Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][C:12]2[S:13][C:14]([S:17][CH3:18])=[N:15][N:16]=2)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])[CH3:3].B(O[O-])=[O:25].[Na+]>C(O)(=O)C.CCOCC>[CH3:20][C:19]([C:7]1[CH:8]=[C:9]([S:11][C:12]2[S:13][C:14]([S:17]([CH3:18])=[O:25])=[N:15][N:16]=2)[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:23])([CH3:22])[CH3:21]
Reactant: O=BO[O-]
Reactant: CSc1nnc(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CS(=O)c1nnc(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A solution of 2,6-bis(1,1-dimethylethyl)-4-[[5-(methylthio)-1,3,4-thiadiazol-2-yl]thio]phenol (0.25 g, 0.68 mmol) and sodium perborate (0.11 g, 0.71 mmol) in acetic acid (20 mL) is stirred at room temperature for 7 hours then stored at 0° C. overnight. The reaction mixture is diluted with ether and washed three times with water, then with a saturated solution of sodium bicarbonate and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a white solid which is chromatographed on silica gel eluting with a gradient of ethyl acetate:hexane (1:9, 2:8, 3:7, then 1:1) yielding 0.16 g (61%) of 2,6-bis(1,1-dimethylethyl)-4-[[5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl]thio]-phenol; mp 162.0°-163.5° C.
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:15]3=[O:26])[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[OH:34][C@@H:29]1[CH2:30][CH2:31][CH2:32][CH2:33][C@H:28]1[NH:27][C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:15]3=[O:26])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CS(=O)c1nc2ccc(Cn3ccnc(N4CCOCC4)c3=O)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=c1c(N2CCOCC2)nccn1Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 130 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
A mixture of 1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3-morpholino pyrazin-2(1H)-one (250 mg, 0.64 mmol), (1R,2R)-2-aminocyclohexanol (221 mg, 1.92 mmol) and DIEA (248 mg, 1.92 mmol) in DMA (6.6 mL) was stirred at 130° C. for 16 h. The reaction mixture was cooled to rt and poured into water (30 mL). The mixture extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one as a light yellow solid (120 mg, 26.5%). 1H NMR (300 MHz, DMSO-d6) δ 7.96 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.18-7.22 (m, 2H), 6.90 (d, J=4.8 Hz, 1H), 5.01 (s, 2H), 4.72 (d, J=5.1 Hz, 1H), 3.65 (s, 8H), 3.55-3.52 (m, 1H), 3.36-3.31 (m, 1H), 2.07-2.02 (m, 1H), 1.90-1.86 (m, 1H), 1.63-1.62 (m, 2H), 1.30-1.22 (m, 4H). LCMS (ESI) m/z 442 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([OH:14])=[O:13])[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)Cc1cccc2ccncc12
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl 2-(isoquinolin-8-yl)acetate (1.8 g) in DCM (10 mL) was added TFA (10 mL) dropwise. The reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was removed to give a residue which was adjusted to pH 3-4 with aqueous ammonia. The precipitate was filtered off and washed with water. The final product was purified (silica gel coulumn chromatography) to afford 2-(isoquinolin-8-yl)acetic acid as a solid (1.2 g, 87%). LC-MS (0.05% TFA): [M+1]+ 188.1. 1H-NMR (DMSO-d6, 400 MHz): 613.0 (brs, 1H), 9.65 (s, 1H), 8.61 (d, 1H, J=4.8 Hz), 8.16 (d, 1H, J=4.8 Hz), 8.05 (d, 1H, J=6.8 Hz), 7.92 (t, 1H), 7.72 (d, 1H, J=6.8 Hz), 4.29 (s, 2H).
Reaction SMILES: N([O-])=O.[K+].N[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([F:14])[C:7]=1[CH3:15].[BrH:16].[OH-].[Na+]>CS(C)=O.[Cu]Br.O>[Br:16][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([F:14])[C:7]=1[CH3:15]
Reactant: Cc1c(N)ccc(C#N)c1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(Br)ccc(C#N)c1F
Yield: 80 %

Procedure:
A mixture of dimethyl sulfoxide (400 mL) and potassium nitrite (22.67 g, 266 mmol) was stirred to dissolve potassium nitrite and 4-amino-2-fluoro-3-methylbenzonitrile (10 g, 66.6 mmol) and copper(I) bromide (1.911 g, 13.32 mmol) were added. Aqueous 48% hydrogen bromide (33 mL, 266 mmol), diluted with dimethyl sulfoxide (200 mL), was added dropwise and the reaction stirred for 2 h. After complete conversion of starting material, the reaction mixture was poured into iced-cold water and neutralized to pH 7 with cold concentrated sodium hydroxide. The resulting solid was collected by filtration to give the desired product (11.4 g, 53.3 mmol, 80% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.47 (d, J=9.37 Hz, 1H), 7.33 (t, 1H), 2.39 (d, J=2.34 Hz, 3H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccn3)c(=O)n12
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc2nc(C(C)N)c(-c3ccccn3)c(=O)n12
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.012 g, 0.039 mmol) in tetrahydrofuran (0.1 mL) and water (0.0285 mL) was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.047 mmol) at room temperature and stirred for 1 hour. To the mixture was added EtOAc and the mixture was extracted twice with 1N HCl. The combined extracts were neutralized with solid sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step. LCMS calculated for C14H15N4OS (M+H)+: m/z=287.1. Found: 287.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Br:11][C:12]1[N:13]([CH3:24])[C:14]([CH2:22]Br)=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1>CN(C)C=O>[Br:11][C:12]1[N:13]([CH3:24])[C:14]([CH2:22][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)c1nc(Br)n(C)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Br)n(C)c1COc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorophenol (1.73 g) in dry N,N-dimethylformamide (60 ml) was added 60% sodium hydride (0.535 g) in small portions. After the addition was complete the resultant solution was stirred at room temperature for 1 h. The product of step (i) (4.0 g) was added and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic phase was washed with saturated potassium carbonate solution (×2), saturated brine (×2) and dried (MgSO4). The solvent was removed under reduced pressure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[C:7]=1[NH2:20])C.C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:19][C:15]1[CH:14]=[C:13]([NH:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]3[C:7]=2[NH:20][C:4](=[O:3])[CH2:5]3)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1cccc(Nc2cccc(N)c2)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cccc(Nc2cccc3c2NC(=O)C3)c1

Procedure:
[2-Amino-3-(3-amino-phenylamino)-phenyl]-acetic acid ethyl ester (0.50 g, 1.7 mmol) is refluxed in 1 N hydrochloric acid for 30 minutes. The reaction mixture is cooled to room temperature and basified with saturated Na2CO3. The mixture is then extracted with ethyl acetate (30 ml×3). The organic layers are combined, dried with Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluted with ethyl acetate-methanol with 0.5% NH3) to give the desired compound. 1H NMR (DMSO-d6) δ 4.93 (s, 2H), 6.06 (d, 1H, J=6.8 Hz), 6.14 (d, 1H, J=8.0 Hz), 6.21 (s, 1H), 6.78 (d, 1H, J=7.2 Hz), 6.85 (t, 2H, J=8.0 Hz), 6.97 (s, 1H), 7.05 (d, 1H, J=8.0 Hz), 9.96 (s, 1H); LC-MS: 240.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][C:14]#[N:15])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21]>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: N#CCOc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: CCN1CCc2ccc(N)cc2CC1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cccc(OCC#N)c4)n3)cc2CC1

Procedure:
The title compound was prepared from [3-(2,5-dichloropyrimidin-4-ylamino)-phenoxy]acetonitrile and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 195 (microwave: 130° C., 2 hours) to afford a white foam (30 mg, 40%). Mp: 104-6° C. LCMS (m/e) 449 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.81 (s, 1H), 7.30 (m, 4H), 7.12 (s, 1H), 7.06 (m, 2H), 6.76 (d, J=6 Hz, 1H), 4.68 (s, 2H), 2.90 (m, 4H), 2.70-2.55 (m, 6H), 1.12 (t. J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:20][CH2:19][CH2:18][C@H:13]2[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].CC(O)=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:20][CH2:19][CH2:18][C@H:13]2[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
N-(3,5-dichlorobenzenesulfonyl)-(L)-proline, methyl ester from Step A was dissolved in ethanol (50 mL) and treated with 0.2N sodium hydroxide (26.6 mL) for 1.5 h at rt. The mixture was acidified with glacial HOAc, concentrated by rotoevaporation, and the residue dissolved in CH2Cl2, washed with water, saturated brine solution, dried over anhydrous Na2SO4, and evaporated to give the title compound; yield 1.4 g.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]2[N:27]=[C:28](Br)[S:29][C:23]=2[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]2[N:27]=[C:28]([O:11][CH:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:10][CH2:9]3)[S:29][C:23]=2[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Reactant: OC1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(OC3CCN(C4CCC4)CC3)sc2C1
Yield: 56.5 %

Procedure:
1-Cyclobutyl-piperidin-4-ol (1.6 grams, 10 mmol) in tetrahydrofuran (20 mL) was treated with cooled and stirred suspension of sodium hydride (0.9 grams, 18 mmol) in tetrahydrofuran (20 mL) slowly over a period of 30 minutes; the reaction mixture was stirred for 1 hour. A solution of 2-Bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (3 grams, 9 mmol, obtained in preparation 1) in tetrahydrofuran (30 mL) was added drop wise over a period of 15 minutes and refluxed the reaction for 6 hours. Reaction mass was quenched with ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (ethylacetate/n-hexane, 1/1) to obtain the title compound (2.0 grams).
Reaction SMILES: [CH2:1]([C:3]1([CH2:48][CH3:49])[C:6](=[O:7])[N:5]([C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])=[O:9])[CH:4]1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([O:40]CC3C=CC=CC=3)[CH2:36][CH2:35]2)=[O:30])=[CH:25][CH:24]=1)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:48]([C:3]1([CH2:1][CH3:2])[C:6](=[O:7])[N:5]([C:8]([NH:10][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13][CH3:14])=[O:9])[CH:4]1[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH2:39]2)=[O:30])=[CH:27][CH:28]=1)[CH3:49]
Reactant: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)NCCN2CCC(OCc3ccccc3)CC2)cc1)c1ccc(C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)NCCN2CCC(O)CC2)cc1)c1ccc(C)cc1

Procedure:
A solution of the amide from step A above in 10 ml of glacial acetic acid containing 22 mg of 10% Pd/C is hydrogenated under 42 lb hydrogen pressure. When TLC indicate completion of the reaction, the mixture is filtered and concentrated in vacuo after the addition of 50 ml toluene. The residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution. The organic layer is dried with sodium sulfate and concentrated in vacuo. The residue is chromatographed on 15 g silica gel using 5% methanol in methylene chloride and yields 96 mg of
Reaction SMILES: [Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:20][C@H:21]3[CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([C:33]([O:35][CH3:36])=[O:34])[CH2:22]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][C:9]([C:18]#[N:19])=[CH:8]3)[CH:3]=1.[ClH:37]>C(Cl)Cl>[ClH:37].[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:20][C@H:21]3[CH2:25][NH:24][C@H:23]([C:33]([O:35][CH3:36])=[O:34])[CH2:22]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][C:9]([C:18]#[N:19])=[CH:8]3)[CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(C#N)ccc3c3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(C#N)ccc3c3cc(OC)c(Br)cc23)CN1
Reaction time: 0.5 h

Procedure:
To a solution of the product mixture from Step 1, 1-tert-butyl 2-methyl (2S,4R)-4-[(8-bromo-3-cyano-9-methoxyphenanthridin-6-yl)oxy]pyrrolidine-1,2-dicarboxylate (419 mg, 0.75 mmol) in DCM (10 mL) was bubbled HCl(g) for 20 min. After stirring for an additional 30 min, the solvent was removed in vacuo to yield methyl (4R)-4-[(8-bromo-3-cyano-9-methoxyphenanthridin-6-yl)oxy]-L-prolinate hydrochloride, which was taken up in DCM (5 mL) and linker intermediate B21, (2S)-cyclopentyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acid (234 mg, 0.83 mmol), TEA (0.314 mL, 2.25 mmol), EDC (187 mg, 0.98 mmol), and HOBT (149 mg, 0.98 mmol) were added. The mixture was stirred at r.t. for 18 h, the solvent was removed in vacuo, and the residue was taken up in EtOAc and extracted with NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 0-10% EtOAc/MeOH/NH3) to yield the title compound. LRMS (M+H)+=721.4.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][C@H:14]([N:18]2[C:24](=[O:25])[CH2:23][CH2:22][NH:21][C@H:20]([CH3:26])[CH2:19]2)[CH2:15][O:16][CH3:17])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:27][C:28]1[CH:29]=[C:30]([N:35]=[C:36]=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([NH:35][C:36]([N:21]2[CH2:22][CH2:23][C:24](=[O:25])[N:18]([C@H:14]([CH2:15][O:16][CH3:17])[CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:7][CH2:6]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:19][C@H:20]2[CH3:26])=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)NCCC1=O
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2ccc(Cl)c(Cl)c2)CCC1=O
Yield: 74 %

Procedure:
In analogy to the procedure described for intermediate 58F, (R)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 65H) and 3,4-dichlorophenyl isocyanate gave the title compound in 74% yield as white solid. MS: 527.2 (MH+, 2Cl).
Reaction SMILES: Cl[C:2]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[B:14]1([OH:24])[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[CH2:16][O:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:24][B:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:2]3[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)=[CH:22][C:17]=2[CH2:16][O:15]1
Reactant: COCOc1cc(C#N)cnc1Cl
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)cnc1Oc1ccc2c(c1)COB2O
Temperature: 80 °C
Yield: 37.5 %

Procedure:
To a mixture of 6-chloro-5-methoxymethoxy-nicotinonitrile (0.68 g, 3.42 mmol) and 3H-benzo[c][1,2]oxaborole-1,5-diol (0.56 g, 3.76 mmol) in DMF (10 mL) was added cesium carbonate (2.45 g, 7.52 mmol). The resulting suspension was heated at 80° C. for overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by flash chromatography on silica gel using 1-100% MeOH/EtOAc gradient elution to yield the title compound (0.40 g, 40%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1 H), 8.24 (s, 1 H), 8.03 (s, 1 H), 7.77 (d, J=8.6 Hz, 1 H), 7.23 (s, 1 H), 7.14 (d, J=7.4 Hz, 1 H), 5.40 (s, 2 H), 4.98 (s, 2 H), 3.45 (s, 3 H); MS (ES) m/z: 313 (M+1)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:50])[C@@H:15]([O:48][CH3:49])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:19][C:18]=1[O:38][Si](C)(C)C(C)(C)C(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-]>CO.CCOC(C)=O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:50])[C@@H:15]([O:48][CH3:49])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:29][C:30]=2[CH3:31])=[CH:19][C:18]=1[OH:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O[Si](C)(C)C(C)(C)C(C)C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (S)-4-benzyl-3-(3-{2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(2S)-methoxy-propionyl)-oxazolidin-2-one (1.6 g, 2.29 mmol) in 10 ml methanol, was added NH4F (169 mg, 4.58 mmol) and the reaction mixture kept at r.t. for 2 hours. It was then diluted with AcOEt, washed with water/ice and brine, the aqueous layer was extracted with AcOEt, the combined organic layers dried over Na2SO4 and evaporated. The crude product (1.22 g) was found to be a mixture of the title compound and of (S)-3-{2-hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionic acid methyl ester and used without purification for the last step.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCCCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCCO)cn1
Yield: 84 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 3-amino-1-propanol instead of 2-aminoethyl isopropylether, to the title compound (200 mg, 84%) which was obtained as a colourless oil. MS: m/e=368.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[C:5]([F:14])=[CH:4][N:3]=1.[CH2:15]1[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=2[O:16]1>>[CH2:15]1[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:19]([NH:20][C:2]3[N:7]=[C:6]([NH:8][N:9]4[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]([F:14])=[CH:4][N:3]=3)=[CH:18][C:17]=2[O:16]1
Reactant: Fc1cnc(Cl)nc1Nn1cccc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nn1cccc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with 3,4-ethylenedioxyaniline to produce N2-(3,4-ethylenedioxyphenyl)-5-Fluoro-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 11.63 (s, 1H), 9.94 (s, 1H), 8.23 (d, 1H, J=4.7 Hz), 6.86 (m, 4H), 6.58 (d, 1H, J=8.8 Hz), 6.12 (t, 2H, J=2.3 Hz), 4.15 (s, 4H). LCMS: ret. time: 17.36 min.; purity: 96%; MS (m/e): 328 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]=1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Reactant: CCOC(=O)c1ccc(CN)nc1
Agent: Cl
Product: CCOC(=O)c1ccc(CNC(=O)c2cc(Cl)cnc2N2CC(Oc3cccc(F)c3)C2)nc1

Procedure:
The title compound (D158) (59 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (50 mg, 0.154 mmol) and ethyl 6-(aminomethyl)nicotinate hydrochloride (33.56 mg, 0.154 mmol, commercially available at Chemimpex#23882).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Br:34]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[Br:34][C:4]1[CH:3]=[N:2][N:1]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=1
Reactant: c1cncc(-n2cccn2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Brc1cnn(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Pyrazol-1-ylpyridine (500 mg, 3.44 mmol) was dissolved in acetonitrile (15 ml), and ammonium cerium(IV) nitrate (944 mg, 1.72 mmol) was added (slightly exothermic). N-Bromosuccinimide (736 mg, 4.13 mmol) was added in portions (slightly exothermic) and the mixture was stirred at room temperature for 30 minutes (min) and then heated under reflux for 3 hours (h). After the mixture had cooled, ethyl acetate was added. The organic phase was washed with water, washed with a sodium sulphate solution and then dried over magnesium sulphate. The solvent was removed on a rotary evaporator under reduced pressure.