Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>>[CH:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cc(F)ccc1C(=O)O
Product: CC(C)c1cc(F)ccc1C(=O)Cl

Procedure:
Reaction of 2-isopropyl-4-fluorobenzoic acid with thionyl chloride affords 2-isopropyl-4-fluorobenzoyl-chloride, which, on reaction with diethylamine, affords 2-isopropyl-4-fluoro-N,N-diethylbenzamide. Reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-isopropyl-4-fluoro-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-isopropyl-6-fluorosaccharin.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>CC(C)=O.[OH-].[Na+].O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NCC(=O)O
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ex-26A: To a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.3 mmol) in acetone (7.5 mL) was added a solution of glycine (0.42 g, 5.7 mmol) in 5% aqueous sodium hydroxide (2.5 mL) and the reaction was stirred for 30 min at room temperature. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo to afford 0.55 g (94%) of (4-acetylbenzenesulfonylamino)acetic acid as a white solid, mp 213–215° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.28 (t, 1H, J=5.4 Hz), 8.12 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4 Hz), 3.64 (d, 2H, J=5.1 Hz), 2.64 (s, 3H). Anal. Calcd. for C10H11NO5S: C, 46.69; H, 4.31; N, 5.44; S, 12.46; Found: C, 46.76; H, 4.43; N, 5.39; S, 12.16.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]=[C:10]3[C:9]2=[O:25])=[CH:4][CH:3]=1>C(Cl)Cl.CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]=[C:10]3[C:9]2=[O:25])=[CH:6][CH:7]=1
Reactant: O=c1c2nc(COc3ccccc3)nn2ccn1-c1ccc(F)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=C1c2nc(COc3ccccc3)nn2CCN1c1ccc(F)cc1
Yield: 6.3 %

Procedure:
A solution of 7-(4-fluoro-phenyl)-2-phenoxymethyl-7H-[1,2,4]triazolo[1,5-a]pyrazin-8-one (26 mg, 0.08 mmol) in a mixture of DCM (1 mL) and MeOH (1 mL) was hydrogenated in a H-Cube reactor (1.0 mL/min, 30 mm Pd/C 10% cartridge, full H2 mode, 100° C., 3 cycles). The solvent was evaporated in vacuo and the residue was purified by RP HPLC, mobile phase (gradient from 80% 0.1% NH4CO3H pH=7.8 solution in H2O, 20% MeOH to 0% 0.1% NH4CO3H pH=7.8 solution in H2O, 100% MeOH) to yield 7-(4-fluoro-phenyl)-2-phenoxymethyl-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-8-one (1.7 mg, 6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 4.11-4.24 (m, 2H), 4.44-4.58 (m, 2H), 5.42 (s, 2H), 6.95-7.02 (m, 2H), 7.04 (t, J=7.4 Hz, 1H), 7.13 (t, J=8.6 Hz, 2H), 7.29-7.49 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][OH:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>O>[C:20]([O:19][CH2:18][C:4]1([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC1=CCc2ccccc2C1(CO)CCC(C)C
Solvent: O
Solvent: c1ccncc1
Product: COC1=CCc2ccccc2C1(CCC(C)C)COC(C)=O
Yield: 81 %

Procedure:
A mixture of Example 179A (0.18 g, 0.7 mmol), acetic anhydride (0.2 mL), and pyridin (1 mL) was stirred at room temperature for 18 h. The solution was diluted with water (3 mL) and extracted with ethyl acetate (2×1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (hexane to 5% ethyl acetate/hexane) afforded product as a colorless oil (0.17 g, 81%). 1H NMR (300 MHz, CDCl3) δ ppm 0.66 (m, 1 H), 0.76 (dd, J=9.56, 6.62 Hz, 6 H), 0.89 (m, 1 H), 1.38 (m, 1 H), 1.61 (m, 1 H), 1.81 (s, 3 H), 1.95 (m, 1 H), 3.50 (s, 2 H), 3.58 (s, 3 H), 4.24 (d, J=10.66 Hz, 1 H), 4.42 (d, J=10.66 Hz, 1 H), 5.01 (t, J=3.49 Hz, 1 H), 7.20 (m, 4 H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[C:23]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2n1Cc1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from [5-(benzyloxy)-1H-indol-2-yl]methyl acetate and 4-tert-butylbenzyl bromide in substantially the same manner, as described in step 3 of Example 4. The product was obtained as a white solid; mp: 132-133° C. Mass spectrum (ESI, [M+H]+) m/z 442. 1H NMR (400MHz, DMSO-d6) δ 7.45 (d, 2H, J=7.33 Hz), 7.38 (t, 2H, J=7.33 Hz), 7.32-7.27 (m, 4H), 7.16 (d, 1H, J=2.30 Hz), 6.88-6.84 (m, 3H), 6.53 (s, 1H), 5.36 (s, 2H), 5.18 (s, 2H), 5.08 (s, 2H), 1.77 (s, 3H), and 1.21 ppm (s, 9H).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:5].[CH3:27][Mg]Br>C1COCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[O:5])[CH3:27])[CH:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(=O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: -40 °C

Procedure:
Under an inert atmosphere a 50 mL four necked flask (flame dried) with a magnetic stirrer was charged with 990 mg (2.65 mmol) (3SR,4RS)-1-benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide in 15 ml THF. The light yellow solution was cooled to −40° C. and 2.2 mL methylmagnesium bromide (3M in diethyl ether) was added drop wise over 5 min. The reaction was slowly warmed up to 0° C. over 2 h. The reaction mixture was quenched slowly with 20 mL aqueous NH4Cl-solution, diluted with 10 mL water and 10 mL ethyl acetate. The aqueous layer was separated and extracted once with 30 mL ethyl acetate. The combined organic layers were washed with 50 mL brine, dried over Na2SO4, filtered off and concentrated under vacuum and used without further purification in the consecutive step. MS (m/e): 327.2 [(M+H)+].
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16].O>C(OC(=O)C)(=O)C>[CH:1]1([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C2CCC2)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(C2CCC2)c([N+](=O)[O-])c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of methyl 4-cyclobutylbenzoate (compound 168.1, 3.80 g, 20.0 mmol, 1.00 equiv) in acetic anhydride (12 mL) 0° C. was added dropwise fuming HNO3 (5 mL, 97%). The resulting mixture was stirred at 30° C. in an oil bath. After 2 h, 30 mL of water was carefully added and the mixture was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with aqueous saturated NaHCO3 (note: gas evolution), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:25) as eluent to furnish 3.00 g (64%) of the title compound as a light yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([C:30]2[N:31]=[CH:32][N:33]3[CH:37]=[CH:36][S:35][C:34]=23)=[O:29])[CH2:11]1)(=O)=O.O>CN(C=O)C>[N:1]([C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([C:30]2[N:31]=[CH:32][N:33]3[CH:37]=[CH:36][S:35][C:34]=23)=[O:29])[CH2:11]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 13 h
Yield: 96.2 %

Procedure:
Sodium azide (87 mg) was added to a solution of 552 mg of 7-[(2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole in 5 ml of DMF, and the mixture was stirred at 100° C. for 13 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation to give 474 mg of a crude product of 7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[C:29]([CH3:36])[C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28]([NH:15][C:12]1[N:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:29]
Reactant: Cc1ccc(-c2cnc(N)nc2)cc1C
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])nc2)cc1C

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 5-(3,4-dimethylphenyl)pyrimidin-2-amine (1.41 g, 7.07 mmol, 1.00 equiv) in dichloromethane (90 mL), and pyridine (1.73 g, 3.00 equiv). This was followed by dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (1.60 g, 7.27 mmol, 1.00 equiv) in dichloromethane (30 mL) with stirring. The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting solution was diluted with 60 mL of dichloromethane. The resulting mixture was washed with 1×30 mL of hydrogen chloride (aq) and 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 100 mL of methanol, to this was added potassium carbonate (5.12 g). The mixture was stirred for 3 h at 30° C. The resulting mixture was concentrated under vacuum and dissolved in 100 mL of ethyl acetate. The resulting mixture was washed with 3×50 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was washed with ethyl acetate:n-hexane (30 mL:30 mL). This resulted in 0.78 g (29%) of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-2-nitrobenzamide as a off-white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][Si:10]([CH3:25])([CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]1[CH2:18][O:17]1>C(O)C>[CH3:25][Si:10]([CH3:9])([CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23])[CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([OH:17])[CH2:18][NH:8][CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCC1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCCN1CCCC1
Temperature: 70 °C

Procedure:
2-Pyrrolidin-1-yl-ethylamine (4.16 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess 2-pyrrolidin-1-yl-ethylamine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][NH2:16]>CCO>[CH3:15][NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CN
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NC
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (42 g, 181 mmol) in EtOH (400 mL) was treated with a solution of methylamine (12.3 g, 397 mmol) in EtOH (100 mL) at 0° C. and the mixture was stirred for 3 h. The mixture was concentrated and then partitioned between H2O (200 mL) and CH2Cl2 (500 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate as a white solid (36.0 g, 88% yield). 1H NMR (300 MHz, CDCl3): 8.59 (s, 1 H), 8.18 (br s, 1 H), 4.31 (q, J=7.2 Hz, 2 H), 3.05 (d, J=4.8 Hz, 3 H), 2.52 (s, 3 H), 1.34 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 228.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([Cl:27])[N:21]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H-].[Na+].I[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([C:20]3[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([Cl:27])[N:21]=3)[CH2:32][CH2:33][CH3:34])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3C)ccc21
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1nc(Cl)ncc1C
Reaction time: 0.5 h
Yield: 361.4 %

Procedure:
To a solution of ethyl((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 408, 800 mg, 0.25 mmol) in DMF (20 mL) was added portion wise NaH (118 mg, 2.97 mmol, 60% dispersion in mineral oil) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodopropane (0.39 mL, 3.96 mmol) was added. After 18 h of stirring at rt, the excess NaH was quenched by the slow addition of brine (40 mL) [H2 evolution]. The product was then extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (4:1 hexanes/EtOAc) to yield the product (403 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, 3H), 1.30 (t, 3H), 1.65 (t, 2H), 1.74-1.79 (m, 1H), 2.06-2.11 (m, 2H) 2.27 (s, 3H), 2.37-2.45 (m, 2H), 2.70-2.74 (dd, 1H), 2.84-2.91 (m, 2H), 3.45-3.55 (m, 3H), 3.73 (t, 2H), 3.97 (t, 2H), 4.16 (q, 2H), 6.68 (d, 1H), 6.6.74 (s, 1H), 7.05 (d, 1H), 7.79 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[NH2:8].Cl[C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[NH:8][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: COc1cccc(-c2cc(F)c(N)c(F)c2)c1
Reactant: O=C(O)c1cccnc1Cl
Product: COc1cccc(-c2cc(F)c(Nc3ncccc3C(=O)O)c(F)c2)c1

Procedure:
In another embodiment (step c2), the aminium salt of 3,5-difluoro-3′-methoxybiphenyl-4-amine from step b) is optionally, dried or semidried to remove or partially remove the solvent. Subsequently, said aminium salt is hydrolyzed in the presence of water under well-known reaction conditions to 3,5-difluoro-3′-methoxybiphenyl-4-amine and finally, 3,5-difluoro-3′-methoxybiphenyl-4-amine in the amine form is reacted with 2-chloronicotinic acid to obtain 2-[(3,5-difluoro-3′-methoxy-1,1′-biphenyl-4-yl)amino]nicotinic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][C:18]3[NH:19][CH:20]=[N:21][CH:22]=3)[C:12]([Br:23])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH:24](=O)[CH2:25][CH2:26][CH3:27].C([BH3-])#N.[Na+]>CO>[Br:23][C:12]1[C:13]([NH:15][CH2:16][CH2:17][C:18]2[NH:19][CH:20]=[N:21][CH:22]=2)=[N:14][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=2)=[N:10][CH:11]=1
Reactant: CCCC=O
Reactant: Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCNc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.6 %

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-[2-(3H-imidazol-4-yl)-ethyl]-pyrimidine-2,4-diamine (1 g, 2.6 mmole, prepared according to procedure 21) was dissolved in MeOH (10 ml), butanal (2.6 ml, 2.9 mmole) was added at room temperature and the reaction mixture was stirred at room temperature for 20 minutes. Sodium cyanoborohydride (266 mg, 3.6 mmole) was added and the reaction mixture was stirred at room temperature overnight. After extraction with ethylacetate/bicarbonate solution (3×) the combined organic layers were washed with saturated NaCl-solution, dried over magnesium sulfate and evaporated. The crude product was purified by flashmaster chromatography (dichloromethane:MeOH 95:5) to provide 5-Bromo-N2-(4-butylamino-phenyl)-N4-[2-(3H-imidazol-4-yl)-ethyl]-pyrimidine-2,4-diamine (130 mg). ESI-MS: 431.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C@@H:21]3[CH2:23][O:22]3)=[C:14](C(=O)C)[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:29].[OH-].[K+]>C(Cl)(Cl)Cl.CO>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:20][C@@H:21]([CH2:23][OH:22])[O:29][C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OC[C@@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@H](CO)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-benzenesulfonyl-2-(S)-oxiranylmethoxy-phenyl)-ethanone (2.04 g; 0.059 mol) and meta-chloroperoxybenzoic acid (4.13 g; 0.018 mol, max. 77%) in chloroform (20 mL) was heated under reflux for 18 hours. After cooling to ambient temperature the mixture was diluted with chloroform, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. This crude residue (0.85 g; 0.0024 mol) dissolved in methanol (5 mL) was added to a solution of 10% aqueous potassium hydroxide (4 mL) at 0° C. The mixture was stirred for 30 minutes at room temperature. Solvent was removed in vacuo, and the residue was dissolve in ethyl acetate, washed with 10% aqueous hydrochloric acid followed by saturated brine, dried (Na2SO4) and concentrated in vacuo to give (7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(R)-yl)-methanol as an oil (1.44 g; 77%): MS (M+H)+ 307.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][NH2:20])[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][NH:20][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCCc1cccc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
Benzenesulfonyl chloride (1.54 mL, 12.00 mmol) was added to [2-(3-bromophenyl)ethyl]amine (2.00 g, 10.00 mmol) and N,N-di-iso-propylethylamine (5.22 mL, 29.99 mmol) in dichloromethane (33 mL) at 0° C. under argon and the reaction was allowed to warm to room temperature and stirred for 16 hours. The dichloromethane was concentrated under vacuum; diethyl ether was then added, followed by 10% citric acid. The solution was extracted with diethyl ether and the organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:4 ethyl acetate:hexanes to give 3.22 g (95%) of N-[2-(3-bromophenyl)ethyl]benzenesulfonamide as a solid. 1H NMR (400 MHz, d6-DMSO): δ 7.77-7.73 (m, 2H), 7.70 (t, J=6 Hz, 1H), 7.62 (d, J=7 Hz, 1H), 7.57 (t, J=8 Hz, 2H), 7.40-7.34 (m, 2H), 7.22 (t, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 2.96 (q, J=7 Hz, 2H), 2.67 (t, J=7 Hz, 2H). ESI-LCMS m/z 340 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]3[CH:27]=[N:26]2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:11][CH:12]=1)[C:3]([OH:6])([CH3:5])[CH3:4].C([O-])(=O)C.[NH4+:42].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[CH3:35][O:34][C:33]1[CH:32]=[CH:31][N:30]=[C:29]2[N:25]([CH:17]([C:16]3[NH:42][C:13]([C:10]4[N:11]=[CH:12][C:7]([CH:2]([OH:1])[C:3]([CH3:5])([OH:6])[CH3:4])=[CH:8][CH:9]=4)=[CH:14][CH:15]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:26]=[CH:27][C:28]=12
Reactant: COc1ccnc2c1cnn2C(CC1CCOCC1)C(=O)CCC(=O)c1ccc(C(O)C(C)(C)O)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccnc2c1cnn2C(CC1CCOCC1)c1ccc(-c2ccc(C(O)C(C)(C)O)cn2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A mixture of 1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-5-(4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (265 mg), ammonium acetate (200 mg), acetic acid (0.20 mL) and ethanol (10 mL) was stirred at room temperature for 6 hr. The reaction solution was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (178 mg, yield 58%) as a colorless amorphous solid from the fraction eluted with ethyl acetate. MS: 492 (MH+).