Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:13][C@H:12]1[NH:8][C@H:9]([CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2)cc1
Reaction time: 0.58 h
Yield: 94.4 %

Procedure:
To a stirred solution of methyl 4-[N-Boc-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.29 g, 3.70 mmol) in CH2Cl2 (30 ml) was added trifluoroacetic acid (10 ml) at rt, and the resulting mixture was stirred for 35 min. The mixture was concentrated in vacuo and poured into aq.NaHCO3, then extracted with CHCl3. The organic layer was washed with water, drying over anhydrous Na2SO4, and concentrated in vacuo to give methyl 4-[5-(R)-methyl-2-(S)-pirrolidinyl methoxy]benzate (871 mg, 95%) as a colorless oil. The product was used for next reactions without further purification. 1H-NMR (CDCl3) δ 1.18 (d, J=6.4 Hz, 3 H), 1.30–1.40 (m, 1 H), 1.59–1.67 (m, 1 H), 1.87–1.97 (m, 2 H), 3.19–3.27 (m, 1 H), 3.49–3.55 (m, 1 H), 3.87 (s, 3 1), 3.89–4.05 (m, 2 H), 6.89 (d, J=8.8 Hz, 2 H), 7.96 (d, J=8.8 Hz, 2 H); MS (ESI) m/z, 250 (M++H)
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.O.[Cu]I.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>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][C:19]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc(Br)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(C#C[Si](C)(C)C)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Under N2, a mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-bromo-N-methylpyridin-2-amine (0.22 g, 0.58 mmol), ethynyltrimethylsilane (0.22 mL, 1.6 mmol), Et3N (0.24 mL, 1.5 mmol), CuI (5.0 mg, 0.03 mmol), PdCl2(PPh3)2 (8.0 mg, 0.01 mmol) and PPh3 (3.0 mg, 0.01 mmol) in DMF (3.0 mL) was stirred at 90° C. for 4 h. The reaction was then cooled to ambient temperature, diluted with water (3 mL), extracted with ethyl acetate (2×10 mL). The combined extracts was washed with brine (2×6 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel to give the titled compound. MS (m/z): 295 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[S:13]1[C:22]2[C:21](=[O:23])[NH:20][C:19]3[CH:24]=[CH:25][CH:26]=[N:27][C:18]=3[NH:17][C:16]=2[CH:15]=[CH:14]1>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:17]1[C:16]2[CH:15]=[CH:14][S:13][C:22]=2[C:21](=[O:23])[NH:20][C:19]2[CH:24]=[CH:25][CH:26]=[N:27][C:18]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C1Nc2cccnc2Nc2ccsc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCl)c2ccsc21

Procedure:
Chloroacetyl chloride (1.9 ml) is added in 20 minutes, contemporaneously with triethylamine (3.4 ml), to a suspension of 4,9-dihydro-10H-pyrido[3,2-b]thieno[3,2-e][1,4]-diazepin-10-one (4.4 g) in dioxane (200 ml), heated to reflux.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]([F:36])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 42.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (71 mg, 0.14 mmol) obtained in step 4 and ethanesulfonamide (73 mg, 0.70 mmol), the title compound (35 mg, 43%) was obtained.
Reaction SMILES: [OH-].[Na+].C([O:5][CH2:6][CH2:7][C:8]1[O:12][CH:11]=[N:10][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C(O)C.O>[OH:5][CH2:6][CH2:7][C:8]1[O:12][CH:11]=[N:10][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=COCCc1ocnc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCc1ocnc1-c1ccccc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
2N Sodium hydroxide (40 ml) was added to a solution of 5-(2-formyloxyethyl)-4-phenyloxazole (12.9 g) in ethanol (40 ml). The mixture was stirred for 30 minutes, then diluted with water (80 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give 10.0 g (97.3%) of 5-(2-hydroxyethyl)-4-phenyloxazole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClCCl.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[CH3:21][S:22]([O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:24])=[O:23]
Reactant: OCCc1cccc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 112.6 %

Procedure:
To a cooled (0° C.) mixture of 46.2 g of 3-fluorobenzenethanol, 40 ml of N,N-diethylethanamine and 500 ml of dichloromethane, there were added dropwise 41.2 g of methanesulfonyl chloride, keeping the temperature below 5° C. After stirring for 18 hours at room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 81 g (100%) of 2-(3-fluorophenyl)ethanol methanesulfonate (ester) (interm. 34).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:11][C:12](/[C:14](/[C:23]#[N:24])=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[SH:25][CH2:26][C@H:27]([C@@H:29]([CH2:31][SH:32])[OH:30])[OH:28]>C(#N)C.C(OCC)(=O)C>[Br:22][C:18]1[N:17]=[C:16]([CH:15]([S:25][CH2:26][CH:27]([OH:28])[CH:29]([OH:30])[CH2:31][SH:32])[CH:14]([C:23]#[N:24])[C:12]([NH:11][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][CH3:1])=[O:13])[CH:21]=[CH:20][CH:19]=1
Reactant: CCC[C@H](NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccccc1
Reactant: O[C@H](CS)[C@H](O)CS
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC(NC(=O)C(C#N)C(SCC(O)C(O)CS)c1cccc(Br)n1)c1ccccc1
Yield: 28.6 %

Procedure:
A solution of WP1130 (18; 0.05 g, 0.13 mmol) in acetonitrile (6 mL) was added to a stirred solution of dithiothreitol (2 g, 13 mmol) in acetonitrile (13 mL) at room temp. After 20 hours TLC [Hxa/EtOAc 1:1] showed a single product and no starting material. The mixture was filtered through a short column of silica gel in acetonitrile, and the filtrate stripped of solvent under reduced pressure. A colorless syrup was obtained. The syrup was dissolved in ethyl acetate and flash chromatographed on a column (35×70 mm) of silica gel in ethyl acetate to afford a clear yellow oil (0.02 g) which began to crystallize upon standing. Mass spec ES+; m/z=560, 562 (m+23) and 538, 540 (m+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of 1-hydroxy-2-methyl-4-nitrobenzene (1.0 g) in N,N-dimethylformamide (10 mL) were added potassium carbonate (1.8 g) and iodomethane (1.3 g) at room temperature and this mixture was stirred at the same temperature for 24 hours. This reaction mixture was poured into water and this resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13](OC)=[O:14])[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][OH:14])[N:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:9]=1
Reactant: COC(=O)c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2cc(CO)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of methyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carboxylate (6.00 g) in tetrahydrofuran (20 mL) was slowly added lithium aluminum hydride (400 mg) at 0° C., and the mixture was stirred for 30 min. Sodium sulfate decahydrate (4.16 g) was added to the reaction mixture, the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give (3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-5-yl)methanol (5.19 g, yield 92%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 146-147° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[O:11][C:10](=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10](=[O:19])[O:11]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-fluorophenyl)-7-methyl-2H-chromen-2-one (24.0, 94.3 mmol), NBS (18.5 g, 103.8 mmol) and benzoyl peroxide (1.14 g, 4.72 mmol) in 470 mL of CCl4 was brought to reflux. The solution was left overnight at reflux and then filtered hot. Once cooled to rt the solvent was removed, the compound was dissolved in CH2Cl2 and a purification was done with a small pad of silica gel using hexane-EtOAc (8/2) to (1/1). The solvent was removed and the solid triturated with hexane-EtOAc and filtered to give the title compound. The remaining solvent was removed to give additional compound contaminated with some starting material and dibromo compound. 1H NMR (400 MHz, acetone-d6): δ 7.67 (2H, m), 7.55 (1H, s), 7.50 (1H, d), 7.40 (3H, m), 6.40 (1H, s) and 4.75 (2H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:7]=1N)=[O:5])[CH3:2].N(OC(C)(C)C)=O>[Cu](Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:13])[F:14])[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CC(F)(F)F)sc1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Product: CCOC(=O)c1csc(CC(F)(F)F)c1
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
2-Amino-5-(2,2,2-trifluoro-ethyl)-thiophene-3-carboxylic acid ethyl ester (1.76 g, 6.96 mmol) was added to a suspension of t-butyl nitrite (10.4 mmol) and copper (II) chloride (26.8 mmol) in IMS (50 mL). The reaction mixture was stirred for 1.5 hours then quenched with saturated aqueous ammonium chloride (7 mL). The solvent was removed under vacuum and the residue partitioned between DCM and water. The organic solution was separated and dried over magnesium sulphate, filtered and the solvent evaporated. The product was purified by column chromatography on silica, eluting with 0%-35% t-butylmethylether in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (1.24 g). 1H NMR (400 MHz, CHCl3-d): δ 8.05 (s, 1H), 7.45 (s, 1H), 4.3 (q, 2H), 3.6 (q, 2H), 1.37 (t, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][N:8]=[C:7]([CH3:15])[CH:6]=1)[CH2:2][CH3:3].C(OC(=O)C)(=O)C.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:15]([C:7]1[CH:6]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][N:8]=1)=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCc1cnc(C)cc1OCCC
Solvent: CC(=O)OC(C)=O
Product: CCCCc1cnc(C=Cc2ccccc2)cc1OCCC

Procedure:
22.6 g of 4-n-propoxy-5-n-butyl-2-picoline and 60 ml of benzaldehyde are heated with 66 ml of acetic anhydride for 16 hours under reflux. After cooling, the mixture is evaporated, 2 N sodium hydroxide solution is added and the whole is extracted with ether. Distillation of the ether residue in a bulb tube at a temperatre of 160°-180° in a high vacuum yields 2-styryl-4-n-propoxy-5-n-butyl-pyridine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][C:19]=1[C:38]([F:41])([F:40])[F:39].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][C:19]=1[C:38]([F:40])([F:41])[F:39]
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(C)O)cc3)no2)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C(F)(F)F)c3)n2)cc1
Temperature: -68 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of oxalyl chloride (758 μL; 8.8 mmol in anhydrous DCM (50 mL) at −68° C. a solution of dimethylsulfoxyde (1.3 mL; 17.7 mmol) dissolved in DCM (10 mL) was added over a period of 5 min. The reaction mixture was stirred for 15 min followed by addition of a solution of 1-(4-{5-[2′-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethanol (1.5 g; 3.5 mmol, obtained in step 3 in DCM (10 mL) within 15 min. After being stirred for 1 h at −68° C., the reaction was allowed to reach −30° C., stirred for 15 min and then re-cooled to −68° C. Triethylamine (1.8 mL; 12.7 mmol) was added and the mixture was allowed to reach RT. The clear yellow solution was partioned between saturated aqueous sodium bicarbonate and ethyl acetate, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by flash chromatography affording the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.67-8.47 (m, 2H), 8.29 (d, J=7.9 Hz, 2H), 8.19 (d, J=8.3 Hz, 2H), 7.67 (d, J=7.9 Hz, 1H), 7.43-7.25 (m, 3H), 7.17 (d, J=7.7 Hz, 1H), 2.67 (s, 3H), 2.02 (s, 3H). HPLC (Method A) Rt 6.00 min (Purity: 99.0%).
Reaction SMILES: C(N=[N+]=[N-])C1C=CC=CC=1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[N+:12]=[N-:13].[C:22]([C:24]1[S:25][C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:27]([CH3:29])[N:28]=1)#[CH:23]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH:23]=[C:22]([C:24]3[S:25][C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:27]([CH3:29])[N:28]=3)[N:13]=[N:12]2)=[CH:16][CH:17]=1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Reactant: [N-]=[N+]=NCc1ccc(F)cc1
Agent: [N-]=[N+]=NCc1ccccc1
Product: CCOC(=O)c1sc(-c2cn(Cc3ccc(F)cc3)nn2)nc1C
Yield: 62 %

Procedure:
Following the procedure as described in Example 2, making variations as necessary to replace benzylazide with 1-(azidomethyl)-4-fluorobenzene to react with ethyl 2-ethynyl-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 62% yield: 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.32-7.23 (m, 2H), 7.05-6.94 (m, 2H), 5.49 (s, 2H), 4.51 (q, J=7.1 Hz, 2H), 2.62 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); MS (ES+) m/z 347.3 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=[C:5](B(O)O)[CH:4]=[C:3]1[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.[Cl:36][C:37]1[N:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[Cl:36][C:37]1[N:42]=[C:41]([C:5]2[CH:4]=[C:3]([C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)[C:2](=[O:1])[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=2)[CH:40]=[CH:39][N:38]=1
Reactant: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 97 °C
Reaction time: 3 h

Procedure:
1.32 g of 6-oxo-1-(2-trimethylsilanylethoxymethyl)-5-[1-(2-trimethylsilanylethoxy-methyl)-1H-benzimidazol-2-yl]-1,6-dihydropyridazine-3-boronic acid, 583 mg of 2,4-dichlorpyrimidine and 3,3 g of cesium carbonate are dissolved in 17 ml of a 1:4 mixture of water and dioxane, and argon is passed through the solution for degassing. After addition of 125 mg of (1,1′-bis(diphenyl-phosphine)ferrocene)palladium(II) chloride-dichloromethane complex, the solution is stirred at 97° C. for 3 hours. For workup, it is diluted with 50 ml of water and extracted several times with ethyl acetate. The combined organic phases are dried using a silica gel cartridge, and the solvent is distilled off. The crude product is purified by preparative RP-HPLC (0-100% acetonitrile in water (+0.01% trifluoroacetic acid)).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N+:10]([CH:13]=[C:14](SC)[S:15][CH3:16])([O-:12])=[O:11]>C(O)C>[N+:10]([CH:13]=[C:14]([S:15][CH3:16])[NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: CCOC(CN)OCC
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Yield: 57.9 %

Procedure:
(a)(i) A solution of aminoacetaldehyde diethylacetal (8 g, 0.06 mol) and 1-nitro-2,2-bis-methylthioethylene (10 g, 0.06 mol) in ethanol (100 ml) was refluxed for 20 hours. The solvent was removed in vacuo. The residue was chromatographed on a silica gel column eluted with carbon tetrachloride/chloroform (7:3) and the product was crystallised from propan-2-ol to give 1-nitro-2-metylthio-2-(2,2-diethoxyethylamino)ethylene (8.7 g, 58%) m.p. 73°-73.5°.
Reaction SMILES: [BH4-].[Li+].[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:11]([C:21](OC)=[O:22])[CH2:10]1)([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C@@H:11]([CH2:21][OH:22])[CH2:10]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CO
Temperature: 20 °C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
2M Lithium borohydride in THF (15.06 ml) was added slowly to a stirred solution of O1-tert-butyl O2-methyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxypyrrolidine-1,2-dicarboxylate (10.35 g) in THF (100 ml) at 0° C. The resulting mixture was allowed to warm to 20° C. and stirred for a further 18 hours. The reaction mixture was quenched with water and evaporated to remove THF. The aqueous residues were extracted with DCM (250 ml). The organic phase was washed sequentially with water (250 ml) and saturated brine (250 ml), dried over Magnesium sulphate, filtered and evaporated to give tert-butyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.32 g). NMR Spectrum: (DMSOd6) 0.01 (6H, s); 0.80-0.82 (9H, m); 1.34 (9H, s); 1.84-1.89 (1H, m); 1.99 (1H, m); 3.00 (1H, m); 3.53-3.57 (4H, m); 4.28 (1H, s); 4.48-4.49 (1H, m).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:26][C:27]3[O:28][C:29]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:30]=4[CH:31]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.F[C:39](F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(OC)C=CC=CC=1>[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:26][C:27]3[O:28][C:29]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:30]=4[CH:31]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)(=[O:5])[CH3:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(C)=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.3 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate was dissolved in 3 ml of anisole, 25 ml of trifluoroacetic acid was added to the above solution with ice cooling, and the resulting mixture was stirred at room temperature for 1 hour. After distilling off trifluoroacetic acid under reduced pressure, the residue thus obtained was adjusted to pH 10-11 with saturated sodium bicarbonate aqueous solution, extracted with chloroform, and then dried. At room temperature, the resulting organic layer was mixed with 2 ml of triethylamine and then with 555 mg of acetyl chloride, followed by stirring at the same temperature for 0.5 hours. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography using a chloroform/ethanol mixture as an eluant to obtain 1.8 g of the title compound.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7]>C(O)(=O)C.[Pt](=O)=O>[F:13][CH:2]([F:1])[CH:3]1[CH2:4][CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][CH2:11][NH:12]1
Reactant: COC(=O)c1ccnc(C(F)F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(C(F)F)C1
Reaction time: 7 h
Yield: 74.7 %

Procedure:
Methyl 2-(difluoromethyl)isonicotinate (2.4 g, 12.82 mmol) was dissolved in acetic acid (40 mL). Platinum(IV) oxide (0.291 g, 1.28 mmol) was added and the mixture was hydrogenated at 5 bar and room temperature for 7 h in a Büchi hydrogenation apparatus. The catalyst was removed by filtration, fresh platinum(IV) oxide (210 mg, 0.92 mmol) was added and the hydrogenation was continued at 5 bar and room temperature for 6 h. The catalyst was removed by filtration and the solvent evaporated. The residue was taken up in DCM and the organic phase was washed with satd NaHCO3. The aqueous phase was extracted with DCM and the combined organic phases were filtered through a phase separator and evaporated. Methyl 2-(difluoromethyl)piperidine-4-carboxylate (1.85 g, 75%) was isolated. MS m/z 194 (M+H)+