Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:16]([CH3:17])=[N:15][C:14]([CH:18]2[CH2:20][CH2:19]2)=[CH:13][C:9]=1[C:10](O)=[O:11])#[N:2].[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:16]([CH3:17])=[N:15][C:14]([CH:18]2[CH2:19][CH2:20]2)=[CH:13][C:9]=1[C:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)=[O:11])#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1nc(C2CC2)cc(C(=O)O)c1OCc1cccc(C#N)c1
Product: Cc1nc(C2CC2)cc(C(=O)Nc2ccc(C#N)cc2)c1OCc1cccc(C#N)c1
Yield: 55.1 %

Procedure:
The amide coupling of 3-(3-cyano-benzyloxy)-6-cyclopropyl-2-methyl-isonicotinic acid (189) (112 mg, 0.4 mmol) and 4-amino-benzonitrile (51 mg, 0.4 mmol), as described in Example 67, gave 3-(3-cyano-benzyloxy)-N-(4-cyano-phenyl)-6-cyclopropyl-2-methyl-isonicotinamide (190) (90.0 mg, 61% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[C:11](B(O)O)=[CH:10][CH:9]=[N:8]1.FC(F)(F)S(O[C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH3:34])=[N:32][N:33]=[C:29]3[C@H:28]([CH2:35][C:36]([NH:38][CH2:39][CH3:40])=[O:37])[N:27]=[C:26]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[C:25]=2[CH:48]=1)(=O)=O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C:26]2[C:25]3[CH:48]=[C:21]([C:11]4[NH:7][N:8]=[CH:9][CH:10]=4)[CH:22]=[CH:23][C:24]=3[N:30]3[C:31]([CH3:34])=[N:32][N:33]=[C:29]3[C@H:28]([CH2:35][C:36]([NH:38][CH2:39][CH3:40])=[O:37])[N:27]=2)=[CH:46][CH:45]=1
Reactant: OB(O)c1ccn[nH]1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccn[nH]3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
Sodium carbonate (43.0 mg), 1H-pyrazole-5-boronic acid (24.8 mg) and bis(triphenylphosphine)palladium(II) chloride (13.0 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added. The reaction mixture was heated at 120° C. for 30 min (microwave). Ethyl acetate (2 ml) was added and the water layer was separated. The organic phase was dried and the solvent evaporated. The residue was chromatographed (0-5% methanol:DCM) and the product further purified by MDAP (formate modifier). The resulting gum was loaded on a 1 g SCX-2 column and washed with ammonia in methanol (2M) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-5-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a brown oil (15.6 mg).
Reaction SMILES: C(OC(=O)COC1C=CC(Cl)=CC=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])(C)(C)C.Br[C:24]1[CH:29]=[C:28]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=1[F:36]>>[F:36][C:25]1[CH:26]=[CH:27][C:28]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])=[CH:29][C:24]=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Product: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Yield: 97 %

Procedure:
Following the general method as outlined in Intermediate 2, starting from 2-bromo-1-fluoro-4-(propylsulfonyl)benzene (Intermediate 106) and trimethylsilylacetilene, the title compound was obtained as a brown liquid in 97% yield.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10]Cl)=[O:9].Cl>C(#N)C.O.C(O)(=O)C>[CH3:4][O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10][O:2][CH3:1])=[O:9]
Reactant: C[O-]
Reactant: COC(=O)CC(=O)CCl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COCC(=O)CC(=O)OC
Temperature: 70 °C
Reaction time: 0.41 h
Yield: 91.7 %

Procedure:
77.4 g of sodium methylate, 97 percent, was suspended in 100 g of acetonitrile at ambient temperature. To this well-stirred suspension, 101.9 g of 97.5 percent 4-chloroacetoacetic acid methyl ester was added by drops through a drip funnel with a drop counter over a 5 to 6 minute period under N2 atmosphere. The temperature rose and was kept by means of cooling at 68° to 70° C. As soon as the heat development slackened, the cooling water was turned off and the reaction mass was heated with 70° C. hot water. This pastelike, mustard-yellow reaction mixture continued to be stirred at 70° C. for 24 to 25 minutes and, with stirring, was then slowly introduced into a solution of 6 g of glacial acetic acid and 215 g of water cooled in an ice bath. At the same time, 37.4 percent hydrochloric acid was introduced drop by drop from a burette. At the same time, the pH was measured by means of a glass electrode and kept between 4.5 and 8 by adjusting the addition rate of the reaction mixture and/or HCl. At the end of the neutralization, the pH was 6.1±0.1. For the neutralization, 56.4 ml of hydrochloric acid were used (37.4 percent) and the temperature was kept at 30° to 35° C. The neutralized mixture was put into a separating funnel. After standing a short time, the resultant layers were separated. The aqueous layer was extracted once with 200 ml and then twice each time with 100 ml of acetonitrile. The united organic phases were concentrated in a rotary evaporator at 30° to 35° C. and ≃20 torr up to a constant weight. The solvent evaporated off was regenerated and used with the next batch. The raw product was distilled at 0.5 to 1.5 torr/90° C. 4-methoxyacetoacetic acid methyl ester was obtained in a yield of 91.7 percent, based on the amount of chloroester used. The purity of the product was 98.8 percent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([SH:9])=[N:7][N:6]=[N:5]1.C([N:12]([CH2:15]C)CC)C.C[N:18](C=O)C>>[NH:1]([CH2:2][CH2:3][N:4]1[C:8]([SH:9])=[N:7][N:6]=[N:5]1)[C:15]([NH2:12])=[NH:18]
Reactant: CN(C)C=O
Reactant: NCCn1nnnc1S
Reactant: CCN(CC)CC
Product: N=C(N)NCCn1nnnc1S
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of 980 mg of 1-(2-aminoethyl)-5-mercapto -1H-tetrazole, 696mg of S-methylisourea sulfate, 2.31 ml of triethylamine and 60 ml of DMF was stirred at 70° C. for 17 hours. Then the solvent was distilled off and the residue was purified by a column chromatography (silica gel=150 g; acetonitrile - water=7:1, then 5:1) to give 335mg of 1-(2-guanidinoethyl)-5-mercapto-1H-tetrazole as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C=O)C>[O:9]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of NaH (765 mg, 31.89 mmol) in DMF (10 mL) was added phenol (1 g, 10.63 mmol) at 25° C. The mixture was heated at reflux temperature for 15 min, and then ethyl 2-bromopropanoate (2.3 g, 12.75 mmol) was added. The resulting mixture was stirred at 25° C. for another 16 h before quenching with water (50 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (1.8 g, 85.7%) as colorless oil which was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24]>>[CH3:1][C:2]1[N:3]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: COCCOCCCl
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: COCCOCCn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 1-chloro-2-{[2-(methyloxy)ethyl]oxy}ethane: MS (ES) m/z 327 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:15]=2)[C@@H:7]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CS(C)=O>[N:36]([CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:15]=2)[C@@H:7]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Yield: 83.4 %

Procedure:
To a solution of [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine (142 mg) in dimethyl sulphoxide (3.0 ml) was added sodium azide (20.1 mg). The solution was stirred for 3 hours at room temperature at which time aqueous ammonium chloride and ethyl acetate were added. The organic phase was separated, washed with water (20 ml), saturated brine (20 ml) dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by MPLC (20% ethyl acetate/hexane) gave [2S,3S]-1-(4-azidobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a white solid (120 mg). 1H NMR (360 MHz,CDCl3) δ 1.20-1.60 (2H, m), 2.22 (2H, m), 2.67 (1H, m), 2.98 (1H, m), 3.27 (2H, m), 3.47 (1H, br s), 3.62 (1H, br s), 3.92 (2H, s), 3.98 (3H, s), 4.47 (1H, d, J=11.0 Hz), 4.81 (1H, d, J=11.0 Hz), 7.26-7.35 (4H, m), 7.44-7.47 (4H, m), 7.69 (1H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])(=[O:4])=[O:3].[NH2:15][NH2:16]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([NH:15][NH2:16])=[O:9])(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc(S(C)(=O)=O)c1
Reactant: NN
Solvent: CO
Product: CS(=O)(=O)c1cccc(C(=O)NN)c1
Temperature: 70 °C
Yield: 80 %

Procedure:
Methyl 3-(methylsulfonyl)benzoate (100 mg, 0.467 mmol) was added to hydrazine (22.44 mg, 0.700 mmol)) in methanol (10 mL) and refluxed for 12 h at 70° C. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the compound was purified by flash column chromatography (3% CH3OH/CH2Cl2) affording the title compound (80 mg, 80% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.07 (d, 1H, J=7.6 Hz), 8.01 (d, 1H, J=7.6 Hz), 7.62 (t, 1H, J=7.6 Hz), 3.04 (s, 3H). ESI-MS: 215.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:18](Br)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1cn(-c2cccc(O)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cccc(OC(C)C)c2)cn1
Yield: 95.1 %

Procedure:
A mixture of 696 mg of the compound prepared in Example 11, 405 mg of isopropyl bromide and 248 mg of potassium carbonate in 15 ml of anhydrous dimethylformamide is heated under nitrogen for one hour to 100° C. With incomplete reaction, equivalent amounts of isopropyl bromide and potassium carbonate are furthermore added two to three times. For working up purposes, the solvent is distilled off and the remaining residue is stirred with water. The thus-obtained crude product is filtered off, dried, and purified by chromatography on silica gel with toluene/ethyl acetate (8:2), thus producing 782 mg (95%) of the title compound as a slightly yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[Cl:21][CH2:22][CH2:23][CH2:24]Br>O1CCCC1>[Cl:21][CH2:22][CH2:23][CH2:24][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: ClCCCBr
Reactant: Cc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(CCCCl)CC2)cc1
Reaction time: 6 h

Procedure:
55.4 ml (0.4 mol) triethylamine were added to a solution of 35.2 g (0.2 mol) 1-(4-methylphenyl)-piperazine and 31.5 g (0.2 mol) 1-chloro-3-bromopropane in 41 ml anhydrous tetrahydrofuran and the reaction mixture then stirred for six hours at 60°-65°C. Thereafter, the crystals which had precipitated out were filtered off with suction and the filtrate was evaporated in a vacuum. There was obtained a quantitative yield of crude 1-(3-chloropropyl)-4-(4-methylphenyl)-piperazine which was purified by rapid distillation at an efficient oil pump vacuum. The yield was 41.23 g (80% of theory); b.p. 147°-150°C/0.05 mm HG; m.p. 34°-36°C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:39]=[CH:38][C:10]2[N:11]([CH2:25][CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6]>O1CCCC1.O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([NH:14][C:12]2[N:11]([CH2:25][CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:10]3[CH:38]=[CH:39][C:7]([C:5]([OH:6])=[O:4])=[CH:8][C:9]=3[N:13]=2)[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1cc(OC)cc(OC)c1)n2CCCN(C)CCc1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3cc(C(=O)O)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide (0.350 g, 4 eq) is added to a solution of methyl-2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylate (1.05 g, 1 eq) in a mixture of tetrahydrofuran (10 ml) and water (5 ml). The mixture is stirred at 65° C. for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Ethyl acetate and water are added to the residue. The mixture is acidified by adding acetic acid to pH 5. After decanting and extracting, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: dichloromethane/ethanol 95/5 to 70/30) produces the expected compound in the form of a white foam (0.93 g, 91% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH2:4]1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=[O:23])=[CH:20][CH:19]=1>>[ClH:24].[CH3:1][N:2]([CH3:16])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH2:4]1
Reactant: CN(C)C1CC=C(c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccc(F)cc3)c2)CC1
Product: Cl

Procedure:
Use a method similar to example 1, use 3-(4-dimethylamino-cyclohex-1-enyl)-phenylamine (enantiomer 2, preparation 3, 169 mg, 0.78 mmol) and 4-fluorobenzoyl chloride (149 mg, 0.94 mmol) to provide 89 mg (34%) of the free base of the title compound: MS (ES): m/z=339.2 (M+H)+; 1H NMR (CDCl3): δ 7.91 (m, 3H), 7.69 (br, 1H), 7.50 (d, 1H), 7.33 (t, 1H), 7.18 (m, 3H), 6.13 (m, 1H), 2.51 (m, 4H), 2.37 (s, 6H), 2.13 (m, 2H), 1.57 (m, 1H). Hydrochloride salt: Anal. cal'd for C21H23FN2O.HCl.0.5H2O: C, 65.70; H, 6.56; N, 7.30. Found: C, 65.30; H, 6.16; N, 7.21.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:26])([CH3:25])[CH2:20][S:21](O)(=[O:23])=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)([Cl:29])=O>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]([CH3:26])([CH3:25])[CH2:20][S:21]([Cl:29])(=[O:23])=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(CS(=O)(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)Cl
Product: CC(C)(CS(=O)(=O)Cl)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
(2-Chlorosulfonyl-1,1-dimethyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester was prepared by an analogous procedure as described in example 26v) starting from 457 mg (1.2 mmol) 2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propane-1-sulfonic acid and 2.3 ml (3.6 equiv.) phosgene (20% in toluene). (2-Chlorosulfonyl-1,1-dimethyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester was obtained in crude form as a colorless oil. Yield: 503 mg
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])[CH2:2][CH3:3].[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CNOC
Reactant: CCCNc1cc(C(F)(F)F)ccc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCNc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 56.8 %

Procedure:
2-Propylamino-4-(trifluoromethyl)benzoic acid (147 mg, 0.594 mmol) in CH2Cl2 was reacted with N,O-dimethylhydroxy amine (82 mg), NMM (0.2 ml) and DMTMM (222 mg) at room temperature overnight. The reaction mixture was quenched by adding H2O (3 ml). The reaction solvent was removed under reduced pressure. Water (30 ml) was added to the resulting residue, which was extracted with ethylacetate (30 ml×3). The combined organic layer was washed with sat. NaHCO3 solution (30 ml), 1N HCl aqueous solution (30 ml) and brine (30 ml), and then dried over MgSO4. The filterate was concentrated in vacuo. The residue was purified with column chromatography to yield the title compound (98 mg, 57%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]=1[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(CO)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
To a solution of dimethyl sulfoxide (21.2 mL, 0.298 mol) in DCM (150 mL) was added oxalyl chloride (5.0 mL, 0.060 mol) at −78° C. under an atmosphere of nitrogen. The resulting mixture was stirred for 20 min. A solution of (4-bromo-3-methylphenyl)methanol (6.0 g, 0.030 mol) in methylene chloride (50 mL) was cannulated into the reaction flask. After stirring for 1.0 h, triethylamine (21 mL, 0.15 mol) was added. The reaction mixture was stirred at −78° C. for 1 h, warmed to room temperature for 1 h. The reaction was quenched with 1 N HCl solution, the aqueous phase was separated and extracted with methylene chloride once. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (5.7 g, 96%). 1H NMR (400 MHz, CDCl3): δ 9.96 (s, 1H), 7.73 (m, 1H), 7.71 (s, 1H), 7.55 (m, 1H), 2.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14]([CH3:40])([C:16]2[N:17]=[CH:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:20]=2)[OH:15])[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1>C(OCC)C>[ClH:1].[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[C:12]([C:14]([CH3:40])([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)[OH:15])=[CH:13][CH:2]=[CH:3][C:4]=2[CH2:9][O:8]1
Reactant: CC1(C)OCc2cc(Cl)cc(C(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2O1
Solvent: CCOCC
Product: CC1(C)OCc2cccc(C(C)(O)c3c[nH]cn3)c2O1
Product: Cl

Procedure:
The process is exactly the same as in 2. above but a temperature of 20° C. is used, starting from alpha-(6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)-alpha-methyl-1-triphenylmethyl-1H-imidazole-4-methanol (prepared in Example 2.B.2.). The yield is practically quantitative; M.P.: 85°-100° C. (decomposition). An analytical sample is prepared by stirring in diethyl ether; M.P.: 72°-90° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[Mg].[Br:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=1)[C:16](N(OC)C)=[O:17].[Cl-].[NH4+]>O1CCCC1>[Br:12][C:13]1[CH:14]=[C:15]([C:16]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=2)=[O:17])[CH:22]=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=1
Reactant: COc1ccc(Br)cc1C
Reactant: CCOc1cc(Br)cc(C(=O)N(C)OC)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1cc(Br)cc(C(=O)c2ccc(OC)c(C)c2)c1
Temperature: 15 °C

Procedure:
A solution of 4-bromo-2-methylanisole (0.984 g, 4.9 mmol) in tetrahydrofuran (3 mL) was added dropwise to magnesium powder (0.127 g, 5.2 mmol) in tetrahydrofuran (1 mL) at room temperature. Under external heating the reaction mixture was brought up to reflux. After complete addition, reflux was maintained for 1 hour. Thereafter the mixture was cooled to 15° C., then diluted with tetrahydrofuran (1 mL) before a solution of 3-bromo-5-ethoxy-N-methoxy-N-methyl-benzamide (1.238 g, 4.3 mmol) in tetrahydrofuran (3 mL) was added dropwise. After complete addition, the mixture was heated to reflux for 1.5 hours. For the working-up, it was cooled to 5° C. and hydrolysed with a saturated solution of ammonium chloride (25 mL). The aqueous layer was extracted twice with ethyl acetate (2×50 mL), thereupon, the organic layers combined, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was chromatographed on silica gel using a gradient of heptane/ethyl acetate=100/0 to 6/1 as the eluent. There were obtained 1.16 g (77% of theory) of the title compound as a colourless oil. Mass (calculated) C17H17BrO3 [348]; (found) [M+H]+=349, 351.
Reaction SMILES: [F:1][C:2]([C:5]1[C:10](O)=[CH:9][CH:8]=[C:7](C)[CH:6]=1)([F:4])[F:3].Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=[O:22].[Cs+].[Cs+]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([O:22][C:8]1[CH:7]=[CH:6][C:5]([C:2]([F:1])([F:3])[F:4])=[CH:10][CH:9]=1)[CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(C(F)(F)F)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Yield: 88.6 %

Procedure:
A mixture of trifluromethyl-p-cresol (9.74 g, 60.1 mmol), ethyl 2-bromopropionate (10.9 g, 60.1 mmol) and Cs2CO3 (39.15 g, 120 mmol) in DMF (450 mL) was heated at 90° C. under N2 for 16 h. The reaction was cooled and filtered using Et2O to rinse the solids. The filtrate was washed with 1 N HCl (200 mL) and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 19.03 g of crude product that was purified by flash chromatography using 6:1 hexanes:acetone to afford 13.96 g (89%) 2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester. Rf=0.63 (1:1 hexanes:acetone). 1NMR.