Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Sodium borohydride (2 mg, 0.053 mmol), followed by MeOH (0.1 mL), was added to a solution of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (14 mg, 0.037 mmol) in CH2Cl2 (0.5 mL) at 0° C. The mixture was allowed to warm to rt. After 30 min at rt, the reaction was quenched with aqueous HCl (1.0 M, 1 mL) and extracted with EtOAc (3×5 mL). The combined organic phase was washed with brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 11 mg (78%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][O:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COc1cc(C)ccc1O
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCCOc1ccc(C)cc1OC

Procedure:
A stirred solution of 2-methoxy-4-methylphenol (5.00 g, 36.2 mmol), 1-bromo-3-methoxypropane (7.06 g, 45.2 mmol) and anhydrous K2CO3 (7.50 g, 64.3 mmol) is refluxed overnight. After cooling, volatiles are removed under reduced pressure, the residue is taken up in water and extracted with AcOEt. The combined organics are washed with brine, dried (Na2SO4) and concentrated. After silica gel chromatography (hexane/AcOEt 3:1) the title compound is obtained as colorless liquid. TLC, Rf (hexane/AcOEt 2:1)=0.34. MS: 211.0 [M+H]+. 1H-NMR (CDCl3): δ 2.13 (m, 2H), 2.33 (s, 3H), 3.38 (s, 3H), 3.61 (m, 2H), 3.88 (s, 3H), 4.12 (m, 2H), 6.7-6.85 (m, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C@@H:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:10])[CH3:9])C.[Li+].[OH-]>C1COCC1.O>[C:8]([NH:7][C@H:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][C:4]([OH:17])=[O:3])(=[O:10])[CH3:9]
Reactant: CCOC(=O)C[C@H](NC(C)=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](CC(=O)O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-14 (0.049 g, 0.102 mmol) in THF (1 mL) and water (0.3 mL) at 0° C. was added 1M LiOH (0.112 ml, 0.112 mmol). After warming to ambient temperature and stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 ethyl acetate/EtOH/water/NH4OH to give 3-15 as a colorless foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([O:16]C)=[O:15])[NH:10][CH:9]=[CH:8]2)=[O:4].C(O)C.[OH-].[Na+].Cl>O>[NH:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: COC(=O)c1cc2cc[nH]c2cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc[nH]c2cc1C(=O)O
Yield: 86.5 %

Procedure:
To a stirred solution of the dimethyl ester produced in step d (1.14 g, 4.9 mmol) in a 5:1 mixture of ethanol:water (12 ml) was added solid sodium hydroxide (0.49 g, 12.4 mmol). The solution was stirred at a gentle reflux for 3 h. The solution was acidified on cooling to pH2 with hydrochloric acid and then evaporated. The residue was azeotroped with ethanol and then toluene and dried under vacuum. The residue was then extracted with hot acetone (5×20 ml) and the combined extracts were evaporated to leave the title compound (870 mg).
Reaction SMILES: [CH2:1]([Si:9]([CH3:12])(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:13]1[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:1]([Si:9]([CH3:12])([CH:24]1[C:25]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:25]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Si](C)(Cl)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Product: CCCCCCCC[Si](C)(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-Octylmethyldichlorosilane (32.68 g, 0.144 mol) and 200 mL of dry THF were charged to a one liter Schlenk flask equipped with an addition funnel. Fluorene anion (49.50 g, 0.288 mol) was dissolved in approximately 200 mL of dry THF and charged to the addition funnel. The temperature of the stirring solution was lowered to -20° C. under positive nitrogen pressure. The fluorene anion was added dropwise over two hours. After the addition of anion was complete the reaction mixture was allowed to warm to room temperature. The solution was then stirred overnight. The solution was washed with three 200 mL aliquots of water, retaining the organic layer after each washing. The organic layer was dried with magnesium sulfate and filtered. The product was recrystallized from a diethyl ether/methanol solution. The yield of this reaction is 10%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CC(C)O
Product: Cc1cc(N2CCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
0.815 g (5 mmol) of 2,4-dichloro-6-methylpyrimidine dissolved in in 5 ml isopropanol were treated under ice-cooling dropwise with 0.71 g (10 mmol) pyrrolidine. The mixture was stirred for 1 h at RT the concentrated in vacuo. The residue was purified on a silica gel chromatography column with CH2Cl2/AcOEt (4/1) as eluent to give 0.72 g (73%) of the desired 2-chloro-4-methyl-6-pyrrolidin-1-yl-pyrimidine as an off-white solid. EI mass spectrum, m/e: 197 (M calculated for C9H12N3Cl: 197).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:31][C:32]#[N:33])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (300 mg, 0.66 mmol), prepared in the previous step, bromoacetonitrile (56 μL, 0.80 mmol) and potassium carbonate (460 mg, 3.32 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 18 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (324 mg, 99%) as an off-white solid, mp154-157° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:26])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.[I:38][C:39]1[CH:47]=[C:43]([C:44](O)=[O:45])[C:42]([NH2:48])=[CH:41][CH:40]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:26])[C@H:6]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:44](=[O:45])[C:43]2[CH:47]=[C:39]([I:38])[CH:40]=[CH:41][C:42]=2[NH2:48])=[CH:23][CH:24]=1)[NH:7][C:8](=[O:17])[C:9]1[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=1[Cl:15])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)[C@H](Cc1ccc(NC(=O)c2cc(I)ccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Amino-N-(2,6-dichlorobenzoyl)-L-phenylalanine Isopropylester, 1-hydroxybenzotriazole monohydrate (11.5 g) and 5-iodoanthranilic acid (17.8 g) were dissolved in dimethylformamide (200 mL) and cooled down to 0° C. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.7 g) was added thereto and stirred at room temperature for 16 hours. The organic layer wherein ethyl acetate (1 L) was added was washed with 0.1N sodium hydroxide aqueous solution (200 mL, 100 mL), water (100 mL), 0.1N hydrochloric acid (200 mL) and saturated aqueous solution of sodium chloride (200 mL, 100 mL), respectively. After drying the organic layer over anhydrous sodium sulfate and removing the solvent, a solid material obtained from a mixed solvent of methylene chloride and hexane was filtered to obtain the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: COC1(c2cc(F)cc(F)c2)CCNC1
Yield: 35.5 %

Procedure:
Preparation according to Example 1. (+)-1-benzyl-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.35 g, 1.15 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.50 ml, 4.6 mmol) refluxed for 2 h, and methanol (10 ml) reflux 1 h Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.087 g, 35%). [a]D=+2.1° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 185-187° C. MS m/z (rel. intensity, 70 eV) 213 (M+, 1), 198 (54), 183 (bp), 171 (85), 141 (47).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[C:9]1([CH2:18][CH2:19][OH:20])[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:8])([CH3:7])[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:18][CH2:19][OH:20])=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCc1ccc(CCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)cc1
Reaction time: 0.75 h

Procedure:
tert-Butyldimethylchlorosilane (9.68 mL) was added to a solution of 2,2′-(1,4-phenylene)diethanol (example 5, step a) (8.64 g) and imidazole (10.21 g) in dry DMF (100 mL) cooled in an ice bath. After 45 min, the reaction mixture was diluted with ethyl acetate, washed three times with water and evaporated in vacuo. Purification was by silica gel chromatography, eluting with 5:1 isohexane:ethyl acetate to give the subtitled compound as a colourless oil. Yield 6.20 g.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(#N)C>[CH2:38]([O:37][C:35]([CH2:34][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (6.0 g) in acetonitrile (100 ml) were added ethyl bromoacetate (7.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6.4 ml). The resulting mixture was stirred at room temperature for one hour, and the reaction was stopped by addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford the title compound as a yellow amorphous solid (6.08 g, yield: 84%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])([O-:10])=[O:9]
Reactant: C[C@H](N)CO
Reactant: O=[N+]([O-])c1ccncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CO)Nc1cnccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 3-fluoro-4-nitropyridine (0.400 mL, 4.05 mmol), (S)-2-aminopropane-1-ol (0.347 mL, 4.46 mmol) and potassium carbonate (0.616 g, 4.46 mmol) in DMF (5.0 mL) was stirred at 60° C. for 2 h. Water was added and the mixture stirred at room temperature to afford a precipitate. The mixture was filtered to afford an orange solid. The filtrate was extracted with dichloromethane. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtrate, and concentrated to afford an orange solid. The solids were combined and purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 0-10% methanol-dichloromethane) to afford (S)-2-(4-nitropyridin-3-ylamino)propane-1-ol (0.668 g, 84%) as an orange solid. MS (ESI, pos. ion) m/z 198.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[CH:26]([CH:27]=[CH:28][C:29](=[O:37])[CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:25][CH2:24][CH:23]1[OH:38]>CC(C)=O.O.[Cr]>[O:38]=[C:23]1[CH2:24][CH2:25][CH:26]([CH:27]=[CH:28][C:29](=[O:37])[CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])[CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([OH:3])=[O:14]
Reactant: CCCCC(CC)C(=O)C=CC1CCC(O)C1CCCCCCCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC(CC)C(=O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Reaction time: 1 h

Procedure:
8N Jones' reagent (0.4 ml.) was added to a stirred solution of 2-(7-hydroxyheptyl)-3-(4-ethyl-3-oxo-1-octenyl)cyclopentanol (0.42 g.) in acetone (4 ml.) at below 20°C. at such a rate that the deep red coloration caused by the addition of one drop of reagent had changed to green before addition of the next drop. The reaction mixture was diluted with sufficient water to dissolve the precipitated chromium salts and then extracted three times with diethyl ether. The combined ether extracts were washed with 2N aqueous sulphuric acid and then added to 10% aqueous sodium carbonate (50 ml.) and stirred for 1 hour. The aqueous layer was separated and covered with a layer of diethyl ether and concentrated hydrochloric acid added dropwise until the pH was 1. The ether layer was separated and the aqueous layer again extracted with diethyl ether. The combined extracts were dried over magnesium sulphate and the ether was removed in vacuo to give 7-[2-oxo-5-(4-ethyl-3-oxo- 1-octenyl)cyclopentyl]-heptanoic acid (0.12 g.), νmax 1620 cm-1, 1680 cm-1, 1700 cm-1 and 1730 cm-1 (liquid film).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2ccnc2)cc1
Reaction time: 4 h
Yield: 89 %

Procedure:
1-(4-nitrophenyl)-1H-imidazole (4.4 g; 23.5 mmoles) is put in solution in anhydrous methanol (140 ml) and palladium on carbon (0.44 g) is added to the medium. The reaction medium is placed under hydrogen for 4 hours. The catalyst is filtered off and the solvent is evapored to dryness. The expected product is obtained in a virtually pure state with a yield of 89% (3.3 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH3:12][CH:13]([N:18]=[C:19]=[S:20])[C:14]([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:19]([NH:18][CH:13]([CH3:12])[C:14]([CH3:17])([CH3:16])[CH3:15])=[S:20])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: CC(N=C=S)C(C)(C)C
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(NC(=S)NC(C)C(C)(C)C)cn1
Temperature: 50 °C
Reaction time: 15 h
Yield: 79596.1 %

Procedure:
To a solution of 2-acetylamino-5-aminopyridine (150 mg, 0.99 mmol) in pyridine (1.5 ml), 213 mg (1.49 mmol) of 1,2,2-trimethylpropyl isothiocyanate was added dropwise, followed by stirring at room temperature for 22 hours, at 50° C. for 5 hours and further at room temperature for 15 hours. Then, the solvent was removed by distillation under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain 232 g of the intended product as a flesh-colored powder (yield: 79%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([C@H:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:46]([C:53](=[O:61])[C:54]3[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=3)[C@@H:45]([CH3:62])[CH2:44]2)[C:40](=[O:42])[CH3:41])=[CH:35][CH:34]=1.[CH2:63]([O:65][C:66]([CH:68]1[CH2:73][CH2:72][CH:71](O)[CH2:70][CH2:69]1)=[O:67])[CH3:64]>C1COCC1>[CH2:63]([O:65][C:66]([CH:68]1[CH2:73][CH2:72][CH:71]([O:60][C:57]2[CH:56]=[CH:55][C:54]([C:53]([N:46]3[C:47]4[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=4)[C@H:43]([N:39]([C:40](=[O:42])[CH3:41])[C:36]4[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=4)[CH2:44][C@@H:45]3[CH3:62])=[O:61])=[CH:59][CH:58]=2)[CH2:70][CH2:69]1)=[O:67])[CH3:64]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(Oc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To a solution of diethyl azodicarboxylate (120 mg) in 5 ml THF at 0° C., was added PPh3 (181 mg). The mixture was stirred for 10 min at 0° C. Then (2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (200 mg) was added. The mixture was stirred for 20 min at 0° C. 4-Hydroxy-cyclohexanecarboxylic acid ethyl ester (80 mg) was added. The final reaction mixture was stirred for overnight at RT. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30/70 hexanes/ethyl acetate gradient) to afford pure (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-cyclohexanecarboxylic acid ethyl ester (100 mg, 37%).
Reaction SMILES: C([C:3]1[C:11]([O:12][CH2:13][C@H:14]([NH:16][C:17](=O)OC(C)(C)C)[CH3:15])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])=O.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:15][C@H:14]1[NH:16][CH2:17][C:3]2=[C:4]3[C:8](=[CH:9][CH:10]=[C:11]2[O:12][CH2:13]1)[N:7]([S:24]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26])[CH:6]=[CH:5]3
Reactant: C[C@H](COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1COc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
tert-Butyl ((1R)-2-{[4-formyl-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}-1-methylethyl)carbamate (Intermediate 19, 0.040 g, 0.087 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The mixture was stirred for 1 hour at room temperature and evaporated. The residue was dissolved in THF (2 mL) and sodium triacetoxyborohydride (37.0 mg, 0.176 mmol) was added. The mixture was stirred for 1 hour, evaporated and purified by flash chromatography using 2.5%-5% MeOH in DCM as the eluent to give the title compound (25 mg) as a white solid. MS m/z 343 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:24][C:25]([OH:30])([CH2:27][C:28]#[CH:29])[CH3:26]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:29]#[C:28][CH2:27][C:25]([CH3:26])([OH:30])[CH3:24])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: C#CCC(C)(C)O
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#CCC(C)(C)O)c3c(Cl)nc(N)nc32)c1C

Procedure:
Sonogashira coupling of 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine with 2-methylpent-4-yn-2-ol (H. Zhang et al., Tetrahedron Lett. 1999, 40, 7851) according to the general procedure A gave the title compound, as a solid. Mp=163-165° C. HPLC Rt=4.98 min.
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C=O)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:2][CH3:1])[CH:11]=1
Reactant: C[S-]
Reactant: BrCc1cccc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
Sodium thiomethoxide (0.616 g, 8.8 mmol) was added to DMF (8 mL) and cooled to 0° C. To this solution was added 1-bromo-3-bromomethyl-benzene (2 g, 8 mmol). The mixture was allowed to warm to rt and stir for 18 h. The mixture was then poured into cold water (50 mL) and extracted with EtOAc (3×20 mL). The organics were combined and dried with sodium sulfate. The solution was concentrated in vacuo to yield the crude product, which was then purified via flash chromatography (5% ethyl acetate-hexanes) to yield 1.3 g (68.5%) of 1-bromo-3-methylsulfanylmethyl-benzene as a pure product. 1H-NMR (methylene chloride-d2) δ 7.48-7.47 (m, 1H), 7.392 (dt, J=7.9, 1.5 Hz, 1H), 7.28-7.207 (m, 2H), 3.64 (s, 2H), 1.99 (s, 3H); LC-MS RT: 3.70, [M+H]+: 354.1.