Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][OH:30])[CH:25]=[CH:26][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH2:28][CH2:29][OH:30])[CH:25]=[CH:26][CH:27]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CCCNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CCCNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 92.3 %

Procedure:
To a solution of 2,5-dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine (0.50 g, 1.6 mmol) (prepared according to Example 10, Step A) and 2-(3-aminophenyl)ethanol (0.30 g, 2.2 mmol) (prepared according to Example 2, Step A) in 1,4-dioxane (13.6 mL) was added p-toluenesulfonic acid monohydrate (0.11 g, 0.58 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc and H2O successively to give the desired product as a light brown gum (0.61 g, 92%). LCMS for C22H26ClN4O2 (M+H)+: m/z=413.1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:11]=[CH:10]2.CN([CH:25]=[O:26])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:11]=[C:10]2[CH:25]=[O:26]
Reactant: O=c1c2ccc(Br)cc2ccn1CCCCl
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(CCCCl)c(=O)c2ccc(Br)cc12
Temperature: 0 °C

Procedure:
Phosphorousoxychloride (2.37 mL) was added dropwise to DMF (10 mL) stirring at 0° C. The resulting mixture was warmed to room temperature over 2 h before being treated with a solution of 6-bromo-2-(3-chloropropyl)isoquinolin-1(2H)-one (Example 10a, 0.85 g) in DMF (10 mL). The resulting solution was heated at 80° C. for 10 h. The cooled reaction was quenched with iced water and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give the subtitle compound (0.91 g).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:2][CH2:3][CH3:4].[CH2:17]([O:19][C@H:20]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](O)=[O:29])=[CH:24][CH:23]=1)[CH3:18].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[C:28](=[O:29])[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:20]([O:19][CH2:17][CH3:18])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1cccc(OC)c1OC
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of N-butyl-N-(2,3-dimethoxybenzyl)amine (1.23 g, 5.5 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0° C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 (3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (120 g) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions afforded 1.07 g (43%) of a pale yellow oil.
Reaction SMILES: CN(C)[C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].C[Mg]Br.Cl.[O:21]1CC[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[C:10]1([CH:8]2[O:7][N:6]=[C:5]([C:3]([C:22](=[O:21])[CH3:23])=[O:4])[CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: CN(C)C(=O)C1=NOC(c2ccccc2)C1
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)C1=NOC(c2ccccc2)C1
Temperature: 0 °C

Procedure:
To a solution of 4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolecarboxamide (i.e. the product of Example 12, Step A) (17 g, 78.0 mmol) in a mixture of tetrahydrofuran (20 mL) and toluene (80 mL) was added methyl magnesium bromide (3.0 M solution in tetrahydrofuran, 28 mL, 84 mmol) over 1 h, while keeping the reaction temperature between −10 and −15° C. The reaction mixture was poured over a mixture of concentrated hydrochloric acid (20 g) and ice (80 g), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined organic extracts were washed with brine (40 mL) and concentrated under reduced pressure to give 14.4 g of 1-(4,5-dihydro-5-phenyl-3-isoxazoyl)ethanone as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[OH:10][CH2:11][CH2:12][C@H:13]1[CH2:15][C@H:14]1[CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1>>[CH3:8][C:6]1[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([CH:14]3[CH2:15][CH:13]3[CH2:12][CH2:11][OH:10])[CH2:17][CH2:18]2)[N:7]=1
Reactant: Cc1cnc(Cl)nc1C
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Product: Cc1cnc(N2CCC(C3CC3CCO)CC2)nc1C
Temperature: 90 °C

Procedure:
The titled compound was prepared from 2-chloro-4,5-dimethylpyrimidine and rac cis-tert-Butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate by a procedure analogous to that described in Example 6, step 2, with the exception of reaction temperature and time. The reaction was heated at 90° C. for 2 h.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]#[C:14][CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:18]([O:17][C:12]([C:13]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)=[N:2][O:1][C:14]=1[CH3:15])=[O:16])[CH3:19]
Reactant: CC#CC(=O)OCC
Reactant: O/N=C(\Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-chloro-benzenecarboximidoyl chloride (26.0 g, 137 mmol) in diethylether (323 mL) was added ethyl 2-butynoate (15.4 g, 16.1 mL, 137 mmol) at 0° C. followed by the dropwise addition of triethylamine (24.1 g, 22.9 mL, 164 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (15.2 g, 42%) which was obtained as a light yellow solid. MS: m/e=266.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[CH:25][CH:26]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[O:32][C:33]=3[CH3:34])=[CH:25][CH:26]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of ethyl [1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (648 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (539 mg, yield 88%), which was then recrystallized from ethyl acetate-hexane. melting point: 87–88° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To 2.39 g (10 mmol) of 1-benzhydryl-3-hydroxyazetidine dissolved in 20 ml of pyridine were added 1.46 g (12 mmol) of dimethylaminopyridine. Thereto was added 12.10 g (11 mmol) of p-toluenesulfonyl chloride at -40° C., followed by gradual increase in the temperature and subsequent 1 day of stirring at room temperature. This was mixed with 150 ml of water, extracted with chloroform (100 ml×3) and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (250 ml, ethyl acetate:hexane 1:2) to yield 2.88 g (73%) of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:19])=[O:18])=[CH:13][CH:12]=1>>[CH2:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[CH:19]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[CH3:9]
Reactant: O=Cc1ccccc1
Reactant: CCc1ccc(C(C)=O)cc1
Product: CCc1ccc(C(=O)C=Cc2ccccc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 4-ethylacetophenone, 1-(4-ethylphenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[S:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH:16]=[CH2:17])=[CH:10][C:9]=1[N+:18]([O-])=O)=[O:4].CO>[Fe].O>[CH3:1][O:2][C:3]([NH:5][C:6](=[S:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH:16]=[CH2:17])=[CH:10][C:9]=1[NH2:18])=[O:4]
Reactant: C=CCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: C=CCSc1ccc(NC(=S)NC(=O)OC)c(N)c1

Procedure:
1.5 G. of 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-(prop-2-en-1-ylthio)benzene is treated for four hours in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform and washed with water, and then the solvent is evaporated affording 1-(3-methoxycarbonyl-2-thioureido)-2-amino-4-(prop-2-en-1-yl-thio)benzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].ClCCl>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:22]([C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
For example, 4-amino-benzoic acid methyl ester, is treated with a sulfonyl halide, in this case 4-methanesulfonyl benzenesulfonyl chloride, in a suitable solvent, such as a 1:1 mixture of dichloromethane and pyridine at ambient temperature for 2-24 hours to yield 4-(4-methanesulfonyl-benzenesulfonylamino)-benzoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:20])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH:5]=[O:6].[CH:21]([Mg]Br)=[CH2:22]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH:21]=[CH2:22])[CH:7]=[C:8]([Br:20])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: C=C[Mg]Br
Reactant: COc1ccc(COc2c(Br)cc(C=O)cc2Br)cc1
Solvent: C1CCOC1
Product: C=CC(O)c1cc(Br)c(OCc2ccc(OC)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 75.3 %

Procedure:
To a stirred solution of 3,5-dibromo-4-(4-methoxybenzyloxy)benzaldehyde (C) (3.04 g, 7.60 mmol) in anhydrous THF (40 mL) under nitrogen, cooled to −76° C., was added dropwise over 15 min vinylmagnesium bromide (1.0 M solution in THF, 11.4 mL, 11.4 mmol), keeping the internal temperature below −70° C. The mixture was stirred at <−70° C. for 65 min, and then quenched with saturated aqueous ammonium chloride solution (6 mL). The stirred mixture was allowed to warm to room temperature, and then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with saturated aqueous sodium chloride (80 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (silica gel, 15% EtOAc/pet. ether) to give 2.45 g (75%) of the title compound as a colourless oil. 1H NMR δ (ppm) (CDCl3): 1.96 (1 H, d, J=3.75 Hz), 3.83 (3 H, s), 4.96 (2 H, s), 5.14 (1 H, t, J=4.58 Hz), 5.27 (1 H, d, J=10.29 Hz), 5.35-5.42 (1 H, m), 5.98 (1 H, ddd, J=17.08, 10.28, 6.28 Hz), 6.90-6.96 (2 H, m), 7.50-7.57 (4 H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (1.016 g, 3.35 mmol) in anhydrous DCM under N2 atmosphere was added 1 M TiCl4 (in DCM, 6.7 mL, 6.7 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.374 g, 7.37 mmol) dropwise. The resulting mixture was stirred for another 24 h after the addition. The reaction mixture was poured into ice-water (100 g), stirred for a while and filtered through a pad of Celite. The filtrate was extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide as light brown solid (899 mg), which was used in the next step without further purification. MS ESI+ve m/z 327 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH:3]=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]([Cl:6])([Cl:5])[CH:3]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[OH:4]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: OC(c1ccc(Cl)cc1)C(Cl)(Cl)Cl
Temperature: 1 °C

Procedure:
A mixture of chlorobenzene (1400 g) and trichloro-acetaldehyde (384 g) is stirred at 0-2° C. Aluminium chloride (274 g) is added in portions over 110 minutes at the same temperature. Occasionally cooling is necessary. The reaction mixture is stirred at 0-5° C. for 5 hours. The reaction mixture is poured into ice/water (3000 g). The organic phase is separated, washed three times with water (500 g each), dried (sodium sulfate) and evaporated. 2,2,2-Trichloro-1-(4-chloro-phenyl)-ethanol is obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2B(O)O)[CH:7]=1.Br[C:26]1[N:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:26]2[N:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[CH:28][CH:27]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)n1
Temperature: 90 °C
Yield: 83.4 %

Procedure:
A mixture of {5′-chloro-2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid (1.32 g, 3.9 mmol), ethyl 6-bromopicolinate (851 mg, 3.7 mmol), potassium carbonate (2.76 g, 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) in 1:1 toluene/ethanol (25 ml) was stirred and heated at 90° C. under nitrogen for 1.5 hours. After cooling and dilution with diethyl ether/water the organic phase was separated, dried (magnesium sulphate) and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/iso-hexane (3:17) to give 1.37 g of white solid. LC/MS t=3.76, [MH+] 444.3
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][C@@H:20]([C:29](=[O:49])[N:30]([CH:46]4[CH2:48][CH2:47]4)[CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:50]([N:57]=[C:58]=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CC#N>[CH:46]1([N:30]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=2)[C:29]([C@@H:20]2[CH2:21][C@H:22]([N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:58]([NH:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:59])[CH2:23][NH:18][CH2:19]2)=[O:49])[CH2:48][CH2:47]1
Reactant: O=C=NCc1ccccc1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCC(C)C)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(CC(C)C)C(=O)NCc3ccccc3)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example ??? using (3R,5S)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-isobutylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester and benzylisocyanate. MS: 574 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.34 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([N:32]2[CH:36]=[N:35][C:34]([CH3:37])=[N:33]2)[CH:29]=[CH:28][C:27]=1[CH2:38][NH2:39]>>[F:25][C:26]1[CH:31]=[C:30]([N:32]2[CH:36]=[N:35][C:34]([CH3:37])=[N:33]2)[CH:29]=[CH:28][C:27]=1[CH2:38][NH:39][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:24]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: Cc1ncn(-c2ccc(CN)c(F)c2)n1
Product: Cc1ncn(-c2ccc(CNC(=O)c3nc4n(c(=O)c3OCc3ccccc3)CCOC4(C)C)c(F)c2)n1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 87, (2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. White crystals; mp 183–185° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.65 (6H, s, 2×CH3), 2.52 (3H, s, CH3), 4.05 (4H, m, 2×CH2), 4.64 (2H, d, J=6.1 Hz, NCH2), 5.33 (2H, s, OCH2), 7.29–7.55 (8H, m, aromatics), 7.84 (1H, broad t, NH), 8.45 (1H, s, CH). Anal. Calcd for C27H27FN6O4: C, 62.54; H, 5.25; N, 16.21. Found: C, 62.41; H, 5.40; N, 16.23.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2.Br[CH2:17][CH2:18][O:19][CH3:20]>>[CH3:20][O:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2
Reactant: COCCBr
Reactant: COC(=O)c1ccc2cccc(O)c2c1
Product: COCCOc1cccc2ccc(C(=O)OC)cc12

Procedure:
Analogously to method C, 2.02 g of methyl 8-hydroxynaphthalene-2-carboxylate [115399-09-2] and 2.08 g of 1-bromo-2-methoxyethane are reacted. The title compound is identified on the basis of the Rf value.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([C@H:17]4[CH2:20][C@H:19](O)[CH2:18]4)=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]4[CH2:20][C@H:19]([N:58]=[N+:59]=[N-:60])[CH2:18]4)=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc([C@H]2C[C@H](O)C2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc([C@H]2C[C@@H](N=[N+]=[N-])C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a stirred solution of trans-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutanol (step 8, 572 mg, 1.6 mmol), triphenylphosphine (623 mg, 2.4 mmol) and diphenylphosphoryl azide (DPPA) (655 mg, 2.4 mmol) in THF (8 mL) was added diethyl azodicarboxylate (415 mg, 2.4 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h, then the mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 506 mg (83%) of the title compound as colorless solids: MS (EI) m/z: 385 (M+); 1H-NMR (CDCl3) δ 7.84 (1H, br.s), 7.42 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.17 (1H, br.s), 3.98–3.88 (1H, m), 3.37–3.25 (1H, m), 2.89–2.75 (2H, m), 2.77 (2H, q, J=7.6 Hz), 2.34–2.23 (2H, m), 1.34 (3H, t, J=7.6 Hz).