Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3].[CH2:23]([O:25][CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](B(O)O)=[C:29]([O:38][CH3:39])[CH:28]=1)[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN1CCCC1=O>[CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:30]2[C:29]([O:38][CH3:39])=[CH:28][C:27]([CH2:26][O:25][CH2:23][CH3:24])=[CH:32][C:31]=2[O:33][CH3:34])=[CH:17][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: CCOCc1cc(OC)c(B(O)O)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC)cc2)c(OC)c1
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 139.4 %

Procedure:
Under nitrogen atmosphere, a mixture of ethyl (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-4-bromobenzene propanoate (11.17 g), 4-ethoxymethyl-2,6-dimethoxyphenylboronic acid (10.80 g), palladium acetate (0.34 g), triphenylphosphine (1.57 g), anhydrous potassium carbonate (12.44 g), N-methylpyrrolidone (56 ml) and water (11 ml) was stirred for 50 minutes at 80° C. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution, dried over magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to yield ethyl (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate (20.4 g) as oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:10]([OH:16])[C:11](=[NH:15])OCC)[CH:6]=[CH:7][C:8]=1[F:9].[NH2:17][CH2:18][CH2:19][CH2:20]N>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([CH:10]([CH:11]2[NH:15][CH2:20][CH:19]=[CH:18][NH:17]2)[OH:16])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: NCCCN
Reactant: CCOC(=N)C(O)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCO
Product: OC(c1ccc(F)c(Br)c1)C1NC=CCN1
Temperature: 120 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of ethyl 2-(3-bromo-4-fluorophenyl)-2-hydroxyethanimidoate Hydrochloride (39.8 g, 127 mmol) and 1,3-diaminopropane (9.43 g, 127 mmol) in ethanol is heated at 120° C. in a sealed tube overnight, cooled to room temperature, concentrated to remove the solvent, diluted with water, stirred vigorously for 1 h and filtered. The filtrate is cooled with an ice bath, made strongly basic with 1 N NaOH, cooled for 1 h in an ice bath and filtered. The filtercake is dried to afford th title compound as a white solid 23.4 g (64% yield), identified by NMR and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 7.59 (m, 1H), 7.30 (m, 1H), 7.10 (t, J=8.4 Hz, 1H), 4.79 (s, 1H), 3.35 (m, 4H), 1.76 (m, 2H); ESI MS m/z 287 [C11H12BrFN2O+H]+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:26]1[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:24][CH3:25])[CH2:20][CH2:21][O:22][CH3:23].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH:69]1[CH2:74][CH2:73][CH:72]([C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:71][CH2:70]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cl-].[Na+].O>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:24][CH3:25])[CH2:20][CH2:21][O:22][CH3:23])[C:26]1[N:31]=[CH:30][C:29]([N:69]2[CH2:74][CH2:73][CH:72]([C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:71][CH2:70]2)=[CH:28][N:27]=1
Reactant: CCN(CCOC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)Cc3cc(C(F)(F)F)ccc3N(CC)CCOC)nc2)CC1

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amine (350 mg) is dissolved in toluene (5 ml) and tris(dibenzylideneacetone)dipalladium (49 mg), sodium tert-butoxide (77 mg), 2-(di-tert-butylphosphino)biphenyl (63 mg) and ethyl piperidine-4-carboxylate (119 μl) and the mixture is stirred under nitrogen flow at room temperature overnight. To the reaction solution is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ethyl acetate=19:1→3:1) to give ethyl 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (212 mg). MS (m/z): 7:36 [M+H]+
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])(C)(C)C.[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([O:21]C)=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>C1COCC1>[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](=[O:21])[CH2:2][C:1]#[N:3])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)c1ccc2cnccc2c1
Reactant: CC#N
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a solution of ACN (1.8 g, 43 mmol) in 90 mL of THF at −78° C. was added tert-butyllithium (25 mL, 1.7 M in heptane). After 20 minutes, methyl isoquinoline-6-carboxylate (2.0 g, 11 mmol) was added slowly in 10 mL of THF. After 1 hour, the reaction was quenched with 100 mL of aqueous NH4Cl and warmed to room temperature. The biphasic mixture was extracted twice with 100 mL of EtOAc, and the combined organic extracts were washed with 100 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded 3-(isoquinolin-6-yl)-3-oxopropanenitrile (2.1 g, 100% yield crude). The product thus obtained was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9]1[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:12]=[CH:13][CH:14]=1.[CH3:26]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9]1[C:10]([N:15]([CH3:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CI
Reactant: CN(c1ccccc1Cl)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(c1ccccc1Cl)c1ccccc1N(C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Compound 4 (0.405 g, 1.14 mmol) was dissolved in 4 mL of dimethylformamide (DMF) and added to KH (0.46 g, 3.42 mmol). The mixture was stirred at room temperature for 10 min. To this, MeI (0.4 mL, 5.7 mmol) was added dropwise. The reaction was allowed to stir at room temperature for 30 min. The reaction was then quenched with deionized H2O and extracted 3 times with 15 mL dichloromethane. The organic layers were combined and washed 3 times with 15 mL of H2O, and 3 times with 15 mL of brine. The organic layers were dried with MgSO4, and solvent was removed under reduced pressure to give the desired product as a yellow powder without further purification (0.362 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ 7.63 (1H, dd, J=8.0, 1.7 Hz), 7.36 (1H, ddd, J=8.8, 7.3, 1.8 Hz), 7.29-7.19 (2H, m), 7.12 (1H, dd. J=8.2, 1.7 Hz), 7.07-6.92 (5H, m), 6.88 (1H, ddd, J=8.2, 7.3, 1.2 Hz), 6.81 (1H, dd, J=7.8, 1.2 Hz), 3.32 (3H, s), 3.27 (3H, s); 13C (75 MHz, CDCl3) δ 146.5 (q), 143.5 (q), 142.1 (q), 138.8 (q), 132.7 (t), 131.0 (t), 128.7 (q), 127.6 (t), 126.2 (t), 124.2 (t), 124.1 (t), 123.7 (t), 123.1 (t), 120.4 (t), 118.8 (t), 38.5, 38.1.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH2:24][C@H:25]([C:27]([NH:29][C@H:30]([C:40]([NH:42][C@H:43]([C:52]([NH:54][C@H:55]([C:65]([NH:67][C@H:68]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:69][O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:66])[CH2:56][CH2:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:53])[CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:41])[CH2:31][CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:28])[CH3:26].FC1C(O)=C(F)C(F)=C(F)C=1F.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:40]([NH:42][C@H:43]([C:52]([NH:54][C@H:55]([C:65]([NH:67][C@H:68]([C:75]([O:77][C:78]([CH3:79])([CH3:81])[CH3:80])=[O:76])[CH2:69][O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:66])[CH2:56][CH2:57][C:58](=[O:64])[O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:53])[CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:41])[CH2:31][CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:28])[CH3:26])=[O:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: C[C@H](N)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
2.59 g. (8 mmoles) of Z-Asn-Gly-OH, 6.65 g. (8 mmoles) of H-Ala-Glu(OtBu)-Asp(OtBu)-Glu(OtBu)-Ser(tBu)-OtBu and 4.86 g. of pentafluorophenol are dissolved in 28 ml. of DMF. The solution is cooled to 0° C, and 1.81 g. (8.8 mmoles) of DCC are added to it. The reaction mixture is stirred at 0° C for 0.5 hours, and stirring is continued at room temperature for 2.5 hours. The separated DCU is removed by filtration; the filtrate is evaporated to dryness, and the residue is triturated with ethyl acetate. 7.3 g. (80.5 %) of Z-25-31-OtBu are obtained. M.p.: 194° C (under decomposition), Rf3 = 0.6.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13]C(=O)C)([CH3:3])[CH3:2].Cl>C(O)C>[CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH2:13])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1C(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Yield: 86.3 %

Procedure:
N-(2-Isopropyl-4-nitro-phenyl)-acetamide (3 g, 13.5 mmol) was dissolved in absolute ethanol (20 mL) and 5N hydrochloric acid (20 mL) was added. The mixture was heated to reflux overnight, cooled to r.t. then concentrated in vacuo to remove the ethanol. The mixture was basified with dilute sodium hydroxide solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (60-120 mesh), eluting with 17% ethyl acetate/petroleum ether to afford 2-isopropyl-4-nitro-phenylamine (2.1 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CC(C)CN(CC(C)C)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(C)C)c1ccc(C(=O)c2ccccc2)cc1N

Procedure:
10.63 g. of 3-nitro-4-(N,N-diisobutylamino)-benzophenone are dissolved in 106 ml. of ethyl acetate, the solution is poured into a hydrogenating apparatus, and 5,3 g. of Raney-nickel are added. The reaction mixture is hydrogenated at room temperature and atmospheric pressure until the uptake of the calculated amount of hydrogen (this requires generally about 1.5 hours). Thereafter the catalyst is removed by filtration and the clear solution is evaporated to dryness under reduced pressure. The obtained 9.4 g. of solid are recrystallized from isopropanol, to yield pure 3-amino-4-(N,N-diisobutylamino)-benzophenone; m.p.: 59°-60° C.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[O:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>>[O:18]1[C:22]2([CH2:27][CH2:26][N:25]([C:3]3[N:4]=[C:5]([CH2:12][C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)[NH:6][C:7](=[O:11])[C:8]=3[C:9]#[N:10])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCC3(CC2)OCCO3)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 544 mg (3.80 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane to give 65 mg (48% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O)[C:3](O)=[O:4].C([O-])([O-])=O.[K+].[K+].Cl.O.[NH2:30][NH2:31]>CO>[CH3:1][C:2]1[C:3](=[O:4])[NH:30][N:31]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=1
Reactant: NN
Reactant: CC(=CC(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(-c2ccc(-c3ccc(F)cc3)cc2)n[nH]c1=O
Reaction time: 6 h

Procedure:
28.4 g of 2-methyl-4-(4'-fluoro-4-biphenylyl)-4-oxo-2-butenoic acid is dissolved in 100 ml of methanol; 15.4 g of K2CO3 is added and the mixture is stirred for 6 hours at 20°. It is then acidified with hydrochloric acid, 5.4 ml of hydrazine hydrate is added and the batch is boiled for 2 hours. Thereafter, it is again acidified; the solution is concentrated and cooled; and the 4-methyl-6-(4'-fluoro-4-biphenylyl)-2,3-dihydropyridazin-3-one obtained is filtered off and washed with water. m.p. 247°-248°.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]([N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>ClCCl>[CH:12]([CH2:13][CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]([N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])=[O:11]
Reactant: O=C(C(CCO)c1ccccc1)N1CCCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCC(C(=O)N1CCCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.4 %

Procedure:
Dimethylsulphoxide (3.97 g, 50.9 mmol) in dichloromethane (25 ml) was added to a solution of oxalyl chloride (3.09 g, 24.4 mmol) at -50° C. in dichloromethane (25 ml). The reaction mixture was kept at this temperature for 5 min, treated with a solution of the product of step (a) (5.54 g, 21.2 mmol) in dichloromethane (30 ml), and, after 1 h, treated with triethylamine (10.72 g, 0.106 mol). The cooling bath was removed and the reaction mixture allowed to warm to room temperature. Water (100 ml) was added and the separated aqueous phase washed with dichloromethane (50 ml). The combined organic phases were washed with brine (50 ml), water (50 ml), dried (Na2SO4) and concentrated in vacuo to afford the title compound as an oil (5.30 g, 96.4%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH2:19][CH2:18]2>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:19][CH2:18]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: O=C(O)c1cccc(S(=O)(=O)N2CCc3cc(Cl)ccc32)c1

Procedure:
3-(chlorosulfonyl)benzoic acid (1.0 g, 4.53 mmol) was treated with 5-chloroindoline (2.08 g, 13.60 mmol) using method A to give 3-(5-chloroindolin-1-ylsulfonyl)benzoic acid as an off white solid. Yield: 720 mg (47%). 1H-NMR: 8.09 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 7.48-7.43 (m, 1H), 7.27-7.23 (m, 2H), 3.97 (t, J=8.5 Hz, 2H) 2.91 (t, J=8.5 Hz, 2H).
Reaction SMILES: [C:1]1([Li])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:26]=[CH:25][C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:28])[CH:21]=3)[C:16](=O)[C:15]=2[CH:14]=1>CCOCC.CC(O)=O>[Br:12][C:13]1[CH:26]=[CH:25][C:24]2[C:15](=[C:16]([C:9]3[C:10]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[CH:6]=[CH:7][CH:8]=3)[C:17]3[C:22]([C:23]=2[C:1]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=2)=[CH:21][C:20]([Br:28])=[CH:19][CH:18]=3)[CH:14]=1
Reactant: [Li]c1cccc2ccccc12
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Solvent: CC(=O)O
Solvent: CCOCC
Product: Brc1ccc2c(-c3cccc4ccccc34)c3cc(Br)ccc3c(-c3cccc4ccccc34)c2c1
Temperature: 130 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
5 g of 1-naphthyl lithium was dissolved in Et2O, and the resulting solution was gradually added dropwise to a solution containing 5 g of 2,6-dibromoanthraquinone dissolved in Et2O. This reaction was carried out on a dry ice bath. Then, the temperature of the reaction material was elevated to room temperature, thereby obtaining an intermediate product. The obtained intermediate product was filtered, thereby obtaining white solids. The white solids thus obtained were dissolved in 100 mL of AcOH, followed by addition of KI and NaH2PO2 and the mixture was stirred at 130° C. for 24 hours. When the reaction was complete, the reaction material was filtered with addition of water. The filtrate was recrystallized from MC and MeOH, thereby obtaining 4 g of 2,6-dibromo-9,10-di-1-naphthylanthracene.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7](I)[CH:6]=[N:5]1.[C:10]([C:12]1[CH:13]=[C:14]([C:18]2[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)#[CH:11]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:24][C:19]1[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10]#[C:11][C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][F:1])[CH:8]=3)[CH:13]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: C#Cc1cccc(-c2cccnc2F)c1
Reactant: FCCn1cc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: FCCn1cc(C#Cc2cccc(-c3cccnc3F)c2)cn1
Temperature: 65 °C
Yield: 75.6 %

Procedure:
To a solution of 1-(2-fluoroethyl)-4-iodo-1H-pyrazole (148 mg, 0.62 mmol) in DMF (5.0 mL) is added dichlorobis(triphenylphosphine)palladium (16 mg, 0.022 mmol), copper iodide (3 mg, 0.015 mmol), TEA (0.53 mL, 3.8 mmol) and 3-(3-ethynylphenyl)-2-fluoropyridine (150 mg, 0.76 mmol). The reaction mixture is heated at 65° C. for 3 h, cooled and quenched with H2O. The aqueous layer is extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 30/70) to afford the title compound (145 mg, 76%) as an oil. MS (+) ES: 310 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6]CN)=[CH:2]1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[N+:9]([CH:12]=[CH:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)([O-:11])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: NCCc1ccoc1
Product: O=[N+]([O-])C=CC1CCOC1
Yield: 55 %

Procedure:
Dichloromethane extraction of tetrahydrofuran-3-carboxaldehyde in water (50%, 2 mL) gave pure aldehyde (0.72 g, 7.2 mM) that was reacted with nitromethane in an analogous manner as used for the preparation of 2-Furan-3-yl-ethylamine above, to yield 3-(2-Nitrovinyl)-tetrahydrofuran (0.57 g, 55% yield) after column chromatography (elution with 30% ethyl acetate/Hexanes). The vinyl-nitro compound was reduced with LAH as described for the synthesis of 2-(furan-2-yl-)ethylamine, except that 1 M HCl/Et2O (5 mL) was added to the filtered solvent prior to evaporation to yield 2-(Tetrahydrofuran-3-yl) ethylamine as the HCl salt (30% yield). ESI-MS (m/z) 116 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:26]>C(O)C>[ClH:26].[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=Cc1ccc2c(c1)CC(N)CC2

Procedure:
A solution of the compound obtained in step d) above (2.7 g, 0.0078 mol) in absolute ethanol (50 ml) is allowed to react at room temperature for 5 hours with 4N HCl absolute ethanol (33 ml).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7](=[CH:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1.C1(N=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:20][N:3]([CH3:2])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:6][C:7](=[CH:10][C:11]([NH:3][CH2:4][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:29][CH:28]=2)=[O:13])[CH2:8][CH2:9]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 264 h
Yield: 14.7 %

Procedure:
(4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (810 mg, 2.73 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (1.13 g, 5.46 mmol) was added. The reaction mixture was stirred at RT for 11 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 16 h. The crude product thereby precipitated out as a beige-coloured solid in a yield of 16% (197 mg). After chromatography on silica gel (20 g) with EA/methanol (4:1), the product was isolated as an oily compound (92 mg) in a yield of 8%.