Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:24]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[C:27]([CH:26]=[C:23]([CH3:24])[CH:22]=1)[CH2:29][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1cc(C)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(OCc2cc(C)cc(C)c2)c1
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (3 g, 16.6 mmol) in DMF (20 ml) was added potassium carbonate (2.99 g, 21.6 mmol) at room temperature followed by drop wise addition of 3,5-Dimethylbenzyl bromide (3.30 g, 16.6 mmol). The reaction mixture was stirred for 16 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH2:14][S:13][CH2:12][C:11]=1[C:15]([O:17][CH3:18])=[O:16].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][S:13][CH:14]=1
Reactant: COC(=O)C1=C(Nc2ccc(I)cc2F)CSC1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cscc1Nc1ccc(I)cc1F
Temperature: 50 °C
Yield: 62.1 %

Procedure:
To a mixture of methyl 4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.2 g, 3.16 mmol) in 10 ml of anhydrous toluene was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (0.78 g, 3.16 mmol). The mixture was refluxed for 2 h. The mixture was cooled to 50° C. and concentrated in vacuo to dryness and cooled to room temperature. To the residue was added ethanol and the mixture was refluxed for several minutes, cooled to room temperature and light blue crystalline product was filtered off and dried in vacuo to afford methyl 4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylate (0.74 g, 62%). 1H NMR (d6-DMSO): 8.78 (s, 1H), 8.42 (d, 1H), 7.64 (d, 1H), 7.46 (d, 1H), 7.37 (t, 1H), 7.14 (s, 1H), 3.85 (s, 3H); MS (EI) for C12H9FINO2S: 378 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][C:12](=[CH2:14])[CH2:11][C@H:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:9]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])C1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>>[CH2:14]=[C:12]1[CH2:13][N:8]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C@H:9]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C@@H:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Product: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 65 °C
Reaction time: 28 h

Procedure:
A mixture of 2-benzyl 3-tert-butyl (2S,3S)-1-benzyl-5-methylenepiperidine-2,3-dicarboxylate from step 1d (2.3 g) and benzyl chloroformate (3 mL) was stirred at 65° C. for 28 h. The excess of the benzyl chloroformate was removed under reduced pressure. The residue was purified through Combiflash (hexane and ethyl acetate: gradient 0 to 10% during 12 min) to give the desired compound 1,2-dibenzyl 3-tert-butyl (2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate (1.40 g). MS (ESI): 488.1 (M+Na+); 366.1 (M+H+—COO(t-Bu)).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]([C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=O)=[C:23](O)[N:24]=2)=[N:11]1.[NH3:38]>C(#N)C>[F:6][C:7]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]3[C:26]([CH3:32])([CH3:31])[C:27](=[O:29])[NH:38][C:23]=3[N:24]=2)=[N:11]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3cccc(F)c3F)c3ncccc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4cccc(F)c4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8 ml of phosphoryl chloride were added to 0.75 g (1.703 mmol) of the compound from Example 75A, and the mixture was stirred at RT overnight. The reaction mixture was then taken up in 120 ml of acetonitrile and, with ice cooling, stirred into 72 ml of concentrated ammonia solution (33% in water). The reaction mixture was stirred at room temperature for 3 days and then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (acetonitrile/water/water+1% TFA—40:55:5). This gave 134 mg of the title compound (19% of theory).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[CH3:25][O:26][CH2:27][CH2:28]Br>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:28][CH2:27][O:26][CH3:25])=[CH:18][CH:17]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COCCBr
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: COCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a vigorously stirred solution of 29 (4 g, 0.013 mol) in anhydrous THF (150 mL) under nitrogen at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.64 g, 0.016 mol). The mixture was stirred for 15 min then tetrabutylammonium iodide (0.5 g, 0.0013 mol) and 2-bromoethyl methyl ether (2.04 g, 0.015 mol) were added and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the material was purified by column chromatography (silica gel, 10:1 methylene chloride/ethyl acetate) to provide 64 (3.1 g, 64%). 1H NMR (300 MHz, CDCl3) δ 1.60 (m, 4H), 2.59 (m, 2H), 3.23 (m, 2H), 3.45 (s, 3H), 3.77 (m, 2H), 4.10 (m, 2H), 5.13 (s, 2H), 6.88 (d, 2H), 7.08 (d, 2H), 7.47 (s, 5H).
Reaction SMILES: N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[I:12]I.[C@@H:14]12[O:21][CH2:20][C@@H:18]([O:19]1)[CH:17]=[CH:16][C:15]2=[O:22]>C(OCC)(=O)C>[I:12][C:16]1[C:15](=[O:22])[C@@H:14]2[O:21][CH2:20][C@H:18]([CH:17]=1)[O:19]2
Reactant: II
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(I)=C[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
150 ml of a dry pyridine-carbon tetrachloride (1:1) solution containing 40 g of iodine, was gradually added at 0° C. to 150 ml of a dry pyridine-carbon tetrachloride (1:1) solution containing 5 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose (disclosed in U.S. Pat. No. 3,926,947) under an inert atmosphere of nitrogen gas. The mixture was stirred at room temperature for two hours. Then, disappearance of the starting material was confirmed by thin layer chromatography, and 200 ml of ethyl acetate was added thereto. The mixture was washed twice with 200 ml of a saturated sodium chloride aqueous solution and once with 200 ml of 20% sodium thiosulfate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane=1:3) to obtain 6.1 g of the desired product (Intermediate No. 5) as slightly yellow crystals. The NMR analytical data and physical data of this product are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:20])([F:19])[S:15]([NH2:18])(=[O:17])=[O:16].C(N(CC)CC)C.[OH-].[Na+].[Na]>O.C(#N)C>[F:13][C:14]([F:20])([F:19])[S:15]([NH:18][S:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:11])=[O:10])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Br
Reactant: NS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(Br)ccc1Br
Temperature: 25 °C
Yield: 87 %

Procedure:
Inside a glove box, a 100 mL round-bottom flask equipped with a reflux condenser, stirring bar, and septum was charged with 2,5-dibromo-benzene-sulfonyl chloride (16.35 g, 50 mmoles), trifluoromethanesulfonamide (7.27 g, 50 mmoles), and acetonitrile (50 mL). Triethylamine (14 mL, 100 mmoles) was added slowly by syringe. The solution was heated to a reflux overnight. The solution was cooled to room temperature and poured into an aqueous solution of sodium hydroxide (4.0 g, 100 mmoles) in 100 mL water. The solvents were evaporated on a rotary evaporator and the solids were dried under vacuum. The solids were recrystallized by dissolving in dioxane at a reflux, treating with decolorizing carbon, filtering the solution, and concentrating the solution at a reflux to 130 mL to induce crystallization. The white crystals were collected by vacuum filtration, washed with dioxane, and dried under vacuum. The recrystallization was repeated to give 19.45 g (83% yield) of N-trifluoromethanesulfonyl-2,5-dibromo-benzene-sulfonamide, sodium salt. The salt was dried overnight in a vacuum oven at 150° C. under a nitrogen purge.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:10][CH:11]=1.[N:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:30]2[CH2:33][CH:32]([O:34][C:35]3[CH:40]=[CH:39][C:38](I)=[CH:37][N:36]=3)[CH2:31]2)=[O:29])=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C.ClCCl>[N:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:30]2[CH2:31][CH:32]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=4)=[CH:37][N:36]=3)[CH2:33]2)=[O:29])=[N:23][CH:22]=1
Reactant: COCCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(Nc1ccncn1)N1CC(Oc2ccc(I)cn2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCOc1cccc(-c2ccc(OC3CN(C(=O)Nc4ccncn4)C3)nc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A solution of 2-[3-(2-Methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Step 5, 109 mg, 0.39 mmol) in THF/H2O (10:1; 3 mL) was added to a microwave vial containing 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyrimidin-4-ylamide (step 4, 104 mg, 0.26 mmol) and potassium carbonate (108 mg, 0.786 mmol). Nitrogen gas was bubbled through the mixture for 5 mins then 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (21 mg, 10 mole %) was added and the vial sealed and heated at 100° C. in microwave synthesiser for 30 min. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and washed through celite (2.5 g IST cartridge). A further 10 mL of ethyl acetate was washed through the celite pad and combined filtrate was washed sequentially with water (30 mL), 1N NaOH solution (30 mL), water (30 mL) then sat. sodium chloride solution (30 mL). Mixture dried over sodium sulphate and filtered. Filtrate solvents were removed in vacuo to afford a brown gum, which was purified by flash chromatography, eluting with a gradient of 50 to 100% ethyl acetate in hexane to a afford a gummy solid. Product was dissolved in dichloromethane (25 mL) and 2N NaOH (aq, 25 mL) was added and mixture stirred vigorously for 1 h. Phases were separated and the organic layer dried over sodium sulphate, filtered and filtrate solvent removed in vacuo to leave a solid, which was triturated with diethyl ether, filtered and dried to afford the title compound as colourless solid (50 mg, 45%)
Reaction SMILES: [N@:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].B(F)(F)F.[CH3:22][CH2:23][O:24]CC.C(O)C>ClCCl>[CH2:11]([O:10][C:8]([NH:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH2:3][O:24][CH2:23][CH3:22])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOCC
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCO
Solvent: ClCCl
Product: CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C

Procedure:
To a stirred solution of (S)-1-benzyl 2-methyl aziridine-1,2-dicarboxylate (prepared according to the literature procedure: Org. Biomol. Chem., 2005, 3, 3357, 2.7 g, 11.4 mmol) in dichloromethane (30 mL), boron trifluoride etherate (0.01 mL, 0.11 mmol) was added at 0° C. followed by absolute ethanol (1.05 g, 22.9 mmol). The reaction mixture was stirred at room temperature for an hour, after which the solution was quenched with saturated bicarbonate solution (2 mL), extracted with dichloromethane (3×25 mL), organic layers were washed with water (25 mL), brine solution (25 mL) and dried over sodium sulfate. The removal of solvents afforded crude product, which was purified by silica gel column chromatography using a gradient of ethyl acetate in pet. ether. Yield: 2.0 g (63%). 1H NMR (400 MHz, DMSO-d6) δ: 1.08 (t, 3H), 3.38-3.46 (m, 2H), 3.57-3.63 (m, 2H), 3.70 (s, 3H), 4.26-4.31 (m, 1H), 5.04 (s, 2H), 7.30-7.39 (m, 5H), 7.73 (d, 1H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([P:14](=[O:27])([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)[CH:2]=1.[H-].[Na+].Cl[C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]=[C:33]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:32]=1>CN(C=O)C>[C:43]1([C:33]2[N:34]=[C:35]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:36]=[C:31]([N:12]3[C:13]4[CH:1]=[CH:2][C:3]([P:14](=[O:27])([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:32]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccc2[nH]c3ccccc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(c1)c1ccccc1n2-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
9H-3-carbazolyl(diphenyl)phosphine oxide (8 g), prepared as above, was dissolved in 120 ml of dry N,N′-dimethylformamide under nitrogen. 1.2 g of sodium hydride was added and stirred at room temperature for 1 h. A solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (U-1, 7.0 g) in dry N,N′-dimethylformamide (50 ml) was then added to the reaction mixture. The reaction was further allowed to stir for 24 h. The product was precipitated by pouring the reaction mixture into water. The solid thus obtained was then washed with methanol, followed by n-hexane and dried under vacuum to obtain 9 g of 9-(4,6-diphenyl-1,3,5-triazin-2-yl)-9H-3-carbazolyl(diphenyl)phosphine oxide, compound 8-8 (71%).
Reaction SMILES: O1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH2:27]([SH:31])[CH2:28][CH2:29][SH:30].B(F)(F)F>>[S:30]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2][S:31][CH2:27][CH2:28][CH2:29]1
Reactant: SCCCS
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCCCS4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.3 mmol) with 1,3-propanedithiol (0.330 mmol), BF3.etherate (catalytic) in tetrahydrofuran (10 ml) at 70-80° C. for 14 hours followed by silica gel column chromatographic purification to provide title compound in 50% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[CH3:13][O-:14].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:14][CH3:13])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(F)(F)F)nc(N)n1

Procedure:
2-Amino-4-ethoxy-6-trifluoromethylpyrimidine of melting point 114°-116° C. was obtained in a similar manner by reacting 2-amino-4-chloro-6-trifluoromethylpyrimidine with sodium methylate in ethanol.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1.CCCCCC>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8]3=[N:13][S:25](=[O:27])(=[O:26])[CH2:24][CH2:23][N:9]3[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of 3-biphenyl-4-ylpyridin-2-amine (700 mg) in dehydrated THF (30 mL) was added to a mixture of sodium hydride (60%, 568 mg) and 2-chloroethanesulfonyl chloride (1390 mg) in dehydrated THF (30 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (652 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([CH3:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ccc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)(F)F
Yield: 97 %

Procedure:
The title compound is prepared in 97% yield (467 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.26 mmol) and 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (373 mg, 1.38 mmol, Amine-69, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]1([C:7]2[N:19]=[C:10]3[C:11]4[C:16]([CH2:17][CH2:18][N:9]3[N:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrNC(=O)C>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[N:19]=[C:10]3[C:11]4[C:16]([CH:17]=[CH:18][N:9]3[N:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3n(n2)CCc2ccccc2-3)cc1
Agent: CC(=O)NBr
Solvent: ClC(Cl)(Cl)Cl
Product: c1ccc(-c2nc3c4ccccc4ccn3n2)cc1
Yield: 79 %

Procedure:
A mixture of 0.5 g. (0.002 mole) of 2-phenyl-5,6-dihydro-s-triazolo[5,1-a]isoquinoline and 0.28 g. (0.002 mole) of N-bromoacetamide in 10 ml. of carbon tetrachloride is refluxed for 5 hours. The crystalline precipitate which forms is filtered and dissolved in methylene chloride. The resulting solution is washed with sodium bicarbonate, then the solvent is evaporated off and the obtained residue recrystallized from ethyl acetate. Yield 79%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:13]I.O>CN(C)C=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[C:7]2=[N:8][CH:9]=1
Reactant: Brc1cnc2c(c1)CCN2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension stirred at 0° C., under an inert atmosphere, of 0.48 g (12.06 mmol) of 60% sodium hydride in 5 mL of dimethylformamide is added dropwise a solution of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 10 mL of dimethylformamide. The mixture is stirred at 0° C. for 15 minutes and then at 20° C. for 45 minutes. A solution of 0.77 mL (12.06 mmol) of methyl iodide in 5 mL of dimethylformamide is then added to this stirred suspension at 0° C. The mixture is then stirred for 48 hours. After this time, 50 mL of water and 50 mL of ethyl acetate are added to the mixture. The aqueous phase is separated out and then extracted with 3×30 mL of ethyl acetate. The organic phases are combined, washed with 2×50 mL of water and then concentrated under reduced pressure. The resulting product is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 0.97 g of the expected product is thus isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]([F:42])([F:41])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([C:32]([F:31])([F:41])[F:42])[CH:34]=2)[CH:6]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.40 g, 0.001 mol) in DMF (10 mL), was added 3-trifluoromethylbenzyl bromide (0.24 g, 0.001 mol) and powdered potassium carbonate (0.96 g, 0.007 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.43 g in 77% yield. 1H NMR (CDCl3) δ 7.40 (d, 1H), 7.37 (s, 1H), 7.24 (m, 7H), 7.19 (m, 6H), 6.83 (d, 1H), 6.62 (s, 1H), 6.59 (dd, 1H), 4.16 (t, 1H), 3.67 (s, 3H), 3.63 (s, 2H), 3.58 (t, 2H), 3.55 (s, 2H), 3.08 (d, 2H), 2.61 (t, 2H), 1.79 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.4, 144.7, 143.7, 142.2, 136.6, 133.8, 133.5, 131.9, 130.8, 130.2, 129.9, 129.8, 127.8, 126.8, 125.1, 125.0, 122.7, 116.8, 115.7, 114.5, 66.8, 61.1, 60.2, 53.5, 51.8, 42.6, 28.2.