Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.CC([O-])(C)C.[K+].[C:22](=[O:24])=[O:23]>CCCCCC.C1COCC1.C(OCC)C.O>[F:6][C:7]1[C:15]([C:22]([OH:24])=[O:23])=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: O=C=O
Reactant: Fc1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(F)ccc2cc[nH]c12
Temperature: 15 °C
Reaction time: 0.08 h

Procedure:
60 ml THF were cooled down to −60° C. under argon and 27 ml of a 1.6M n-BuLi solution (42.9 mmol) in hexane were added followed by 2.9 g of 6-fluoro-1H-indole (21 mmol) in 12 ml THF (addition over 25 min, temperature between −72 and −70° C.). After 5 min additional stirring at this temperature, a solution of 4.8 g of potassium tert-butylate (42.9 mmol) in 18 ml THF were added at the same temperature over 30 min. The reaction mixture was then stirred for 2 h at −72° C. and then treated with a large excess of solid CO2 over 1.5 h (temperature raised by 15° C.). To the brown/orange suspension, 40 ml of water were added, and after addition of diethylether the phases were separated, the aqueous phase extracted with 2× diethylether. Finally the aqueous phase was treated with conc HCl until pH 1 and extracted twice with diethylether. The combined organic phases were then washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, and crystallized from diethylether/hexane, leading to 1.9 g 6-fluoro-1H-indole-7-carboxylic acid, as a light brown solid (51%). MS: 177.9 (M−H)−
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:15][S:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)(C)C>[CH2:12]([NH:11][C:4]1[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:25][CH:24]=2)[N:3]=1)[CH:14]=[CH2:13]
Reactant: Clc1nc(NC2CC2)c2occc2n1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: C=CCNc1nc(Nc2ccc(S(C)(=O)=O)cc2)nc2ccoc12
Temperature: 100 °C
Yield: 27.8 %

Procedure:
A vial was charged with 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (0.09 g, 0.429 mmol, Preparation #A.1), 4-(methylsulfonyl)aniline (0.077 g, 0.451 mmol, Oakwood), X-Phos (0.020 g, 0.043 mmol), Pd2dba3 (0.020 g, 0.021 mmol), K2CO3 (0.062 g, 0.451 mmol) and t-BuOH (3.5 mL). The vial was purged with argon and heated at about 100° C. overnight. The mixture was diluted with CHCl3 (about 10 mL) passed through a SiCO3 SPE cartridge and concentrated. The crude product was purified by preparative reverse phase HPLC (Table 2, Method a) to provide N4-allyl-N2-(4-(methylsulfonyl)phenyl)furo[3,2-d]pyrimidine-2,4-diamine (0.041 g, 27%): 1H NMR (DMSO-d6) δ 9.53 (s, 1H), 8.11 (d, J=2.1 Hz, 1H), 8.02 (m, 3H), 7.72 (d, J=8.9 Hz, 2H), 6.80 (d, J=2.1 Hz, 1H), 6.00 (ddd, J=17.1, 10.2, 5.1 Hz, 1H), 5.22 (dd, J=17.1, 1.6 Hz, 1H), 5.11 (dd, J=10.5, 1.6 Hz, 1H), 4.14 (dd, J=5.1 Hz, 2H), 3.11 (s, 3H). Syk IC50=B.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C([O-])([O-])=[O:16].[Na+].[Na+].OO>CC(C)=O>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([NH2:8])=[O:16]
Reactant: COC(Cc1ncccc1C#N)OC
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(Cc1ncccc1C(N)=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
A mixture of 2-(2,2-dimethoxyethyl)nicotinonitrile (7 g, 36.42 mmol), aqueous Na2CO3 (3 N, 145 mL), H2O2 (15%, 145 mL) in acetone (73 mL) was stirred at room temperature for 14 h. After removal of acetone, the residue was diluted with water and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 1:1 and with EtOAc) to yield 2-(2,2-dimethoxyethyl)nicotinamide as a solid (6 g, yield 78%). ESI MS: m/z 211 [M+H]+, 233 [M+Na]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[C:14](=[O:28])[N:15]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C>[CH3:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[C:14](=[O:28])[N:15]([CH2:20][C:21]([OH:23])=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(S(=O)(=O)Nc2ccc(C)n(CC(=O)OC(C)(C)C)c2=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C)n(CC(=O)O)c2=O)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
HCl gas was bubbled through a stirred suspension of 3-(3-methylphenylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (2.0 g, 5.09 mmol), as prepared in the preceding step, in ethyl acetate (50 mL) at 0° C. until a solution was formed. After warming to room temperature over 2 h, a thick suspension was formed. The mixture was degassed with nitrogen and filtered to give the title compound as a white solid (1.36 g, 80%). 1H-NMR (300 MHz, DMSO-d6) δ9.38 (s, 1H), 7.62 (m, 2H), 7.41 (m, 2H), 7.25 (d, 1H, J=8 Hz), 6.09 (d, 1H, J=8 Hz), 4.67 (s, 2H), 2.35 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].N([O-])=O.[Na+].Cl>CN(C)C=O>[N:13]1([C:5]2[CH:6]=[C:7]([CH:12]=[C:3]([C:1]3[NH:20][N:19]=[N:18][N:2]=3)[CH:4]=2)[C:8]([O:10][CH3:11])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)cc(-n2cccc2)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nnn[nH]2)cc(-n2cccc2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
The mixture of methyl 5-cyano-3-(pyrrol-1-yl)benzoate (3.0 g), sodium azide (5.2 g) and ammonium chloride (4.3 g) in N,N-dimethylformamide (12 ml) was stirred for 4 hours at 120°-125° C. The mixture was added to the ice-water (100 ml) and to the mixture was added sodium nitrite (5.5 g). The mixture was adjusted to pH 1 with 6N-hydrochloric acid and stirred for 30 minutes. The mixture was extracted with ethyl acetate. The extract layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with diisopropyl ether to give methyl 3-(pyrrol-1-yl)-5-(1H-tetrazol-5-yl)benzoate (3.35 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[O:10])[CH:7]=1.[H-].[Na+].[C:33]([CH:37]1[CH2:39][O:38]1)([CH3:36])([CH3:35])[CH3:34].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH2:39][CH:37]([OH:38])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[O:16])=[O:10])[CH:7]=1
Reactant: CC(C)(C)C1CO1
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCNC4=O)cc3Cl)ccn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCN(CC(O)C(C)(C)C)C4=O)cc3Cl)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
A 0° C. solution of Example C9 (0.30 g, 0.696 mmol) in DMF (3 mL) was treated with NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred at RT for 0.5 h, treated drop-wise with 2-(tert-butyl)oxirane (0.139 g, 1.393 mmol), stirred at RT for 1 h, then heated at 60° C. overnight. Additional 2-(tert-butyl)oxirane (0.1 mL) was added, the mixture heated at 60° C. for 7 h, cooled to RT, treated with additional NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred for 20 min, treated with -(tert-butyl)oxirane (0.139 g, 1.393 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide (29 mg, 7.5%). 1H NMR (400 MHz, DMSO-d6): δ 10.95 (d, J=2.7 Hz, 1 H), 8.41 (d, J=8.1 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.57 (d, J=11.3 Hz, 1 H), 7.20 (d, J=2.5 Hz, 1 H), 6.64 (dd, J=5.7, 2.5 Hz, 1 H), 4.84 (d, J=5.5 Hz, 1 H), 3.84 (s, 3 H), 3.80 (m, 2 H), 3.58 (m, 2 H), 3.31 (m, 2 H), 3.05 (m, 1 H), 0.87 (s, 9H); MS (ESI) m/z: (M+H+): 531.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]=2[N:5]=[CH:4][CH:3]=1.[C:17]([NH:24][CH2:25][C:26](O)=[O:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C.O>CCOC(C)=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CN(C=O)C>[C:20]([O:19][C:17]([NH:24][CH2:25][C:26]([N:8]1[CH:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:11]=2[CH2:10][CH2:9]1)=[O:27])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)CC1NCCc2c(Cl)ccnc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC1c2nccc(Cl)c2CCN1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
94-6. To a stirred solution of methyl 2-(4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetate (320 mg, 1.33 mmol), Boc-glycine (233 mg, 1.33 mmol) and triethylamine (0.37 mL, 2.66 mmol) in AcOEt (7 mL), T3P (0.93 mL, 1.59 mmol, 50% m/m in DMF) was added and the solution was stirred at RT for 16 h. Water was added and the mixture was extracted with AcOEt (2×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera One, eluent: gradient from 0% AcOEt in cyclohexane to 100% AcOEt in cyclohexane in 21 min) to yield the title compound as a clear oil (510 mg). UPLC-MS: MS 398.1 (M+H+); UPLC rt 0.95 min.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][O:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29](B(O)O)=[CH:28][N:27]=1.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.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COc1ncc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)c(OC)n1
Temperature: 90 °C

Procedure:
Industrial methylated spirits (IMS; 15 mL) and water (5 mL) were degassed thoroughly. tert-butyl 4-bromophenethylcarbamate (1.08 g, 3.63 mmol), sodium carbonate (1.54 g, 14.52 mmol), palladium tetrakis (0.42 g, 0.36 mmol) and 2,4-dimethoxy-5-pyrimidinylboronic acid (1.00 g, 5.44 mmol) were added and the reaction mixture heated to 90° C. for 18 hours. No starting material was observed by LCMS. Water (100 ml) and ethyl acetate (300 ml) were added and the organic layer separated. The organic layer was washed with water (100 ml), dried (MgSO4) and concentrated to give a yellow oil. The crude residue was subject to column chromatography (20 to 60% ethyl acetate/hexane) to give a yellow oil, tert-butyl 4-(2,4-dimethoxypyrimidin-5-yl)phenethylcarbamate, which crystallized on standing (1.18 g, 3.28 mmol, 91%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][O:22][CH3:23])[C:4]([NH:6][C@@H:7]([CH2:18][O:19][CH3:20])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5].[C:24](=[O:27])([O-:26])[O-:25].[K+].[K+]>CN(C=O)C.O>[CH3:20][O:19][CH2:18][C@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([NH:2][CH2:11][C:12]1[O:27][C:24](=[O:26])[O:25][C:13]=1[CH3:14])[CH2:21][O:22][CH3:23])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: COC[C@H](NC(=O)[C@@H](N)COC)C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](NCc1oc(=O)oc1C)C(=O)N[C@@H](COC)C(=O)OCc1ccccc1
Reaction time: 2.5 h

Procedure:
Referring to FIG. 38, 4-(bromomethyl)-5-methyl-1,3-dioxo-2-one (278 mg. 1.44 mmol) was added to (S)-benzyl 2-((S)-2-amino-3-methoxypropanamido)-3-methoxypropanoate hydrochloride salt (1.0 g, 2.88 mmol) and potassium carbonate (400 mg, 2.88 mmol) in DMF (15 mL) at 0° C. The reaction was stirred at 0° for 2.5 hours and then diluted with water and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by Biotage flash column chromatography to give product as a yellow oil. MS for C20H26N2O8 m/z: 423 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O)=[O:7])([O-])=O>C(OCC)(=O)C.Cl.[Pd]>[CH:10]1[CH:11]=[CH:12][N:8]2[C:6](=[O:7])[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[NH:1][CH2:13][C:9]=12
Reactant: O=Cc1cccn1C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2NCc2cccn21
Reaction time: 1.75 h
Yield: 82.1 %

Procedure:
A mixture of 1.5 g of N-(2-nitrobenzoyl)-pyrrole-2-carboxaldehyde in 50 ml of ethyl acetate, 2 drops of concentrated HCl and 0.3 g of 10% Pd/C is shaken in a Parr apparatus under hydrogen pressure for 1.75 hours. The mixture is filtered, 0.4 g of 10% Pd/C added and the mixture shaken in a Parr apparatus under hydrogen pressure for 2 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 1.0 g of a yellow oil. The residue is purified on thick layer chromatography plates by elution with 4:1 ethyl acetate:hexane to give 107 mg of the desired product as an oily solid.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(C)(C)C#N)=NC(C)(C)C#N.C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:40][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Temperature: 0 °C

Procedure:
27.4 g (0.1 mol) of tert-butyl 2-cyclopentyl-2-(4-methylphenyl)-acetate are dissolved in 200 ml of carbon tetrachloride and the solution is heated to boiling point. After an addition of 0.82 g of azobisisobutyronitrile, 18.7 g (0.105 mol) of n-bromosuccinimide are added in portions, the mixture is subsequently refluxed for 1 hour and cooled to 0° C., and succinimide is filtered off. After concentration of the filtrate, the product precipitates. It is washed with petroleum ether (40/60) and dried. Yield: 20 g (57% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[OH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[OH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:31]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(C)(O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(OC(=O)CC(C)(C)O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.1 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (200 mg; 0.487 mmol), 3-hydroxy-3-methylbutanoic acid (74.4 g, 0.63 mmol), triethylamine (0.11 mL, 0.79 mmol) and 4-dimethylaminopyridine (64.0 mg, 0.524 mmol) in tetrahydrofuran (10.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144.9 mg, 0.76 mmol) at room temperature. The mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-60% ethyl acetate/n-hexane gradient mixture to give the title compound (103.3 mg, 0.20 mmol, 41%) as a colorless amorphous.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([CH3:13])[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:15].[Na+].[Cl-].[Na+]>CO.O>[C:1]1([S:7]([CH2:8][CH:9]([CH3:13])[CH2:10][CH2:11][OH:12])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(CCO)CSc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CCO)CS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.96 g of 4-phenylthio-3-methyl-1-butanol were dissolved in 100 ml of methanol, a solution of 2.57 g of sodium metaperiodate in 50 ml of water added, and the mixture stirred at room temperature overnight. Then, an aqueous solution of sodium chloride was added, the resulting mixture extracted with diethyl ether, the ether layer washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the ether distilled off. There was obtained a slightly yellow liquid. This was purified by silica gel column chromatography (developing solvent: methylene chloride-ethyl acetate) to give 1.60 g of a colorless to slightly yellow liquid. The characteristic signals of this substance on its 1H-NMR spectrum were as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:20]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[N:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>COCCOC.[Cu]I>[CH2:17]([O:16][C:13]1[N:12]=[CH:11][C:10]([C:9]2[O:19][C:2]3[CH:3]=[C:4]([C@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]4)[CH:5]=[CH:6][C:7]=3[N:8]=2)=[CH:15][CH:14]=1)[CH3:18]
Reactant: CCOc1ccc(C(=O)Nc2ccc([C@@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2Br)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOc1ccc(-c2nc3ccc([C@@H]4CN(C(=O)OC(C)(C)C)CCO4)cc3o2)cn1
Temperature: 125 °C
Yield: 40 %

Procedure:
(R)-tert-Butyl 2-(3-bromo-4-(6-ethoxynicotinamido)phenyl)morpholine-4-carboxylate (100 mg, 0.2 mmol), cesium carbonate (130 mg, 0.4 mmol), 1,10-phenanthroline (3.6 mg, 0.02 mmol), copper(I) iodide (1.9 mg, 0.01 mmol) were mixed together in 1,2-dimethoxyethane (2 ml). The suspension was degassed with Argon and was heated overnight under Argon at 125° C. The mixture was cooled and poured into ethylacetate and filtered. The filtrate was absorbed on silica gel and separated by chromatography (gradient 10% to 50% EtOAc in heptane) to afford an off-white solid (34 mg, 40%). MS (ISP): 426.6 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C@:8]([CH3:12])([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[F:15][C:16]([F:32])([F:31])[O:17][C:18]1[CH:30]=[CH:29][C:21]([O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:12][C@:8]([OH:11])([CH2:7][O:6][C:5]1[CH:13]=[CH:14][C:2]([N:26]2[CH2:27][CH2:28][CH:23]([O:22][C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:31])[F:32])=[CH:30][CH:29]=3)[CH2:24][CH2:25]2)=[CH:3][CH:4]=1)[CH2:9][OH:10]
Reactant: C[C@@](O)(CO)COc1ccc(Br)cc1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: C[C@@](O)(CO)COc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
(R)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diol (87.96 g, 336.9 mmol, optical purity of 92.2% ee), 4-[4-(trifluoromethoxy)phenoxy]piperidine (80 g, 306.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2dba3, 701 mg, 0.77 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (780 mg, 1.84 mmol), sodium tert-butoxide (33.85 g, 352.2 mmol), and toluene (240 ml) were mixed, followed by stirring under an argon atmosphere at 70° C. for 6 hours. After cooling, an ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with toluene. Thereafter, the organic layer was distilled off under reduced pressure, obtaining a crude product of (R)-2-methyl-3-(4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenoxy)propane-1,2-diol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-].[N+:10]([O-])([OH:12])=[O:11].P(Br)(Br)Br.C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Br:8])[N:3]=1
Reactant: [O-][n+]1c(Br)cccc1Br
Reactant: O=[N+]([O-])O
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)nc(Br)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of 20 g (78 mmol) of 2,6-dibromopyridine 1-oxide is warmed to 40° C. in 70 ml of H2SO4. Nitrating acid (70 ml of H2SO4 and 34 ml of fuming HNO3) is added to the solution at this temperature. The reaction mixture is heated at 90° C. for 3 h. After cooling, the reaction mixture is poured into 800 ml of ice-water. The solid which has precipitated out is filtered off and washed with water. After drying, the 2,6-dibromo-4-nitropyridine 1-oxide (17.9 g) is suspended in 200 ml of chloroform, 6 ml of phosphorus tribromide (64 mmol) are added at room temperature, and the mixture is stirred for 1 h and then heated under reflux for 2 days. After cooling, the solution is poured into 500 ml of ice-water, and the mixture is neutralised using solid NaHCO3. The aqueous phase is separated off and extracted a number of times with CHCl3, and the combined organic phases are washed with a sodium thiosulfate solution and then with water, dried and evaporated. The residue is recrystallised from EtOH. Yield: 41.7 g (148 mmol), 70% of theory.