Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(-c3ccc(C#N)cc3)c2n1C
Temperature: 140 °C
Yield: 33.8 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (100 mg, 0.27 mmol), 4-cyanobenzeneboronic acid (51 mg, 0.35 mmol), Pd(PPh3)4 (31 mg, 0.03 mmol) and Cs2CO3 (175 mg, 0.54 mmol) in dioxane (3 mL) and H2O (1.5 mL) was heated for 30 min by microwave irradiation at 140° C. The reaction solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was dissolved in DCM and the fine precipitate filtered and washed with DCM. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford 423 as a white solid (36 mg, 34%). LCMS (Method K): RT 2.30 min [M+H]+ 395. 1H NMR (DMSO-d6, 400 MHz): δ 8.04 (1H, s), 7.96-7.94 (2H, m), 7.72-7.67 (4H, m), 7.32 (2H, bs), 7.27, (1H, dd, J=8.0, 7.5 Hz), 7.07 (1H, dd, J=7.5, 1.0 Hz), 5.66 (1H, dq, J=7.0, 7.0 Hz), 3.28 (3H, s), 1.60 (3H, d, J=7.0 Hz)
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.O=S(Cl)[Cl:21].Cl>>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][Cl:21])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCC[C@H]1CC[C@H](CO)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC[C@H]1CC[C@H](CCl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Over an ice water bath, 37 g (0.22 mol) of trans-4-butylcyclohexyl methanol and 18 g (0.23 mol) of anhydrous pyridine were stirred and 32 g (0.27 mol) of SOCl2 was added drop-wise to the mixture. The resulting reaction product was stirred on a mantle heater at a temperature of between about 105 and 110° C. for 3 hours. The reaction product was cooled to room temperature and poured into a breaker containing concentrated hydrochloric acid and ice. The oily layer was separated out and the aqueous layer was extracted with chloroform. The two layers were combined and washed with an aqueous 10% hydrochloric acid solution and water. The chloroform was distilled off. The oily residue was distilled in a vacuum (b.p. 80° C./3 mmHg) to yield 38 g (0.20 mol) of trans-4-butylcyclohexyl chloromethane.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[CH:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[O:16])[CH3:7]>O1CCOCC1>[OH:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH:6]([CH3:7])[CH2:5][OH:4]
Reactant: COC(=O)C(C)Oc1ccccc1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(CO)Oc1ccccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Lithium borohydride (458 mg; 21 mmol; 3 eq.) was added to a solution of 2-(2-formyl-phenoxy)-propionic acid methyl ester (1.46 mg; 7 mmol; 1 eq.) in 1,4-dioxane (20 mL) and the resulting mixture was stirred at room temperature for 2 hours. After dilution with EA, the solution was washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (960 mg, 75%) as colourless oil. 1H NMR (DMSO-d6) δ 7.37-7.32 (m, 1H), 7.21-7.14 (m, 1H), 6.67 (d, J=8.3 Hz, 1H), 6.90 (dt, J=1.0, 7.4 Hz, 1H), 4.95 (t, J=5.7 Hz, 1H), 4.86 (t, J=5.7 Hz, 1H), 4.59-4.33 (m, 3H), 3.56-3.40 (m, 2H), 1.20 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:12][OH:13])=[CH:4][CH:3]=1.[CH2:16](I)[CH3:17].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:12][O:13][CH2:16][CH3:17])=[CH:14][CH:15]=1
Reactant: CCI
Reactant: OCC1CCCN1Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1CCCN1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[1-(4-Bromo-benzyl)-pyrrolidin-2-yl]-methanol (269 mg, 1.0 mmol) and EtI (234 mg, 1.5 mmol) is mixed at 0° C. in DMF (DMF) (10 mL). To this mixture is then added NaH (60 mg, 60% suspension in mineral oil, 1.5 mmol). The resulting mixture is stirred at room temperature for 1 h before aqueous workup. The resulting residue is directly used in the next step.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:17]([F:20])([F:19])[F:18])[CH:4]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([OH:16])=[O:15])[CH:6]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].CCN=C=NCCCN(C)C>C(Cl)Cl>[F:20][C:17]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[O:15])[CH:6]=[CH:1][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccnc1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
To a warmed (40° C.) suspension of niflumic acid (10.0 g, 35.4 mmol) and 4-nitrophenol (4.9 g, 35.4 mmol) in CH2Cl2 (80 mL) was added a suspension of EDCI (6.8 g, 35.4 mmol) in CH2Cl2 (20 mL). The reaction was stirred for 16 h, and then cooled to room temperature. The solution was quenched with water (50 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with water and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by trituration with Hex:CH2Cl2 to afford 4-Nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.5 g, 31%): LCMS RT: 4.03 min, MH+: 404.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20]2)[C:16]1=[O:31])(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:24]([N:19]1[CH2:18][CH:17]2[CH:21]([CH2:22][CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:31])[CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)OC1CCC2CN(Cc3ccccc3)CC2C1=O
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)C(O)CCC2CN(Cc3ccccc3)CC21
Temperature: 0 °C
Yield: 26.8 %

Procedure:
To a suspension of 27.6 g of 2-methoxyphenylmagnesium bromide in 60 cm' of tetrahydrofuran are added dropwise, at room temperature and with stirring, a solution of 4.7 g of (3aRS,5RS,7aSR)-5-acetoxy-2-benzyl-4-perhydroisoindolone in 90 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 3 hours, treated with 200 cm3 of saturated aqueous ammonium chloride solution and taken up in 200 cm3 of ethyl ether and 100 g of ice. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 80 cm3 of petroleum ether and then chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 1 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (95/5 by volume) and collecting 25 cm3 fractions. Fractions 14 to 21 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1.55 g of (3aRS,4RS,5RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol are obtained, melting at 140° C.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=1>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:24]1[CH:25]=[CH:26][C:22]([NH:21][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])=[N:23]1)[CH3:32]
Reactant: CCOC(=O)Cn1ccc(N)n1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Product: CCOC(=O)Cn1ccc(NC(=O)c2cc(-c3cc(F)cc(F)c3)cc(C)n2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using Ethyl (3-Amino-1-pyrazolyl)acetate instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=401.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC(Cl)(Cl)C.C(C1CC(=CN(C)C)C=C(C(C)(C)C)C=1O)(C)(C)C>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Reactant: C=C(C)C(=O)O
Agent: CN(C)C=C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)OCCCCOc1ccc(C(=O)O)cc1
Yield: 60 %

Procedure:
A solution of 282 g of 4-(4′-hydroxybutoxy)benzoic acid (1.34 mol), 325 ml of freshly distilled methacrylic acid (3.35 mol), 0.3 g of 2,6 di-tert-butyl-4-(dimethylaminomethylene)phenol (Ethanox® 703) and 23.7 g of p-toluenesulfonic acid in 1.1 l of 1,1,1-trichloroethane was refluxed for 10 hours on a water separator. The reaction mixture was cooled to 60° C.-70° C. and stirred into 2.51 of petroleum ether, and the precipitate was filtered off. After washing with petroleum ether, the precipitate was dried under reduced pressure at room temperature for 24 hours, giving 223.7 g of 4-(4′-methacryloxybutoxy)benzoic acid (yield 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[NH2:17].[N:22]#[C:23]Br>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[CH2:7][C:8]2[C:9](=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[N:17]=[C:23]1[NH2:22]
Reactant: COc1ccccc1CNCc1ccc([N+](=O)[O-])cc1N
Reactant: N#CBr
Product: COc1ccccc1CN1Cc2ccc([N+](=O)[O-])cc2N=C1N

Procedure:
The title compound was synthesized according to EXAMPLE 63, section 1.8 starting from 2-[(2-methoxybenzylamino)methyl]-5-nitrophenylamine by reaction with cyanogen bromide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH3:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH:30]=O)[CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH2:30][C:21]2[CH:20]=[C:19]([CH3:18])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Product: Cc1ccc(N2CCN(CCNCc3cc(C)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 39.3 %

Procedure:
Compound 25 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]2([CH3:20])[OH:13])=[C:4]([O:21][CH3:22])[N:3]=1.C1C(=O)N([I:30])C(=O)C1>C1COCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:30])[N:8]2[C@H:11]2[C@:12]([CH3:20])([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][OH:19])[O:17]2)=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Solvent: C1CCOC1
Product: COc1nc(N)nc2c1nc(I)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Temperature: 35 °C
Reaction time: 72 h
Yield: 46.5 %

Procedure:
2-Amino-6-methoxy-9-(2-C-methyl-β-D-ribofuranosyl)purine (1.5 g, 4.82 mmol) was suspended in dry THF (40 mL) and 1 mol eq. of NIS (1.1 g, 4.82 mmol) was added. The mixture was warmed to 35° C. and stirred in the dark for 3 days. After that time, solution was concentrated and the resulting solid was purified by silica gel chromatography using 1-4% (gradient) of MeOH in chloroform to yield 980 mg (47% yield) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[O:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=[O:5])[NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1nccs1)c1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
2-hydroxy-N-1,3-thiazol-2-ylbenzamide (502, 267.1 mg, 1.21 mmol) was placed into a 10 mL round bottom flask equipped with a stirbar and a septum with a dry nitrogen inlet. Dichloromethane (5.0 mL) and triethylamine (500 μL, 3.59 mmol) were added to form a light pink solution. Methanesulfonyl chloride (100 μL, 1.3 mmol) in dichloromethane (ca. 1.0 mL) was added dropwise to the stirring solution over ca. 30 seconds, and the reaction was stirred at room temperature for ca. 20 minutes before being quenched into saturated NaHCO3, and extracted with dichloromethane. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was recrystallized from hexanes/ethyl acetate to yield (284 mg, 78%) of 11 as a colorless crystalline solid. Example 11 (2-thiazol-2-ylcarbamoyl)phenyl methanesulfonate) has the empirical formula C11H10N2O4S and a molecular weight of 298.34.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[O:4].C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1>[Ir].C1(C)C=CC=CC=1>[C:3]([O:2][CH3:1])(=[O:4])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6]
Reactant: COC(=O)C(=O)c1ccccc1
Agent: [Ir]
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.5 %

Procedure:
Five percent Ir/C (38.4 mg, 0.01 mmole), methyl benzoyl formate (164.2 mg, 1.0 mmole), (−) cinchonidine (3.8 mg, 0.013 mmole) and toluene (5 ml) were mixed in an autoclave and were agitated for five hours at room temperature under hydrogen at a pressure of 50 atmospheres. The cross-linked Ir/C cluster composition was removedby filtration after the reaction. The filtrate was concentrated, and the residue was purified using PTLC to obtain (R)-methyl mandelate (145.4 mg, 87.5% yield). The asymmetric yield was 2.0% ee.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:1][C:2](=[O:3])[C:4]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=3[O:11]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(O)ccc1O2
Yield: 82.6 %

Procedure:
A solution of 2,5-dihydroxyacetophenone (15 g, 98 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g, 100 mmol) and pyrrolidine (21 mL, 260 mmol) in methanol (146 mL) was stirred at reflux for 23 h and concentrated under vacuum to produce a red oily crude material. The oily crude material was purified by ISCO (330 g column) chromatography using 27 to 80% ethyl acetate in hexane to afford the product of step 1 (27 g, 82%), mp 72-74° C. (ethyl acetate, ether and hexane), MS m/z=332 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH:25]([CH3:27])[CH3:26]
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)c(OC(C)C)c2s1
Yield: 81 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6, potassium carbonate and 2-bromopropane in DMF was reacted to give 0.046 g (81%) of the desired compound 11. 1H NMR (DMSO) δ 10.83 (br s, 1H, NH), 7.55 (d, 1H, J=8.5 Hz, ArH), 7.31 (d, 1H, J=8.6 Hz, ArH), 6.71 (br s, 1H, NH), 4.69 (hept, 1H, J=6.0 Hz, CH), 3.18 (m, 2H, CH2), 1.32 (d, 6H, J=6.1 Hz, CH3), 1.09 (t, 3H, J=7.2 Hz, CH3); LC/MS 358 (MH+); RP-HPLC RT 3.42 minutes.
Reaction SMILES: [C:1]([C:3]1[C:11]([C:12]#[N:13])=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].CC(C)([O-])C.[K+]>CO>[CH2:15]([N:8]1[N:7]=[C:6]2[CH:10]=[C:11]([C:12]#[N:13])[C:3]([C:1]#[N:2])=[CH:4][C:5]2=[N:9]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: N#Cc1cc2nn[nH]c2cc1C#N
Reactant: CCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCCn1nc2cc(C#N)c(C#N)cc2n1
Temperature: 25 °C

Procedure:
5,6-Dicyano-1H-benzotriazole (169 mg, 1.0 mmol), 1-bromooctane (195 mg, 1.0 mmol), potassium tert-butoxide (113 mg, 1 mmol), and methanol (5 mL) were mixed in a round-bottomed flask equipped with a condenser. The reaction mixture was refluxed overnight. The mixture was cooled down to room temperature and methanol was removed with a rotary evaporator. The resulting mixture was then extracted with CHCl3 and the organic phase was washed with water and dried over Na2SO4. The resulting off-white solid was purified by column chromatography (80 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.I[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(I)cc1
Reactant: O=C1NCC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(N2CC(c3cccc(C(F)(F)F)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)cc1
Temperature: 100 °C

Procedure:
A reaction tube charged with 1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (20.0 mg, 0.0462 mmol), 4-iodoanisole (13.0 mg, 0.0554 mmol), K3PO4 (19.6 mg, 0.0924 mmol), and catalytic amount of CuI is purged with nitrogen. 1,4-Dioxane (0.5 mL) and catalytic amount of trans-1,2-diaminocyclohexane are added via syringe. The reaction mixture is heated at 100° C. overnight, cooled down to room temperature, quenched with saturated NH4Cl aqueous solution (5 mL), and extracted with EtOAc (3×3 mL). The combined organic layer is concentrated and purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C29H22ClF3N2O3 (M+H+) 539.1, found 539.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=3.C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:84]1[CH2:89][CH2:88][O:87][CH2:86][CH2:85]1>>[O:87]1[CH2:88][CH2:89][N:84]([C:2]2[CH:3]=[C:4]([F:24])[C:5]3[N:6]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:7]4[C:12]([S:13][C:14]=3[CH:15]=2)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=4)[CH2:85][CH2:86]1
Reactant: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(Br)cc(F)c21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(N3CCOCC3)cc(F)c21

Procedure:
To a stirred solution of 3,7-dibromo-1-fluoro-10-Boc-phenothiazine (8) (290 mg, 0.6 mmol) in toluene (10 mL) Pd(dba)2 (17.3 mg, 0.03 mmol), BINAP (13.5 mg, 0.02 mmol), Cs2CO3 (390 mg, 1.2 mmol) and morpholine (70 mg, 0.8 mmol) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].Cl.[F:16][C:17]([F:33])([F:32])[C:18]1[CH:31]=[CH:30][C:21]([CH2:22][NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])=[CH:20][CH:19]=1>C(O)C>[ClH:14].[NH2:29][C:27]1[NH:26][C:24]([NH:23][CH2:22][C:21]2[CH:30]=[CH:31][C:18]([C:17]([F:16])([F:32])[F:33])=[CH:19][CH:20]=2)=[N:25][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:28]=1
Reactant: CCCCCCCCCCCC=O
Reactant: N=C(N)NC(=N)NCc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCC1N=C(N)NC(NCc2ccc(C(F)(F)F)cc2)=N1

Procedure:
100 ml of ethanol, 5.6 ml (25.4 mmol) of 1-dodecanal and 0.7 ml of concentrated hydrochloric acid were added to 5.0 g (16.9 mmol) of N1-(4-trifluoromethylbenzyl)-biguanide hydrochloride, and the mixture was refluxed for 26 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)). An aqueous acetonitrile solution was added to the eluate to obtain 2.4 g of colorless crystals having a melting point of 144 to 149° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:41][CH2:40][C:32]2([O:36][C@H:35]3[CH2:37][CH2:38][CH2:39][C@H:34]3[O:33]2)[CH2:31][CH2:30]1.C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[OH:36][C@H:35]1[CH2:37][CH2:38][CH2:39][C@H:34]1[O:33][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:41][CH2:40]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2CCC[C@H]2O3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[C@@H]3CCC[C@@H]3O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydro-3a′H-spiro[cyclohexane-1,2′-cyclopenta[d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.2 g), sodium cyanoborohydride (0.65 g), boron trifluoride-diethyl ether complex (1.3 mL) and tetrahydrofuran (30 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.82 g, 72%).