Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>C1COCC1>[O:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(COc2ccccc2)cc(COc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(COc2ccccc2)cc(COc2ccccc2)c1
Yield: 99.2 %

Procedure:
Methyl 3,5-diphenoxymethylbenzoate (525 mg 1.51 mM) 2.0M sodium hydroxide (2.3 n 4.6 mm) methanol (5 ml) water (3 ml) and THF (10 ml) were stirred together at room temperature for 3 hours. After concentrating to ½ volume the mixture was acidified with 2.0M hydrochloric acid and partitioned between ethyl acetate and water. The organic extracts were washed with water, dried (magnesium sulphate) filtered and evaporated to give 3,5-diphenoxymethylbenzoic acid as a colourless solid (500 mg, 99%); H1 NMR δ (d6-DMSO) 5.19 (4 H s) 6.9–7.18 (6 H m) 7.28 (4 H t) 7.78 (1 H s) 7.95 (2 H s); MS [MH]− 333.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:7]1([C:12](=[O:15])[NH:13][OH:14])[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:6]([C:7]3([C:12](=[O:15])[NH:13][OH:14])[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:5][CH2:4][C:3]([OH:32])=[O:2])(=[O:17])=[O:18])=[CH:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A solution of 3-[(4'-fluorobiphenyl-4-sulfonyl)-(1-hydroxycarbamoylcyclopentyl)amino]-propionic acid methyl ester (8.9 grams, 19.2 mmole) in methanol (500 mL) was treated with aqueous 1 N sodium hydroxide solution (95 mL, 95 mmole) and stirred at room temperature for 5.5 hours. The mixture was concentrated to remove methanol, diluted with water, acidified with 6 N aqueous hydrochloric acid solution and extracted with ethyl acetate. After washing with water and brine the organic extract was dried over magnesium sulfate and concentrated to afford 3-[(4'-fluorobiphenyl-4-sulfonyl)-(1-hydroxycarbamoyl-cyclopentyl)amino]propionic acid as a white foam which was crystallized from ethyl acetate (6.74 grams, 78%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4].Cl[C:21]1[C:22]2[N:29]=[N:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:23]=2[N:24]=[CH:25][N:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[C:23]2[N:24]=[CH:25][N:26]=[C:21]([O:18][C@@H:13]([CH2:14][O:15][CH2:16][CH3:17])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][N:9]=3)=[O:19])[C:22]=2[N:29]=[N:28]1
Reactant: Clc1ccccc1-n1nnc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1nnn2-c1ccccc1Cl)C(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
Sodium hydride (82 mg, 2.05 mmol) was added to (S)—N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H4) (177 mg, 0.75 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (Intermediate AP2) (200 mg, 0.75 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 60% EtOAc in isohexane to afford the product (136 mg, 38.9%). 1H NMR (400 MHz, CDCl3) δ1.24 (t, 3H), 3.61-3.74 (m, 2H), 4.13-4.21 (m, 2H), 6.13 (t, 1H), 7.51-7.62 (m, 3H), 7.67-7.71 (m, 1H), 7.93-7.98 (m, 1H), 8.36-8.40 (m, 1H), 8.57-8.59 (m, 1H), 8.71 (s, 1H), 9.19 (s, 1H); m/z (ESI+) (M+H)+=463.23; HPLC tR=2.43 min
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(OCC)(=O)C.CCCCCCC>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@:2]([NH:1][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[C@](N)(CO)c1cc(Br)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCCl
Product: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)cc1

Procedure:
A solution of (R)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol (5.0 g, 20.2 mmol) and 4-methoxybenzaldehyde (2.8 g, 20.2 mmol) in 1,2-dichloroethane (150 ml) was treated with sodium triacetoxyborohydride (8.81 g, 40.3 mmol) at room temperature. TLC check (eluent: heptane:ethyl acetate=1:1) showed complete reaction after 30 minutes. For the workup, to the reaction mixture were added ethyl acetate (250 ml) and saturated sodium hydrogen-carbonate solution (100 ml). The aqueous layer was separated, and then extracted with ethyl acetate (250 ml). The combined organic layers were washed with saturated sodium chloride solution (100 ml), thereafter dried over sodium sulfate and evaporated at reduced pressure. After chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent, (R)-2-(5-bromo-2-fluoro-phenyl)-2-(4-methoxy-benzylamino)-propan-1-ol was obtained as a colorless oil (7.29 g, 98% of theory). Mass (calculated) C17H19BrFNO2 [368.25]; (found) [M+H]+=368, [M+2-H]+=370.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:14][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH:1]=[O:2])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OCC)cc1C=O
Temperature: 60 °C
Yield: 89.6 %

Procedure:
To a stirred solution of ethyl 3-formyl-4-hydroxybenzoate [see: Skattebol, Acta. Chemica. Scandinavica 1999, 53, 258] (1.9 g, 10.0 mmol) and anhydrous K2CO3 (2.7 g, 19.5 mmol) in acetone (30 mL) is added allyl bromide (1.7 mL, 19.8 mmol). The mixture is heated in a 60° C. oil bath for 2 h. The mixture is cooled to rt, filtered and concentrated in vacuo to afford 2.1 g (92%) of ethyl 4-(allyloxy)-3-formylbenzoate as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.5, 8.5, 8.2, 7.1, 6.1, 5.5, 5.4, 4.8, 4.4, 1.4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].C([NH:29][CH2:30][C:31](O)=[O:32])(OC(C)(C)C)=O>>[Cl:19][CH:18]([Cl:20])[C:16]([NH:15][CH:12]([CH2:13][F:14])[CH:11]([O:21][C:31](=[O:32])[CH2:30][NH2:29])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CS(=O)(=O)c1ccc(C(OC(=O)CN)C(CF)NC(=O)C(Cl)Cl)cc1
Yield: 80 %

Procedure:
By following the general procedures II and III using 12.9 g of florfenicol and 6.9 g of N-Boc glycine, the prodrug (13.2 g, 80% yield) was obtained as white powder after the crude solids were dried under reduced pressure at 50° C. for 6 days; H1-NMR (DMSO-d6), δ=3.2 ppm (m, 3H), 3.9 ppm (s, 2H), 4.3-4.7 ppm (m, 3H), 6.1 ppm (s, 1H), 6.8 ppm (s, 1H), 7.7 ppm (d, 2H), 7.9 ppm (d, 2H), 8.6 ppm (br, 3H), 9.4 ppm (d, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH2:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:38])[C:27]=2[C:26]([OH:39])=[CH:25][C:24]=1Cl>CN1CCCC1=O>[NH2:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:38])[C:27]=2[C:26]([OH:39])=[CH:25][C:24]=1[O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][OH:8]
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: CC(CCO)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(CCO)CCOc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 25 parts of 3-methyl-1,5-pentanediol, 12 parts of N-methylpyrrolidone, 2.6 parts of phenol and 3.3 parts of potassium carbonate is mixed with 8 parts of 1-amino-4-hydroxy-2-chloroanthraquinone at 130°C and stirred for 3 hours at 130°C and 2 hours at 140°C under nitrogen. After working up, 6 parts of 1-amino-2-(5'-hydroxy-3'-methylpentoxy)-4-hydroxyanthraquinone melting at from 134° to 135°C are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]=[CH:10][N:11](C)C)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.N[OH:16]>CO>[Br:1][C:2]1[C:3]([NH:9][CH:10]=[N:11][OH:16])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NO
Reactant: CN(C)C=Nc1nc(Br)cnc1Br
Agent: Cl
Solvent: CO
Product: ON=CNc1nc(Br)cnc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N′-(3,6-dibromo-pyrazin-2-yl)-N,N-dimethylformamidine (18.6 g, 60.80 mmol) in methanol (200 mL) is added hydroxylamine hydrochloride (5.91 g, 85.12 mmol) in one portion. The reaction is stirred at room temperature for 16 hours. The solvent is evaporated and the solid residue is treated with cold (ice cooling) water and collected by filtration. The precipitate is washed twice with water and petroleum ether and dried in vacuo yielding the title compound. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 7.82 (br s, 1H), 8.21 (s, 1H), 8.34 (m, 1H), 11.17 (br s, 1H). LCMS: Rt 3.17 min (98.7%), m/z (APCI) 295 (M+H)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][O:6][C:7]1[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:8]=1.Cl[Sn]Cl.[OH-].[Na+]>O.Cl.C(O)(=O)C>[CH3:5][O:6][C:7]1[C:12]([NH:13][NH2:1])=[CH:11][C:10]([CH3:14])=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:8]=1
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(N)cc1C
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(NN)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of NaNO2 (0.555 g, 8.04 mmol) in water (3 ml) is added to a stirred solution of 2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-ylamine (2 g, 6.1 mmol) in concentrated HCl (3 ml), water (3 ml) and acetic acid (8 ml) below 0° C. over 20 minutes. The mixture is added to a stirred solution of SnCl2 2H2O (3.53 g, 15.7 mmol) in 4N HCl (9 ml) at 0° C. over 15 minutes. The mixture is stirred at 0° C. for 20 minutes and at room temperature for 30 minutes. The mixture is basified by NaOH solution at 0° C. and extracted with EtOAc. The combined extracts are dried over Na2SO4 and concentrated under reduced pressure to give [2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-hydrazine. Rf (hexane/EtOAc=1:1)=0.24.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](OCC)=[O:15])=[N:11][C:10]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:5][CH:4]=1.[Na]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([NH2:1])=[O:15])=[N:11][C:10]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Reactant: N
Agent: [Na]
Solvent: CO
Product: NC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Reaction time: 3 h
Yield: 76 %

Procedure:
Part A: Gaseous NH3 is led through a stirred solution of ethyl 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.65 gram, 4.0 mmol) in methanol (25 mL) at room temperature. A small piece of sodium metal is added. After stirring the resulting mixture for three hours the precipitate is collected by filtration, washed with a small portion of methanol and dried to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide (1.16 gram, 76% yield), melting point 195-198° C. 1H-NMR (200 MHz, CDCl3): δ 7.48 (br s, 1H), 7.22-7.35 (m, 4H), 7.05-7.20 (m, 3H) 5.55-5.65 (M, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.O>CN(C=O)C.CCOC(C)=O>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: BrCc1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Methyl 3-(4-hydroxyphenyl)propanoate (0.5 g, 2.77 mmol) in dry DMF (10 ml) is added potassium carbonate (0.76 g, 5.55 mmol) followed by 4-(bromomethyl)pyridine hydrobromide (0.7 g, 2.77 mmol). The reaction mixture is stirred at room temperature overnight then poured into water (80 ml) and extracted with EtOAc (40 ml). The organic phase is washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield a dark brown oil. Chromatography (SiO2, EtOAc) yields 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid methyl ester as a colourless oil; [M+H]+ 272.0
Reaction SMILES: O[CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][CH:22]3CCCC[O:23]3)[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:3][CH:4]([CH3:6])[CH3:5]>C(O)=O.[Zn]>[CH:22]([O:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[C:7]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:8]([O:30][CH:31]([CH3:33])[CH3:32])[CH:9]=[N:10][C:11]=2[N:12]([CH3:29])[C:13]1=[O:28])=[O:23]
Reactant: CC(C)CC(O)c1c(OC(C)C)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: [Zn]
Solvent: O=CO
Product: CC(C)CCc1c(OC(C)C)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 80 °C
Yield: 94.3 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 0.13 mmol) in HCOOH (2 mL) was added Zn dust (42 mg, 0.65 mmol). The reaction was heated at 80° C. for 1 h, cooled to RT and filtered. The filtrate was concentrated and dried to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(5-isopentyl-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (48 mg, 82.7% yield) as a white solid. LCMS: MH+ 392 and TR=2.964 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:14]2[S:15][C:16](I)=[CH:17][C:18]=2[P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[S:12][CH:13]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][C:37]=1[P:38]([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])=[O:39])CCC.[Cu]C#N.[F-].[K+]>C1(C)C=CC=CC=1>[CH2:22]([O:21][P:19]([C:18]1[CH:17]=[CH:16][S:15][C:14]=1[C:11]1[S:12][C:13]([C:35]2[S:34][CH:33]=[C:37]([P:38]([O:40][CH2:41][CH3:42])([O:43][CH2:44][CH3:45])=[O:39])[CH:36]=2)=[C:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=1)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sccc1P(=O)(OCC)OCC
Reactant: CCOP(=O)(OCC)c1csc(-c2sc(I)cc2P(=O)(OCC)OCC)c1
Agent: N#C[Cu]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1csc(-c2sc(-c3sccc3P(=O)(OCC)OCC)cc2P(=O)(OCC)OCC)c1
Yield: 70 %

Procedure:
At room temperature, 0.1129 g (0.2 mmols) of 4,3′-bis(diethoxyphosphoryl)-5′-iodo-[2,2′]-bithiophene and 0.0092 g (0.008 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in 2 ml of toluene, to which 0.1018 g (0.2 mmols) of 2-(tributylstannyl)-3-(diethoxyphosphoryl)thiophene and 0.0036 g (0.04 mmols) of commercially available copper(I) cyanide were added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 2.5 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution added, followed by stirring for 1 hour. The resulting solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=1:2 and ethyl acetate:hexane=1:1) to obtain the specified substance in the form of a yellow oil at a yield of 0.0919 g (yield: 70%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N:11]([CH3:13])[CH3:12])=[N:8][C:7]=2[CH:14]=1.Br>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH3:12][N:11]([CH3:13])[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:14][C:7]=2[N:8]=1
Reactant: COc1ccc2oc(N(C)C)nc2c1
Agent: Br
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CN(C)c1nc2cc(O)ccc2o1
Temperature: 105 °C
Yield: 92.4 %

Procedure:
A mixture of (5-methoxy-benzooxazol-2-yl)-dimethyl-amine (6.41 g, 0.03 mol), tetrabutylphosphonium bromide (1.13 g, 3.34 mmol), and 48% HBr (40 mL) was stirred at 105° C. for twenty-five hours before it was cooled to room temperature, neutralized with 10N NaOH (30 mL) to pH=8. The resulting precipitate was filtered, washed with water, and dried in vacuo to give the title compound as a pale brown solid (4.94 g): 1H NMR (CDCl3, 200 MHz): δ=7.05 (m, 1H), 6.86 (m, 1H), 6.48 (m, 1H), 3.19 (s, 6H).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([NH:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)CCc1cccc(F)c1
Reactant: COC(=O)/C=C(/C)N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C(/C)NC(=O)CCc1cccc(F)c1
Yield: 50.9 %

Procedure:
To a solution of (Z)-methyl 3-aminobut-2-enoate (1.70 g, 14.8 mmol) and pyridine (1.30 g, 16.4 mmol) in DCM (25 mL) was added a solution of 3-(3-fluorophenyl)propanoyl chloride (2.77 g, 14.8 mmol) in DCM (5 mL) dropwise with stirring. At the end of addition, the mixture was stirred further at rt for 1 h. It was then washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (2.00 g, 51%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH:9]=O)=[CH:3][CH:2]=1.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[C:11]1([N:17]2[CH:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:8]=[CH:9][NH:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNc1ccccc1
Reactant: O=C/C=C/c1ccccc1
Solvent: CC(=O)O
Product: C1=CC(c2ccccc2)N(c2ccccc2)N1

Procedure:
13.2 g Zimtaldehyde (cinnamaldehyde) was condensed with 10.8 g Phenylhydrazine in 300 ml boiling acetic acid over 2 hours. At room temperature the sediment was filtered, washed with ethanol and dried.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](=[O:9])[CH3:8])[CH2:3][CH2:2]1.[CH3:10][N:11]([CH:13](OC)OC)[CH3:12]>>[CH3:10][N:11]([CH3:13])/[CH:12]=[CH:8]/[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:9]
Reactant: CC(=O)C1CCOCC1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)C1CCOCC1
Temperature: 100 °C

Procedure:
To a sealed tube were added 1-(tetrahydro-2H-pyran-4-yl)ethanone (3.00 g, 23.4 mmol) and DMF-DMA (6.2 mL, 46.8 mmol). The reaction mixture was heated at 100° C. overnight. The resulting mixture was concentrated under reduced pressure to afford 4.00 g (crude) of the title compound as light yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[O:5]1[CH2:9][CH2:8][CH:7]([CH2:10]OS(C)(=O)=O)[CH2:6]1>CN(C=O)C.O>[N:1]([CH2:10][CH:7]1[CH2:8][CH2:9][O:5][CH2:6]1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OCC1CCOC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCOC1
Temperature: 50 °C
Yield: 61.7 %

Procedure:
Add sodium azide (1.5 g, 23 mmol, 1.5 equiv) to a solution of methanesulfonic acid tetrahydro-furan-3-ylmethyl ester (2.76 g, 15.3 mmol, 1 equiv) in anhydr DMF (10 mL). Heat the reaction mixture at 50° C. for 16 h. Dilute the reaction mixture with H2O (100 mL) and extract with Et2O (2×50 mL). Wash the combined organic layers with H2O (2×50 mL), dry (anhydr Na2SO4), and rotary evaporate (40° C.) to yield 1.20 g (61.6%) of 3-azidomethyl-tetrahydro-furan as a nearly-colorless liquid.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]([CH:10]([F:12])[F:11])([F:9])F)([F:4])([F:3])[F:2]>[Ni]>[C:1]([CH2:5][O:6][C:7]([CH:10]([F:12])[F:11])([C:10]([C:1]([F:4])([F:3])[F:2])([F:12])[F:11])[F:9])([F:2])([F:3])[F:4]
Reactant: FC(F)C(F)(F)OCC(F)(F)F
Agent: [Ni]
Product: FC(F)C(F)(OCC(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.4 %

Procedure:
CF3CH2OCF2CF2H (60 g, 0.3 mol), SbF5 (10 g, 0.045 mol) and TFE (20 g, 0.2 mol) were charged into a 400 mL Hastelloy™ nickel alloy tube and agitated at 25° C. for 12 hours. Fractionation of the liquid product gave CF3CH2OCF(C2F5)CF2H, 42 g (46.4% yield), b.p. 65.2-65.8° C. (see Table 1). No formation of PTFE was observed.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([F:9])([F:8])[F:7])[CH3:3].Cl[C:11]1[C:16]([C:17]#[N:18])=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=2)[C:14]([C:29]#[N:30])=[C:13]([S:31][CH2:32][C:33]2[N:34]=[C:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)[S:36][CH:37]=2)[N:12]=1.Cl.FC(F)(F)CNC>CN(C=O)C.O.C1COCC1>[Cl:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]2[S:36][CH:37]=[C:33]([CH2:32][S:31][C:13]3[C:14]([C:29]#[N:30])=[C:15]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:24]=4)[C:16]([C:17]#[N:18])=[C:11]([N:4]([CH2:2][CH3:3])[CH2:5][C:6]([F:9])([F:8])[F:7])[N:12]=3)[N:34]=2)=[CH:43][CH:42]=1
Reactant: CCNCC(F)(F)F
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CNCC(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC(F)(F)F)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
133 mg (0.81 mmol) of N-ethyl-2,2,2-trifluoroethanamine hydrochloride were dissolved in 2 ml of DMF, 130 mg Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. The mixture was then warmed to 60° C. and stirred at this temperature overnight. In a separate flask, another 87 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 88 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at 100° C. for 4.5 h. The mixture was then diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 37 mg (41% of theory) of the target compound.