Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([CH2:15][N:16]([CH:33]([CH3:35])[CH3:34])[C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=2)[C@H:12]([CH2:36][OH:37])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH:38]1([CH2:44][N:45]([CH3:49])[C:46](Cl)=[O:47])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([CH2:15][N:16]([CH:33]([CH3:34])[CH3:35])[C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=2)[C@H:12]([CH2:36][O:37][C:46](=[O:47])[N:45]([CH2:44][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH3:49])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Reactant: CN(CC1CCCCC1)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2COC(=O)N(C)CC2CCCCC2)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a stirred suspension of NaH (60% oily dispersion, 17 mg, 0.42 mmol) in THF (2 mL) is added at 0° C. (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 0.303 mmol) in THF (3 mL). The resulting solution is stirred 30 min before the addition of a solution of cyclohexylmethyl-methyl-carbamoyl chloride (80 mg, 0.421 mmol) in THF (3 mL). The mixture is further stirred overnight at RT and poured into an aqueous solution of NH4Cl. AcOEt is added, the layers are separated and the aqueous one extracted twice with AcOEt. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 95:5). TLC, Rf (CH2Cl2/MeOH 95:5)=0.25. MS (LC-MS): 648 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.83 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH2:10][Br:22])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(C)ccc1NC(=O)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1cc(CBr)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 11.1 (1.0 mmol) in benzene (2.0 mL) is added N-bromosuccinimide (1 equivalent) and benzoyl peroxide (0.33 equivalent). The reaction mixture is refluxed overnight under N2. After cooling to room temperature, the solution is diluted with EtOAc, washed with H2O, brine, dried, filtered and concentrated under reduced pressure. The crude product is purified by flash column chromatography on silica gel to provide 5-bromomethyl-2-(4-chloro-benzoylamino)-benzoic acid methyl ester (compound 11.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1.C(Cl)Cl>C(O)(=O)C>[N:23]1([C:21]([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[CH:31]=[CH:35][CH:34]=[CH:33]3)=[CH:7][C:6]=2[NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(C(=O)N2CCCCC2)c(NS(=O)(=O)c2cccc3nsnc23)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(c1ccc(-n2cccc2)cc1NS(=O)(=O)c1cccc2nsnc12)N1CCCCC1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
To a stirred solution of benzo[1,2,5]thiadiazole-4-sulfonic acid [5-amino-2-(piperidine-1-carbonyl)-phenyl]-amide (EXAMPLE 24; 25 mg, 0.06 mmol) in glacial acetic acid (3 mL) was added 2,5-dimethoxytetrahydrofuran (8 μL, 0.06 mmol). The reaction mixture was heated to 120° C. for 45 min after which it was cooled to room temperature. The mixture was taken up to 4 mL of DCM and washed with water. The organic layer was removed, dried and purified by preparative reversed-phase HPLC (acetonitrile/water, 0.05% TFA) to afford the title compound (12 mg, 0.02 mmol, 43%). MS (ESI): m/z 468 [M+H]+, 490 [M+Na]+. HPLC (reversed-phase): RT=9.71 min (single peak). 1H NMR (400 MHz, CDCl3): (rotameric broadening) 9.15 (s, 1H), 8.26 (dd, J=7.0 Hz, 1.0 Hz, 1H), 8.22 (dd, J=8.8 Hz, 1.0 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.67 (dd, J=8.8 Hz, 7 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.05 (m, 3H), 6.35 (t, J=2.2 Hz, 2H), 3.23 (bs, 4H), 1.61 (m, 2H), 1.48 (bs, 4H).
Reaction SMILES: [CH3:1][C:2](Cl)([CH3:7])[C:3]([Cl:6])=[N:4][OH:5].[C:9](=O)([O-])[O-:10].[Ca+2]>CO>[CH3:1][C:2]([CH3:7])([O:10][CH3:9])[C:3]([Cl:6])=[N:4][OH:5]
Reactant: CC(C)(Cl)C(Cl)=NO
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COC(C)(C)C(Cl)=NO
Yield: 79 %

Procedure:
A mixture of 50 g (0.32 mol) of 2-methyl-1,2-dichloro-1-oximino-propane, 50 g (0.5 mol) of finely powdered calcium carbonate and 500 ml of absolute methanol is heated at the boiling point for 30 minutes, while cooling under reflux. The mixture is filtered, the filtrate is concentrated and the residue is extracted several times with ether. The ether phase is dried over sodium sulphate and filtered and the filtrate is concentrated. 38.4 g of 2,2-dimethyl-2-methoxy-1-chloro-1-oximino-ethane are obtained in the form of white crystals of melting point 95° C., and the yield is 79% of theory:
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20].[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:35][CH:34]=[C:33](OS(C(F)(F)F)(=O)=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])[CH3:25].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O.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]>[CH3:26][C:24]([O:27][C:28]([N:30]1[CH2:31][CH:32]=[C:33]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]3=[O:19])=[CH:5][C:4]=2[F:20])[CH2:34][CH2:35]1)=[O:29])([CH3:23])[CH3:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 108 h

Procedure:
A mixture of (S)-(−)-N-[[3-[4-trimethylstannyl-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (690 mg), 3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (step 2 of EXAMPLE 20, 500mg), tris(dibenzylideneacetone)dipalladium(0) (14 mg) and triphenylarsine (37 mg) in N-methyl-2-pyrrolidinone (7.5 mL) is degassed, stirred under N2 at ambient temperature for 4.5 days, diluted with ethyl acetate, washed with water (3×40 mL) and saline (20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 120g), eluting with a gradient of methanol/methylene chloride (1/99-2/98), and those fraction having an Rf=0.27 by TLC (methanol/chloroform, 2×5/95) are pooled and concentrated to give the title compound, 1H NMR (CDCl3, 400 MHz) 7.39, 7.22, 7.13, 7.01, 5.92, 4.82, 4.06, 3.80, 3.67, 3.61, 2.47, 2.03, 1.49 δ.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:27]1[CH:31]=[CH:30][C:29](B(O)O)=[N:28]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[NH:27]1[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:8])=[CH:30][CH:29]=[N:28]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1
Reactant: OB(O)c1cc[nH]n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(-c2ccn[nH]2)c1

Procedure:
5-Bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 15.1, 60 mg, 0.139 mmol) and (1H-pyrazol-3-yl)boronic acid (62.4 mg, 0.558 mmol), Pd(PPh3)2Cl2 (11.75 mg, 0.017 mmol), Na2CO3 (73.9 mg, 0.697 mmol), DME (592 μL), water (169 μL) and EtOH (85 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 130° C. for 30 min. Additional 1-H-Pyrazole-3-boronic acid, (31.2 mg, 0.279 mmol) was added to the RM and was subjected to further MW irradiation at 130° C. for 30 min. The RM was diluted with THF (2 mL), treated with Si-Thiol (1.44 mmol/g, 58.1 mg, 0.084 mmol)., centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 10% to 15% in 6 min) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=418.4 [M+H]+, m/z=462.2 [M+formic acid-H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.90 (m, 4H) 3.19 (t, J=6.21 Hz, 4H) 6.40 (d, J=1.88 Hz, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.75 (br. s, 1H) 7.87 (d, J=9.03 Hz, 2H) 8.04 (d, J=2.26 Hz, 1H) 8.75 (d, J=2.38 Hz, 1H) 10.22 (br. s, 1H) 12.70-13.19 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].C(CCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[F:33][C:34]1[C:35]([O:44][CH3:45])=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39]C)=[O:38]>C1COCC1>[F:33][C:34]1[C:35]([O:44][CH3:45])=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([OH:39])=[O:38]
Reactant: COC(=O)c1cccc(F)c1OC
Agent: CC(C)(C)[O-]
Agent: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1c(F)cccc1C(=O)O
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 133.4 %

Procedure:
Solid potassium t-butoxide (4.48 g) was added under argon to a stirred, ice-cooled mixture of (3-carboxypropyl)triphenylphosphonium bromide (6.44 g) and (-)-[2,3-trans]-tetrahydro-5-hydroxy-3-hydroxymethyl-2-o-methoxyphenylfuran (B) (2.24 g) in dry THF (75 ml). The mixture was stirred for 15 minutes at 4° C., then for 1 hour at ambient temperature and was then poured into ice-water (150 ml). The mixture obtained was washed with ether (2×50 ml) to remove the bulk of the neutral material. The aqueous phase was acidified to pH 4 with 1 M hydrochloric acid and extracted with ether (1×100 ml, 2×50 ml). These combined extracts were washed successively with water (2×50 ml) and saturated brine (2×50 ml), then dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with ether/hexane/acetic acid (80:20:1 v/v) to give (-)-erythro-4(Z)-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoic acid (C) as a colourless oil (2.76 g); 22 [α]D -68.3° (c 1.1, methanol); NMR: 1.92 (1H,m), 2.0-2.6 (6H,m), 3.67 (2H,m), 3.82 (3H,s), 5.21 (1H,d J=5 Hz), 5.37 (2H,m), 6.87 (1H,dd J=8,1 Hz), 6.98 (1H,td J=7,1 Hz), 7.25 (1H,m), 7.42 (1H,dd J=7,1 Hz); m/e 294 (M+).
Reaction SMILES: B.[Br:2][C:3]1[C:28]([F:29])=[CH:27][C:6]2[O:7][C:8]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:9]=3[C@H:10]3[C@H:15]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH2:14][CH2:13][C:12](=O)[N:11]3[C:5]=2[CH:4]=1.O>C1COCC1.C(OCC)(=O)C>[Br:2][C:3]1[C:28]([F:29])=[CH:27][C:6]2[O:7][C:8]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:9]=3[C@H:10]3[C@H:15]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH2:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1
Reactant: COC(=O)N[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Agent: B
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Temperature: 30 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
Borane (1.0 M in THF, 38.3 mL, 38.3 mmol) was added dropwise to a stirred solution of methyl (±)-(cis)-(7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamate (38.2 mmol) in THF (200 mL). The resulting mixture was stirred at 30° C. for 1 h. Subsequently, water was added dropwise until evolution of gas ceased. The resulting mixture was stirred for 1 h and then diluted with ethyl acetate (300 mL) and washed with brine. After drying (Na2SO4) the solvent was evaporated under reduced pressure to yield the crude title compound (16.7 g, 100%). (m/z)=439+441 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1>O1CCCC1.O>[CH2:9]([S:10][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(SCc2ccccc2)nc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 440 mg) in tetrahydrofuran (40 mL) was added dropwise phenylmethanethiol (1.37 g) at room temperature, 2-bromo-5-fluoropyridine (1.76 g) was added to the reaction mixture, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was diluted with water and concentrated under reduced pressure. The residual aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane→hexane-ethyl acetate=97:3) to give the title compound as a crude brown oil (yield 244 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:20][C@H:19]([CH2:21][O:22][C:23]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C@@H:17]([OH:18])[CH2:16]3)[CH:13]=[N:14][C:7]=12.N1C=CC=CC=1.[CH:52]([N:55]([CH:69]([CH3:71])[CH3:70])[P:56](N(C(C)C)C(C)C)[O:57]CCC#N)([CH3:54])[CH3:53].N1C=NN=N1>C(#N)C.O.CO>[C:15]([CH2:16][CH2:17][O:18][P:56]([N:55]([CH:69]([CH3:71])[CH3:70])[CH:52]([CH3:54])[CH3:53])[OH:57])#[N:12].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:20][C@H:19]([CH2:21][O:22][C:23]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C@@H:17]([OH:18])[CH2:16]3)[CH:13]=[N:14][C:7]=12
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(-c5cccs5)ccnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1nnn[nH]1
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CC(C)N(C(C)C)P(O)OCCC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 7 (425 mg, 0.69 mmol) was azeotroped three times with anhydrous pyridine and then three times with anhydrous acetonitrile. This was dissolved in anhydrous acetonitrile (4.6 ml), followed by addition of 2-cyanoethyl tetraisopropylphosphorodiamidite (262 μl, 0.82 mmol)) and a 0.45 M acetonitrile solution of tetrazole (1.68 ml). This mixture was stirred for 1 hour at room temperature. After addition of anhydrous methanol (90 μl), the mixture was poured into water (50 ml) and extracted with 1% triethylamine (v/v)-containing methylene chloride (50 ml×3). After drying over Na2SO4, the solvent was distilled off under reduced pressure. The residue was purified by flash silica gel chromatography using 2% triethylamine (v/v)-containing hexane:ethyl acetate (4:1 to 3:2) as an elution solvent to give 490 mg of Compound 8 in a yield of 87%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]#[C:15][C:16]2[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:8][CH:7]=1>CO>[Cl:22][C:19]1[N:18]=[CH:17][C:16]([C:15]#[C:14][C:13]#[C:12][C:9]2[CH:8]=[CH:7][C:6]([C:5]([OH:23])=[O:4])=[CH:11][CH:10]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(C#CC#Cc2ccc(Cl)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C#CC#Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A 6M aq. solution of NaOH (15 ml) was added to a stirred solution of 4-[4-(6-Chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoic acid methyl ester. (9.06 g, 30 mmol) in MeOH (350 ml) at rt. The reaction solution was heated to reflux for 3 hours. The reaction stayed a mixture and did not turn clear. HPLC and LCMS indicated that the reaction was forming side products. The reaction was cooled to rt and some MeOH (˜200 ml) was removed by evaporation under reduced pressure. Water (400 ml) was added to the mixture. Cone. HCl was added drop wise to the stirred solution until acidic by pH paper (pH2). The yellow precipitate that formed was collected by suction filtration. The solid was washed with water (3×20 ml) and hexane (2×20 ml) to give the crude product HPLC indicated that there was approximately 40% product in the mixture. The crude reaction product was purified by flash chromatography using EtOAc (8-10%)/hexane as eluant. The pure fractions were evaporated and dried in vacuo to give 42 g of product 3 in 50% yield.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:42]>C1COCC1>[Br:42][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:6][CH:7]=1
Reactant: CCOC(=O)CC(Cc1nc(CO)co1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(Cc1nc(CBr)co1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To a solution of ethyl (±)-4-(4-hydroxymethyl-1,3-oxazol-2-yl)-3-phenylbutanoate (1.3 g, 4.49 mmole) in dry THF (20 mL) was added PPh3 (1.41 g, 5.39 mmole) then CBr4 (1.79 g, 5.39 mmole) at 0° C. After 20 min, the mixture was warmed to RT. After 2 hr, the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (20% EtOAc/hexanes) to give the title compound (1.38 g, 87%) as a colorless oil: MS (ES) m/e 352 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(O)C>[CH:18](=[N:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
16.3 g (100 mmol) of 4-amino-5-imidazolecarboxamide hydrochloride was suspended in 200 ml ethanol, and 27.8 ml (200 mmol) of triethylamine was added to the suspension and dissolved. To the solution, 10.2 ml (100 mmol) of benzaldehyde was added and the mixture was heated for 8 hours while refluxing. After the addition of 400 ml of distilled water, the reaction mixture was stirred for one hour at 0° C. A solid precipitate produced was collected by filtration, washed with distilled water, then with ethanol, and dried under reduced pressure to obtain 20.8 g of the title compound (yield 97%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:3][CH:4]=1)(=[O:21])=[O:20]
Reactant: OCCc1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Temperature: -20 °C

Procedure:
2-(4-Hydroxyphenyl)ethanol(356 g, 2.58 mol, 1.0 eq) was dissolved in methylene chloride (3500 ml) and triethyl amine (653 g, 6.44 mol, 2.5 eq). The mixture was cooled to −20° C. Methanesulfonyl chloride (657 g, 5.74 mol. 2.2 eq) was then added keeping the temperature between −25° C. and −15° C. When the conversion was >95% salts were formed which were filtered off and washed with methylene chloride (600 ml). The organic layer was washed first with saturated sodium hydrogencarbonate solution (700 ml) at 20° C. followed by water (700 ml). The methylene chloride was evaporated to dryness and the remaining residue was then used in the subsequent step.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[N:2]1.I[C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[NH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: Nc1cccc2[nH]ncc12
Reactant: COC(=O)c1cccc(I)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Temperature: 100 °C
Yield: 20.1 %

Procedure:
1H-Indazol-4-amine (81 mg, 0.61 mmol) and methyl 3-iodobenzoate (160 mg, 0.61 mmol) were dissolved in DMF (1 mL) in a microwave tube. Copper (I) iodide (23 mg, 0.12 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (34 mg, 0.24 mmol) and potassium carbonate (169 mg, 1.22 mmol) were added and the mixture heated by microwave (250 W) at 100° C. for 20 minutes. The mixture was filtered through a cartridge, washing with DCM (5 mL) and the filtrate was evaporated to dryness and purified by mass-directed autopreparation. The appropriate fractions were evaporated, dissolved in DCM (10 mL), washed with aqueous sodium bicarbonate, and evaporated to give the title compound (32.7 mg).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)=[O:18])=[CH:15][C:14]=2[Br:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43].CO>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:42]([O:34][C:5]1[C:6]([CH2:31][CH2:32][CH3:33])=[C:7]([CH:29]=[CH:30][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[O:18])=[CH:15][C:14]=1[Br:28])(=[O:44])[CH3:43]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OC3CCCCO3)cc2Br)ccc(C(C)=O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2ccc(C(=O)OC3CCCCO3)cc2Br)ccc(C(C)=O)c1OC(C)=O
Reaction time: 0.5 h

Procedure:
In methylene chloride (20 ml) was dissolved tetrahydropyranyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoate (1.4 g). To the solution were added triethylamine (6 ml) and 4-dimethylaminopyridine (15 mg), to which was added dropwise acetic anhydride (5 ml) under ice-cooling. The mixture was stirred for 30 minutes under ice-cooling, and there was added methanol (5 ml). The mixture was left standing for a while, and there was added chloroform (50 ml). The mixture was washed with a 5% aqueous solution of sodium hydrogen carbonate and then with water, followed by drying (sodium sulfate). The solvent was evaporated off and the residue was purified by means of a silica-gel column-chromatography to give 3 g of tetrahydropyranyl 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoate as colorless oily substance.