Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5]([CH:15]([CH3:17])[CH3:16])[N:4]=1)=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:16][CH:15]([N:5]1[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:7][C:3]([CH2:1][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4]1)[CH3:17]
Reactant: CC(C)n1nc(C=O)cc1C(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)n1nc(CN2CCOCC2)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 3-formyl-1-(1-methylethyl)-1H-pyrazole-5-carboxylate (491 mg) was dissolved in anhydrous DCM (20 ml), morpholine (0.198 ml) was added and the mixture was stirred under nitrogen for 2 h at RT. Sodium triacetoxyborohydride (873 mg) was added and the mixture was stirred at RT for 18 h. Sodium bicarbonate solution (50 ml) and DCM (50 ml) were added and separated and the aqueous layer was re-extracted with DCM (2×50 ml) and separated by hydrophobic frit. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (50 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 30 mins to give the title compound (628 mg) as a colourless oil.
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([CH:8]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
A solution of 14.2 g (33.9 mmol) of N-(t-butyl)-4-(benzyloxycarbonyl)-1-(t-butyloxycarbonyl)piperazine-2-carboxamide in 100 ml of dichloromethane was treated with 20 ml of trifluoroacetic acid. The resulting solution was stirred at ambient temperature for 3 h, concentrated in vacuo, and treated with 800 ml of ethyl acetate. The solution was washed with 1 N NaOH. The aqueous layer was extracted with two portions of ethyl acetate, and the combined organic layers were washed with saturated brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using first 2% then 4% methanol in chloroform provided 8.42 g (78%) of the desired compound. 1H NMR (CDCl3)δ1.34 (s, 9H), 2.8 (m, 1H), 3.0 (m, 3H), 3.21 (dd, J=9, 4 Hz, 1H), 3.9 (m, 1H), 4.2 (m, 1H), 5.14 (AA', 2H), 6.6 (br, 1H), 7.3-7.4 (m, 5H). Mass spectrum: (M+H)+ =320.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=2)[CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21]CC=C)=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:25])=[C:11]2[CH3:26])[CH2:5][CH2:4]1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=2)[CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:25])=[C:11]2[CH3:26])[CH2:4][CH2:5]1)#[N:2]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C2(C#N)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: Cc1c(C)n(Cc2cccc(C3(C#N)CC3)c2)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of allyl 1-(3-(1-cyanocyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (375 mg, 0.98 mmol) and morpholine (0.8 mL, 9.2 mmol) in THF (8 mL) was degassed and then Pd(PPh3)4 (117 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was dissolved in Methanol and acidified to pH 4. The precipitate was collected and washed with water to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:14]([N:35]1[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]1)=[O:16])([CH3:17])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: OC1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCC(O)CC1)O2
Yield: 33.3 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 370 mg CDI (2.28 mmol) and 222 mg 4-hydroxypiperidine (2.20 mmol) produced 222 mg of a (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-hydroxypiperidin-1-yl)methanone as a white foam.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][CH:13]([CH2:17][C:18]#[CH:19])[C:14](=[O:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[S:1]([O:12][CH:13]([CH2:17][C:18]#[CH:19])[C:14](=[O:16])[CH3:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CCC(O)C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC(OS(=O)(=O)c1ccc(C)cc1)C(C)=O
Reaction time: 2.5 h
Yield: 55.3 %

Procedure:
Tosyl chloride (3.81 g) was added to a solution of 3-hydroxy-5-hexyn-2-one (2.24 g) and triethylamine (2.424 g) in methylene chloride (20 ml) under ice-cooling. After being stirred for 2.5 hours, the mixture was washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (60 g) using methylene chloride as an eluent to give an oil of 3-tosyloxy-5-hexyn-2-one (2.94 g).
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=[O:5])#[N:2].[NH2:9][C:10]([NH2:12])=[S:11].C[O-].[Na+]>>[NH2:2][C:1]1[CH:3]=[C:4]([OH:5])[N:12]=[C:10]([SH:11])[N:9]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Product: Nc1cc(O)nc(S)n1

Procedure:
According to a method described by Baker, Joseph, and Schaub, J. Org. Chem. 19, p. 631 (1954) ethyl cyanoacetate is reacted with thiourea in the presence of sodium methoxide to give 4-amino-6-hydroxy-2-mercaptopyrimidine which is methylated in situ to obtain 4-amino-6-hydroxy-2-(methylthio)pyrimidine. Chlorination of the latter compound with phosphorus oxychloride in dimethylaniline gives the desired 4-amino-6-chloro-2-(methylthio)pyrimidine. Yields using this method are uncertain.
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([C:6](O)=O)=[N:2]1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[NH2:19])[NH:15][C:14](=[O:20])[C:13]2([CH3:22])[CH3:21]>>[CH3:21][C:13]1([CH3:22])[C:12]2[C:16](=[CH:17][C:18]3[NH:19][C:6]([C:3]4[CH:4]=[N:5][S:1][N:2]=4)=[N:9][C:10]=3[CH:11]=2)[NH:15][C:14]1=[O:20]
Reactant: O=C(O)c1cnsn1
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4cnsn4)nc3cc21
Temperature: 0 °C

Procedure:
2.0 g. (15.3 mmol) 1,2,5-thiadiazole-3-carboxylic acid and 2.6 g. (13.6 mmol) 5,6-diamino-3,3-dimethyl-indolin-2-one are heated in 40 ml. polyphosphoric acid under an atmosphere of nitrogen for 2 hours at 160° C. The warm solution is poured on to ice water, worked up and the crystals obtained are filtered off with suction. The residue is again suspended in water, neutralised with an aqueous solution of ammonia, filtered off with suction and recrystallised from methanol with the addition of charcoal. Yield: 2.6 g. (66% of theory); m.p. >300° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si](C)(C)C.[CH2:25](O)[CH2:26][OH:27]>>[CH2:26]1[O:27][C:11]2([CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[O:13][CH2:25]1
Reactant: OCCO
Reactant: O=C1CC(c2ccccc2)NC(c2ccccc2)C1
Agent: C[Si](C)(C)Cl
Product: c1ccc(C2CC3(CC(c4ccccc4)N2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a stirred suspension of 10.0 g (40 mmol) of 2,6-diphenyl-4-piperidone in 150 mL of ethylene glycol chilled to 0° C. is added 35 mL (275 mmol) of chlorotrimethylsilane over a one-hour period. The reaction mixture is warmed to room temperature and stirred for 15 hours. The reaction mixture is then quenched by carefully pouring it into 600 mL of saturated aqueous sodium bicarbonate solution. The product is extracted into ether (4×200 mL). The ether solution is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The residue is recrystallized from methanol to yield 8.1 g (69%) of the title compound as a white solid, melting at 125°-127° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21]S(C1C=CC(C)=CC=1)(=O)=O.[CH3:32][O:33][C:34](=[O:53])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][C:38]=1[CH2:44][CH2:45][NH:46][C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:32][O:33][C:34](=[O:53])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:21][CH2:20][CH2:19][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:39][C:38]=1[CH2:44][CH2:45][NH:46][C:47]([O:49][CH:50]([CH3:51])[CH3:52])=[O:48]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(N4CCOCC4)cc3)oc2C)cc1
Reactant: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(N4CCOCC4)cc3)oc2C)cc1CCNC(=O)OC(C)C
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[5-methyl-2-(4-morpholin-4-yl-phenyl)-oxazol-4-yl]-ethyl ester (44 mg, 0.10 mmol; Preparation 5) and 3-[4-hydroxy-2-(2-isopropoxycarbonylamino-ethyl)-phenyl]-propionic acid methyl ester (31 mg, 0.10 mmol) in DMF (1.0 mL) was treated with K2CO3 (30 mg). The resulting suspension was stirred at 65° C. for 16 h and diluted with water (10 mL). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified using silica gel chromatography (50% EtOAc/hexanes to yield 3-(2-(2-isopropoxycarbonylamino-ethyl)-4-{2-[5-methyl-2-(4-morpholin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]C)=O)[N:3]=[CH:2]1.[F:10][C:11]1[CH:12]=[C:13]([Mg]Br)[CH:14]=[C:15]([F:17])[CH:16]=1>O1CCCC1>[F:10][C:11]1[CH:12]=[C:13]([C:6]([C:13]2[CH:12]=[C:11]([F:10])[CH:16]=[C:15]([F:17])[CH:14]=2)([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)[OH:8])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: COC(=O)c1c[nH]cn1
Solvent: C1CCOC1
Product: OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)c1c[nH]cn1
Yield: 73 %

Procedure:
Methyl 4-imidazolecarboxylate 0.80 g (6.34 mmol) was placed in a flask and under argon 50 ml (25 mmol) of a 0.5M 3,5-difluorophenylmagnesium bromide solution in tetrahydrofuran were added. The mixture was refluxed for 2 hours and then most of the solvent was evaporated. Water was added with cooling, and the mixture was extracted twice with ethyl acetate. The combined organic extracts were concentrated and the residue was purified by flash chromatography (silica gel, heptane/ethyl acetate 8:2) to yield 1.5 g (73%) of bis-(3,5-difluoro-phenyl)-(1H-imidazol-4-yl)-methanol as a white solid; MS (ISP): 305.1 ((M-OH)+); 323.4 ((M+H)+.).
Reaction SMILES: S(=O)(=O)(O)O.CO.[NH2:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24][CH3:25])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:26](=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24][CH3:25])=[CH:14][C:10]=1[C:11]([O:13][CH3:26])=[O:12]
Reactant: COc1cc(C(=O)O)c(N)cc1-c1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(OC)c(-c2ccccc2)cc1N
Temperature: 25 °C

Procedure:
Under ice-cooling, concentrated sulfuric acid (1 mL) was added to a methanol (10 mL) suspension of the obtained 2-amino-5-methoxy-4-phenylbenzoic acid, followed by heating to reflux for 6 hours. The reaction mixture was cooled to room temperature and adjusted to a pH of 8.0 with a saturated aqueous solution of sodium bicarbonate, and then chloroform was added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.24 g of methyl 2-amino-5-methoxy-4-phenylbenzoate as a brown solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[C:16]([Si](C)(C)C)([F:19])([F:18])[F:17]>C(#N)C.C(OCC)C>[F:17][C:16]([F:19])([F:18])[C:8](=[O:9])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:12][C:11]([OH:10])=[O:13]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(O)C=C(C(=O)C(F)(F)F)c1ccccc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a stirred solution of phenylmaleic anhydride (18.7 g, 0.107 mol) in acetonitrile (180 ml) at 0° C. (ice/water/sodium chloride bath—temperature of the bath −10° C.), was added CsF (18.6 g, 0.127 mol), followed by the drop-wise addition of CF3SiMe3 (18.58 ml, 0.127 mol), under nitrogen. The reaction mixture was stirred for 1 h, and was then diluted with diethyl ether and extracted with 2M sodium hydroxide (200 ml). The separated aqueous layer was acidified to pH=1 by the addition of conc. hydrochloric acid. This mixture was extracted with dichloromethane. The separated organic layer was dried (Na2SO4), and the solvent was evaporated in vacuo to yield D1 (22.6 g, 86%) as a mixture of isomers (80/11 ratio by LCMS). C11H7F3O3 requires 244; Found 243 (M-H−).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH:21]1([CH2:24][NH2:25])[CH2:23][CH2:22]1.CN1CCOCC1>CO>[CH:21]1([CH2:24][NH:25][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[CH2:23][CH2:22]1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCC1CC1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCC3CC3)cc2s1
Yield: 24.8 %

Procedure:
the title compound (27 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), C-cyclopropylmethylamine (53 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 364.5 (M+1, 100%). Yield=21%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([Cl:12])[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(Cl)c1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-methyl-benzoic acid (6.45 g, 30 mmol,), N-chlorosuccinimide (4.67 g, 35 mmol), and palladium (II) acetate (0.675 g, 3 mmol) in dry DMF (35 mL) was heated under a nitrogen atmosphere at 100° C. for 36 h. After this time, the reaction mixture was cooled to ambient temperature and poured into water. The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic extracts washed with aqueous sodium thiosulphate (30 mL) and then brine (30 mL). The remaining organic solution was dried over anhydrous MgSO4, filtered, and concentrated to give 4-bromo-2-chloro-6-methyl-benzoic acid. The product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1>O>[Cl:11][C:4]1[N:3]=[C:2]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1N1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
2,6-Dichloro-3-nitropyridine (10 g, 51.8 mmol) and sodium carbonate (8.8 g, 82.9 mmol) were added to anhydrous N,N-dimethylformamide (250 ml). 1,2,3,4-tetrahydroisoquinoline (7.14 ml, 82.9 mmol) was added at 0° C. to the reaction mixture, which was then stirred for 2 hours at 0° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 10 g of the titled compound as yellow solid. (Yield: 81%).
Reaction SMILES: [CH2:1]([S:3][C:4](SCC)=[C:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:8])[CH3:2].[O-:26]Cl.[Na+]>C(O)(C(F)(F)F)=O.O>[CH2:1]([S:3][C:4](=[O:26])[CH:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCSC(SCC)=C(CC(=O)c1ccc(C(F)(F)F)cc1)C(F)(F)F
Reactant: [O-]Cl
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCSC(=O)C(CC(=O)c1ccc(C(F)(F)F)cc1)C(F)(F)F

Procedure:
A mixture of 4,4-bis-ethylsulfanyl-3-trifluoromethyl-1-(4-trifluoromethyl-phenyl)-but-3-en-1-one (example C.26 step 3) (36.96 g, 92 mmol) in TFA (54.3 mL) and water (5.8 mL) was refluxed for 18 h under nitrogen atmosphere, the exhaust of the reaction was passed through a NaOCl solution to trap the liberated ethyl mercaptane. The volatiles were evaporated and the mixture was diluted with water and extracted with TBME, the organic layer was washed with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a brown oil (31.2 g, 95%), which was used without further purification [according to J. Fluorine Chem. 2001, 107, 281.]. MS (EI) 339.0 [(M−F)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]2[N:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)=[CH:21][C:12]3=2)=[CH:5][CH:4]=1.CO>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]2[N:18]=[CH:19][C:20]([C:22]4[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=4)=[CH:21][C:12]3=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc([N+](=O)[O-])c5)cc4c3c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc(N)c5)cc4c3c2)cc1
Reaction time: 16 h
Yield: 77.8 %

Procedure:
6-(4-methoxyphenyl)-3-(3-nitrophenyl)-9H-pyrido[2,3-b]indole (35 mg, 0.09 mmol, 1 equiv.), is dissolved in anhydrous THF (1 ml), MeOH (8 ml), and palladium on charcoal (10 mg, 0.009 mmol, 0.1 equiv.), are then added in an autoclave which is flushed with argon and then pressurized with H2 (10 bar). The reaction is carried out at room temperature for 16 hours. The mixture is then filtered over Mite and washed with AcOEt. The green solid obtained is washed with methanol to afford the product as a slightly green solid (26 mg, 0.07 mmol), in 79% yield.
Reaction SMILES: I[CH2:2][I:3].[NH2:4][C:5]1[N:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])[C:8]([CH2:15][O:16][CH2:17][CH3:18])=[N:7][C:6]=1C#N.N(OCCC(C)C)=O>C(Cl)(Cl)Cl>[CH2:17]([O:16][CH2:15][C:8]1[N:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])[C:2]([I:3])=[C:6]([C:5]#[N:4])[N:7]=1)[CH3:18]
Reactant: CCOCc1nc(C#N)c(N)n1CC(C)(C)O
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc(C#N)c(I)n1CC(C)(C)O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
Diiodomethane (14.5 ml, 180 mmol) was added under argon with stirring to a suspension of 5-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile (4.36 g, 18.3 mmol) in chloroform (170 mL). The reaction mixture was heated to 80° C., a solution of isoamyl nitrite (9.86 ml, 73.2 mmol) in chloroform (30 mL) was added with a syringe pump over a period of 40 min and the mixture was stirred for another 30 min at 80° C. After cooling to room temperature the mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 20% to 50% ethyl acetate in heptane) to give the title compound (3.66 g, 57%) as brown oil; LC-MS (UV peak area, ESI) 90%, 350.0374 (MH+).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.Br[CH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([O:16][CH3:17])=[O:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([O:1][CH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([O:16][CH3:17])=[O:15])[N:7]=1
Reactant: CCCCC(Br)C(=O)OC
Reactant: COc1cc(OC)nc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(Oc1nc(OC)cc(OC)n1)C(=O)OC
Temperature: 25 °C
Yield: 73.7 %

Procedure:
3.5 g of 2-hydroxy-4,6-dimethoxypyrimidine, 4.7 g of methyl 2-bromohexanoate, 50 ml of N,N-dimethylformamide and 3.3 g of anhydrous potassium carbonate were stirred at a temperature of from 85° to 90° C. for 3 hours. The reaction mixture was cooled to room temperature and then diluted with water. This aqueous mixture was extracted with ethyl ether. The ethyl ether extract was washed with water and dried. Then, ethyl ether was removed by distillation under reduced pressure to obtain a slightly yellow oily substance. The slightly yellow oily substance was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =6/1) to obtain 4.7 g of the desired product.
Reaction SMILES: C(OC([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:31])=O)(C)(C)C.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([N:11]3[CH2:10][CH:9]([CH3:31])[NH:8][CH:13]([CH3:14])[CH2:12]3)=[O:30])=[CH:17][CH:18]=2)=[CH:27][C:26]=1[O:28][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]
Reactant: Cc1ccccc1CBr
Reactant: C[C@@H]1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1COc1cc(-c2ccc(C(=O)N3CC(C)NC(C)C3)cc2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a mixture of (2R,6S)-4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-bromomethyl-2-methyl-benzene (47 mg, 0.25 mmol) in DMF(2 mL) was added 2 M Cs2CO3 (0.35 mL, 0.7 mmol) followed by water (0.5 mL). The mixture was stirred at room temperature overnight. LCMS showed the reaction was completed, DMF was removed, followed by addition of 4 N HCl in dioxane (2 mL) and the reaction was stirred at room temperature for 3 hr. The volatiles were removed followed by addition of methanol. This solution was purified by prep-HPLC to afford {4-[6-Amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone (47 mg, yield 46.6%).