino)cyclobutanecarboxylic acid hydrochloride (686 mg, 101%). 1H NMR (400 MHz, DMSO-d6): δ 10.86 (br s, 1H), 3.56-3.48 (m, 1H), 2.83-2.73 (m, 1H), 2.58 (d, J=4.9 Hz, 6H), 2.41-2.33 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)[CH:10]=[C:9]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2=[O:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:1][C:2]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2=[O:31]
Reactant: CCOC(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CCO)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate (350 mg, 0.63 mmol) obtained in Step 5 was dissolved in THF (25 ml) and tetrabutylammonium fluoride (1M THF solution; 1.9 ml, 1.9 mmol) was added. The mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (279 mg, yield quant) as a pale-yellow solid.
Reaction SMILES: [C:1]1([CH:7]([NH2:30])[CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>C(Cl)(Cl)Cl>[C:1]1([CH:7]([NH:30][C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:15][CH2:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(CCCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Reactant: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)NC(CCCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Reaction time: 3 h

Procedure:
2 Grams of 6-[4-(4-phenyl-4-aminobutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril was dissolved in 30 ml of chloroform, then to this solution was added 0.76 ml of isobutyl chloroformate at 0° C.-5° C. The reaction mixture was stirred at the same temperature for 3 hours, then concentrated. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =40:1), then converted into an oxalate by stirring with oxalic acid in acetone, and the oxalate was recrystallized from ethanol-water to yield 1.9 g of 6-[4-(4-phenyl-4-isobutoxycarbonylaminobutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.oxalate. White powdery substance. Melting point: 221° C.-222° C.
Reaction SMILES: C[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8](C(C)C)[CH:7]=[CH:6][CH:5]=2.C[Si](C)(Cl)Cl>>[CH2:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC1=Cc2c(cccc2C(C)C)C1
Agent: C[Si](C)(Cl)Cl
Product: C1=Cc2ccccc2C1
Yield: 16.7 %

Procedure:
3.9 g (22.7 mmol) of indene b4 were reacted with dimethyldichlorosilane and the mixture was worked up, analogously to instructions I.4. Column chromatography gave, in addition to 0.44 g of unused indene, 3.0 g of product b5 as a yellow oil (isomers). The yield as 65% with respect to Si and 73% with respect to the starting material reacted.