Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (500 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide (85.0 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH:17]=[CH:16][N:15]=[CH:14]1>C(O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCCn1ccnc1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 1.63 g of isatoic anhydride, 1.39 g of 1H-imidazole-1-butanamine and 25 ml of ethanol was stirred at room temperature for 22 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and cooled. The desired product was isolated by filtration, mp 91°14 93° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[C:9]1([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:21][CH:22]1[CH2:25][CH2:24][CH2:23]1.[Li+].[I-]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH:22]1([CH2:21][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([O:18][CH3:19])=[O:17])[CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)Cc1ccccc1
Reactant: BrCC1CCC1
Agent: [I-]
Agent: [Li+]
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CC1CCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of freshly prepared lithium diisopropylamine (76.5 mmol) in 500 mL of tetrahydrofuran at 0° C. was added methyl phenylacetate (10.44 g, 69.50 mmol) in 125 mL tetrahydrofuran dropwise over 30 minutes. After stirring at 0° C. for 1 hour the reaction mixture was cooled to −78° C. and treated with 50 mL of hexamethylphosphoric triamide followed by the dropwise addition of bromomethyl cyclobutane (9.37 mL, 83.4 mmol) and LiI (200 mg). The reaction mixture was stirred for 18 hours warming to 25° C. The reaction was quenched over 1 L of water containing 250 mL of sat. NH4Cl and extracted 3× with ethyl acetate. The combined organic layers were washed sequentially with saturated sodium bicarbonate, brine, and dried over MgSO4 yielding the crude product as an oil that was used without further purification. 1H NMR (300 MHz, CDCl3): δ ppm 1.59 m, 2 H) 1.89 m, 5 H) 2.17 m, 2 H) 3.47 (t, J=7.54 Hz, 1 H) 3.64 (s, 3 H) 7.31 (m, 5 H). MS (ESI+) m/z=236 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([OH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1C2=C(CCCC2)C(O)N1c1ccc(Cl)cc1F
Reaction time: 1 h
Yield: 89.9 %

Procedure:
In 400 ml of ethanol was dissolved 40.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1,3-dione, and 2.4 g of sodium borohydride was added to the solution with stirring over a 30-minute period, while cooling was effected suitably to maintain the reaction temperature at 20° to 30° C. After stirring was continued at room temperature for one hour, the reaction mixture was neutralized with dilute acetic acid and concentrated to about one third of the original volume. Upon cooling, there resulted crystals, which were collected by filtration, washed with water and dried, thereby affording 36.2 g (yield of 90%) of the subject compound. Recrystallization from ethyl acetate yielded white crystals, m.p. 178°-179° C.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20](Br)=[O:21].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:19][C:20]([NH:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[Cl:23])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1Cl
Reactant: c1ccc(CC2NCCc3ccccc32)cc1
Product: O=C(CN1CCc2ccccc2C1Cc1ccccc1)NCc1ccccc1Cl

Procedure:
prepared by reaction of 1-Benzyl-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-chlorobenzylamine
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[CH2:9]1[O:11][CH2:10]1.[OH-].[K+]>O>[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O:5][CH2:9][CH2:10][OH:11])[CH3:2]
Reactant: C1CO1
Reactant: CCP(=O)(O)CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCP(=O)(CCO)OCCO
Yield: 95 %

Procedure:
A 500 ml five-neck flask equipped with gas inlet tube, thermometer, high-performance stirrer and reflux condenser with gas incineration is charged with 138 g (1 mol) of ethyl(2-hydroxyethyl)phosphinic acid (produced as in Example 8) and ethylene oxide is passed in. A reaction temperature of 70° C. is set, followed by further reaction for 1 h. The ethylene oxide takeup is 64.8 g. The acid number of the product is less than 1 mg KOH/g. 173 g (95% of theory) of 2-hydroxyethyl ethyl(2-hydroxyethyl)phosphinate as colorless, water-clear liquid were obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].CS(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O>CN(P(N(C)C)(N(C)C)=O)C>[F:20][C:19]([F:22])([F:21])[CH2:18][O:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To prewashed sodium hydride (0.61 g, 25.5 mmol) in 10 ml of hexamethylphosphorotriamide (HMPT) is added 4-nitrophenol (3.55 g, 25.5 mmol) in 10 ml of HMPT at 25°-30°. Five ml more of HMPT is added and the mixture is warmed gently to 45°-50° for 30 min. 2,2,2-Trifluoroethyl methansulfonate (5.0 g, 28.0 mmol) and HMPT (1 ml) are then added and the mixture is heated to 146°-151° for 20 hours. The reaction mixture is cooled to RT and is then poured into ice water and extracted with ether (3X). The combined ether layers are washed with water and brine, dried, filtered and rotoevaporated to give 4-(2,2,2-trifluoroethoxy)nitrobenzene.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][C:17]([N:19]1[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][C@H:20]1[CH3:34])=[O:18])[CH3:6])C.O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:8]([CH:13]=1)[O:7][CH:5]([CH3:6])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)Oc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(Oc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of 2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-propionic acid ethyl ester (0.075 g, 0.15 mmol) in methanol (0.4 mL), tetrahydrofuran (0.4 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (0.010 g, 0.24 mmol). The resulting mixture was stirred at ambient temperature for three hours. The reaction was acidifed to pH 4 with 0.2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration with methylene chloride/diethyl ether to give the title compound (0.066 g, LRMS: 479.2, 481.2).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[N+:7]([O-:9])=[O:8].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13](OB(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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>[N+:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O-:9])=[O:8]
Reactant: Cc1ccc(OB(O)O)cc1
Reactant: O=[N+]([O-])c1sccc1Br
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccsc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A mixture of 0.8 g of 3-bromo-2-nitrothiophene, 0.52 g of 4-tolylboric acid, 5 ml of a 2M-aqueous potassium carbonate solution, 2.5 ml of ethanol and 30 ml of toluene was stirred at room temperature for 30 minutes in a nitrogen atmosphere. Successively 0.15 g of Pd(PPh3)4 was added and refluxed by heating for 7 hours. After separating into two layers, the organic layer was washed with water and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.56 g (70% yield) of the product as a yellow crystal. 1H-NMR(CDCl3, δ value):2.42(3H, s), 7.01(1H, d, J=5.1), 7.25(2H, d, J=8.1), 7.37(2H, d, J=8.1), 7.47(1H, d, J=5.1)
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]=3[C:5]=2[N:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[O:26]1CC[CH2:28][CH2:27]1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:27]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]=3[C:5]=2[N:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])(=[O:26])[CH3:28]
Reactant: On1c(-c2ccccc2Cl)nc2c3ccc4ccccc4c3ccc21
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)On1c(-c2ccccc2Cl)nc2c3ccc4ccccc4c3ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4 parts of 1-hydroxy-2-(2-chlorophenyl)-phenanthroimidazole in 30 parts of tetrahydrofuran are initially taken, and 2 parts of pyridine and 3.6 parts of acetic anhydride are then added. Tne mixture is stirred for five hours at room temperature, after which 40 parts of ethyl acetate are added to the resulting solution. The organic phase thus obtained is washed several times with water and dried over sodium sulfate, after which the solvent is stripped off. The solid which remains is recrystallized from methyl ethyl ketone/cyclohexane.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]1([NH2:17])[CH2:16][CH2:15]1>C(O)C>[CH3:13][C:14]1([NH:17][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:16][CH2:15]1
Reactant: CC1(N)CC1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CC1(NC[C@H](O)c2ccc3nnnn3c2)CC1
Yield: 62.7 %

Procedure:
A solution of 375 mg (2.31 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid 6-yl)oxirane and 950 mg of (1-methylcyclopropyl)amine in 1 ml of absolute ethanol was heated at 70° C. for 4 hours in a sealed reaction tube. The reaction mixture was concentrated under reduced pressure and the residue chromatographed on silica gel plates (95:5:1 methylene chloride: methanol:conc. ammonium hydroxide) to give 338 mg of product, m.p. 72°-73° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1.O>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
A solution of 1.48 g of 3-aminobenzene sulfonic acid in 1:1 tetrahydrofuran/water was treated at 0° C. with 1.43 g of sodium bicarbonate. After 5 min, 1.30 g of acetic anhydride was added dropwise and the reaction allowed to warm to ambient temperature under an atmosphere of nitrogen over 14 h. The reaction mixture was passed through a column of Amberlyst 15 ion exchange resin, eluted with water, and concentrated in vacuo to yield an oil which upon treatment with benzene and azeotropic removal of water in vacuo yielded 1.8 g of the title product as a white crystalline solid. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: C([SiH2]O[C:7](C)(C)[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)([OH:27])[CH2:17][C:18]2[O:23][C:22]([CH3:25])([CH3:24])[O:21][C:20](=[O:26])[CH:19]=2)=[CH:10][C:9]=1[CH2:33][CH3:34])(C)(C)C>CCO.[OH-].[OH-].[Pd+2]>[CH:28]1([C:16]([OH:27])([CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[C:9]([CH2:33][CH3:34])[CH:10]=2)[CH2:17][C:18]2[O:23][C:22]([CH3:24])([CH3:25])[O:21][C:20](=[O:26])[CH:19]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCc1cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1C(C)(C)O[SiH2]C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(CCC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1C
Reaction time: 15 h

Procedure:
To a solution of 6-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-phenyl]-2-cyclopentyl-2-hydroxy-but-3-ynyl}-2,2-dimethyl-[1,3]dioxin-4-one (1.0 g) in EtOH (50 mL) was added Pd(OH)2 (20 wt %, 100 mg). The reaction was stirred under H2 atmosphere for 15 hours. The reaction was filtered through a pad of celite and the solvent was removed under reduced pressure to afford the desired product. 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3H), 1.43-1.69 (m, 8H), 1.71 (s, 6H), 1.79-1.85 (m, 2H), 2.05-2.16 (m, 1H), 2.27 (s, 3H), 2.44-2.66 (m, 6H), 5.37 (s, 1H), 6.89-6.95 (m, 2H), 7.04-7.08 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[Na+].Br[CH2:13][CH2:14][O:15][CH3:16]>C(O)C.O>[CH3:16][O:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COCCBr
Reactant: OCc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCOc1cccc(CO)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxybenzyl alcohol (27A) (12.41 g, 100 mmol) in ethanol (150 mL) was added aqueous NaOH (10 N, 10 mL), followed by 1-bromo-2-methoxyethane (27B) (13.9 g). The reaction mixture was heated to reflux overnight. Then the reaction mixture was allowed to cool to RT, and diluted with water. The mixture was subsequently extracted with CH2Cl2, and the combined organic phase was dried with anhydrous MgSO4 filtered, and concentrated in vacuum to give the product (27C) a yellow oil, which was used for the next reaction without further purification. 1H NMR (300 MHz, CDCl3): δ 1.82 (br, 1H), 3.44 (s, 3H), 3.74 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J=4.8 Hz), 4.65 (s, 2H), 6.84-6.95 (m, 3H), 7.22-7.26 (m, 1H). LCMS: purity >94%. ESI-MS: M/Z 183(M+H)+.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:5][S:4][CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1)#[N:16].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C.O.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>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][C:19]=3[CH3:26])=[CH:3][S:4][CH:5]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2cscc2Br)cc1
Reactant: Cc1cc(C#N)ccc1B(O)O
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cscc2-c2ccc(C#N)cc2C)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
To a mixture of 3-bromo-4-(4-methoxyphenyl)thiophene (Scheme I, 2, X1=4-methoxyphenyl) (1.7 g, 6.316 mmol), 4-cyano-2-methylphenylboronic acid (Scheme I, 2A, X2=4-cyano-2-methylphenyl) (1.535 g, 6.316 mmol), sodium carbonate (1.34 g, 12.63 mmol), toluene (60 mL) in a mixture of ethanol (36 mL) and water (24 mL) under nitrogen was added Pd(PPh3)4 (0.7 g, 0.606 mmol). The mixture was stirred at 80° C. for 5 h, poured into water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic extracts were dried over anhydrous magnesium sulfate (6 g), evaporated, and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=50:1) to give 4-(4-(4-methoxyphenyl)thiophen-3-yl)-3-methylbenzonitrile (Scheme I, 3, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (1.34 g, yield 69.4%). 1H NMR (DMSO-d6 400 MHz): δ 7.68-7.65 (m, 3H), 7.58 (d, J=3.2 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 3.70 (s, 3H), 1.79 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([NH2:16])=O)[CH:10]=[CH:11][CH:12]=1>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]#[N:16])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(CC(N)=O)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cccc(CC#N)c1
Reaction time: 2 h

Procedure:
Thionyl chloride (1249 ml) was added dropwise to dry dimethylformamide (400 ml) stirring at 0°-5° C. under nitrogen over a period of about 2 hours. 3-Methoxyphenylacetamide (403.7 g) was added portionwise over a period of 45 minutes to the above solution under nitrogen maintaining the temperature between 0°-5° C. The reaction mixture was then stirred at 0°-5° C. for a further 2 hours. The reaction mixture was poured carefully onto ice/water (6 l). The aqueous mixture was extracted with ether. The extracts were washed with water, dried over magnesium sulphate and evaporated in vacuo to give a red liquid. The crude product was distilled (110°-112° C./12 mm Hg) to give 3-methoxyphenylacetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C@H:15]2[CH2:18][C@H:17]([NH:19]C(=O)OC(C)(C)C)[C:16]2([CH3:28])[CH3:27])[C:11]([C:29]#[N:30])=[CH:10][N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@H:17]1[CH2:18][C@H:15]([NH:14][C:12]2[C:11]([C:29]#[N:30])=[CH:10][N:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]3[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)[C:16]1([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C[C@@H]1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of tert-butyl ((1S,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (100 mg, 0.21 mmol) in dry DCM (2 mL) was added TFA (1.5 mL) dropwise under cooling in an ice-water bath. The resulting mixture was stirred at room temperature for 30 min. After removal of the organic solvents, the residue was neutralized with ammonia and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by standard methods to afford the title compound (49.7 mg, 0.13 mmol, 64% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.06 (s, 1H), 7.29-7.15 (m, 4H), 4.33 (dd, J1=5.6 Hz, J2=9.2 Hz, 1H), 3.72-3.50 (m, 2H), 3.18-3.12 (m, 1H), 2.93-2.86 (m, 2H), 2.45-2.39 (m, 1H), 2.17-2.12 (m, 1H), 1.20 (s, 3H), 0.98 (s 3H). MS (ESI) m/z 371.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:23]([CH3:24])[CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Dimethylamine were converted to yield [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-dimethyl-amine as white semisolid, MS: 391(MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[N:6][CH:5]=1.[CH3:12][C:13]1[O:17][N:16]=[C:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:14]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH3:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: Cc1onc(C2CCOCC2)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(C3CCOCC3)noc2C)nc1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a stirred solution of 6-hydroxy-nicotinic acid methyl ester (1.67 g, 10.9 mmol) and [5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-yl]-methanol (2.15 g, 10.9 mmol) in THF (55 mL) at 5° C. under argon was added triphenylphosphine (10.6 g, 39 mmol), then diisopropyl azodicarboxylate (40%, 6.5 mL, 14.2 mmol) was added dropwise. The reaction mixture was warmed to room temperature for 2 h. The reaction mixture was then extracted with tert-butyl methyl ether, and washed with aqueous HCl (2 N) and the organic extract washed with water, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:0 to 1:1) afforded the title compound (1.31 g, 36%) as a white solid. MS: m/e=333.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)[CH2:3]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:37]I>CC#N.C1(C)C=CC=CC=1>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)([F:12])[CH2:3][I:37]
Reactant: II
Reactant: Cc1ccc(C(F)(F)CO)nc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1ccc(C(F)(F)CI)nc1
Temperature: 90 °C
Yield: 32 %

Procedure:
2,2-Difluoro-2-(5-methyl-pyridin-2-yl)-ethanol (8.5 g, 0.05 mol), as prepared in the previous step, was dissolved into toluene:CH3CN (98 mL, 2:1) and cooled to 0° C. To this solution was added PPh3 (19.3 g, 0.074 mol, 1.5×), imidazole (6.7 g, 0.098 mol, 2×) and I2 (18.7 g, 0.074 mol, 1.5×). The reaction was heated to 90° C., then was cooled to RT and concentrated in vacuo to afford a thick amber oil. Purification via flash chromatography (CH2Cl2) afforded the product as a clear oil (4.6 g, 0.016 mol, 33% yield). 1H NMR (300 Hz, CDCl3) δ 8.48 (s, 1H), 7.61 (m, 1H), 3.92 (t, J=14.7 Hz), 2.41 (s, 3H); LC/MS (m/z) [M+1]+ 284.1 (calculated for C8H9F2IN, 284.07).