Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C1C=CC=CN=1)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173 mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), and tert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambient temperature overnight, dissolved in 350 mL EtOAc, washed with 10% citric acid (3×200 mL), water (2×200 mL), brine, dried with MgSO4, filtered, and concentrated to yield title compound. (20 g, 84%) APCI (AP−): 344.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:41][C:38]2([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: NC1(c2cnccn2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cnccn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.015 g, 0.011 mmol, 1.2 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.034 g (66%). 1H NMR (400 MHz, CD3OD): δ 8.60 (d, J=1.6 Hz, 1H), 8.52 (m, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.98-7.95 (m, 2H), 7.92 (dd, J=1.6, 7.8 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.73-1.71 (m, 2H), 1.47-1.43 (m, 2H). 19F NMR (376.57 MHz, CD3OD) 6-77.68 (TFA), −112.27, −122.72 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)Br
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
Ethyl 2-bromopropionate (0.125 moles) was diluted with 75 ml of toluene, and morpholine (0.3 moles) was added thereto, followed by stirring for 10 hours at room temperature. White solid was removed by filtration, and then the filtrate was distilled to obtain 2-morpholinopropionic acid ethyl ester (0.105 moles).
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([CH3:23])[C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([CH3:23])[C:14]([CH:21]=[O:29])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.40 g) in a mixed solvent of acetone (8.00 mL)-acetonitrile (8.00 mL)-water (8.00 mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodium periodate (1.24 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:32]([N:26]1[CH2:27][CH:9]2[CH:8]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=[CH:11][C:10]2=[O:13])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)C=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12

Procedure:
Trifluoroacetic acid (2 drops) is added to a solution of 4,4-diphenyl-cyclohexa-2,5-dien-1-one (7.7 g) and N-butoxymethyl-N-trimethylsilylmethylbenzylamine (11 cc) in dry dichloromethane (80 cc) and the reaction mixture is refluxed for 1 hour and a half. Additional N-butoxymethyl-N-trimethylsilylmethylbenzylamine (5 cc) and trifluoroacetic acid (2 drops) are added and the reaction mixture is heated for 1 hour and a half. The reaction mixture is treated with potassium carbonate (3 g) and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl ether (15 cc). The crystals obtained are drained, washed with isopropyl ether (2×5 cc) and dried; (3aRS,7aRS)-2-benzyl-7,7-diphenyl-2,3,3a,4,7,7a-hexahydro-4-1H-isoindolone (4.4 g) melting at 132° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)CCC.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)=[CH:7][C:6]=3[C:5]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(-c3cccs3)cc21
Reaction time: 1 h

Procedure:
A mixture of 2,7-dibromo-9,9-dihexylfluorene (7) (8.0 g, 16 mmol), 2-tributylstannylthiophene (2.98 g, 8.0 mmol), tetrakis(triphenylphosphine)palladium (0) (200 mg, 1.73×10−4 mol) aqueous sodium carbonate (2M, 2 cm3), toluene (5 cm3) and ethanol (2 cm3) was heated under reflux for 24 h under argon. Toluene and ethanol were removed and hexane (10 cm3) and aqueous KI (2%, 10 cm3) added and the mixture stirred vigorously for 1 h. Diethyl ether (10 cm3) and dilute HCl(aq)(3M, 10 cm3) were added, the aqueous layer separated and washed with diethyl ether (2×10 cm3). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to a dark brown oil which was purified by column chromatography [silica gel, hexane] to yield a pale jade coloured oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([C:17](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](C=O)=[CH:36]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:37]3[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:35]([CH3:34])[CH:36]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Reactant: Cn1cc(C=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3cn(C)c4ccccc34)C1)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
TEA (0.14 ml, 1.0 mmol) was added to suspension of Intermediate 2 (290 mg, 0.86 mmol) in DCM (10 ml). The mixture was stirred at RT for 10 min and then the pH value was adjusted to 5 with AcOH. The mixture was treated with N-methyl-indol-3-carbaldehyde (164 mg, 1.03 mmol) and NaBH(OAc)3 (219 mg, 1.03 mmol) following the procedure described in Example 31, A, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (380 mg) as a light orange solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[N+:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C-:19]>C1COCC1>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:14][CH:19]=[N:18][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (20 mL, 144 mmol) was added to a solution of 4-chlorobenzoyl chloride (8.4 g, 48 mmol) in THF (100 mL) at 0° C. Ethyl 2-isocyanoacetate (6.0 g, 53 mmol) was added dropwise and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column with ethyl acetate and hexanes as eluents to give the desired compound. MS (m/z) 252.1 [M+H]+.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(CC)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.67 h
Yield: 93 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 7.92 g of (RS)-2-(2-buten-1-yl)-6-ethyl-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.36 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 150 ml of dichoromethane and, after the addition of 30 ml of water and 30 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 6.94 g (93%) of (RS)-2-(2-oxoethyl)-6-ethyl-indanone were obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2>C(O)CCC>[CH3:21][N:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)[N:7]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1ccccc1CCc1ccnc(Cl)n1)S(C)(=O)=O
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: CCCCO
Product: CN(c1ccccc1CCc1ccnc(Nc2ccc3c(c2)CCC(=O)N3)n1)S(C)(=O)=O
Temperature: 120 °C
Yield: 25.7 %

Procedure:
200 mg of N-{2-[2-(2-chloropyrimidin-4-yl)ethyl]phenyl}-N-methylmethanesulfonamide and 70 mg of 6-amino-3,4-dihydroquinolin-2(1H)-one are dissolved in 3 ml of n-butanol and warmed at 120° C. for 12 h in a sealed vessel. After cooling to room temperature, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 50 mg of the title compound as colourless solid;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O:11][B:12](OC(C)C)[O:13]C(C)C)(C)C.[Li]CCCC.[C:26]1([N:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:12]([OH:13])[OH:11].[C:26]1([N:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccccn1
Agent: OCCN(CCO)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under nitrogen, a stirred solution of 2-bromopyridine (843 g, 5.33 mol) and triisopropylborate (1.20 kg, 6.40 mol) in THF (6.74 l) was cooled to −75° C. A 1.6M solution of n-BuLi in hexanes (4.00 l, 6.40 mol) was added at such a rate that the temperature did not exceed −67° C. After completion of the addition, the reaction was allowed to warm to room temperature and stirred at this temperature for 16 hours. After this time, a solution of N-phenyldiethanolamine (966 g, 5.33 mol) in THF (966 ml) was added and the resulting mixture heated at reflux for 4 hours. The solvent was distilled and replaced with isopropanol until the head temperature was 76° C. (distilling 11.3 l and adding in 8.4 l of isopropanol during the process). The mixture was cooled to room temperature and stirred at this temperature for 12 hours. The mixture was filtered, the solid washed with isopropanol (1.7 l) and dried in vacuo overnight at 40° C. to give 1605 g of the subtitle compound. Analysis by 1H NMR showed a ratio of pyridine: N-phenyldiethanolamine (or lithium alkoxide): isopropyl of 1:1.25:1.55.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(O)(=O)C.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:3]=[CH:20][C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1
Reactant: CN(N)c1ccccc1
Reactant: O=Cc1ccncc1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(N=Cc1ccncc1)c1ccccc1
Temperature: 0 °C

Procedure:
One equivalent of methyl phenylhydrazine (58.76 g; 0.4809 mol, compound 2) was diluted in 50 ml of ethanol and 1.5 ml of acetic acid in a three-necked flask on which was mounted a condenser. The reaction medium was then stirred at 0° C. Using a dropping funnel, 1 equivalent of 4-pyridinecarboxaldehyde (51.5 g; 0.4808 mol, compound 1) was added. After addition of the aldehyde, the reaction medium was heated at 65° C. (oilbath temperature) for 13 hours.
Reaction SMILES: C([NH:18][C@H:19]([C:29]([NH:31][C:32]1[CH:50]=[CH:49][C:35]([O:36][C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][C:41]([NH2:46])=[C:40]3[C:47]#[N:48])=[CH:34][CH:33]=1)=[O:30])[CH2:20][O:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>C(Cl)(Cl)Cl>[C:25]([O:24][C:22]([O:21][CH2:20][C@@H:19]([C:29]([NH:31][C:32]1[CH:50]=[CH:49][C:35]([O:36][C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][C:41]([NH2:46])=[C:40]3[C:47]#[N:48])=[CH:34][CH:33]=1)=[O:30])[NH2:18])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(Oc2ccc3[nH]c(N)c(C#N)c3c2)cc1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)OC[C@H](N)C(=O)Nc1ccc(Oc2ccc3[nH]c(N)c(C#N)c3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A solution of 5-[4-({N-FMOC-O-t-butoxycarbonylseryl}amino)phenoxy]-2-amino-1H-indole-3-carbonitrile (1.45 g; 2.3 mmol) in CHCl3, (30 ml) was treated dropwise with piperidine (3.25 ml). The mixture was stirred for 3 hours at room temperature and was directly purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 (2.5 to 10% MeOH). The appropriate fractions were evaporated to give 5-[4-(O-t-butoxycarbonylserylamino)phenoxy]-2-amino-1H-indole-3-carbonitrile as a white solid (878 mg).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>C1C=CC=CC=1>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([Cl:20])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccc(-c2ccccc2)cc1
Yield: 100.8 %

Procedure:
A suspension of 4-biphenyl acetic acid (8.48 g, 40 mmole) in dry benzene was cooled and stirred in an ice bath and oxalyl chloride (5.0 ml, 57.5 mmole) was added, followed dropwise by a solution of dry dimethylformamide (0.5 ml) in dry benzene. After the vigorous gas evolution subsided, the resulting solution was stirred at room temperature for 30 minutes. It was then evaporated and dried in vacuo (oil pump ~30) to afford 4-biphenylacetyl chloride as a solid (9.3 g, ~100%). This was used for reaction without further characterization. The above acid chloride was dissolved in CH2C12 (400 ml), stirred in an ice bath and a solution of sodium azide (3.9 g, 60 mmole) and (n-Bu)4N+H-SO4 (1.0 g) in water (120 ml) was added. (Ref. J. R. Pfister and W. E. Wyman, Synthesis, 38 (1983). The mixture was then stirred vigorously in the ice bath. After 45 minutes, the CH2Cl2 layer was separated, washed with water and brine, dried (MgSO4 anhydrous) and evaporated in vacuo (at ~25° ; CAUTION: DO NOT HEAT) to afford the title compound as a solid (8.5 g, 90.4%). The IR spectrum (Nujol) showed a weak peak at 2273 cm-1 (N=C=O) and a very strong peak at 2140 cm-1 (N3). It showed only one spot on tlc (silica gel, EtOAc-hexane, 1:1) and was used in the next step without further characterization.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:21])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccccc1C(=O)O
Product: CCCCCCCCOc1ccccc1C(=O)Cl

Procedure:
First, octyloxybenzoic acid was heated in thionyl chloride under reflux until complete dissolution. Excess thionyl chloride was removed by vacuum distillation. Thus there was obtained octyloxybenzoic acid chloride.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[SH:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@@H:21]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]3[OH:23])[N:19]=[CH:20][C:13]=12.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@@H:21]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]3[OH:23])[N:19]=[CH:20][C:13]=12)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCC=Cc1ccccc1
Reactant: OC[C@H]1O[C@@H](n2ncc3c(S)ncnc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](n2ncc3c(SCC=Cc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 40 °C

Procedure:
Cinnamyl bromide (3.04 g) was added to a stirred solution of 4-mercapto-1-β-D-ribofuranosylpyrazolo[3,4-d]-pyrimidine (4.0 g) and potassium carbonate (2.13 g) in N,N-dimethylformamide. The solution was heated (40° C. on an oil bath) for 2 hours. After cooling the reaction mixture was poured into water (0.6 l) and the resultant precipitate was collected and washed with water. The 4-cinnamylthio-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine so obtained was recrystallised from methanol, washed with water and dried (in vacuo at 55° C.), yield 3.2 g, m.p. 165°-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH3:38])[S:36][CH:37]=1>C(O)C.O.O.C(O)C>[CH3:38][C:35]1[S:36][CH:37]=[C:33]([CH2:32][N:10]([CH2:11][C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:9][CH2:8][N:7]([CH2:32][C:33]2[N:34]=[C:35]([CH3:38])[S:36][CH:37]=2)[CH2:6][C:5]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:34]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COc1cc(CNCCNCc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Solvent: O
Solvent: CCO
Product: COc1cc(CN(CCN(Cc2cc(OC)c(OC)c(OC)c2)Cc2csc(C)n2)Cc2csc(C)n2)cc(OC)c1OC
Temperature: 45 °C

Procedure:
1.5 g N,N'-bis-(3,4,5-trimethoxybenzyl) ethylenediamine dichlorhydrate were solubilized in 30 ml of a 1:1 ethanol/water mixture. The pH of the solution was brought to 11 using a soda solution. A solution of 1.25 g 4-chloromethyl-2-methylthiazole in solution in 10 ml water were added all at once. The mixture was heated for 5 hours at 45° C., while maintaining the pH at between 10 and 11 by adding a soda solution. After cooling, the ethanol was evaporated under a vacuum and the mixture was acidified to a pH of 1 using concentrated HCl. Extraction was carried out using 3×25 ml dichloromethane, then the organic phase was dried and dry-evaporation effected. The oil obtained was taken up in 10 ml ethanol +0.5 ml concentrated HCl. The resultant precipitate was filtered and washed in ethylic ether. The solid was then recrystallized in 20 ml isopropanol containing 1% water. In this way, 600 mg of a white powder having a melting point of 190° C. was obtained, whose proton NMR spectrum (400 MHZ) and ultimate analysis matched the expected structure (existing as a dichlorhydrate).
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10](O[C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[NH2:15][NH2:16].Cl>C(O)(C)C>[OH:14][C:13]1[C:3]2[C:4](=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:1][CH:2]=2)[C:10]([OH:11])=[N:16][N:15]=1
Reactant: NN
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Solvent: CC(C)O
Product: O=C(O)c1ccc2c(O)nnc(O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A mixture of 1,2,4 benzenetricarboxylic anhydride (5 g, 0.026 mol) and anhydrous hydrazine (1.67 g, 0.052 mol) in isopropyl alcohol (50 mL) was refluxed for 5 hours. The resulting mixture was neutralized with concentrated HCl and stirred at room temperature for an additional 1 hour. The mixture was filtered and the white residue washed with isopropyl alcohol to provide 1,4-dihydroxy-phthalazine-6-carboxylic acid (5.1 g, 95%) as a white solid.