Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:35][CH2:36][C:37](=N)OCC.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>ClCCCl>[Si:27]([O:26][CH2:25][C@@H:13]([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:37]1[CH2:36][Cl:35])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 73.3 %

Procedure:
tert-Butyl (4S)-4-[(3-aminoquinolin-4-yl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate (1.65 g, 3.48 mmol) was dissolved in 35 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (1.18 g, 7.47 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated NaHCO3 solution and 100 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 25-100% ethyl acetate/hexanes) gave tert-butyl (4S)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentylcarbamate (1.36 g) as a golden foam.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26](=[O:27])[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([C:9]3[N:13]=[CH:12][N:11]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=4)[N:10]=3)=[CH:5][CH:4]=2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: CNc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 60.7 %

Procedure:
A suspension of 4-[1-(4-trifluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine (1.2 g, 3.7 mmol) in EtOH (4 mL) was treated with 1H-benzotriazole (0.48 g, 4.0 mmol) and formaldehyde (0.5 mL of 37% aqueous, 6 mmol), and the solution was heated to 40° C. for 10 min. Upon cooling, a solid formed, which was collected by filtration. There was obtained 1.33 g of the triazole adduct as a light yellow solid, mp 185-187° C. This material (1.2 g, 2.66 mmol) was dissolved in THF (20 mL) and treated with NaBH4 (0.11 g, 2.9 mmol). The solution was stirred at ambient temperature for 30 min, then heated to reflux for 1 h. After cooling, the solution was poured onto water (30 mL) and extracted with ether. Drying and concentration, followed by silica gel chromatography (75:25 Hexanes:EtOAc) furnished methyl-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-amine (0.76 g, 86%) as a white solid, mp 121-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.78 (d, J=9.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 6.68 (d, J=8.8 Hz, 2H), 3.96 (s, 1H), 2.91 (s, 3H); ELMS m/z 499 (M+). A portion of this amine (0.11 g, 0.33 mmol) was dissolved in dry THF (2 mL) and treated with 4-nitrophenyl chloroformate (0.069 g, 0.34 mmol). The solid which formed over 10 min was collected by filtration and air-dried to give an off-white solid (0.10 g): mp 145-147° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.28 (d, J=8 Hz, 4H), 7.8 (d, J=8 Hz, 2H), 7.50-7.3 (m, 6H) 3.55 (s, 3H); EIMS m/z 499 (M+).
Reaction SMILES: O[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc(-c3nc(C)cs3)c(=O)n(C)c2O)cc1
Product: COc1ccc(-c2cc(-c3nc(C)cs3)c(=O)n(C)c2Cl)cc1
Reaction time: 1.5 h

Procedure:
6-Hydroxy-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one (0.13 g) was dissolved in freshly distilled POCl3 (5 cm3) under N2 and heated to refiux for 1.5 h. The excess reagent was then removed by evaporation and the residue partitioned between ethyl acetate (100 cm3) and saturated sodium bicarbonate solution (50 cm3). The aqueous layer was washed with ethyl acetate (2×100 cm3) and the combined organic phase dried (MgSO4) and evaporated. Purification on silica gel eluting with ethyl acetate-hexane mixtures afforded 6-chloro-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one as a yellow powder. δH (250 MHz; CDCl3); 2.49 (3H, s), 3.86 (3H, s), 3.93 (3H, s), 6.96 (2H, d, J8.7 Hz), 7.01 (1H, s) 7.33 (2H, d, J8.7 Hz) and 8.60 (1H, s).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:18]=[N:17][C:16]=2[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:29]([C:16]1[N:17]=[N:18][C:19]([O:21][CH:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 4-(4-benzyloxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine (Example 1, 14 mmol, 6.04 g) in methanol/ethyl acetate (100 mL, 1/1) was added 10% palladium on activated carbon (10% by weight, 0.60 g). The mixture was repeatedly de-gassed under vacuum, filled with hydrogen for 3 times. Then hydrogen balloons were attached to the reaction, which was stirred at room temperature for 2 hours. TLC/LCMS monitored to completion. The mixture was then filtered through celite, the celite cake was washed with 1/1 methanol/ethyl acetate for 3 times, and the organic layers were combined and condensed to give 4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-phenol as a white powder (4.06 g, 85% yield), which was used directly in the next step.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:17].O>C(OCC)C>[Br:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OC(Cc1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: BrC(Cc1ccccc1)c1ccccc1
Temperature: -10 °C
Yield: 84 %

Procedure:
To a solution of 12.0 (60.5 mmol) of 1,2-diphenylethanol in 50 mL of dry diethyl ether, 11.0 g (3.80 mL, 40.0 mmol) of PBr3 was added with vigorous stirring at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 350 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and evaporated to dryness. This procedure gave 13.2 g (84%) of the title product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)[CH3:8])[CH:2]=1.CI.[O-][CH2:20]C.[Na+]>C(O)C>[CH3:20][S:15][C:12]1[NH:11][C:10](=[O:16])[C:9]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH3:8])=[CH:14][N:13]=1
Reactant: CC[O-]
Reactant: CC(c1cccnc1)c1c[nH]c(=S)[nH]c1=O
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1ncc(C(C)c2cccnc2)c(=O)[nH]1

Procedure:
Treatment of 5-(1-(3-pyridyl)ethyl)-2-thiouracil with methyl iodide and sodium ethoxide in ethanol at 0°, followed by acidification gave 2-methylthio-5-[1-(3-pyridyl)ethyl]-4-pyrimidone m.p. 201°-204°.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:42])[NH:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[CH:30][C:29]=2[F:41])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:34][C:33]1[CH:32]=[C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:29]([F:41])[C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:14])([CH3:42])[N:27]1[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cc(F)c(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Reaction time: 24 h
Yield: 56.5 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (0.339 g, 1.51 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate (0.3 g, 0.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.458 ml, 2.65 mmol) in 1,4-dioxane (2 ml). The stirring was continued for 24 hours then the volatiles were removed under vacuum and the crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane. Pre fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (0.202 g, 36%) as a white solid. The material was combined with another batch (0.36 g) and purified by preparative HPLC (Chiralpak IA column, 20 μm silica, 20 mm diameter, 250 mm length), Heptane:IPA 70:30 at 80 ml/min (4 injections). Fractions containing the desired compounds were evaporated to yield (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1, first eluted, 217 mg) and (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 2, second eluted, 165 mg). Analysis was done on Chiralpak IA column, 5 μm silica, 4.6 mm diameter, 50 mm length, Heptane:IPA 70:30 at 2 ml/min. 1H NMR (400 MHz, DMSO, 30° C.) δ 0.50 (3H, d), 1.02 (3H, s), 1.30 (3H, s), 2.11 (1H, dd), 2.62 (2H, d), 2.80 (1H, d), 2.99 (1H, dd), 3.74 (3H, s), 4.09-4.23 (1H, m), 4.29 (1H, d), 5.09 (1H, s), 6.81 (1H, d), 6.97 (2H, dt), 7.16 (1H, d), 7.39 (1H, d), 7.53 (2H, d), 7.64 (1H, d), 10.44 (1H, s). m/z: ES+ [M+H]+ 471.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH:9]([CH2:12][NH2:13])[C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1[C:11]2[CH2:10][CH:9]([CH2:12][NH:13][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][OH:24])[C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCC1Cc2ccccc2Cc2ccccc21
Reactant: O=C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(CCCCO)NCC1Cc2ccccc2Cc2ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine, γmaxCHCl3 3390, 3300 cm-1, (52.3 g, 0.234 mole), is combined with δ-valerolactone (35 g, 0.35 mole). The mixture is heated for 2 hr. at 150° C (oil bath temperature). After partial cooling, ethanol (250 ml) is added followed by a solution of potassium carbonate (50 g, 0.36 mole) in water (150 ml). The two-phase mixture is stirred at 60° C overnight. The ethanol is removed under reduced pressure and the residual mixture extracted with chloroform. The chloroform solution is washed with water, dried and taken to dryness. The residue is crystallized from benzene (750 ml) -ether (ca 800 ml) affording N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)methyl]-5-hydroxyvaleramide, m.p. 96° - 98° C, γ maxCHCl3 3630, 3445, 3350, 1663 cm-1.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH2:2][S:1][C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a mixture of methyl mercaptoacetate (5.30 g, 50 mmol) and triphenylmethanol (13.0 g, 50 mmol) in chloroform (20 mL) was added trifloroacetic acid (5 mL) in 5 min. After stirring at room temperature for 1 h, the volatiles were removed in vacuo. The crude product was purified by recrystallization (dichloromethane/Hexane=1/2) to provide Tritylsulfanyl-acetic acid methyl ester (15.9 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.44-7.38 (m, 6H), 7.34-7.18 (m, 9H), 3.58 (s, 3H), 2.98 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:35][CH2:34][CH2:33][C@@H:29]1[C:30]([OH:32])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:28]1[CH2:35][CH2:34][CH2:33][C@@H:29]1[C:30]([OH:32])=[O:31]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C(O)[C@H]1CCCN1Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (96.1 mg, 0.257 mmol) and D-(+)-proline (88.6 mg, 0.770 mmol) according to Reference R and the general procedure for reductive amination to give (R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)pyrrolidine-2-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.2 (M++1).
Reaction SMILES: O.O.[NH2:3][CH:4]([C:8]1[N:9]=[C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[S:11][CH:12]=1)[C:5]([OH:7])=[O:6].Cl[C:25]([N:27]1[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[C:28]1=[O:36])=[O:26]>C1COCC1.O>[O:36]=[C:28]1[N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:30][CH2:31][N:27]1[C:25]([NH:3][CH:4]([C:8]1[N:9]=[C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[S:11][CH:12]=1)[C:5]([OH:7])=[O:6])=[O:26]
Reactant: NC(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCN(C(=O)NC(C(=O)O)c2csc(NC(=O)OCc3ccccc3)n2)C1=O

Procedure:
The compound is prepared analogously to Example 6 (a) from 15 g of α-amino-α-(2-benzyloxycarbonylamino-thiazol-4-yl)-acetic acid dihydrate in THF/water (1:1) and 10.9 g 1-chlorocarbonyl-2-oxo-3-methylsulfonyl-imidazolidine in a pH-range from 7.5 to 8.0. 14.1 g (65% of theory) are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[CH3:14][Sn](C)(C)C.C(Cl)(Cl)Cl>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: C[Sn](C)(C)C
Reactant: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Temperature: 140 °C
Reaction time: 12 h
Yield: 74.1 %

Procedure:
To a solution of 7-bromo-5-nitroindoline (0.65 g, 2.7 mmol) in 10 mL of DMF were added tetramethyltin (1.0 mL, 7.3 mmol) and bis(triphenylphosphine) palladium(II) chloride (0.10 g) in a portion and resulting mixture was stirred in sealed tube for 12 h at 140° C. The reaction mixture was concentrated in vacuo, providing a dark oily residue which was subjected to column chromatography (CHCl3, neat) to yield 0.35 g (2.0 mmol, 74%) of the desired product.
Reaction SMILES: C[O-].[Na+].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:19][CH2:20][CH2:21][CH2:22]Br>CO>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:22][CH2:21][CH2:20][Br:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: BrCCCBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: Clc1ccc(-c2ccc(OCCCBr)cc2)cc1

Procedure:
A methanolic solution of sodium methoxide prepared by dissolving sodium (35.7 g) in anhydrous methanol (300 ml) was treated with 4-(4-chlorophenyl)phenol (311 g) and the resulting solution was added to a stirred solution of 1,3-dibromopropane (850 ml) in anhydrous methanol (500 ml) at reflux during a period of 6 hours. The mixture was stirred at reflux for a further period of 18 hours and was then evaporated to dryness in vacuo. The crystalline residue was triturated with petroleum ether (b.p. 40°-60° C.), filtered off and dried, and was then triturated with aqueous potassium hydroxide solution (1500 ml; 5% w/v), filtered off, washed well with water and dried. The solid was subjected to fractional crystallisation from a mixture of isopropanol and acetone. The first crop was discarded. The second crop (161 g) was dissolved in acetone, filtered, and evaporated. The third crop (53 g) was recrystallised from ethanol. The fourth crop was recrystallised from isopropanol and then twice from ethanol. The purified second, third and fourth crops were combined and dissolved in acetone, and the solution was filtered through diatomaceous earth. It was concentrated in vacuo to a volume of 300 ml and was then diluted with a mixture of methanol (200 ml) and water (500 ml). The resulting solid was filtered off and washed with water to give 3-[4-(4-chlorophenyl)phenoxy]propyl bromide (194 g), m.p. 103°-105° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1.Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](Cl)=[O:31].C(=O)([O-])[O-].[K+].[K+].CCC(C)=O>O>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C(Cl)c1ccccn1
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1nc(NC(=O)c2ccccn2)ccc1Oc1nc(OC)cc(OC)n1
Yield: 40.7 %

Procedure:
2.0 g (6.5 mmol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate, 1.2 g (6.5 mmol) of picolinoyl chloride hydrochloride and 2.0 g (14.8 mmol) of potassium carbonate were added to 30 ml of MEK, and the mixture was refluxed for 6 hours under stirring. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off to obtain crude crystals. The crude crystals were washed with diisopropyl ether-ethyl acetate to obtain the desired product as colorless needle-like crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:12]
Reactant: NCCOCCO
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C(=O)NCCOCCO)cc21
Yield: 51.5 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (50 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid (80 mg), 2-(2-amino-ethoxy)-ethanol (24 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 495.5.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]/[CH3:22]>>[C:14]1([C@@H:12]([N:8]2[C:6]3=[N:7][C:2](/[CH:20]=[CH:21]\[CH3:22])=[CH:3][N:4]=[C:5]3[N:10]=[C:9]2[OH:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C/C=C\B(O)O
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Product: C/C=C\c1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 90 °C
Yield: 63 %

Procedure:
A scintillation vial equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), (Z)-prop-1-enyl boronic acid (2.0 equiv) and (DPPF)PdCl2 (0.10 equiv). The vial was fitted with a septum-lined cap and purged with nitrogen for 5-10 min. To this mixture was added dioxane (16.6 volume equivalents) and degassed 2 N K2CO3 (4.2 volume equivalents) by syringe. The resulting mixture was heated to 90° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with twice with saturated aq. NaHCO3, and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound (63%) as an off-white foam. LCMS m/z (APCI)=281.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]2)[C:5]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:4]([CH3:30])[N:3]=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]2)[C:5]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:4]([CH3:30])[N:3]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(CC(N)=O)CC1
Reactant: Cc1cccc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN(CC(N)=O)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-{4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piperazin-1-yl}-acetamide (20 mg, 0.05 mmol), 2,6-dimethylphenylboronic acid (21 mg, 0.14 mmol) and 2 M sodium carbonate (0.14 mL, 0.28 mmol) in dioxane (1 mL) is degassed with bubbling argon for 20 min. Pd(PPh3)4 (2.9 mg, 5 mol %) is added and the reaction mixture is heated at 100° C. under nitrogen with magnetic stirring. After 18 h, the reaction mixture is partitioned between EtOAc (10 mL) and water (2 mL), the organic layer is separated, washed with brine (2 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain a dark oil. Purification on silica gel (3% MeOH/CH2Cl2/0.1% NH4OH) provides the title compound as a colorless film. LC/MS (Method 3), M+H=502.3, Rt=2.43 min.; 1H NMR (CDCl3) δ=7.07-7.19 (m, 4H), 6.82 (m, 2H), 5.44 (br s, 1H), 4.97 (s, 2H), 3.57 (br s, 4H), 3.02 (s, 2H), 2.91 (m, 1H), 2.62 (m, 4H) 2.56 (s, 3H), 2.22 (s, 3H), 2.16 (s, 6H), 1.28 (d, 6H).