Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:22][NH2:23].C1COCC1>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([S:12]([NH:23][CH3:22])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(C(=O)OC)c1Cl
Yield: 72 %

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added a 2M solution of methylamine in THF (5.6 mL, 11.2 mmol). Purification of the product (2:1 hex:EtOAc) provided methyl 2-chloro-3-[(methylamino)sulfonyl]benzoate (430 mg, 72%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.23 (dd, 1H, J=7.9, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.48 (t, 1H, J=7.9 Hz), 5.16 (q, 1H, J=5.2 Hz), 3.94 (s, 3H), 2.62 (d, 3H, J=5.3 Hz); ESI-MS 264 (M+H). Methyl 2-chloro-3-[(methylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 250 (M+H), 272 (M+Na).
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[Cl:33][C:34]1[CH:43]=[CH:42][C:37]([C:38](=O)[CH2:39]Br)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]2[N:1]=[C:2]([N:4]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=3)[S:3][CH:39]=2)=[CH:36][CH:35]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc(-c3ccc(Cl)cc3)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 4-chlorophenacyl bromide.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][C:11]2[CH:14]=[CH:15][O:16][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19].[CH2:20]=O>C(O)(=O)C>[CH3:17][N:18]([CH2:20][C:15]1[O:16][C:10]2[CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:13][CH2:12][C:11]=2[CH:14]=1)[CH3:19]
Reactant: c1ccc(CC2Cc3occc3CN2)cc1
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CC(Cc1ccccc1)NC2
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.030 g (4.829 mmol) of 6-benzyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 30 ml of acetic acid, 0.52 g (5.80 mmol) of 50% aqueous dimethylamine and 0.47 g (5.80 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 15 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: Cl[CH:2]1[NH+:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([O:23][CH3:24])=[C:4]([O:25][CH3:26])[C:3]1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3.[Cl-].[CH2:28]([Mg]Br)[CH3:29].O1CC[CH2:34][CH2:33]1>C(OCC)C>[CH2:33]([C:2]1([CH2:28][CH3:29])[N:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([O:23][CH3:24])=[C:4]([O:25][CH3:26])[C:3]1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3)[CH3:34]
Reactant: COc1ccc2c(c1OC)C(Cl)[NH+]1CCc3cc4c(cc3C1=C2)OCO4
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Agent: [Cl-]
Solvent: CCOCC
Product: CCC1(CC)c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of 8-chloro-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; chloride (0.5 g, 1.2 mmol) in anhydrous diethyl ether (50 mL) at 0° C. was added a solution of ethylmagnesium bromide in tetrahydrofuran (3 M, 4.4 mL, 13 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (30 mL). The mixture was extracted with diethyl ether (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8,8-diethyl 9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (320 mg, 67%). LC/MS m/e calcd for C24H27NO4 (M+H)+: 394.49, observed: 394.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79 (t, J=6.32 Hz, 6 H) 1.78-1.95 (m, 2 H) 2.02-2.18 (m, 2 H) 2.73 (s, 2 H) 3.19 (s, 2 H) 3.74 (d, J=12.88 Hz, 6 H) 5.34 (s, 1 H) 5.99 (s, 2 H) 6.52 (d, J=8.34 Hz, 1 H) 6.74 (s, 1 H) 6.79 (d, J=8.08 Hz, 1 H) 7.18 (s, 1 H).
Reaction SMILES: [OH2:1].[C-]#N.[K+].[C:5](=[C:8]([O:10][C:11]([C:14]([C:17]([O:20][C:21]([F:24])([F:23])[F:22])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])[F:9])([F:7])[F:6].OS(O)(=O)=O.COCC[O:34][CH3:35]>>[C:35]([C:5]([CH:8]([O:10][C:11]([C:14]([C:17]([O:20][C:21]([F:22])([F:23])[F:24])([F:18])[F:19])([F:16])[F:15])([F:13])[F:12])[F:9])([F:7])[F:6])([OH:34])=[O:1]
Reactant: O
Reactant: COCCOC
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Agent: O=S(=O)(O)O
Agent: [C-]#N
Agent: [K+]
Product: O=C(O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture consisting of 120 ml H2O, 250 ml ethyleneglycol dimethylether and 26.3 g KCN was heated to 50° C. 110 g MV31 (CF2═CF—O—(CF2)3—O—CF3) were added to the mixture over a period of 35 min. During the addition of MV31 the temperature of the reaction mixture rose to 57° C. The reaction mixture was cooled down to 25° C. before 55 ml concentrated H2SO4 were added. The bottom phase was collected and washed with water. Afterwards, the organic phase was mixed with the same volume of conc. H2SO4 and agitated for 1 h at room temperature. Distillation from the reaction mixture yielded HOOC—CF2—CHF—O—(CF2)3—O—CF3 (overall yield 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[C:25](=[O:26])[CH2:24][N:23]([CH3:27])[C:22]2=[O:28])[CH:17]=[C:18]([Cl:20])[CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:24]3([C:25](=[O:26])[N:21]([C:16]4[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[CH:15]=4)[C:22](=[O:28])[N:23]3[CH3:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: ClC(CCBr)c1ccc(Br)cc1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(3-bromo-1-chloropropyl)benzene (Preparation 7) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione, the above titled compound was obtained after reverse phase HPLC purification (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O/TFA: 80/20/0.05). 1H NMR (CDCl3): 7.44 (2H, d, J=8.4 Hz), 7.25 (1H, m), 6.95-7 (4H, m), 4.05 (1H, t, J=10.1 Hz), 3.22 (3H, s), 2.65-2.85 (1H, br q), 2.4-2.65 (2H, m), 2.1-2.3 (1H, br q).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.Cl.[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[C:30]([CH2:37][O:38][CH2:39][CH3:40])=[N:29][C:24]=3[CH:25]=[N:26][C:27]=2[CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[N:48]12[CH2:58][CH2:57][CH2:56][N:55]=[C:54]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2>ClCCl>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:2][CH2:3][CH2:4][S:5]4(=[O:7])=[O:6])[C:30]([CH2:37][O:38][CH2:39][CH3:40])=[N:29][C:24]=3[CH:25]=[N:26][C:27]=2[CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:48]12[CH2:58][CH2:57][CH2:56][N:55]=[C:54]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Reaction time: 17 h

Procedure:
3-Chloropropanesulfonyl chloride (4.58 mL, 37.7 mmol) was added dropwise to a solution of 4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-1-amine dihydrochloride (12.1 g, 25.3 mmol) and triethylamine (14.0 mL, 101 mmol) in dichloromethane (168 mL) at room temperature. The solution was stirred for 17 hours, then transferred to a separatory funnel and washed with 5% aqueous sodium carbonate, water, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (168 mL) and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (5.70 mL, 38 mmol). The solution was stirred for 40 hours, then the DMF was removed under reduced pressure. The residue was dissolved in dichloromethane and washed repeatedly with water then saturated aqueous sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to afford 7-(benzyloxy)-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline in almost quantitative yield with some residual 1,8-diazabicyclo[5.4.0]undec-7-ene as a brown oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[NH4+]>CO.O>[F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[N:15][OH:16]
Reactant: O=Cc1ccnc(C(F)(F)F)c1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: ON=Cc1ccnc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-2-trifluoromethyl-pyridine-4-carbaldehyde (0.495 g, 2.05 mmol) in MeOH (17.6 mL) and water (2.9 mL) were added hydroxylamine hydrochloride (0.214 g, 3.08 mmol) and ammonium acetate (0.474 g, 6.15 mmol), and the resulting mixture was stirred at RT overnight. Volatile were removed in vacuo, and the residue was suspended in CH2Cl2/MeOH 9:1. The precipitate was filtered off, washed with CH2Cl2 and dried to afford the title compound as a white solid. MS (LC/MS): 209.0 [M+H]+; tR (HPLC conditions c): 4.28 min.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH3:15]>>[Cl:1][C:2]1[N:11]=[C:10]([N:14]([CH3:15])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNC
Product: CN(C)c1nc(Cl)nc2ccccc12

Procedure:
Prepared as in Example 38 from 2,4-dichloroquinazoline and dimethylamine. 1H NMR (400 MHz, CDCl3) δ3.42 (s, 6H), 7.42-7.39 (m, 1H), 7.72-7.70 (m, 1H), 7.79-7.77 (m, 1H), 8.03-8.01 (m, 1H). MS 208 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CO[C:15](OC)([CH3:17])[CH3:16]>C(Cl)(Cl)Cl>[CH2:6]([C@@H:2]1[O:1][C:15]([CH3:17])([CH3:16])[O:4][C:3]1=[O:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: COC(C)(C)OC
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)[C@H](Cc2ccccc2)O1
Yield: 97.5 %

Procedure:
A solution of (S)-2-Hydroxy-3-phenyl-propionic acid (1.662 g, 10.0 mmol), 2,2-dimethoxypropane (8.328 g, 80.0 mmol) and PPTSA (1.257 g, 5.0 mmol) in chloroform was stirred at 70° C. for one hour, concentrated, dissolved in dichloromethane and purified on silica gel with 10% EtOAc-PE which gave the title compound (2.010 g, 97%) as a white solid.
Reaction SMILES: C(Cl)(=O)OCC.[CH3:7][C:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([CH3:12])[C:9](O)=[O:10].C(N(CC)CC)C.[N-:25]=[N+:26]=[N-:27].[Na+]>CC(C)=O.O>[CH3:7][C:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([CH3:12])[C:9]([N:25]=[N+:26]=[N-:27])=[O:10]
Reactant: CC(C)(C(=O)O)c1cccs1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C(=O)N=[N+]=[N-])c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
10.6 ml of ethyl chlorocarbonate were gradually added, keeping the temperature below 0° C., to a solution of 15.8 g of 2-methyl-2-(2-thienyl)propionic acid [prepared as described in step (ii) above] and 15.6 ml of triethylamine in 210 ml of acetone. The reaction mixture was stirred at 0° C. for 2 hours, after which 110 ml of an aqueous solution containing 10.3 g of sodium azide were added to the mixture at 0° C. The reaction mixture was then stirred at 0° C. for 2 hours, diluted with water, and extracted three times with diethyl ether. The combined organic extracts were washed with 1N aqueous hydrochloric acid, with an aqueous solution of sodium hydrogencarbonate, and with a saturated solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure to give 18.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.Cl.[NH2:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29].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>>[N:30]1([C:28](=[O:29])[CH2:27][NH:26][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:22])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCC(=O)N1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCOCC3)ccc21
Yield: 55.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)-amide (75 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-amino-1-morpholino-1-ethanone hydrochloride (56 mg), HBTU (127 mg), and DIEA (73 uL). LC/MS: m/z 485.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.53 (t, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 4.16 (d, 2H), 3.64 (s, 3H), 3.63-3.60 (m, 2H), 3.58 (t, 2H), 3.55-3.50 (m, 2H), 3.50-3.45 (m, 2H).
Reaction SMILES: BrC1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:4]C=1.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[CH:34])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26].O.[CH3:36][CH2:37]CCCCC>CCN(CC)CC.[Cu]I.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>[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([C:23]#[C:24][C:25]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH3:22])=[CH:18][CH:19]=3)=[CH:4][CH:26]=2)=[CH:32][CH:31]=1)[CH2:34][CH2:36][CH3:37]
Reactant: CCCc1ccc(C#Cc2ccc(Br)c3ccccc23)cc1
Reactant: CCCCCCC
Reactant: C#Cc1ccc(CCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(C#Cc3ccc(CCC)cc3)c3ccccc23)cc1

Procedure:
2.35 g (6.3 mmol) of 1-bromo-4-(4-n-propylphenylethynyl)naphthalene and 1.33 g (8.4 mmol) of 4-n-butylphenylacetylene are initially introduced in 40 ml of NEt3, 60 mg (0.3 mmol) of copper(I) iodide and 200 mg (0.3 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and the mixture is refluxed for 18 h. The batch is cooled, water and heptane are added, and the phases are separated. The organic phase is washed with saturated ammonium chloride solution and subsequently with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated in a rotary evaporator. The residue of compound (1) is purified by column chromatography (SiO2, heptane), and the further purification is carried out by recrystallisation from isopropanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].CO.[Li+].[OH-].Cl>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a stirred solution of methyl 3-cyano-4-methoxybenzoate (1.1 g, 5.70 mmol) in a mixture of THF (70 mL), MeOH (70 mL) and water (5 mL) was added LiOH (0.97 g, 23.01 mmol) at RT and the reaction mixture was then stirred at RT for 1 h. The reaction mixture was acidified to pH ˜2 with 2 N HCl and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford 3-cyano-4-methoxybenzoic acid (1.0 g, 100%) as a solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1)=[O:2].C([OH:18])(C)C>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[C:13]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([C:1]([OH:18])=[O:2])=[CH:12]2)=[CH:7][CH:8]=1)#[N:14]
Reactant: CC(C)O
Reactant: N#Cc1ccc2ccc(C=O)cc2c1
Agent: [Cr+3]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc2ccc(C(=O)O)cc2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
7-Formyl-2-naphthalenecarbonitrile obtained in Reference Example 1 (3.0 g) was dissolved in 50 ml of acetone. The solution was cooled to 0° C. with stirring, and a solution prepared by dissolving 10 g of chromium oxide (IV) in 11 ml of concentrated sulfuric acid and 50 ml of water was added until the mixture becomes orange yellow. The reaction solution was stirred at 0° C. for 90 minutes and then at room temperature for 45 minutes, followed by the addition of 2 ml of isopropyl alcohol. The reaction solution was evaporated, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with saturated sodium bicarbonate aqueous solution, the saturated sodium bicarbonate layer was adjusted to pH 1 by adding concentrated sulfuric acid, and the thus precipitated solid matter was collected by filtration to give 1.94 g of 7-cyano-2-naphthalenecarboxylic acid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)=[CH:18]\[CH2:19][O:20][C:21]2[C:26]3[O:27][CH:28]=[CH:29][C:25]=3[C:24]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N:4]1([CH2:1][C:2]#[C:3][C:11]2[CH:12]=[CH:13][C:14](/[C:17](/[C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][CH:38]=3)=[CH:18]\[CH2:19][O:20][C:21]3[C:26]4[O:27][CH:28]=[CH:29][C:25]=4[C:24]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)c2occc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(F)(F)F)cc2)c2occc12
Temperature: 0 °C
Reaction time: 120 h

Procedure:
N-Propargylmorpholine (0.64 g, 5.1 mmol) was added under nitrogen atmosphere to a degassed solution of ethyl (Z)-[7-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-benzo[b]furan-4-yl]oxyacetate (0.68 g, 1.09 mmol) in a mixture of tetrahydrofuran (20 mL) and triethylamine (10 mL) The solution was cooled to 0° C., tetrakis(triphenylphosphine)palladium (0.17 g, 0.147 mmol) and copper(I) iodide (0.03 g, 0.16 mmol) were added. The reaction mixture was stirred at ambient temperature for 120 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding ethyl (E)-[7-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]benzo[b]furan-4-yl]oxyacetate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.ClCCl>[CH3:11][C:10]1[C:2]2[NH:1][C:22](=[O:24])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 282.8 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (9.07 g, 60 mmol) in THF (60 mL) was added simultaneously diisopropylethylamine (20.9 mL) and a solution of triphosgene (5.94 g, 20 mmol) in dichloromethane (60 mL) over 30 minutes period. After the addition was completed, the mixture stirred at ambient temperature for 16 hours. Solid was filtered and washed with ether (2×100 mL) and H2O (3×50 mL), and dried in high vacuum to afford the title compound (10.02 g, 94% yield) as a white solid. 1H NMR (DMSO) δ 11.02 (s, 1H), 7.76 (d, 1H, J=7.7 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.17–7.13 (m, 1H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[N:9][C:8]([CH2:20][NH:21][CH:22]=O)=[CH:7][N:6]=1)=[O:4].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:22]=[N:21][CH:20]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4]
Reactant: COC(=O)c1ncc(CNC=O)nc1Nc1ccc(I)cc1F
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 95 °C
Yield: 41.2 %

Procedure:
To a suspension of 3-(2-fluoro-4-iodo-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (480 mg, 1.12 mmol) in toluene (18 mL) was added phosphorous oxychloride (0.42 mL, 4.4 mmol, 4.0 eq.), and the reaction mixture was heated at 95° C. for 1 hour. The reaction mixture was cooled to RT and then quenched with a saturated aqueous solution of sodium bicarbonate (2 mL). The resultant residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanol in ethyl acetate) to give a yellow oil. Crystallization from dichloromethane ether hexane afforded the desired product as a yellow solid (190 mg, 41.3%). LCMS (method C): RT=2.45 min, [M+H]+=413.