Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3[CH:37]=[C:38]4[C@:43]([CH:45]=[O:46])([CH2:44][C:35]=3[CH:34]=[N:33]2)[CH2:42][N:41]([S:47]([C:50]2[CH:51]=[C:52]([CH3:56])[CH:53]=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH2:40][CH2:39]4)=[CH:28][CH:27]=1.O>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3[CH:37]=[C:38]4[C:43]([C@H:45]([C:6]5[N:7]=[CH:8][CH:9]=[CH:10][N:11]=5)[OH:46])([CH2:44][C:35]=3[CH:34]=[N:33]2)[CH2:42][N:41]([S:47]([C:50]2[CH:51]=[C:52]([CH3:56])[CH:53]=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH2:40][CH2:39]4)=[CH:28][CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C=O)C2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)CC3([C@@H](O)c3ncccn3)C2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of 2-(tributylstannyl)pyrimidine (428 μl, 1.351 mmol) in dry tetrahydrofuran (5 mL) was added butyllithium (2.5 M in hexanes) (554 μl, 1.384 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours. A solution of (R)-1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (200 mg, 0.443 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was stirred for 1.5 hours at −78° C. Water (25 mL) was added and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was partitioned between acetonitrile (25 mL) and hexanes (15 mL). The hexane layer was discarded. The acetonitrile layer was concentrated in vacuo to give a pale orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)methanol (75 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.27 min, m+H=532.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:39]([NH:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: O=C=Nc1ccccc1
Product: Cc1cc(F)ccc1-c1nc(NCCNC(=O)Nc2ccccc2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 79 %

Procedure:
The title compound from Example 157 (42.3 mg, 0.0001 mol) was treated with phenylisocyanate (11.9 mg, 0.00011 mol) in the same manner as described in Example 158. Purification afforded 43 mg (79%) of the title compound as a red solid (m.p. 142°-148°) LC MS (m/e)=545 (MH+). Rt=2.34 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.CCN(CC)CC.[C:22](Cl)(=[O:24])[CH3:23]>O>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:22](=[O:24])[CH3:23])[CH2:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
A solution of 3,3-dimethyl-6-nitroindoline (Example 4, 190.5 g) in 1200 mL IPAC, Et3N (200.6 g) was charged to a 1-L jacketed reactor, followed by the drop-wise addition of acetyl chloride (155.4 g) while maintaining reaction temperature<25° C. The reaction contents were stirred for 1 h at 20-25° C. 1200 mL D.I. water was charged slowly at T<30° C. to form a suspension. The product was isolated by filtration. Wet cake was washed with D.I. water (200 mL×2) and heptane (200 mL), and was dried at 50° C. under vacuum until constant weight. (193 g, 83.2 wt % adjusted yield, 99.15 A %, 99.5 wt % (dry))
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccnc(N2CCOCC2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccnc(N5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 45.8 %

Procedure:
In a similar fashion compound to CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 2-Morpholin-4-yl-pyridine-4-carbaldehyde (36.0 mg, 0.187 mmol) and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to yield 36.32 mg (46%) of the title compound. (300 MHz, DMSO-d6) 12.35 (s, 1H), 8.26 (s, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.38 (s, 2H), 7.25 (s, 1H), 6.39 (s, 2H), 5.15 (s, 1H), 3.75 (s, 4H), 3.54 (s, 4H), 2.90 (s, 1H), 2.80 (s, 1H), 2.62 (s, 1H), 2.26 (s, 1H), 1.38 (s, 1H). MS=466 (M+H), HPLC: 1.76 min. (G Method)
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C1COCC1>[CH2:12]([NH:14][C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:16])[CH3:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
NaH (0.9 g, 37.5 mmol) was added in portions to a 0° C. cooled solution of indole (2.93 g, 25 mmol) in THF (100 mL). After 30 min, ethyl isocyanate (1.78 g, 25 mmol) was added dropwise. The reaction mixture was stirred at RT overnight, then was quenched with 25% citric acid in water (50 mL) and extracted with ethyl acetate (3 X). These organic extracts were combined, dried (MgSo4), and recrystallized from ether/hexanes to afford 1.3 g of N-(ethylaminocarbonyl)indole as a tan solid, a 28% yield. m.p. 71-73° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.O.[Cl:9][C:10]1[S:14][C:13]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:41])[N:21]([CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)[C:22]3=[O:27])=[O:16])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Cl:9][C:10]1[S:14][C:13]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:41])[N:21]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:22]3=[O:27])=[O:16])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc2c1C(=O)N(C1CCNCC1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
50 ml of a mixture of TFA and water (9:1) are added dropwise to an ice-cooled mixture of 1.82 g (3.71 mmol) of tert-butyl 4-(4-{[(5-chloro-2-thienyl)carbonyl]-amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)tetrahydro-1(2H)-pyridine-carboxylate in 50 ml of chloroform. The ice-cooling is removed and the mixture is stirred at room temperature for 1.5 h and then concentrated. The residue is taken up in dichloromethane/methanol and washed with sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The crude product can be purified further by crystallization with ether. Yield: 1.185 g (78% of theory); MS (DCI, NH4): m/z (%)=390 (M+H, 100).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[I:11][C:12]1[CH:13]=[C:14]([C:6]2[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Ic1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2cccc(I)c2)o1
Yield: 25.9 %

Procedure:
5-Formyl-2-furanboronic acid (280 mg, 2 mmol) and 1,3-diiodobenzene (660 mg, 2 mmol) were dissolved in 1,2-dimethoxyethane (15 mL), tetrakis(triphenylphosphine)palladium (114 mg, 0.1 mmol) was added thereto, 2 mol/L sodium carbonate (4.6 mL) was then added thereto, and the mixture was heated to reflux for 3 hours while stirring. After the reaction was completed water (20 mL) was added, and extraction with ethyl acetate (20 mL×2) was carried out. The organic layer was washed with saturated brine, water was removed using anhydrous sodium sulfate, the solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give 5-(3-iodophenyl)furan-2-carbaldehyde in a yield of 155 mg (yield 25.9%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[Br:35][CH2:36][C:37](Br)=[O:38].O>O1CCCC1>[C:18]([C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([N:2]([CH3:1])[C:37](=[O:38])[CH2:36][Br:35])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNc1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Reactant: O=C(Br)CBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)CBr)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Three grams of [7-[3-(methylamino)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl methanone was dissolved in 150 ml of tetrahydrofuran. The solution was stirred as 2 ml of diisopropylethylamine, and then 2.3 g of bromoacetyl bromide were added. A precipitate formed immediately. The mixture was stirred at room temperature for 18 hours. A 150 ml portion of water was then added, the mixture heated until solution occurred, and then cooled at -10° C. A precipitate of the desired compound was obtained. It was collected, washed with water, and dried at 60° C. in vacuo giving 1.7 g, mp 175°-177° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:7][C:6]=1[O:21][CH3:22])[CH3:2].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:36])[F:37])[CH:27]=3)(=[O:34])=[O:33])[CH:14]=2)=[CH:7][C:6]=1[O:21][CH3:22])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2cccc(N)c2)cc1OC
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1OC

Procedure:
2-Methoxy-4-[3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=493.3 (M−H), was prepared in analogy to example 1, steps A to D. Step A was performed using 4-amino-2-methoxy-benzoic acid ethyl ester and yielded 2-methoxy-4-(3-nitro-benzoylamino)-benzoic acid ethyl ester. This was reduced to 4-(3-amino-benzoylamino)-2-methoxy-benzoic acid ethyl ester in step B. This was coupled with 3-trifluoromethyl-benzenesulfonyl chloride in step C, yielding 2-methoxy-4-[3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][NH:24][CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([N:24]([CH3:23])[CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CNCc1cccnc1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2c(N(C)Cc3cccnc3)cccc2n1

Procedure:
The title compound, MS: m/e=385.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 2-methoxybenzylamine and N-methyl-3-picolylamine.
Reaction SMILES: CB(O)O.[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:27]=[C:26]5[N:28]=[C:29]([O:31][C@H:32]6[C@H:36]7[O:37][CH2:38][C@@H:39]([OH:40])[C@H:35]7[O:34][CH2:33]6)[NH:30][C:25]5=[CH:24][C:23]=4Cl)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:9]=[N:8][CH:7]=[N:6]1.[C:42](=O)([O-])[O-].[K+].[K+]>[Pd+2].O1CCOCC1>[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:27]=[C:26]5[N:28]=[C:29]([O:31][C@H:32]6[C@H:36]7[O:37][CH2:38][C@@H:39]([OH:40])[C@H:35]7[O:34][CH2:33]6)[NH:30][C:25]5=[CH:24][C:23]=4[CH3:42])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccc(-n5cncn5)cc4)cc3)c(Cl)cc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CB(O)O
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2[nH]c(O[C@@H]3CO[C@H]4[C@@H]3OC[C@H]4O)nc2nc1-c1ccc(-c2ccc(-n3cncn3)cc2)cc1
Temperature: 140 °C

Procedure:
Methyl boronic acid (174 mg, 2.90 mmol), (3R,3aR,6R,6aR)-6-((5-(4′-(1H-1,2,4-triazol-1-yl)-[1,1′-biphenyl]-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (150 mg, 0.290 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (86 mg, 0.116 mmol) were added as solids to a microwave tube, followed by degassed 1,4-dioxane (2 mL) and 2 M aqueous potassium carbonate (1741 uL, 3.48 mmol). The tube was sealed and heated to 140° C. in a microwave for 30 minutes. The organic phase of the reaction was removed and evaporated under reduced pressure. The crude mixture was diluted in DMSO (2 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 5%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from water/acetonitrile to give the title compound as white solid. LC-MS: calculated for C22H24N6O4 496.19 observed m/e: 497.24 (M+H)+ (Rt 0.79/2.5 min); 1H NMR δ (ppm) ((CD3)2SO):
Reaction SMILES: C([Al:3](CC)CC)C.[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].O>O1CCCC1>[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[Al+3:3]
Reactant: CC[Al](CC)CC
Agent: CC(=O)Oc1ccccc1C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: [Al+3]

Procedure:
3.8 g of triethyl aluminum were dissolved in 70 ml of tetrahydrofuran. Under ice cooling, a solution of 10.8 g of o-acetoxybenzoate dissolved in 200 ml of tetrahydrofuran was added dropwise little by little to the above solution in nitrogen gas current. After completion of the dropwise addition, the temperature of the mixture was returned to room temperature, and it was thrown into a great quantity of water. The precipitated crude crystals were recovered by filtration and dried under reduced pressure to yield 10 g of white aluminum tris-(o-acetoxybenzoate) having a molecular weight of about 545 and an average degree of polymerization of about 1. The infrared absorption spectrum of the resulting salt was as follows:
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[CH3:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1.O>CS(C)=O.CS(C)=O.O1CCCC1.O1CCCC1>[CH3:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]2[O:15][CH2:2]2)[N:13]=1
Reactant: Cc1nc(C=O)cs1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C2CO2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.2 g (0.048 mol) of Trimethylsulphonium iodide are dissolved in 42 ml of dimethyl sulphoxide and added dropwise to a stirred solution, which is maintained at 0° C., of 1.14 g of sodium hydride in 50 ml of dimethyl sulphoxide/tetrahydrofuran (1:1). After 60 minutes, a solution of 6.1 g of 2-methyl-4-formylthiazole in 25 ml of tetrahydrofuran is added dropwise at 0° C., and the mixture is stirred at room temperature for 3 hours. It is then cooled to 0° C., 9.6 ml of water are added dropwise, and the mixture is extracted with ether. The ethereal phase is extracted by shaking 2× with water, dried and concentrated. The resulting oil is purified on a silica gel column using toluene/ethyl acetate (65:35) as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=S)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.O1CCOCC1.[NH:35]([C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[N:40]=[C:39]([NH2:49])[N:38]=1)[NH2:36]>O>[CH2:10]([C:9]1[N:35]([C:37]2[N:42]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[N:40]=[C:39]([NH2:49])[N:38]=2)[N:36]=[C:6]([C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccccc1)NC(=S)c1ccc(Cl)cc1
Reactant: NNc1nc(N)nc(-c2ccccn2)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-c2ccccn2)nc(-n2nc(-c3ccc(Cl)cc3)nc2Cc2ccccc2)n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
To a solution of N-(4-chloro-thiobenzoyl)-2-phenyl-acetamide (0.536 g, 1.85 mmol) and sodium acetate (ca. 0.25 g) in 1:1 acetic acid/1,4-dioxane (30 mL) was added 4-hydrazino-6-pyridin-2-yl-[1,3,5]triazin-2-ylamine (0.376 g, 1.85 mmol). The solution was heated to 90° C. and stirred for 15 hours. The reaction mixture was allowed to cool to room temperature, and water (100 mL) was added. The precipitate was removed by filtration, triturated with hot ethanol (300 mL), and dried to provide 0.489 g (60%) of the product as a white solid: 1H NMR (DMSO-d6) δ 8.78 (d, J=4.3 Hz, 1H), 8.32 (d, J=6.1 Hz, 2H), 8.22 (d, J=7.8 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.96 (dt, J=1.5, 7.8 Hz, 1H), 7.62–7.57 (m, 3H), 7.36–7.26 (m, 2H), 7.24–7.22 (m, 2H), 7.19–7.16 (m, 1H), 4.90 (s, 2H) ppm.
Reaction SMILES: [NH2:1][CH:2]([C:8]1([S:21][CH2:22][CH2:23][OH:24])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:14]([N:11]1[CH2:12][CH2:13][C:8]([CH:2]([NH:1][S:36]([C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:25][C:26]#[C:27][CH3:28])=[CH:35][CH:34]=2)(=[O:38])=[O:37])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([S:21][CH2:22][CH2:23][OH:24])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(N)C1(SCCO)CCN(Cc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OCC)C2(SCCO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl amino{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}acetate (2.1 g, 5 mmol) and 4-but-2-ynyloxy benzenesulfonyl chloride (1.24 g, 5.1 mmol) in dichloromethane (200 ml) at 0° C., N,N-diisopropylethylamine (3.0 g, 23.6 mmol) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 4 h and quenched with water. The reaction mixture was washed with water, dried over anhydrous MgSO4, filtered and concentrated. It was purified by silica gel column chromatography eluting with 80% ethyl acetate:hexane to give ethyl {1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)acetate as a brown oil; Yield: 1.0 g (85%); Electrospray Mass Spec: 561 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[CH2:18]([S:22]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]
Reactant: NC1Cc2ccccc2C1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NC1Cc2ccccc2C1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To 87.44 g of 2-aminoindane dissolved in 800 ml of methylene chloride was added 66.43 g of triethylamine, and 102.8 g of n-butylsulfonyl chloride was added dropwise thereto under ice cooling. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with diluted hydrochloric acid and dried, and then the solvent was removed. The resulting crystals were recrystallized from isopropyl ether to obtain 151.12 g of 2-n-butylsulfonylaminoindane.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].Cl.[CH3:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C.Cl>ClCCl>[CH3:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][NH:16][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCNS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
Trifluoromethanesulfonyl chloride (0.23 mL, 2.16 mmol) was added dropwise to a solution of 4-amino-butyric acid methyl ester hydrochloride (0.30 g, 1.96 mmol) and triethylamine (0.68 mL, 4.90 mmol) in dichloromethane and stirred at room temperature for 18 hours. 1N HCl was added and the product was extracted with dichloromethane, dried with magnesium sulfate and evaporated to give the title compound (0.42 g, 85%). 1H-NMR (CDCl3): δ 4.89 (s, 1H), 3.12 (t, 2H, J=7.2 Hz), 2.94 (s, 3H), 2.41 (t, 2H, J=7.2 Hz), 1.84 (m, 2H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[NH:21]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2)[C:22]([CH3:24])=[O:23]>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([NH:21][C:22](=[O:23])[CH3:24])[CH:26]=4)[NH:30][C:29]3=[O:34])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[C:7]([NH2:6])(=[O:18])[CH3:8]
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CC(N)=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(NC(C)=O)cc43)c(C)c2C1=O
Yield: 57.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-acetamino-1,3-dihydro-indol-2-one as starting materials to give N-{3-[5-2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide (52 mg, 57.9%) as a light yellow solid.