Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C@@H:6]([C:9]([SH:12])([CH3:11])[CH3:10])[CH2:5]1)([OH:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([S:12][C:9]([C@H:6]1[CH2:5][C@H:4]([C:1]([OH:3])=[O:2])[CH2:8][S:7]1)([CH3:10])[CH3:11])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(S)[C@H]1C[C@H](C(=O)O)CS1
Solvent: c1ccncc1
Product: CC(=O)SC(C)(C)[C@H]1C[C@H](C(=O)O)CS1
Temperature: 25 °C
Yield: 72 %

Procedure:
trans-4-carboxy-2-(1-mercapto-1-methylethyl)tetrahydrothiophene (compound No. 8-1, 50 mg) was dissolved in a mixture of acetic anhydride (1 ml) and pyridine (1 ml) and the mixture was stirred over night at room temperature. The reaction mixture was concentrated in vacuo and the oily residue was purified by a silica gel column chromatography to give 43 mg (72%) of the titled compound (compound No. 13-1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH2:31])=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.[CH:32](=O)[CH3:33].[BH3-]C#N.[Na+]>CO.CC(O)=O.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH:31][CH2:32][CH3:33])=[N:6][C:7]([CH:18]3[CH2:19][CH2:20]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:2][CH2:3]1
Reactant: CC=O
Reactant: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a solution of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine (0.15 g, 0.33 mmol) in MeOH (3.3 mL) was sequentially added acetaldehyde (22 mg, 0.5 mmol) and AcOH (5 drops). This mixture was stirred for 30 min before addition of NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). Stir at rt overnight. Add additional acetic acid (2 drops), acetaldehyde (29 μL, 0.5 mmol) and NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). After 2 hr, add additional acetic acid (2 drops), acetaldehyde (29 μL, 0.5 mmol) and NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). After 3 hr, dilute mixture with EtOAc and wash with sat. aq. NaHCO3 and extract with EtOAc (3×40 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 100% ethyl acetate) to afford 0.16 g (44%) of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N2-ethyl-2,3-dihydro-1H-indene-1,2-diamine as a solid: 1H NMR (CDCl3) δ 0.84–1.05, 1.62–1.75, 2.78–2.86, 3.31–3.37, 3.52, 5.22, 5.52, 7.28–7.51; MS (ESI+) for C27H28Cl2N4 m/z 479 (M+H)+.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:42])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(O)cc2Cl)c1=O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cc(Cl)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To 10 ml of DMF, 0.8 g (2.2 mmol) of 3-(2-chloro-4-hydroxy-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 0.42 g (3.0 mmol) of potassium carbonate and 0.56 g (3.3 mmol) of ethyl 2-bromopropionate were added, followed by heating and stirring at 60° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.90 g (yield: 94%) of the desired product.
Reaction SMILES: Cl[Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[C:12]([Mg]Br)#[CH:13]>O1CCCC1>[CH2:4]([O:3][Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[C:12]#[CH:13])[CH3:5]
Reactant: C#C[Mg]Br
Reactant: CCO[Si](Cl)(OCC)OCC
Solvent: C1CCOC1
Product: C#C[Si](OCC)(OCC)OCC
Temperature: 23 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Chlorotriethoxysilane (2.0 mL, 10 mmol, 1.0 equiv) was added to a stirred solution of 0.5M ethynylmagnesium bromide (20 mL, 10 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) at −78° C. The resulting heterogeneous light brown mixture was immediately warmed to 23° C. and stirred for 1 h. The resulting homogeneous light brown solution was heated to 50° C. and stirred for 4 h. The cooled reaction mixture was concentrated under vacuum. The resulting tan powder was slurried in hexane (50 mL), vacuum filtered, and rinsed with additional hexane (3×25 mL). The filtrates were dried over magnesium sulfate, gravity filtered, and concentrated under vacuum to provide the title compound as a pale yellow oil (1.5 g, 80% yield): IR (thin film) 3252 (w), 2976 (s), 2929 (m), 2913 (w), 2890 (m), 2046 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 3.90 (q, J=7 Hz, 6H), 2.35 (s, 1H), 1.23 (t, J=7 Hz, 9H).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH2:12])[N:11]=2)[N:8]=1.Cl[C:14](OC1C=CC(C(OC)=O)=CC=1)=[O:15].[CH2:27]([CH2:29][NH2:30])[OH:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[OH:28][CH2:27][CH2:29][NH:30][C:14]([NH:12][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([I:2])=[N:8][N:7]2[CH:9]=1)=[O:15]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: NCCO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCO)Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-iodoimidazo[1,2-b]pyridazin-2-amine hydrochloride (250 mg, 0.843 mmol) and DMAP (227 mg, 1.855 mmol) in DCM (Volume: 5.0 mL) was added methyl 4-(chlorocarbonyloxy)benzoate (199 mg, 0.927 mmol) at 25° C. The reaction was stirred at 25° C. for 1 hr to provide a dark green heterogeneous mixture which was filtered. The solid was resuspended in DCM (Volume: 5.0 mL), treated with ethanolamine (2M in MeOH, 0.843 mL, 1.686 mmol) at room temperature, and then stirred for an additional 1 hr. The reaction was then evaporated to dryness via rotary evaporation, and the resulting residue was suspended in EtOAc (Volume: 10.0 mL). The mixture was filtered, and the resulting black solid was dried under high vacuum and used without further purification.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH:7]([CH2:12][C:13]#[CH:14])[C:8]([O:10][CH3:11])=[CH2:9].C(N(CC)CC)C>C(Cl)Cl>[S:1]([O:6][CH:7]([CH2:12][C:13]#[CH:14])[C:8]([O:10][CH3:11])=[CH2:9])([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCC(O)C(=C)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCC(OS(C)(=O)=O)C(=C)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Mesyl chloride (1.73 ml) was added dropwise to a solution of 3-hydroxy-2-methoxy-1-hexen-5-yne (2 g) and triethylamine (3.32 ml) in methylene chloride (20 ml) under ice-cooling over a period of 10 minutes. After being stirred for 48 hours at room temperature the mixture was washed successively with water, aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate, and evaporated in vacuo to give 3-mesyloxy-2-methoxy-1-hexen-5-yne (3.45 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:29])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH2:17][CH2:18][N:19](C)[C:20](=O)OC(C)(C)C)[CH2:15][CH2:14][S:13][C:12]=2[CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][NH:19][CH2:18][CH2:17][N:16]1[CH2:15][CH2:14][S:13][C:12]2[CH:28]=[C:8]([NH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[NH:29])[CH:9]=[CH:10][C:11]1=2
Reactant: CN(CCN1CCSc2cc(NC(=N)c3ccco3)ccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN1CCSc2cc(NC(=N)c3ccco3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of tert-butyl 2-(7-(furan-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(methyl)carbamate (0.823 g, 1.978 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and was treated with trifluoroacetic acid (5 mL). The mixture was stirred at 0° C. under argon atmosphere for 2 hours. The mixture was quenched with 1N NaOH solution (70 mL) and transferred to a separatory funnel. The solution was diluted with water (50 mL) and extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was concentrated and subjected to flash chromatography on silica gel (5-15% (2M NH3MeOH):CH2Cl2). The collected fractions were concentrated to give compound 20 as a yellow viscous oil (0.47 g, 76%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.44-7.43 (m, 1H), 6.77-6.74 (m, 2H), 6.70 (d, J=2.4 Hz, 1H), 6.62 (dd, J=2.4, 8.7 Hz, 1H), 3.59-3.56 (m, 2H), 3.47 (s, 1H), 3.40 (t, J=6.6 Hz, 2H), 3.05-3.01 (m, 2H), 2.81 (t, J=6.3, 2H), 2.48 (s, 3H); ESI-MS (m/z, %): 319, 317 (MH+, 96), 260 (100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][C:10]([C:18]5[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]6[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]6)[CH:19]=5)([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:4][C:3]=1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[CH2:37]([CH:39]1[O:41][CH2:40]1)Cl.[OH-].[Na+].CC([CH2:47][C:48]([CH3:50])=[O:49])C>CS(C)=O>[CH2:37]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][C:10]([C:18]5[CH:23]=[CH:22][C:21]([O:24][CH2:47][CH:48]6[O:49][CH2:50]6)=[C:20]([CH:25]6[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]6)[CH:19]=5)([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:4][C:3]=1[CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[CH:39]1[O:41][CH2:40]1
Reactant: Oc1ccc(C23CC4CC(C2)CC(c2ccc(O)c(C5CCCCC5)c2)(C4)C3)cc1C1CCCCC1
Reactant: ClCC1CO1
Reactant: CC(=O)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1cc(OCC2CO2)c(C2CCCCC2)cc1C12CC3CC(C1)CC(c1ccc(OCC4CO4)c(C4CCCCC4)c1)(C3)C2
Temperature: 45 °C

Procedure:
In a mixed solvent composed of 14 mL of MIBK and 30 mL of DMSO, 10 g (20.6 mmol) of 1,3-bis(4-hydroxy-3-cyclohexylphenyl)adamantane (product of Honshu Chemical Industry Co., Ltd.) were dissolved, to which 15 g of epichlorohydrin were added. The mixture was then heated to 45° C. with stirring, added with 2.0 g (50 mmol) of sodium hydroxide over 0.5 hour, and further stirred for 6 hours. Thereafter, the obtained reaction liquid was cooled to room temperature and added with 50 mL of MIBK. The organic layer was washed with 50 mL of pure water, then one time with 50 mL of 0.1 mol/L hydrochloric acid and twice with 50 mL of pure water. The organic phase was separated and concentrated to give 12.2 g of yellow viscous liquid containing BCHP13-EPO.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)([OH:7])[CH3:6])[CH3:2].[Cl-].[NH4+].[In]>C(O)C.ClCCl>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[C:20]([F:23])([F:21])[F:22])[NH:9][C:8]([C:5]([OH:7])([CH3:6])[CH2:4][S:3][CH2:1][CH3:2])=[CH:16]2
Reactant: CCSCC(C)(O)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: CCSCC(C)(O)c1cc2cc(N)c(C(F)(F)F)cc2[nH]1

Procedure:
A solution of 1-ethylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol (0.35 g, 1.0 mmol) in ethanol. (20 mL) was prepared. To the solution was then added saturated ammonium chloride solution (20 mL). Indium was added (1.15 g, 10 mmol) and the reaction heated to reflux. After one-half hour the reaction was complete. The reaction mixture was filtered through Celite and the Celite washed with water and diethyl ether. The layers were separated and the aqueous layer extracted with diethyl ether. The organic layers were dried over magnesium sulfate, filtered, and evaporated to yield a residue. The residue was dissolved in dichloromethane and purified by column chromatography eluting with 1:1 diethyl ether/hexanes to yield the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[O:1]1[C:11]2([CH2:12][CH2:13][O:8][CH2:9][CH2:10]2)[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1
Reactant: OCC(CO)CO
Reactant: O=C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: OCC1COC2(CCOCC2)OC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (3.3 g, 31.1 mmol), tetrahydro-4H-pyran-4-one (3.12 g, 31.2 mmol), p-toluenesulfonic acid monohydrate (268 mg, 1.41 mmol) and benzene (68.3 ml) was refluxed in a round bottom flask equipped with a cooling tube and Dean-Stark for 6 hours. After cooled to room temperature, triethylamine (1 ml) was added to the reaction mixture and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel: 200 g, elution solvent: heptane, heptane/ethyl acetate=1/1, 1/3) to obtain the title compound (3.80 g, yield: 64.9%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>COCCOC.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>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
439 mg (0.38 mmol) Pd(PPh3)4 was added under argon at room temperature (r.t.) to a solution of 823 mg (3.76 mmol) 5-bromo-pyridine-2-carbaldehyde in 30 ml 1,2-dimethoxyethane and stirred for 15 min. 14.5 ml (29.0 mmol) of 2 M sodium carbonate solution and 1.00 g (5.27 mmol) 4-trifluoromethyl-phenylboronic acid were added and the mixture heated to boiling temperature for 18 hours (h). The reaction mixture was cooled to room temperature (r.t.), filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 630 mg (48%) of 5-(4-trifluoromethyl-phenyl)-pyridine-2-carbaldehyde.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13].[N:24]#[C:25]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])[C:25]#[N:24]
Reactant: O=C(CNc1nc2ccccc2s1)N1CCCc2ccccc21
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CN(CC(=O)N1CCCc2ccccc21)c1nc2ccccc2s1
Reaction time: 12 h
Yield: 21.9 %

Procedure:
To a suspension of compound 83 (340 g, 1.05 mmol) in dry CH3CN (10 mL) were added cyanogen bromide (5M in CH3CN) (0.42 mL, 2.1 mmol) and K2CO3 (580 g, 4.2 mmol). The reaction was heated to reflux for 4 h under N2. 0.84 mL (4.2 mmol) of cyanogen bromide was added and the reflux was continued for 12 h. The reaction mixture was diluted with EtOAc (50 mL). The solids were filtered off, filtrate was concentrated, and the yellow residue was purified by column chromatography (20% EtOAc in hexanes) to afford 84 as an off-white solid (80 mg, 28%). MS m/z: 349 (M+H)+. Anal. Calcd. For, C19H16N4OS.0.6 H2O: C, 63.53; H, 4.83; N, 15.60; S, 8.92. Found: C, 63.24; H, 4.67; N, 15.25; S, 8.76.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:32]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:47][CH:43]3[CH2:44][CH2:45][CH2:46][N:42]3[C:40]([O:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:41])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN2C(=O)OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2CCCN2C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 50.2 %

Procedure:
In a dry round bottom flask, charge 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.5 g; 0.0036 mol; 1.0 equiv) in dry DMF (30 mL) and cool to 0° C. Add NaH (0.26 g; 0.011 mol; 3.0 equiv) in portions under nitrogen and stir at RT for 30 min. Add 2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid benzyl ester (2.46 g; 0.0072 mol; 2.0 equiv) at RT and heat at 40° C. overnight. Quench with cold water and extract in EA. Wash the organic layer with water and brine. Dry over anhydrous sodium sulfate and concentrate. Purify the crude residue on silica (100-200 mesh) with 10 to 20% EA/hexanes to give the title compound (1.14 g; 51.6%). (ES+): m/z=631 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[NH:14][C:13]([CH:15]=[C:16]4[N:40]=[C:19]([C:20]([C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=5)=[C:21]5[NH:31][C:24](=[CH:25][C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)[CH:6]=[CH:7][CH:8]=1.[C:41]([C:43]1[C:49](=O)[C:48](Cl)=[C:47](Cl)[C:45](=O)[C:44]=1[C:53]#N)#N.[CH2:55]1[CH2:59]OC[CH2:56]1>>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([C:20]2[C:21]3[NH:31][C:24]([CH:25]=[C:26]4[N:30]=[C:29]([C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=5)=[C:10]5[NH:14][C:13](=[C:15]([CH2:56][CH2:55][CH2:59][CH2:53][CH2:44][CH2:45][CH2:47][CH2:48][CH2:49][CH2:43][CH3:41])[C:16]6[CH:17]=[CH:18][C:19]=2[N:40]=6)[CH:12]=[CH:11]5)[CH:28]=[CH:27]4)=[CH:23][CH:22]=3)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(-c2c3nc(cc4ccc([nH]4)c(-c4cccc(OC)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Reactant: C1CCOC1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: CCCCCCCCCCCc1c2nc(c(-c3cccc(OC)c3)c3ccc(cc4nc(c(-c5cccc(OC)c5)c5ccc1[nH]5)C=C4)[nH]3)C=C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5,15-bis-(3-Methoxy-phenyl)-porphyrin (100 mg, 0.19 mmol) is dissolved in anhydrous THF (30 mL) at −50° C. under an argon atmosphere. The organolithium reagent described above (5 mL) is added dropwise to the mixture. After 5 min the cooling bath is removed and the mixture is warmed to room temperature. After stirring at room temperature for 15 min the reaction is quenched by slow addition of water (2 mL). After 15 min the mixture is oxidized by the addition of DDQ (4 mL, 0.4 mmol, 0.1 M in THF) and stirred for a further 15 min. The mixture is filtered through alumna (neutral, Brockman grade+) and purified by column chromatography on silica gel eluting with hexane:dichloromethane (4:1 by vol.). The first fraction is collected and crystallised from methanol:dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17](I)[N:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][NH:31][CH3:32])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.CC(N(C)C)=O>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17]([N:31]([CH2:30][C:29]4[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=4)[CH3:32])[N:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Reactant: CNCc1ccc(F)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 43.9 %

Procedure:
Part C. To a sealed tube was added 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (100 mg, 0.22 mmol, 1.0 equiv), 4-fluoro-N-methyl-benzylamine (58 μL, 0.44 mmol, 2.0 equiv), diisopropylethylamine (17 μL, 0.44 mmol, 2.0 equiv) and dimethyl acetamide (1 mL). The reaction mixture was stirred at 100° C. After 5 hr, the reaction mixture was cooled to room temperature and diluted with dichloromethane, washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography [SiO2, ethyl acetate/heptane, 10:90 to 70:30, v/v] and recrystallization from ether/pentane to afford 2-{6-[(4-fluoro-benzyl)-methyl-amino]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (45 mg, 44%). 1H NMR (400 MHz, CD2Cl2) δ 8.57 (s, 1H), 8.06 (s, 1H), 7.24-7.34 (m, 4H), 6.98-7.05 (m, 4H), 6.18 (bs, 1H), 4.80 (s, 2H), 4.54 (d, J=8.0 Hz, 2H), 3.13 (s, 3H), 2.70 (s, 3H); HRMS (M+H)+=466.15.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[C:14]([C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[CH:8][N:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]=2[CH:11]=1)#[N:15]
Reactant: COC(=O)c1cc(C#N)cc2c1ccn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cc(C(=O)O)c2ccn(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-cyano-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid methyl ester (0.34 g, 1.2 mmol) in a mixture of MeOH—H2O (20 mL:5 mL) is added 2 N aqueous NaOH (40 mL) and the mixture is warmed at reflux. After 1 hour, the reaction is cooled to room temperature. The solution is acidified with 2 N aqueous HCl (pH=3). The solid is collected by filtration, washed with CH2Cl2 and dried to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.C1C[O:29]CC1>>[CH3:16][C:12]1[N:11]=[C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:29])=[CH:8][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=Cc1ccc(Oc2cccc(C)n2)cc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: Cc1cccc(Oc2ccc(CCO)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128 %

Procedure:
To the solution of 2-[(4-ethenylphenyl)oxy]-6-methylpyridine (1.23 g, 5.82 mmol) in dry THF (20 mL), was added 9-BBN (17 mL, 8.50 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (3M, 7 mL), and 30% H2O2 (7.2 mL). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.71 g, 7.46 mmol, 128% yield) as a colorless oil. LCMS: rt=2.07 min, [M+H+]=230