Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]([CH3:17])=[C:8]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClS([N:37]=[C:38]=O)(=O)=O.CN(C)C=O>C(#N)C>[C:38]([C:7]1[C:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)(=[O:26])=[O:27])=[C:9]([CH3:17])[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=1[CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)#[N:37]
Reactant: CCOC(=O)Cn1c(C2CCCC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(5-cyclopentyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (2.54 g, 5.54 mmol) in acetonitrile (28 mL) was added chlorosulfonyl isocyanate (0.818 ml, 9.42 mmol). The reaction was stirred at room temperature for 30 minutes, after which the starting pyrrole had still not been consumed. The reaction was then heated to 55° C. for 30 minutes after which the starting pyrrole was consumed (by LCMS analysis). To the reaction mixture at 55° C. was added N,N-dimethylformamide (0.729 ml, 9.42 mmol). The reaction was stirred at 55° C. for 30 minutes after which analysis of the reaction (by LCMS) indicated that the reaction to afford the desired product was complete. The reaction was quenched by the addition of water, and extracted with dichloromethane (3×50 mL), dried (sodium sulfate), filtered and concentrated to a deep maroon residue. Purification was achieved by silica gel chromatography (Luknova 240 g, 20 mL/min) using 1 to 7% of a 7:1 acetonitrile/methanol solution in dichloromethane over 70 minutes. The product ethyl 2-(3-cyano-2-cyclopentyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (747 mg, 1.55 mmol, 28% yield) was isolated as a white foam. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.01 (d, 1H), 7.40 (dd, 1H), 7.30 (ddd, 1H), 6.99 (d, 1H), 4.59 (s, 2H), 4.30 (s, 2H), 4.27 (q, 2H), 3.32-3.36 (m, 4H), 2.96 (m, 1H), 1.84-2.09 (m, 13H, composite of multiple shifts), 1.63-1.71 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:9]5[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 96.4 %

Procedure:
tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (147 mg, 0.386 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (93 mg, 0.43 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (193 mg, 96%) as a yellow oil: ESI MS m/z 519 [M+H]+.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][OH:25])[C@H:11]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Cl[S:47]([NH2:50])(=[O:49])=[O:48]>C(#N)C>[C:1]([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][O:25][S:47]([NH2:50])(=[O:49])=[O:48])[C@H:11]1[O:26][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Reactant: NS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: NS(=O)(=O)OC[C@H]1C[C@@H](NC(=O)c2ccncc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a solution of (1S,2R,3R,5R)-3-(hydroxymethyl)-5-(isonicotinoylamino)cyclopentane-1,2-diyl dibenzoate (160. mg, 0.350 mmol) in ACN (10.0 mL) at 0° C. was added DBU (0.0600 mL, 0.401 mmol) and the mixture was stirred for 15 min. A freshly prepared 1.40 M solution of chlorosulfonamide (0.500 mL, 0.700 mmol, as prepared in Example 1d) was then added dropwise via syringe and the mixture was stirred for 2.5 h at 0° C. before being allowed to warm to rt. The mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in E)CM to afford the title compound (50.0 mg, 27%). LC/MS: Rt=1.57 min, ES+ 540. (FA standard).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[N+:20]([O-])=O.O=[Si]=O>C(O)C.[Ru]>[CH3:4][O:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[NH2:20]
Reactant: COc1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ru]
Agent: NN
Agent: O=[Si]=O
Solvent: O
Solvent: CCO
Product: COc1cc(Br)ccc1-c1ccc(Br)cc1N
Temperature: 67.5 °C
Yield: 95.4 %

Procedure:
A solution of hydrazine hydrate (19.4 mL, 400 mmol) in ethanol (20 mL) was added dropwise into a suspension of 2-methoxy-2′-nitro-4,4′-dibromobiphenyl (15, 25.77 g, 66.59 mmol) and 5% Ru/C (2.69 g, 1.33 mmol) in ethanol (250 mL) maintained at 65-70° C. The reaction mixture was then refluxed for 7 h. The hot reaction mixture was passed through Celite 545 (1 cm thick), and the filtrate was evaporated to give an off-white powder (22.69 g, 95.46%): mp 94.5-97° C.; HPLC method 3 tR=18.57 min (97.9 area %); 1H NMR δ 3.40 (br s, 2 H), 3.80 (s, 3 H), 6.9-7.2 (m, 6 H); EI-MS m/z 355 (M+). Anal. (C13H11ONBr2) C, H, N.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(O)c1cc(I)ccn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)ccn1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 4-iodopicolinic acid 11a (7.0 g, 18.6 mmol) in MeOH (70 mL) at 23° C. was added concentrated sulfuric acid (350 μL), and the reaction mixture was refluxed for 48 h. The reaction mixture was cooled to room temperature and concentrated to yield the desired product 4-iodopicolinic acid methyl ester 11b (4.4 g, 90%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 8.52 (t, J=0.6, 1.5, 1), 8.40 (d, J=5.1, 1), 7.86–7.88 (dd, J=0.6, 5.1, 1), 4.02 (s, 3); MS (ESPOS): 263.9 [M+H]; 285.9 [M+Na].
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[C:34]#[CH:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.ClCCl.CO.N>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[C:34]#[C:35][C:2]3[CH:18]=[CH:17][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(O)C1CCN(Cc2ccc(I)cc2)CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)C1CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 2-[1-(4-iodobenzyl)piperidin-4-yl]propan-2-ol and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 45 mg (30% of theory); melting point: 194-195° C.; C30H31ClN2O2 (M=487.04); calc.: molecular ion peak (M+H)+: 487/489; found: molecular ion peak (M+H)+: 487/489; Rf value: 0.3 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccc([N+](=O)[O-])cn1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccc([N+](=O)[O-])cn2)c1C

Procedure:
Similar to Example 1, equimolar amounts of (5-nitropyridin-2-yl)hydrazine and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 117° C.-119° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(OCC)(=O)C.[H][H]>C(O)C.[Pt](=O)=O>[F:1][C:2]1[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:5]=[C:6]([NH2:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2cccn2)c(F)c1

Procedure:
A solution of 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole (3 g, 14.5 mmol) and platinum(IV) oxide (100 mg) in ethanol (100 ml) with ethyl acetate (100 ml) was reduced under 40 psi hydrogen for 30 min, then filtered and the solvent removed, to give 5-fluoro-4-(pyrazol-1-yl)phenylamine as a colourless oil: MS (ES+) m/z 178 [M+H]+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2].Cl[CH2:15][C:16]12[CH2:23][CH2:22][CH2:21][N:20]1[CH2:19][CH2:18][CH2:17]2>>[N:20]12[CH2:21][CH2:22][CH2:23][C:16]1([CH2:15][N:3]([C:4]1[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=1)[CH:1]=[O:2])[CH2:17][CH2:18][CH2:19]2
Reactant: ClCC12CCCN1CCC2
Reactant: O=CNc1cccc2ccccc12
Product: O=CN(CC12CCCN1CCC2)c1cccc2ccccc12

Procedure:
The procedures described in Example 2 were repeated except that N-formyl-1-naphthylamine (1.83 g, 10.7 mmol ) and 5-chloromethyl-1-azabicyclo[3.3.0]octane (hydrochloride, 2.30 g, 11.7 mmol) were employed. In this case, the desired compound was obtained as a colorless liquid (3.02 g, 95.9%
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]C)=[O:11])=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[C:6]=2[CH:18]=1.O[Li].O>O1CCOCC1.O>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:21])=[O:22])=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[C:6]=2[CH:18]=1
Reactant: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a suspension of methyl 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate (2.90 g, 6.92 mmol) in 1,4-dioxane/H2O (30 mL/5 mL) was added LiOH.H2O (870 mg, 20.75 mmol). The mixture was stirred at room temperature overnight. Then it was concentrated in vacuo, diluted with water, acidized with HCl (aq. 2 M) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated give the product of 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (2.50 g, yield: 89%). It was used for the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 9.16 (br s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 3.17 (s., 6H), 2.82 (d, J=4.4 Hz, 3H). (M+H)+: 405/407.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([C:30]6[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(-c2cccnc2)cc1

Procedure:
The title compound, white solid (109 mg, 85%), MS (ISP) m/z=512.6 [(M+H)+], mp 235° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-(pyridin-3-yl)-benzoic acid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=O.O.[NH2:13][NH2:14]>C(C(CCCC)CO)C>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[N:13][NH2:14]
Reactant: NN
Reactant: O=C1Nc2ccccc2C1=O
Solvent: O
Solvent: CCCCC(CC)CO
Product: NN=C1Nc2ccccc2C1=O
Reaction time: 1 h

Procedure:
40.39 g of isatin (0.27 mol, purity 98.2%) were initially charged into a 500 ml four-neck flask and 200 ml of 2-ethylhexanol were added. With stirring (KPG, 250 rpm), 13.1 ml of hydrazine hydrate (13.5 g, 0.27 mol, purity 100.6%) were added within 15 minutes, which caused the temperature to increase from 23° C. to 45° C. and an intensely orange suspension to form. The reaction mixture was heated further and held at 50° C. for 60 minutes to form isatin hydrazone (yellow suspension). Afterwards, 6.12 g of DABCO (55 mmol, 98%) were added and the reaction mixture heated for a further about 0.5 hour until the DABCO had dissolved. The suspension was then charged in portions into 35 ml of 2-ethylhexanol in a receiver vessel which had been preheated to 145-150° C. Since addition of the cold suspension to the preheated 2-ethylhexanol resulted in an immediate temperature decrease which slowed the nitrogen elimination, the isatin hydrazone suspension was added in portions of each about 5 ml at intervals of 2-3 min to avoid this, so that the temperature in the receiver could be maintained in the target range of 140-145° C. Occasionally, an extension of the interval of up to 5 min was necessary. During the metering in (1.5-2 h), the reaction suspension foamed vigorously, particularly at the end of the reaction. During the nitrogen elimination, about 6.5 g of a biphasic mixture of water and some 2-ethylhexanol were distilled off. In this distillate 1, no hydrazine was found. The reaction mixture was held until complete conversion (about another 1.5 hours) at 140-145° C. (IPC control, GC: complete consumption of the hydrazone at 0.1-0.2 area %). 185 ml of 2-ethylhexanol were then distilled off at 90-95° C. (20-30 mbar, contained 0.02% by weight of hydrazine). The reaction solution was cooled to 55° C. and 80 g of MTBE were added. The reaction solution was cooled to 5° C. (in 0.5-1 h, then left to stand overnight at RT) to crystallize the 2-oxindole. The crystals were filtered off, washed with 3×5 ml of cold MTBE (0° C.) and sucked to dryness. 30.0 g of damp product were obtained which were dried for about 48 hours in a vacuum drying cupboard (80-90° C. and 50-65 mbar) to constant weight. Altogether, 23.9 g of dry 2-oxindole product (light brown) were obtained which corresponded to an overall yield of 66.5%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([OH:13])=[C:8]([CH:11]=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[Br:15]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:15][C:6]1[C:7]([OH:13])=[C:8]([CH:11]=[O:12])[CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)CCc2cc(O)c(C=O)cc21
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCc2c1cc(C=O)c(O)c2Br
Yield: 90.8 %

Procedure:
A solution of 3.1 g (16.3 mmol) 1,1-dimethyl-5-hydroxyindan-6-carboxaldehyde and 3.1 g (17.4 mmol) of N-bromosuccinimide in 50 ml of methylene chloride was stirred at ambient temperature for 2 days. Water (50 ml) was added. The organic phase was dried and evaporated. The residue was filtered through silica gel (20 g) using a gradient from hexane to 2:98 (v/v) ether:hexane as eluent. There was obtained 4.0 g (14.8 mmol, 91%) of 4-bromo-1,1-dimethyl-5-hydroxyindan-6-carboxaldehyde as yellow crystals after crystallization from ethanol; mp 77.5°-78.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C.[I-].[K+]>[F:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C(CCCCl)c1c[nH]c2ccc(F)cc12
Reactant: C1CNCCN1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCCN1CCNCC1)c1c[nH]c2ccc(F)cc12
Temperature: 80 °C
Yield: 129.6 %

Procedure:
To a magnetically stirred solution of 4-chloro-1-(5-fluoro-1H-indol-3-yl)-butan-1-one (10.93 g, 45.6 mmol) in acetonitrile (100 ml), piperazine (20.33 g ml, 236 mmol) and a small amount of potassium iodide (0.1 g) were added, and the resulting mixture was heated at 80° C. for 48 hours. The formed solid material was removed by filtration and the residue was concentrated in vacuo to give 37 g crude yield. This crude product was further purified by column chromatography (gradient: ethylacetate/methanol/25% aqueous ammonia=90/5/5 to methanol) to give 17.1 g crude 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)-butan-1-one. Then this crude 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)-butan-1 -one (10.71 g, 0.389 mol) was dissolved in dichloromethane (500 ml) and Boc2O (25.53 g, 0.117 mol) was added. The resulting mixture was stirred for 4 hours at room temperature. The mixture was successively washed with 5% aqueous NaHCO3 and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Subsequent column chromatography (gradient: dichloro-methane/methanol=99/1 to dichloro-methane/methanol=90/10 (v/v)) gave pure 4-[4-(5-fluoro-1H-indol-3-yl)-4-oxobutyl]-piperazine-1-carboxylic acid tert-butyl ester (3.85 g, 37% yield). 1H-NMR (400 MHz, DMSO-d6) δ 1.38 (s, 9H), 1.80 (quintet, J=7, 2H), 2.25-2.35 (m, 6H), 2.84 (t, J=7, 2H), 3.22-3.32 (m, 4H), 7.06 (dt, J˜9 and 3, 1H), 7.47 (dd, J˜9 and 5, 1H), 7.85 (dd, J˜9 and 3, 1H), 8.38 (s, 1H), 12.01 (brs, 1H).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[N-].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH3:13]>>[O:11]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][O:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:12][CH3:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: CCOc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCC(=O)C=[N+]=[N-]
Product: CCCCCCC(=O)COS(=O)(=O)c1ccc(OCC)cc1
Yield: 59 %

Procedure:
A 1.0 g quantity of 1-diazo-2-octanone is dissolved in 30 ml of dixoane, and 2.0 g of p-ethoxybenzenesulfonic acid is slowly added to the solution at room temperature. The mixture is stirred until no nitrogen is evolved. The reaction mixture is distilled in a vacuum to remove the solvent, and the residue is extracted with 50 ml of ether, washed with water and dried over anhydrous sodium sulfate. The dried product is distilled in a vacuum to remove the solvent and obtain an oily product, which is purified by column chromatography (silica gel, developer solvent chloroform), affording 1.26 g of 2-oxooctyl-p-ethoxybenzene sulfonate (Compound 46), m.p. 38° to 39° C. Yield 59.0%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH2:11])[CH2:6]1)=[O:4].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:6][C@H:7]([NH:11][C:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:18])[C@@H:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)[C@@H](O)C1
Reactant: O=C(O)c1cccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2cccs2)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a stirred solution of the (1R,3S,4S)-3-amino-4-hydroxy-cyclopentanecarboxylic acid methyl ester (300 mg) at r.t. in DMF (7.0 ml) under an argon atmosphere were added N-ethyldiisopropylmine (0.96 ml), 2-thiophene carboxylic acid (314 mg) and BOP (1.04 g). The mixture was then stirred at r.t. for 19 h. The clear brown solution was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give (1R,3S,4S)-3-hydroxy-4-[(thiophene-2-carbonyl)-amino]-cyclopentanecarboxylic acid methyl ester as light brown gum. MS: 270.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[N:9]=[CH:10]2)=[CH:5][CH:4]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[NH:31][C:30]([NH2:33])=[N:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:18]1[CH:19]=[CH:20][N:16]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[N:31]=[C:30]([NH:33][C:13]([C:8]3[N:9]=[CH:10][C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)=[O:15])[NH:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: COc1ccc2cc(C(=O)O)ncc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ncc2c1
Yield: 84 %

Procedure:
71.8 mg (84%) of 7-methoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was prepared according to General Procedure A using 41 mg (0.2 mmol) of 7-methoxy-isoquinoline-3-carboxylic acid, 48 mg (0.2 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 100 mg (0.246 mmol) of HBTU, 0.07 mL (0.4 mmol) of DIEA and 2 mL of DMF stirring at 80° C. for 2 h. LCMS: 428 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[C:11]([C:16]([OH:18])=[O:17])=[N:12][CH:13]=[CH:14][N:15]=2)=O)=[C:6]([CH3:21])[CH:5]=1)[CH3:2].[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.C(OC(=O)C)(=O)C>O>[CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]2([N:38]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=3)[C:35]3[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[CH:33][CH:34]=3)[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[C:16](=[O:18])[O:17]2)=[C:6]([CH3:21])[CH:5]=1)[CH3:2]
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Reactant: CCN(CC)c1ccc(C(=O)c2nccnc2C(=O)O)c(C)c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(CC)CC)cc3C)OC(=O)c3nccnc32)cc1

Procedure:
A mixture containing 3.1 g. of 3-[4-(diethylamino)-2-methylbenzoyl]-2-pyrazinecarboxylic acid, 3.1 g. of 4,4'-dioctyldiphenylamine and 25 ml. of acetic anhydride was stirred in a warm water bath for 3 hours. The reaction mixture was poured into water and the resulting solid was collected and recrystallized from hexane to give 7-[4-(diethylamino)-2-methylphenyl]-7-[bis(4-octylphenyl)amino]furo[3,4-b]pyrazine-5(7H)-one as a light tan solid, m.p. 180°-187° C. A toluene solution of this product contacted with acidic clay or phenolic resin developed a violet image.