Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[N:3]=1.[CH3:11][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([CH:6]([OH:7])[CH3:11])=[CH:8][CH:9]=1
Reactant: Cc1nc(Cl)ccc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc(Cl)ccc1C(C)O
Temperature: -78 °C

Procedure:
6-Chloro-2-methylnicotinaldehyde (300 mg, 1.93 mmol) was taken up in THF (9.6 ml) under argon and cooled to −78° C. Methylmagnesium bromide (1.29 ml, 3.86 mmol) was added dropwise over 5 minutes. The reaction temperature was maintained at −78° C. for 20 minutes, then was allowed to warm to 0° C. over 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and allowed to warm to room temperature. The reaction mixture was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (10-75% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)CCl.[NH2:19][C@@H:20]([CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22]>C(Cl)Cl>[C:1]([NH:19][C@@H:20]([CH2:29][N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:22])(=[O:14])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reactant: CCCCCCOCCOCC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCOCCOCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 3 h
Yield: 47.3 %

Procedure:
Methylene chloride (40 ml), 3,6-dioxadodecanoic acid (1.086 g, 5.325 mmol) and EDC (1.167 g, 6.090 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (959.1 mg, 4.064 mmol), followed by stirring for 3 hours. EDC (719.3 mg, 3.752 mmol) was added thereto and the mixture was further stirred for 3 days. After evaporating the solvent under reduced pressure, a saturated sodium hydrogen carbonate solution (70 ml) was added, followed by extraction with ethyl acetate (100 ml). After washed with water (70 ml) and saturated brine (70 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:methanol=30:1) to obtain the title compound (812.3 mg, yield 47.4%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:9]=[C:8]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)[S:7][C:6]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)Cc1ccsc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred solution of 0.05 g (0.22 mmol) of 15 and 27 uL (0.22 mmol) of 4-chlorobenzoyl chloride in 5 mL of dry CH2Cl2 was added 15 mg (0.11 mmol) of AlCl3 in three portions at room temperature. The resulting mixture was stirred overnight. The reaction mixture was slowly poured onto 5 g of ice and allowed to warm to room temperature. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/Hex 1:9) to give 0.04 g (50%) of [5-(4-chlorobenzoyl)-2-phenylthiophene-3-yl]acetic acid methyl ester as a white solid: 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J=8.2 Hz, 2H), 7.61 (s, 1H), 7.50-7.43 (m, 3H), 3.71 (s, 3H), 3.67 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 186.5, 171.1, 150.1, 140.8, 138.6, 137.3, 136.2, 132.6, 130.5, 129.2, 128.9, 128.8, 128.7, 52.2, 34.1; IR (KBr) cm−1 2949, 1737, 1623; LREIMS C20H15ClO3S requires 370.04. Found: 370 ([M+], 100%), 310 (40%), 139 (59%).
Reaction SMILES: [C:1]([CH:3]1[C:7](=[O:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:3]1([CH3:16])[C:7](=[O:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1CC(=O)C(C)(C#N)C1
Yield: 55.1 %

Procedure:
To a solution of 1,1-dimethylethyl 3-cyano-4-oxo-1-pyrrolidinecarboxylate (3.9 g, 18.6 mmol) in acetone (185 mL) were added K2CO3 (3.07 g, 22.3 mmol) and MeI (1.39 mL, 22.3 mmol). After 12 h at reflux, the solution was cooled and the solid precipitate filtered. The filtrate was then concentrated and the residue purified by column chromatography (silica, 0.5% MeOH in DCM (1% NH4OH)) affording the title compound (2.3 g, 55%) as a yellow oil: LCMS (ES) m/e 225 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([NH:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:13]([NH:12][CH:10]3[C:11]4[C:7](=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])[CH2:8][CH2:9]3)[O:14][CH2:15][C:16]=2[CH:22]=1)=[O:27]
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: O=C(Cl)CCl
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Yield: 97.2 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (620 mg, 2.00 mmol) and chloroacetyl chloride (168 ul, 2.10 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as a light yellow solid (750 mg, 97%), MS (ISP) m/e=386.1 [(M+H)+] and 388 [(M+2+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1>[O:16]=[C:15]1[C:14]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12][N:11]1[C@@H:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:35]
Reactant: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Yield: 109 %

Procedure:
Deprotection of (S)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (183 mg, 0.382 mmol, 1 equiv) was accomplished in 3 hours in the presence of 4M hydrogen chloride solution in dioxane at ambient temperature. The resulting mixture was concentrated and dried in vacuo to afford the hydrogen chloride salt of the title compound as a white solid (158 mg, quant); 1H NMR (400 MHz, DMSO-d6): δ 1.82 (d, 2H, J=14.4 Hz), 2.67-2.77 (m, 2H); 2.93 (bs, 1H); 3.35-3.39 (m, 2H); 3.75 (s, 3H); 4.21 (d, 1H, J=4.8 Hz); 4.84 (d, 1H, J=4.4 Hz); 5.93 (s, 1H); 6.84 (t, 1H, J=7.2 Hz); 6.96 (d, 2H, J=8 Hz); 7.21-7.25 (m, 2H); 7.41-7.47 (m, 4H); 7.53 (s, 1H); 9.06 (bs, 1H); 9.14 (bs, 1H); MS for C22H25N3O3 m/z 399.93 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10](F)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[OH-:15].[K+].Cl>O>[F:1][C:2]1[C:10]([OH:15])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(O)c(F)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a 1 L reactor equipped with mechanical stirrer, addition funnel, thermocouple, reflux condenser and nitrogen inlet was charged 4,5-Difluoro-2-nitrobenzoic acid (82 g, 0.4 mol, 1 eq) and water (120 mL) to form a suspension. The suspension was heated to about 50° C. Solution of KOH in water (45 wt. %, 161 g, 1.3 mol, 3.25 eq) was slowly added over about 20 min so that the temperature of the exothermic reaction mixture was kept at 80-90° C. After addition, the mixture was stirred at about 80° C. for about half hour, until HPLC sample showed complete conversion. The mixture was cooled down to room temperature, acidified to pH 1 with concentrated HCl solution (105 ml, 1.26 mol, 3.2 eq), and extracted with 2-methyltetrahydrofuran (630 mL). The layers were separated. The upper organic layer was washed with water (150 mL), and distilled under vacuum to minimum volume. The dark brown residue was stirred in 200 mL of mixed solvent of toluene/methylcyclohexane (v/v, 2:1) to give a suspension. The slurry was filtered. The desired product, 4-fluoro-5-hydroxy-2-nitrobenzoic acid, was obtained as an off-white solid after drying under vacuum (68 g, 85% yield). 1H NMR (DMSO-d6, 400 MHz) δ 13.64 (br, 1H), 11.84 (br, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.25 (d, J=12.1 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz) δ 166.0, 151.6, 150.3, 150.2, 149.1, 138.4, 138.3, 127.0, 117.3, 113.7, 113.5.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(Cl)(Cl)Cl>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][N:5]([C:6]1[CH:11]=[N:10][CH:9]=[N:8][CH:7]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(CNc2cncnc2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N(Cc1ccc(Cl)cc1Cl)c1cncnc1
Yield: 68.5 %

Procedure:
2.80 g (11 mmol) of N-(2,4-dichlorobenzyl)-N-(pyrimidin-5-yl)amine are dissolved in 5 ml of glacial acetic acid and then 5 ml of acetic anhydride and 3 drops of concentrated sulfuric acid are added to the solution. With stirring, the reaction mixture is boiled under reflux for 11/2 hours and subsequently cooled. 30 ml of chloroform are added to the mixture, the acetic acid is removed by extraction with water and the separated solution of chloroform is dried over sodium sulfate. The sodium sulfate is filtered off and the chloroform is then evaporated off in vacuo at 80° C. and the residue is recrystallised from a mixture of 5 ml of toluene and 5 ml of cyclohexane, affording 2.23 g (68.5% of theory) of N-(2,4-dichlorobenzyl)-N-(pyrimidin-5-yl)acetamide, m.p. 134°-136° C. A further 0.90 g (27.6% of theory) of pure product is obtained by purifying the product formed in the filtrate through a column of silica gel (eluant: ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29](OCC)=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[CH2:29][OH:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 112 %

Procedure:
3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (136 mg, 0.285 mmol) was dissolved in 25 ml of THF. LiBH4 (9.3 mg, 0.428 mmol) was added and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of pH2 buffer and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH 95/5) to give 139 mg (quantitative) of 3-[4-(3-Fluoro-benzenesulfonyl)-2-hydroxymethyl-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=O)[CH2:30][CH2:29]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:34]([CH:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CN1CCC(C(=O)O)CC1
Product: CON=C1C[C@@H](c2noc(C3CCN(C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 85 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-1-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 1-methyl-4-piperidinecarboxylic acid, the title compound was obtained in 85% yield (96.9% purity by HPLC).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2(O)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]([C:23]3[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=3[F:33])(O)[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:6]([F:35])[C:5]([F:36])=[C:4]([F:37])[C:3]=1[F:38].[I-].[K+].[PH2]([O-])=O.[Na+]>C(O)(=O)C>[F:1][C:2]1[C:7]([C:8]2[C:9]3[C:14]([C:15]([C:23]4[C:24]([F:33])=[C:25]([F:32])[C:26]([F:31])=[C:27]([F:30])[C:28]=4[F:29])=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]([F:35])[C:5]([F:36])=[C:4]([F:37])[C:3]=1[F:38]
Reactant: OC1(c2c(F)c(F)c(F)c(F)c2F)c2ccccc2C(O)(c2c(F)c(F)c(F)c(F)c2F)c2ccccc21
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: Fc1c(F)c(F)c(-c2c3ccccc3c(-c3c(F)c(F)c(F)c(F)c3F)c3ccccc23)c(F)c1F
Yield: 39.2 %

Procedure:
The reduction of the diol was accomplished by taking 5.44 g of 9,10-bis(pentafluorophenyl)-9,10-dihydro-9,10-anthracenediol in 50 mL of acetic acid and refluxing it with 9 g of potassium iodide and 9 g of sodium hypophosphite for 4 hours. After cooling, white crystals were filtered off. The crude product was recrystallized using a 1:1 mixture of toluene and hexane to yield 2.00 g of 9,10-bis(pentafluorophenyl)anthracene with a melting point of 337-338° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:23])[CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:41])([F:40])[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([O:23][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][C:25]([F:24])([F:40])[F:41])=[CH:28][CH:29]=2)=[CH:38][CH:37]=1)[CH2:11][O:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CC(C)[Si](OC[C@H](O)COCc1ccccc1)(C(C)C)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)[Si](OC[C@H](COCc1ccccc1)Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
1,1′-Diisopropyl azodicarboxylate (7.70 mL, 0.039 mol) was added dropwise at 5° C. to a solution of the alcohol 79 (12.40 g, 0.037 mol), 4′-(trifluoromethoxy)[1,1′-biphenyl]-4-ol (reported by Edsall et al., 2003, via Suzuki coupling of 4-bromophenol and boronic acid 44) (8.29 g, 0.033 mol) and triphenylphosphine (10.26 g, 0.039 mol) in anhydrous benzene (25 mL) and the solution was stirred at 20° C. for 18 h. The product was adsorbed directly onto silica by concentration under reduced pressure, and chromatography on silica gel, eluting with EtOAc/petroleum ether (1:19), gave 4-[((1S)-2-(benzyloxy)-1-{[(triisopropylsilyl)oxy]methyl}ethyl)oxy]-4′-(trifluoromethoxy)-1,1′-biphenyl (80) (14.30 g, 69%) as a colourless oil: [α]19 +5.9° (c, 6.95, CHCl3); 1H NMR (CDCl3) δ 7.72 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 7.35-7.24 (m, 5H), 7.06 (d, J=8.8 Hz, 2H), 4.64-4.57 (m, 1H), 4.52 (s, 2H), 3.98-3.87 (m, 2H), 3.76-3.65 (m, 2H), 1.08-0.98 (m, 21H). APCI MS m/z 576 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]([NH:5][NH:6][C:7]([NH2:9])=[O:8])=O.[OH-].[K+].S(=O)(=O)(O)O>>[C:2]([C:3]1[NH:5][NH:6][C:7](=[O:8])[N:9]=1)([CH3:11])([CH3:10])[CH3:1]
Reactant: CC(C)(C)C(=O)NNC(N)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1nc(=O)[nH][nH]1
Temperature: 100 °C
Yield: 45 %

Procedure:
To the white powder of the trimethylacetyl semicarbazide obtained was added 1500 ml of a 5% aqueous potassium hydroxide solution, and the mixture was heated to 100° C. while stirring. After the contents were completely dissolved, the solution was further heated at 100° C. for one hour, and the reaction mixture then cooled and neutralized by an addition of conc. sulfuric acid. The white precipitates formed were collected by filtration, washed with water, and then dried under a reduced pressure to yield 64 g of white powder of 3-tert-butyl-1H-1,2,4-triazole-5-one. (yield 45%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28].[CH2:30]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42][CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:30]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][O:28][C:27](=[O:29])[CH2:26][CH2:25][C:3]2[CH:4]=[CH:5][C:6]([C:8]([N:10]3[CH2:19][C:18]4[CH:17]=[N:16][N:15]([CH3:20])[C:14]=4[NH:13][C:12]4[CH:21]=[CH:22][CH:23]=[CH:24][C:11]3=4)=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:42][CH2:41]1)=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
WSCD (107 mg, 0.54 mmol) and DMAP (33 mg, 0.27 mmol) were added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (106 mg, 0.27 mmol) and 4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (81 mg, 0.32 mmol) in di-chloromethane (5 ml) and DIEA (0.095 ml, 0.54 mmol). The mixture was stirred for 3 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (44 mg, 26%).
Reaction SMILES: [Br:1]Br.Br(F)(F)F.[C:7]1([C:13]([F:16])([F:15])[F:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[Br:1][C:9]1[CH:8]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:12]=[CH:11][CH:10]=1
Reactant: FC(F)(F)c1ccccc1
Reactant: BrBr
Solvent: O
Product: FC(F)(F)c1cccc(Br)c1
Yield: 97.7 %

Procedure:
24 gr of bromine and 14 gr of brominetrifluoride were placed in a 50 ml three necked flask. The mixture was stirred vigorously and swept by the aid of a stream of dry nitrogen into a 250 ml three necked flask equipped with a mechanical stirrer, thermometer and double faced condensor, containing 60 gr of benzotrifluoride. Both mixtures were stirred vigorously and icy water was circulated through the condensor, until all the mixture was swept over to the second flask. When no mixture was left in the first flask the reaction was stopped and treated as described in example 21. 25 gr of benzotrifluoride was recovered under distillation and 33 gr of 3-bromobenzotrifluoride was obtained, 61% yield based on reacted benzotrifluoride.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([O:51][C:52](=[O:73])[C@@H:53]([O:55][C:56]1[CH:61]=[C:60](Cl)[N:59]=[C:58]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:57]=1)[CH3:54])[CH3:50]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:49]([O:51][C:52](=[O:73])[C@@H:53]([O:55][C:56]1[CH:61]=[C:60]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[N:59]=[C:58]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:57]=1)[CH3:54])[CH3:50]
Reactant: CCOC(=O)[C@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.13 g), tris(dibenzylideneacetone)dipalladium (0) (58 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (42 mg), cesium carbonate (0.31 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2S)-propanoic acid ethyl ester (product of step i) (0.25 g) and dioxane (10 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (3:7) as eluent to give the subtitle compound as clear, colourless oil. Yield: 0.28 g
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH3:2].Cl.Cl.[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1>>[CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([NH:21][CH3:20])=[O:36])=[CH:24][C:25]=3[CH3:35])[CH2:34][CH2:33]2)[CH:5]=1)[CH3:2]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Agent: Cl
Product: CCOc1cc(CN2CCN(c3ccc(C(=O)NC)cc3C)CC2)cc2c1OC(C)C(=O)N2

Procedure:
Using 398B and N,3-dimethyl-4-(piperazin-1-yl)benzamide-2HCl in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (t, J=6.95 Hz, 3H) 1.41 (d, J=6.82 Hz, 3H) 2.26 (s, 3H) 2.52-2.57 (m, 4H) 2.75 (d, J=4.29 Hz, 3H) 2.89 (br. s., 4H) 3.42 (s, 2H) 4.04 (d, J=7.07 Hz, 2H) 4.55-4.65 (m, 1H) 6.52 (s, 1H) 6.63 (s, 1H) 7.03 (d, J=8.34 Hz, 1H) 7.58-7.67 (m, 2H) 8.24 (d, J=4.04 Hz, 1H) 10.57 (s, 1 H). ESI-MS: m/z 453.4 (M+H)+. mp 173.4-180.5° C.