Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](/[CH:9]=[C:10](\[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)/[C:11]([F:14])([F:13])[F:12])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]([CH2:34][Si](C)(C)C)[CH2:31]OC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O>[Cl-:21].[CH2:23]([NH+:30]1[CH2:34][CH:9]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)([C:11]([F:14])([F:12])[F:13])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=S(/C=C(\c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(c1ccccc1)C1C[NH+](Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Product: [Cl-]
Yield: 170.9 %

Procedure:
Trifluoroacetic acid (9 μL, 128 μmol) was added to (1E)-2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfoxide (1.00 g, 93% purity, 2.56 mmol) in toluene (1.28 mL). N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (911 mg, 3.84 mmol) in toluene (8.75 mL) was added at room temperature over one hour. The solvents of the reaction mixture were removed and the crude product was taken up in iso-propanol and the pH was adjusted to 3 with 3.6% hydrochloric acid. After two hours the formed crystals were filtered off. 1-Benzyl-3-(3,5-dichlorophenyl)-4-(phenylsulfinyl)-3-(trifluoro-methyl)pyrrolidinium chloride (1.17 g, 95% purity, 86% yield) was obtained. The hydrochloride was suspended in aqueous sodium hydroxide (2 N, 5 mL) and ethyl acetate was added. The mixture was stirred until two clear phases were formed. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. This procedure yielded 1-benzyl-3-(3,5-dichlorophenyl)-4-(phenylsulfinyl)-3-(trifluoromethyl)pyrrolidine (1.07 g, 95% purity, 80% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1.[Na+].[Cl-]>CN1C(=O)CCC1>[CH3:52][O:51][C:49](=[O:50])[C:48]1[CH:53]=[CH:54][C:45]([NH:44][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Reactant: COC(=O)c1ccc(N)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(NC(=O)CCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
Hexadecanedioic acid mono-tert-butyl ester (0.4 g, 1.17 mmol) was dissolved in NMP (6 mL). N-Ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.223 g, 0.1.17 mmol) and 1-hydroxy-7-azabenzotriazole (0.159 g, 1.17 mmol) was added and the mixture was stirred at 50° C. for 1 hour and then allowed to cool to room temperature. Diisopropylethylamin (0.6 mL, 3.5 mmol) was added followed by methyl 4-aminobenzoate (0.353 g, 2.34 mmol). The mixture was stirred overnight under nitrogen at room temperature. The mixture was poured into saturated aqueous NaCl (50 mL), washed with diethylether (3×100 mL between ethyl acetate. The organic phases were collected, dried (Na2SO4) and solvent removed in vacuo. The crude material was purified on silica using ethyl acetate/heptane (50:50), to give pure 4-(15-tert-Butoxycarbonylpentadecanoylamino)benzoic acid methyl ester (235 mg, 42%)
Reaction SMILES: [C:1]([O:9][CH:10]([C@H:16]1[O:25][C@@H:19]2[O:20][C:21](C)([CH3:23])[O:22][C@@H:18]2[CH2:17]1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].[OH:33]S(O)(=O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(O)(=O)C>[C:1]([O:9][CH:10]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[C@@H:16]1[CH2:17][C@@H:18]([O:22][C:26](=[O:28])[CH3:27])[CH:19]([O:20][C:21](=[O:33])[CH3:23])[O:25]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)O[C@H]2O[C@H](C(OC(=O)c3ccccc3)C3CCCC3)C[C@H]2O1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC1O[C@H](C(OC(=O)c2ccccc2)C2CCCC2)C[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-cyclopentyl-methyl] benzoate (compound 11b, 800 mg, 2.3 mmol) in the mixture of acetic acid (2 mL) and acetic acid anhydride (2 mL) was added H2SO4 (0.2 mmol). After being stirred at room temperature for 24 hours, the solution was diluted by EtOAc (40 mL) and adjusted to pH 5.0 by addition of saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 480 mg of [cyclopentyl-[(2S,4R)-4,5-diacetoxytetrahydrofuran-2-yl]methyl] benzoate (compound 11c).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])=[C:24]([CH3:37])[CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:31]([C:30]3[CH:29]=[C:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=4[CH3:37])[CH:36]=[CH:35][CH:34]=3)=[O:32])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(Oc2ccc(N)c3ccccc23)n1
Reactant: Cc1cc(F)ccc1-c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nccc(Oc2ccc(NC(=O)c3cccc(-c4ccc(F)cc4C)c3)c3ccccc23)n1
Yield: 13.5 %

Procedure:
4-(2-Methylsulfanylpyrimidin-4-yloxy)-naphthalen-1-ylamine (320 mg, 1 mmol), 3-(4-fluoro-2-methylphenyl)benzoic acid (230 mg, 1.0 mmol), HBTU (569 mg, 1.5 mmol) and diisopropylethylamine (0.53 ml, 3.0 mmol) are stirred at room temperature in anhydrous dimethylformamide (5 ml) for 1 day. The mixture is then poured into ethyl acetate (100 ml) and washed with water (100 ml). The organic layer is then dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 20-30-40% ethyl acetate in hexanes to give product as a pink solid recrystalized from ethyl acetate/hexanes to give 4′-fluoro-2′-methyl-biphenyl-3-carboxylic acid[4-(2-methylsulfanylpyrimidin-4-yloxy)-naphthalen-1-yl]-amide as pink crystals (67 mg). 1H NMR 400 MHz (CDCl3) 8.30(d, 1H, J=6 Hz), 8.14(s, 1H), 8.0(d, 1H, J=8 Hz), 7.86-7.92(m, 4H), 7.44-7.56(m, 4H), 7.28(d, 1H, J=8.4), 7.18(m, 1H), 6.9-6.97(m, 2H), 6.46(d, 1H, J=5.6 Hz), 2.23(d, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][N:8]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=O)=[CH:17][C:16]=2[S:15](=[O:25])(=[O:24])[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C(OP([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47]P(OCC)(OCC)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)(=O)OCC)C>CS(C)=O.CN1CCCC1=O>[CH3:7][N:8]1[C:21]2[CH:20]=[CH:3][C:2]([CH:5]=[CH:47][C:44]3[CH:43]=[CH:42][C:41]([C:38]4[CH:37]=[CH:36][C:35]([CH:34]=[CH:22][C:18]5[CH:19]=[CH:20][C:21]6[N:8]([CH3:7])[C:9]7[C:14]([S:15](=[O:25])(=[O:24])[C:16]=6[CH:17]=5)=[CH:13][CH:12]=[CH:11][CH:10]=7)=[CH:40][CH:39]=4)=[CH:46][CH:45]=3)=[CH:1][C:16]=2[S:15](=[O:25])(=[O:24])[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CC(C)(C)[O-]
Reactant: CCOP(=O)(Cc1ccc(-c2ccc(CP(=O)(OCC)OCC)cc2)cc1)OCC
Reactant: CN1c2ccccc2S(=O)(=O)c2cc(C=O)ccc21
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CN1c2ccccc2S(=O)(=O)c2cc(C=Cc3ccc(-c4ccc(C=Cc5ccc6c(c5)S(=O)(=O)c5ccccc5N6C)cc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.02 g (9.05 mmol) of potassium tert-butoxide and then 2.20 g (8.05 mmol) of 10-methyl-5,5-dioxophenothiazine-3-carbaldehyde (Example 21) were added under nitrogen at room temperature with stirring to a solution of 1.82 g (4.00 mmol) of diethyl[4′-(diethoxyphosphorylmethyl)biphenyl-4-ylmethyl]phosphonate in 41 ml of dimethyl sulfoxide dried over molecular sieve. After stirring at room temperature for four hours, the reaction solution was diluted with 90 ml of methanol and stirred for a further 15 min. The precipitate was filtered off, washed with 220 ml of methanol and dried at 35° C. under reduced pressure. The crude product (2.50 g) was recrystallized in 58 ml of dimethyl sulfoxide. After solvent residues had been removed under high vacuum at 200° C., 1.64 g (59% of theory) of analytically pure yellow solid having a melting point of 360° C. were obtained, whose solution in N-methylpyrrolidone fluoresced at λ=460 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]3[C:9]=2[CH2:10][CH2:11][N:12]([CH3:21])[CH2:13]3)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>[Ni].CO>[ClH:1].[NH2:18][C:15]1[CH:16]=[CH:17][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]2[C:14]=1[CH2:13][N:12]([CH3:21])[CH2:11][CH2:10]2
Reactant: CN1CCc2c(-c3ccc(Cl)cc3)ccc([N+](=O)[O-])c2C1
Agent: [Ni]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CN1CCc2c(-c3ccc(Cl)cc3)ccc(N)c2C1
Product: Cl
Reaction time: 1.5 h

Procedure:
A mixture of 5-(4-Chlorophenyl)-N-methyl-8-nitro-1,2,3,4-tetrahydroiso-quinoline (3.47 g, 11.5 mmol), sulphuric acid (1 ml, 12 mmol), Raney nickel (1 ml, 50% slurry in water) and methanol (150 ml) was stirred under hydrogen for 1.5 h. The crude mixture was filtered through celite and was evaporated. Yield 3.2 g (90%). Mp 213-215° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]([CH3:34])[CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([N:25]([CH3:34])[CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:23][N:24]=3)[CH:21]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN(CCN1CCOCC1)c1nnc2ccc(F)cn12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 7 h
Yield: 51.1 %

Procedure:
To a solution of Intermediate A (225 mg, 1.38 mmol) in DMF (3 mL) was added NaH (60% in oil, 150 mg, 3.75 mmol) and the mixture stirred at RT for 20 min, before Intermediate 45c (350 mg, 1.25 mmol) was added. This mixture was stirred at 60° C. for 7 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-20% [2M NH3 in MeOH] in DCM, gave the title compound as an orange oil (270 mg, 51%). LCMS (Method 4): Rt 0.22 min, m/z 423 [MH+].
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH3:9])C(=O)C2=CC=CC=C12.[ClH:29]>>[ClH:29].[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:8]([CH3:9])[CH2:7][CH2:6][NH2:5])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Product: CC(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
37.3 g of 1-phthalimido-3-(4'-fluoro-4-biphenylyl)butane are boiled for 6 hours with 400 ml of 20% aqueous hydrochloric acid, evaporated and worked up using sodium hydroxide solution and ether to give 3-(4'-fluoro-4-biphenylyl)butylamine, hydrochloride, m.p. 222°-224°.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[N:8]1([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9]1.CN(C)C=O.O>ClCCl>[C:6]([C:12]1[N:8]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(-n2cccc2C#N)c1
Reaction time: 1 h

Procedure:
Chlorosulfonyl isocyanate (18.2 ml) was dropwise added to a solution of methyl 3-(pyrrol-1-yl)benzoate (35.0 g) in dichloromethane (350 ml) at -10°~20° C. and the mixture was stirred for 1 hour at the same temperature. To the mixture was dropwise added N,N-dimethylformamide (105 ml) at the same temperature and the mixture was stirred for 1 hour at 0°-5° C. The reaction mixture was poured into water. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution and water. The organic solution was dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(2-cyanopyrrol-1-yl)benzoate (30.67 g).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37](O)=[O:38])[CH:30]=2)=[CH:25][CH:24]=1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37]([NH:2][C:3]3([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]3)=[O:38])[CH:30]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2C)CCC(F)(F)CC1
Reaction time: 0.08 h

Procedure:
2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). 3.07 ml of triethylamine were added dropwise at 20° C., the mixture was stirred for 5 min, and 2.61 g (10 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetic acid (EP 2029531 A1 and US 2009/298828 A1) were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 3.6 g (73% of theory) of the title compound of melting point 186° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][CH2:21][CH2:22][C:23]#[CH:24]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][CH2:22][CH2:21][O:20][CH3:19])[CH:3]=1)=[O:17]
Reactant: C#CCCOC
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: COCCC#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of 25 with 4-methoxy-but-1-yne yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methoxybut-1-ynyl)phenyl)propyl)acetamide as a dark yellow oil. Yield (0.51 g, 51%). Compound could not be purified completely and was forwarded as such into the next step.
Reaction SMILES: BrC[C:3]1[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:17]([Cl:27])[CH:16]=[CH:15][C:4]=1[C:5]([O:7][Si](C(C)(C)C)(C)C)=[O:6].COC(=O)[C@H](CS)NC(=O)[C@H](CO)NC(OC(C)(C)C)=O.N12CCCN=C1CCCCC2.C(O)(=O)C>C(Cl)Cl>[Si:20]([O:19][C:18]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:27])[C:5]([OH:7])=[O:6])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)c1ccc(Cl)c(O[Si](C)(C)C(C)(C)C)c1CBr
Agent: COC(=O)[C@H](CS)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)O)ccc1Cl
Reaction time: 3 h

Procedure:
To a solution of 5.1 g of tert-butyldimethylsilyl 2-bromomethyl-3-(tert-butyldimethylsilyloxy)-4-chlorobenzoate and 3.52 g of N-[N-(tert-butoxycarbonyl)-L-seryl]-L-cysteine methyl ester in 55 ml of methylene chloride was added within 30 minutes, at 0° C., a solution of 1.59 g of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in 15 ml of methylene chloride. Stirring was continued for 3 hours at 0° C., and subsequently the mixture was diluted with methylene chloride and stirred together with 100 ml of 1N aqueous acetic acid. The organic phase was washed with 10% sodium chloride solution, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was chromatographed on MCI-Gel CHP20P using as eluent a mixture of acetonitrile-water containing 40-0% water. The product was eluted with pure acetonitrile. Evaporation of the solvent afforded 2.7 g of 2-[[[(R)-2-[(S)-1-tert-butoxyformamido )-3-hydroxypropionylamino]-2-methoxycarbonyl-ethyl ]thio]methyl]-3 -(tert-butyldimethylsilyloxy)-4-chlorobenzoic acid as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.I[CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[N:8]2[CH2:22][CH2:23][CH3:24])=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:3]=1
Reactant: CCCI
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Product: CCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-(2-Chloro-6-morpholino-9H-purin-8-yl)propan-2-ol (100 mg) was treated with iodopropane via General Procedure C to give crude intermediate 2-(2-chloro-6-morpholino-9-propyl-9H-purin-8-yl)propan-2-ol which was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and was purified via reverse phase HPLC to give 34 mg of 104 as a white solid. MS (Q1) 399.3 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:16]C.Cl.N1C=CC=CC=1>Cl>[OH:16][C:3]1[CH:4]=[C:5]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(C(=O)C(C)C)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
8.0 g of 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone are treated with 64 g of pyridine hydrochloride and stirred at 180° for 45 minutes. After cooling the reaction mixture is poured into 500 ml of ice-water, whereupon it is made acid with 20 ml of 3N hydrochloric acid and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated in a water-let vacuum. After crystallization from methylene chloride/n-hexane there is obtained 3',4'-dihydroxy-2-methyl-5'-nitropropiophenone in the form of yellow crystals of m.p. 98°-99°.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:5])=[C:2]=[O:3].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([NH:27]C(=O)C)[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:16][C:2]([NH:1][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)[CH3:5])=[O:3])[CH:26]=[CH:25][CH:24]=2
Reactant: CC(N=C=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Nc1cc2c(N)cccc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(NC(=O)Nc1cccc2cnc(N)cc12)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-(1-Isocyanatoethyl)-4-(trifluoromethyl)benzene (1.64 mmol) in toluene (8 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (220 mg, 1.09 mmol) and DIEA (1.4 mL). The mixture was heated at 80° C. for 6 hours, cooled to room temperature, and the precipitate was collected by filtration. The solid was triturated with 97:3 CH2Cl2:CH3OH and stirred as a suspension in 48% aqueous HBr (8 mL) at 60° C. for 4 hours. After cooling to room temperature, the mixture was poured into concentrated NH4OH (20 mL) and filtered. The solid was washed with water and air-dried to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.64 (s, 1H), 7.91 (d, 1H), 7.58-7.74 (m, 4H), 7.22-7.36 (m, 3H), 7.14-7.18 (m, 2H), 6.97 (s, 1H), 4.94 (m, 1H), 1.44 (d, 3H, J=6.8 Hz); MS (ESI+) m/z 375 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([C:39]1[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45](Cl)=[O:46])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].[Si](I)(C)(C)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:45](=[O:46])[CH2:44][O:43][C:42]2[CH:48]=[CH:49][C:39]([C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:40][CH:41]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([C:39]1[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45]([NH:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)[CH2:20][C:10]2[C:9]([OH:8])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([Cl:19])[CH:11]=2)=[O:46])=[CH:41][CH:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1ccc(-c2cccc(C(N)Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)c2)s1
Reactant: CC(C)(C)c1ccc(OCC(=O)Cl)cc1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(C(Cc3cc(Cl)c4cccnc4c3O)NC(=O)COc3ccc(C(C)(C)C)cc3)c2)s1
Product: Cc1ccc(-c2cccc(C(Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)NC(=O)COc3ccc(C(C)(C)C)cc3)c2)s1
Yield: 126.6 %

Procedure:
N-{2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-[3-(5-methyl-thiophen-2-yl)-phenyl]-ethyl}-2-(4-tert-butyl-phenoxy)-acetamide was prepared from 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-[3-(5-methyl-2-thienyl)phenyl]ethanamine (0.414 mmol) and 4-tert-butyl-phenoxyacetyl chloride (0.455 mmol, 1.1 eq.) according to the general procedure described above (Alternate General Procedure for N-Acylations). Ethyl acetate was used in place of dichloromethane in the workup procedure. Crude product obtained was a white solid that was subjected to the conditions described above for TMSI-mediated O-benzyl deprotection Crude product obtained was a brown solid that was purified by column chromatography using 5% methanol/dichloromethane to give the title compound as a white solid (0.262 mmol, 64% for 2 steps). MS (ESI) m/z 585.4.
Reaction SMILES: Br[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:25][NH:26][CH3:27]>CN(C=O)C>[CH3:25][N:26]([CH3:27])[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: O=Cc1ccc(-c2nc3nc(Br)nn3cc2-c2ccccc2)cc1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To 200 mg 4-(2-bromo-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 52) in 6 ml DMF are added 0.24 ml of a dimethylamin solution (60% in water). The mixture is heated under microwave irradiation to 100° C. for 2.5 hours. The solvent is removed and the solid residue is treated with ethyl acetate/petrolether (1:1) and stirred for 2 hours. The desired product is filtered, dried and is used without further purification.