Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3ccccc3)c2OC1C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(Cl)cc(CCc3ccccc3)c2OC1C(F)(F)F
Reaction time: 4 h
Yield: 68.9 %

Procedure:
Ethyl 6-chloro-8-(2-phenylethynyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.30 g, 0.74 mmol) was dissolved in ethanol, mixed with Pt2O catalyst and reduced under a hydrogen atmosphere at 20 psi for 4 h at room temperature. The mixture was filtered, stripped and purified by flash chromatography on silica gel, giving ethyl 6-chloro-8-(2-phenylethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.21 g, 0.51 mmol). The product structure was consistent with 1H, 19F and 13C NMR analyses.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[CH:12]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC.C(OCC)(=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:12]=[CH2:2])[CH:14]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cc(Br)ccc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a suspension of methyl(triphenyl)-phosphonium bromide (15.5 g, 43 mmol) in THF (60 ml) were added at −78° C. BuLi (27 ml, 1.6 M in hexane, 43.2 mmol) and 5-bromo-2-fluoro-benzaldehyde (877 mg, 43 mmol). The reaction mixture was stirred 18 hours at r.t. After work-up and purification by chromatography (hexane/ethyl acetate 9/1 to 4/1) 5.7 g (28.5 mmol, 72%) of the title compound were obtained, 1H-NMR (300 MHz, CDCl3): δ=7.62 (dd, 1H), 7.26-7.36 (m, 1H), 6.93 (t, 1H), 6.79 (dd, 1H), 5.42 (d, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[Cl:41][C:42]1[S:46][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:44][CH:43]=1>O1CCCC1.O>[Cl:41][C:42]1[S:46][C:45]([S:47]([N:14]2[C:10]([C:9]3[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=3)=[C:11]([F:25])[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13]2)(=[O:49])=[O:48])=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(Cl)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a suspension of sodium hydride (60% in oil, 24.0 mg) in tetrahydrofuran (2 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) under ice-cooling, and the mixture was stirred for 15 min. 15-Crown-5 (133 mg) and a solution of 5-chlorothiophene-2-sulfonyl chloride in tetrahydrofuran (1 mL) were added dropwise and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield 229 mg, 98%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[ClH:31].[H][H]>CO.[PdH2]>[ClH:31].[C:27]([Si:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(Cc2ccccc2)C1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [PdH2]
Agent: Cl
Solvent: CO
Product: CC(C)(C)[Si](O[C@@H]1CCNC1)(c1ccccc1)c1ccccc1

Procedure:
(3R)-1-Benzyl-3-(tert-butyldiphenyl-silyloxy)pyrrolidine (1.18 g) was dissolved in methanol (12 ml), 1N hydrochloric acid (240 μl) and palladium hydride (221 mg) were added, and hydrogen was introduced to conduct catalytic reduction under normal pressure at room temperature for 4.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to solid under reduced pressure to obtain crude (3R)-3-(tert-butyldiphenyl-silyloxy)pyrrolidine hydrochloride (984 mg).
Reaction SMILES: [F:1][C:2]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH:16]2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]3[O:41][CH2:40][C:39](=[O:42])[N:38]([CH2:43][CH2:44]OS(C4C=CC(C)=CC=4)(=O)=O)[C:37]=3[CH:56]=2)=[CH:11][CH:10]=1.[N-:62]=[N+:63]=[N-:64].[Na+]>CN(C)C=O>[N:62]([CH2:44][CH2:43][N:38]1[C:37]2[CH:56]=[C:33]([CH2:32][O:31][CH:16]3[CH:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]5[CH:57]=[C:58]([F:61])[CH:59]=[CH:60][C:2]=5[F:1])=[CH:10][CH:11]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH2:17]3)[CH:34]=[CH:35][C:36]=2[O:41][CH2:40][C:39]1=[O:42])=[N+:63]=[N-:64]
Reactant: Cc1ccc(S(=O)(=O)OCCN2C(=O)COc3ccc(COC4CN(C(=O)OCc5ccccc5)CCC4c4ccc(OCCCOc5cc(F)ccc5F)cc4)cc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
A solution of 0.880 g of benzyl 4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}-3-{3-oxo-4-[2-(toluene-4-sulphonyloxy)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy}piperidine-1-carboxylate and 0.532 g of sodium azide in 10 ml of N,N-dimethylformamide is stirred at 65° C. over 90 minutes. The reaction mixture is poured onto water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.11 (1:2 EtOAc-heptane). Rt=5.82
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.IC1C=C2C(C(N)=CC=N2)=CC=1.[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)CCC>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Clc1ccnc2cc(I)ccc12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Nc1ccnc2cc(I)ccc12
Solvent: CCCCO
Product: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Temperature: 120 °C

Procedure:
4-Chloro-7-iodoquinoline (10 g, 34 mmol) [Semenov, V. P.; Studenikov, A. N. Synthesis of 7-iodo-4-aminoquinoline derivatives. Khim. Geterotsikl. Soedin. (1980), Issue 7, 972-5] and 4-phenoxyaniline (6.38 g, 34 mmol) in butanol (75 ml) were heated at gentle reflux (120° C.) overnight (18 hrs). On cooling the resultant precipitate was collected by filtration and washed with acetonitrile (2×50 ml). The resultant solid was suspended in chloroform (500 ml) and 2N sodium carbonate solution (300 ml) and heated at 75° C. for 45 mins. On cooling the resultant precipitate was collected by filtration, washed with water (2×50 ml) and dried to yield the product as a pale brown solid. (9.95 g, 66%) δ H [2H6] DMSO 8.35 (3H, m), 8.20 (1H, s), 8.10 (1H, d), 7.85 (1H, s), 7.35 (4H, m), 7.15 (4H, d), 6.75 (1H, d).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.CCN(C(C)C)C(C)C.[NH2:23][C@@H:24]1[C@H:28]([CH2:29][CH3:30])[CH2:27][C@H:26]([NH:31][S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH2:25]1.Cl>CN(C=O)C.CCOC(C)=O>[CH2:29]([C@H:28]1[C@@H:24]([NH:23][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[NH:11][CH:12]=[CH:13][C:3]=23)[CH2:25][C@@H:26]([NH:31][S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:33])=[O:34])[CH2:27]1)[CH3:30]
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1Cl
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2[nH]ccc12
Temperature: 60 °C
Yield: 42.6 %

Procedure:
To a mixture of 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.158 g, 0.800 mmol) in DMF (8.7 mL) was added DIEA (0.419 mL, 2.399 mmol) and N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide•hydrochloride (0.215 g, 0.800 mmol). The reaction mixture was heated at about 60° C. for about 60 h. The temperature was increased to about 70° C. for about 2 h then DIEA (0.279 mL, 1.599 mmol) and N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide hydrochloride (0.093 g, 0.346 mmol) were added. The reaction mixture was heated at about 70° C. for about 2 h. Additional N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide hydrochloride (0.060 g, 0.223 mmol) was added and the reaction mixture was heated at about 70° C. for about 30 min. Additional DIEA (0.279 mL, 1.599 mmol) was added and the reaction mixture was heated at about 70° C. for about 1 h. The reaction mixture was cooled to ambient temperature and concd in vacuo. The residue was dissolved in EtOAc (25 mL) and washed with water (20 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide (0.134 g, 41%) as an orange solid: LC/MS (Table 1, Method n) Rt=0.66 min; MS m/z 394 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl.CCOC(C)=O.C(Cl)Cl>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2cn3cc(F)ccc3n2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(-c2cn3cc(F)ccc3n2)cc1
Yield: 81.7 %

Procedure:
Prepared as described in the Nitro Reduction section using 6-fluoro-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0.45 g, 1.75 mmol) and tin (II) dichloride dihydrate (1.97 g, 8.75 mmol) in EtOH (25 ml) to give the title compound (0.325 g, 82%) as a pale yellow solid after work-up and flash chromatography (4:1 EtOAc/DCM).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[C:11]2[N:12]=[CH:13][N:14]=[C:15]([OH:16])[C:10]2=[N:9]1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=2)=[C:11]2[N:12]=[CH:13][N:14]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:15](=[O:16])[C:10]2=[N:9]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ncnc2c(-c3ccc(C(F)(F)F)cc3)n(-c3ccccc3Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(C(F)(F)F)cc3)c2ncn1CC(F)(F)F
Reaction time: 8 h

Procedure:
To a stirred mixture of 2-(2-chlorophenyl)-3-(4-(trifluoromethyl)phenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-2A-2b: 100 mg, 0.26 mmol) and Cs2CO3(85 mg, 0.26 mmol) in DMF (1.5 ml) was added a DMSO solution (0.1 ml) of 2,2,2-trifluoroethyl trifluoromethanesulfonate (60 mg, 0.26 mmol). After stirring overnight, the reaction mixture was extracted from water with ethyl acetate. The organic solution was washed with half saturated aqueous NaCl and then concentrated in vacuo. The crude residue was purified on a Biotage™ Flash 12S column using 20% ethyl acetate in hexanes as eluant to give the title compound 2A-2 (65 mg, 53%) as a solid: +ES MS (M+1) 473.4; 1H NMR (CD3OD) δ 8.17 (s, 1H), 7.73–7.52 (m, 8H), 4.83 (q, J=9.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[F:38]C1C=C(B(O)O)C=CC=1F>>[F:38][C:7]1[CH:6]=[C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:33])[F:35])[CH:26]=4)[N:24]=3)[CH2:18][CH2:19]2)[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3,4-difluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=533, obsd.=533).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH2:5].[CH3:6][S:7][CH2:8][C:9](O)=[O:10].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][S:2][CH2:3][CH2:4][NH:5][C:9](=[O:10])[CH2:8][S:7][CH3:6]
Reactant: CSCCN
Reactant: CSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CSCCNC(=O)CSC
Temperature: 25 °C

Procedure:
6 ml of 2-methylthio-ethylamine is dissolved in 250 ml of methylene chloride, mixed with 6.84 g of S-methyl-thioglycolic acid and with 7.42 g of N-hydroxysuccinimide and mixed drop by drop with 13.3 g of dicyclohexylcarbodiimide in 250 ml of methylene chloride under a cover-gas atmosphere. It is stirred, for 3 more hours at room temperature. The precipitate is filtered off, the filtrate is washed twice with semi-saturated sodium bicarbonate solution and once with water, dried with sodium sulfate and concentrated by evaporation. The residue is purified by chromatography with the mobile solvent system of methylene chloride/methanol: Yield 10 g=86.7% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH:55]=2)[CH:50]=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:58]([O:57][C:54]1[CH:55]=[C:56]2[C:51]([CH:50]=[CH:49][CH:48]=[C:47]2[NH:46][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:52][CH:53]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc2ccc(OCc3ccccc3)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2ccc(OCc3ccccc3)cc12
Reaction time: 18 h

Procedure:
To N-(tert-butoxycarbonyl)glycine (527 mg, 3.01 mmol) in dry CH2Cl2 (5 mL) under argon were added PYBOP (1.65 g, 3.16 mmol), 1-amino-7-benzyloxynaphthalene, as described above in Step J, (750 mg, 3.01 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.16 mmol). The reaction mixture was stirred for 18 hrs, then partitioned between CH2Cl2 (200 mL) and 10% aqueous citric acid (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was sufficiently pure for use in the next reaction.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[OH:25]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[O:25][C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C#N)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(C#N)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: NNc1ccccc1
Reactant: CCc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CCc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 87 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-ethyl-phenyl)-1H-pyridazin-4-one (A-4) and phenylhydrazine according to the method described for Example 1 in 87% yield. MS: M=343.1 (M+H)+
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1)[C:2]#[CH:3].C(=O)([O-])[O-].[K+].[K+].I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>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.C(#N)C.O.CN(C)C=O>[C:28]1([C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][N:7]2[C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=[C:11]([NH2:20])[C:10]=3[N:9]=[CH:8]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCOCCn1cnc2c(N)nc3ccccc3c21
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2c1ncn2CCOCC#Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (10 g, 37.6 mmol), anhydrous N,N-dimethylformamide (150 mL) and potassium carbonate (6.23 g, 45.1 mmol) was heated to 70° C. Iodobenzene (4.43 mL, 39.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.53 g, 0.75 mol), and copper(I) iodide (0.29 g, 1.50 mmol) were added and the mixture was allowed to stir for 0.5 hour. The temperature was raised to about 85° C. After 1.5 hours analysis by HPLC (reverse phase, acetonitrile/water with 0.1% trifluoroacetic acid) indicated that the reaction was complete. The mixture was allowed to cool to ambient temperature and then it was filtered. The filtrate was concentrated under reduced pressure. The residue was purified twice by flash chromatography (95/5 dichloromethane/methanol) to provide 2.7 g of 1-{2-[(3-phenyl-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 196-197° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:14]C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])[CH3:2].C(OCC)=[O:18].[Na].C(O)C>O>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([CH:14]=[O:18])[C:4]([O:3][CH2:1][CH3:2])=[O:16]
Reactant: CCOC=O
Reactant: CCOC(=O)C(CC)c1ccccc1OC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 2-methoxy-phenylacetic acid ethyl ester (11 g), ethyl formate (8.2 ml) and sodium (1.5 g) was added drop by drop with ethanol (5 ml) at 0° C., and the resulting mixture was stirred for 2 days at room temperature. Water was added, the organic layer was separated, the aqueous phase was washed with diethyl ether and extracted three times with ethyl acetate. The combined extracts were washed with water, dried and evaporated, to give 2 g of ethyl 2-(2-methoxy-phenyl)-3-oxo-propionate. The compound described above (2 g) was dissolved in water (50 ml), added with sodium carbonate (0.95 g), and the resulting mixture was added drop by drop with a solution of benzydamine (1.1 g) in water. The mixture was then heated under stirring for 10 hours at 60° C., acidified and extracted 3 times with methylene chloride. The combined extracts were washed with an 8% sodium bicarbonate aqueous solution, with water, dried and evaporated. The solid residue was crystallized from diethyl ether, to give the title product as a white solid (0.4 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:54]=[CH:53][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[C:24](=[O:44])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:43])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([O:41][CH3:42])[CH:35]=4)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:45][C:46]([OH:48])=[O:47])[C:24](=[O:44])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:43])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([O:41][CH3:42])[CH:35]=4)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:53][CH:54]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(C)c(OC)c4)cc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(C)c(OC)c4)cc3)cc2)cc1
Temperature: 30 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
Prepared using General Procedures 6 and 8: To 2-(3-methoxy-4-methylphenyl)acetic acid (14.1 mg, 0.08 mmol) were added HOBT (12.0 mg, 0.08 mmol) in DMF (0.1 mL) and EDC (15.0 mg, 0.08 mmol) in DMF (0.1 mL). After stirring at room temperature for 30 min, 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (30 mg, 0.05 mmol) and TEA (0.019 mL, 0.10 mmol) in DMF (0.3 mL) were added. The reaction was stirred for 18 h then purified by preparative HPLC to provide 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate. To 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate in DCM (1.0 mL) was added TFA (0.2 mL). The reaction was stirred at 30° C. for 6 h. The reaction was concentrated to afford 22.3 mg (65%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)acetic acid 4. LCMS-ESI (m/z) calculated for C40H44N2O8: 680; no m/z observed, tR=11.45 min (Method 2). 1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.06 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.43 (d, J=7.2 Hz, 1H), 7.40-7.28 (m, 3H), 7.24 (d, J=8.5 Hz, 2H), 7.17-7.02 (m, 3H), 6.91 (s, 1H), 6.79 (d, J=7.5 Hz, 1H), 4.62 (d, J=36.2 Hz, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.95 (d, J=28.6 Hz, 2H), 3.77 (s, 3H), 3.60 (s, 2H), 2.10 (s, 3H), 1.74 (dd, J=9.8, 4.8 Hz, 2H), 1.48-1.24 (m, 8H), 0.86 (d, J=7.0 Hz, 3H).