Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14](=[O:28])[N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[Cl:29].[OH-].[Li+]>CO.O.O1CCCC1>[Cl:29][C:7]1[C:8]([CH2:12][O:13][C:14](=[O:28])[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)COc1cccc(COC(=O)N(c2ccccc2)c2ccccc2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(COC(=O)N(c2ccccc2)c2ccccc2)c1Cl
Reaction time: 8 h
Yield: 76.1 %

Procedure:
{2-Chloro-3-[(diphenylcarbamoyloxy)methyl]phenoxy}acetic acid methyl ester (0.64 g, 1.5 mmol) was dissolved in a mixture of methanol (20 mL), water (5 mL), and tetrahydrofuran (2 mL). An aqueous solution of lithium hydroxide (0.07 g, 1.65 mmol) was added and the mixture was allowed to stir overnight. The mixture was concentrated in vacuo, and the residue diluted with water and washed with diethyl ether. The aqueous layer was acidified with 3M hydrochloric acid forming a white precipitate which was filtered and dried. Recrystallization from methanol gave {2-chloro-3-[(diphenylcarbamoyloxy)methyl]phenoxy}acetic acid as white needles (0.47 g, 76.5%); m.p. 182.2-182.9° C.; 1H NMR 4.66 (s, 2H), 5.30 (s, 2H), 6.83 (dt, J=7.5Hz, 2H), 7.11 (t, J=8.0Hz), 7.28 (m, 10H); 13C NMR 64.98 (t), 66.02 (t), 112.96 (d), 121.62 (d), 126.27 (d), 126.93 (d), 127.02 (d), 128.94 (d), 135.79 (s), 142.34 (s), 153.68 (s), 154.27 (s), 170.26 (s). Analysis for C22H18ClNO5: Calcd.: C, 64.16; H, 4.41; N, 3.40. Found: C, 64.30; H, 4.39; N, 3.56.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([N:9]1[CH2:28][CH2:27][C:12]2[N:13]=[C:14]([NH:17][CH:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:15]=[CH:16][C:11]=2[CH2:10]1)=[O:8])[CH2:2][C:3]#[CH:4].[Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[N:42]([Si](C)(C)C)=[N+:43]=[N-:44]>CN(C)C=O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[NH:17][C:14]1[N:15]=[CH:16][C:11]2[CH2:10][N:9]([C:7](=[O:8])[CH2:6][O:5][CH2:1][CH2:2][C:3]3[N:42]=[N:43][NH:44][CH:4]=3)[CH2:28][CH2:27][C:12]=2[N:13]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CCCOCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COCCc1c[nH]nn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Yield: 39.5 %

Procedure:
Sparge a solution of 2-(but-3-yn-1-yloxy)-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (8.15 g, 21.7 mmol) and L-ascorbic acid sodium salt (8.58 g, 43.3 mmol) in dimethylformamide (60 mL) and water (60 mL) with nitrogen for ten minutes, then evacuate and backfill with nitrogen three times. Add copper (II) sulfate pentahydrate (1.08 g, 4.33 mmol) and heat to 90° C., then add azidotrimethylsilane (23.1 mL, 20.0 g, 173 mmol) dropwise and stir for one hour. Cool reaction mixture to 23° C. and pour into water (50 mL). Extract this mixture with ethyl acetate (4×50 mL). Combine the organic extracts and wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the resulting crude product by silica gel column chromatography (gradient elution: 0 to 10% methanol in ethyl acetate) to give the title compound (3.60 g, 40%). MS (m/z): 420 (M+1).
Reaction SMILES: C[N+](C)=CCl.[Cl-].[Cl-].[CH2:8]([NH:10][C:11]([C:13]1[S:17][C:16](SC)=[N:15][C:14]=1[NH2:20])=O)C>>[S:17]1[C:13]2[CH:11]=[N:10][CH:8]=[N:20][C:14]=2[N:15]=[CH:16]1
Reactant: CCNC(=O)c1sc(SC)nc1N
Agent: C[N+](C)=CCl
Agent: [Cl-]
Product: c1ncc2scnc2n1

Procedure:
Reaction of N-cyanobismethylthiomethyl-eneimine with ethyl thioglycollate gives ethyl 2-methylthio-4-aminothiazole-5-carboxamide. Cyclization with formamide or equivalent, followed by desulfurization of the methylthio gives a thiazolopyrimidone, which can be activated by Vilsmeier reagent, and the chloride displaced by the desired amine to give the desired thiazolo[4,5-d]pyrimidine derivatives as shown above.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][OH:16])[CH:8]=2)[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:1][C:2]1([CH3:22])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][O:16][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)[CH:8]=2)[O:3]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Yield: 76.4 %

Procedure:
0.5 g of (RS)-2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptanol dissolved in 35 ml THF were treated with 480 mg of triphenylphosphine, 275 mg of methyl 4-hydroxybenzoate and 0.28 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 30 ml of water and one portion of 30 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes), giving 550 mg of (RS)-methyl 4-[2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptyloxy]-benzoate as a pale yellow oil. 1H NMR (CDCl3): 7.95 (d, J=8.8 Hz, 2H), 7.10 (d, J=2.2 Hz, 1H), 6.94 (dd, J=8.3, 2.2 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.3 Hz, 1H), 4.20-4.00 (m, 2H), 3.87 (s, 3H), 3.05-2.90 (m, 1H), 1.95-1.85 (m, 1H), 1.82 (s, 2H), 1.70-1.60 (m, 1H), 1.34 (s, 6H), 1.33 (s, 3H), 1.32 (s, 3H), 1.30-1.20 (m, 6H), 0.90-0.80 (m, 3H).
Reaction SMILES: S1(CCCC1)(=O)=O.[F-:8].[Cs+].Br[C:11]1[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:14]=[C:13]([C:28]#[N:29])[C:12]=1[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31]>CCOCC>[C:28]([C:13]1[C:12]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[C:11]([F:8])[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:14]=1)#[N:29]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Reactant: [F-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(F)c1S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
A mixture of dry sulpholane (15 ml) and 4 Å molecular sieve (3.0 g) was stirred under nitrogen with caesium fluoride (2.4 g) at 60° C. for 1/2 hour. To this was added 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethanesulphonylpyrazole (2.0 g) and the mixture stirred at 60° C. for 2 hours, and left overnight at room temperature. This was diluted with ether (50 ml), filtered, and washed with water (100 ml). The aqueous layer was reextracted with ether (3×50 ml) and the combined organic solution re-washed with water (4×50 ml), dried over anhydrous magnesium sulphate, and evaporated in vacuo to give an oil. Purification by chromatography, eluting with ether/hexane (1:4) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoro-4-trifluoromethanesulphonylpyrazole (0.17 g), m.p. 95°-98° C., in the form of a white solid, after recrystallisation from hexane.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.F[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:5]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 24 %

Procedure:
As described for Example 12, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone was converted to the title compound (40 mg, 24%) which was obtained as an off-white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][O:18][CH2:19][C@H:20]([O:30][CH2:31][C:32]([CH3:34])=[CH2:33])[C@@H:21]([O:25][CH2:26][C:27]([CH3:29])=[CH2:28])[C@@H:22]([OH:24])[CH3:23])[C:13](OC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C1COCC1.O.CCOC(C)=O.C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:23][C@@H:22]1[O:24][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][O:18][CH2:19][C@H:20]([O:30][CH2:31][C:32]([CH3:34])=[CH2:33])[C@H:21]1[O:25][CH2:26][C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)CO[C@@H]([C@H](C)O)[C@H](COC[C@H](NC(=O)OCc1ccccc1)C(=O)OC)OCC(=C)C
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)COC[C@@H]1OCC(=C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 62.7 %

Procedure:
To a solution of (S)-methyl 2-(benzyloxycarbonylamino)-3-((2S,3S,4S)-4-hydroxy-2,3-bis(2-methylallyloxy)pentyloxy)propanoate (480 mg, 1.001 mmol) in THF/H2O (18 mL, 2:1 ratio) was added LiOH (71.9 mg, 3.00 mmol) and the solution was allowed to stir for 40 minutes (min) at ambient temperature. The crude reaction mixture was diluted with EtOAc and washed with 1 Normal (N) aqueous HCl. The phases were separated and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to furnish the intermediate acid as a colorless oil which was dissolved in anhydrous toluene (50 mL) and added to a solution of MNBA (521 mg, 1.512 mmol) and DMAP (693 mg, 5.67 mmol) in toluene (180 mL) over the course of 3 h via syringe pump. After the addition was completed the reaction mixture was stirred for 1 h, concentrated, and purified by flash chromatography (SiO2) to afford the title compound as a white foam (281 mg, 62%): 1H NMR (400 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 5.55 (d, J=7.7 Hz, 1H), 5.10 (s, 2H), 5.01-4.91 (m, 3H), 4.85 (d, J=1.2 Hz, 2H), 4.69 (dd, J=12.1, 6.7 Hz, 1H), 4.32 (d, J=11.7 Hz, 1H), 3.99-3.89 (m, 4H), 3.85 (d, J=11.3 Hz, 1H), 3.74 (dd, J=11.9, 4.5 Hz, 1H), 3.60-3.51 (m, 1H), 3.33-3.23 (m, 2H), 1.72 (d, J=6.2 Hz, 6H), 1.44 (d, J=6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.85, 155.71, 142.26, 142.02, 136.10, 128.57, 128.25, 128.11, 112.33, 112.02, 84.95, 83.01, 77.63, 75.87, 74.89, 74.66, 72.86, 67.14, 54.26, 19.81, 19.66, 18.63; ESIMS m/z 470.3 ([M+Na]+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>>[N+:14]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:16])=[O:15]
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Phenyl-2-(1H)-pyrazinone (5 g) was added in portions during 30 minutes to a stirred mixture of fuming nitric acid (30 ml) and sulphuric acid (5 ml) at -5° C. The mixture was stirred in the cold for 30 minutes, and the temperature of the mixture was then allowed to rise to 10° C. The mixture was then poured into ice-water (250 ml) to give 5-(4-nitrophenyl)-2(1H)-pyrazinone recrystallised from dimethylformamide, m.p. 336°-8° C., δ(DMSO-d6) 8.15 and 8.30 (2d, 3- and 6-protons of pyrazinone ring), 8.18 (m, phenyl); νmax (Nujol mull) 3200-2500 (NH), 1690, 1675, 1545, 1510, 1349, 860 and 750 cm-1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:15]2[CH2:26][CH2:25][N:24]3[C:17](=[CH:18][C:19]4[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]=43)[C:16]2=[O:29])=[N:8][CH:9]=[CH:10][C:11]=1B(O)O)(=[O:3])[CH3:2].Br[C:31]1[CH:32]=[C:33]([NH:39][C:40]2[CH:52]=[C:43]3[CH2:44][N:45]([CH2:48][CH2:49][O:50][CH3:51])[CH2:46][CH2:47][N:42]3[N:41]=2)[C:34](=[O:38])[N:35]([CH3:37])[CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:15]2[CH2:26][CH2:25][N:24]3[C:17](=[CH:18][C:19]4[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]=43)[C:16]2=[O:29])=[N:8][CH:9]=[CH:10][C:11]=1[C:31]1[CH:32]=[C:33]([NH:39][C:40]2[CH:52]=[C:43]3[CH2:44][N:45]([CH2:48][CH2:49][O:50][CH3:51])[CH2:46][CH2:47][N:42]3[N:41]=2)[C:34](=[O:38])[N:35]([CH3:37])[CH:36]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COCCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (198 mg, 0.50 mmol), 296f (190 mg, 0.50 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), Pd(dppf)Cl2 (21 mg, 0.025 mmol), acetonitrile (8 mL), and water (0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The water layer was extracted with dichloromethane (2×20 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 296g (163 mg, 50%) as a yellow solid. MS-ESI: [M+H]+ 654.9
Reaction SMILES: BrBr.Cl[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>C(Cl)Cl.CN(C)C=O.O>[C:7]([C:6]1([O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])[CH2:4][CH2:5]1)(=[O:9])[CH3:8]
Reactant: Oc1ccccc1Cl
Reactant: CC(=O)CCCCl
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)C1(Oc2ccccc2Cl)CC1
Reaction time: 0.25 h
Yield: 52.9 %

Procedure:
A solution of 134 g (0.84 mol) of bromine in 130 ml of methylene chloride is added dropwise at 10° C. with stirring to a mixture of 100 g (0.83 mol) of 5-chloropentan-2-one and 400 ml of methylene chloride. After completion of the addition, the reaction mixture is stirred for a further 15 minutes and then poured into 500 ml of water. The organic phase is separated off, washed successively with 5% strength aqueous sodium carbonate solution and with water, then dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. The residue is taken up in 200 ml of dimethylformamide, and the resulting solution is added dropwise at 60° C. to a mixture of 230 g of potassium carbonate, 106 g (0.83 mol) of 2-chlorophenol and 400 ml of dimethylformamide. The reaction mixture is initially stirred for 4 hours at 60° C. and then for 4 hours at 90° C. The mixture is then filtered from the solid residue with suction, the solvent is stripped off under reduced pressure and the remaining residue is taken up in a mixture of ethyl acetate and toluene. The organic phase is washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. The remaining residue is subjected to a vacuum distillation. In this manner, 92.5 g (53% of theory) of 1-acetyl-1-(2-chlorophenoxy)-cyclopropane are obtained in the form of a liquid of boiling point 81° C./0.2 mbar.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(OC)C=CC=CC=1.[Cl:20][S:21](O)(=[O:23])=[O:22]>ClCCCl>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[S:21]([Cl:20])(=[O:23])=[O:22]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: COc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 4-nitroanisole (3.1 g; 20 mmol) in 1,2-dichloroethane (20 mL), 2 mL of chlorosulfonic acid was added at 0° C. The resulting reaction mixture was gradually warmed to room temperature and then heated to reflux for 2 h at which time all the anisole had been consumed. The reaction mixture was then cooled to room temperature and diluted with chloroform (30 mL). The contents were then transferred to a separatory funnel, washed with water (50 mL), and the layers were separated. The aqueous layer was then extracted with chloroform (30 mL). The combined organic layers was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue obtained was purified by silica gel flash column chromatography using ethyl acetate/hexanes as eluant (1:5 to 1:1 gradient) to afford 2-methoxy-5-nitrobenzenesulfonyl chloride as a dark brown solid. 1H NMR (CDCl3, 400 MHz): δ 4.21 (s, 3H), 7.28 (d, 1H), 8.59 (dd, 1H), 8.88 (d, 1H) ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1)=[O:28]
Reactant: CSc1nccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
2-[2-(Methylthio)-6-pyrimidinyl]-4H-1,3-benzothiazine-4-one (0.30 g, 1.50 mmol) was dissolved in chloroform (100 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.50 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.18 g, 55%) as pale yellow crystals.
Reaction SMILES: [C:1]([NH2:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)Br.[P:14]([OH:17])([OH:16])[OH:15]>O1CCOCC1.O>[C:2]1([C:1]([NH2:9])([P:14]([OH:17])(=[O:15])[OH:16])[P:14]([OH:17])(=[O:16])[OH:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OP(O)O
Reactant: NC(=O)c1ccccc1
Agent: BrP(Br)Br
Solvent: O
Solvent: C1COCCO1
Product: NC(c1ccccc1)(P(=O)(O)O)P(=O)(O)O

Procedure:
120 parts of benzamide were suspended in 300 parts of dioxan and reacted with 541 parts of phosphorus tribromide. Then 82 parts of phosphorous acid dissolved in dioxan were added at about 20°C, and the mixture was heated at 60° to 70° C for 3 to 4 hours. The reaction mixture was poured on ice and then concentrated. Subsequently, the mixture was extracted with acetone and then with ether. The residue was isolated, dissolved in water and precipitated again with ethyl acetate/acetone. The precipitate, the trihydrate of 1-phenyl-1-aminomethane-1,1-diphosphonic acid was isolated and dried in air. The yield amounts to 18%, based on PBr3.
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:7][C:8](OCC)=[O:9])#[N:6].[C:13]1([CH:19]=[C:20]2[C:25](=[O:26])[C:24](=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][S:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[O:9]=[C:8]1[O:26][C:25]2[C:24](=[CH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][S:22][CH2:21][C:20]=2[CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]1[C:5]#[N:6]
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC1C(=O)OC2=C(CSCC2=Cc2ccccc2)C1c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of NaOEt (from 555 mg, 92 mg atom Na in absolute EtOH) in 100 ml of absolute EtOH is added ethyl cyanoacetate (2.44 g, 22 mmole) dissolved in 50 ml of absolute EtOH. This is heated at reflux temperature for 2 hours, cooled slightly and tetrahydro-3,5-bis(phenylmethylene)-4H-thiopyran-4-one (5.84 g, 20 mmole) is added at once. The mixture quickly turns orange-red for ca. 10 minutes, changing to yellow (yellow solids in orange-red solution) as heating is continued for 2 hours.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:29]=1>O1CCOCC1.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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:26]2[CH:27]=[C:28]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH:29]=[C:24]([Cl:23])[CH:25]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: O=C(c1cc(Cl)cc(B(O)O)c1)N1CCOCC1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3cc(Cl)cc(C(=O)N4CCOCC4)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
Cs2CO3 (682 mg, 2.10 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (3-chloro-5-(morpholine-4-carbonyl)phenyl)boronic acid (210 mg, 0.78 mmol) in dioxane: water (8 mL: 4 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (40 mg, 0.035 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 80-90% ethyl acetate in pet-ether to afford 46 mg (Yield: 47.0%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([CH2:13][NH2:14])[OH:12]>O1CCOCC1.CC(OC)(C)C>[Cl:1][C:2]1[C:3]([NH:14][CH2:13][CH2:11][OH:12])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Reactant: NCCO
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: N#Cc1cnc(NCCO)c(Cl)c1
Temperature: 80 °C
Yield: 89.3 %

Procedure:
A mixture of 5,6-dichloro-nicotinonitrile (Bionet GC-0755, 500 mg, 2.89 mmol) and ethanolamine (0.87 mL, 14.45 mmol) was prepared in anhydrous dioxane (5 mL) and heated at 80° C. for 24 hours. The reaction mixture was diluted with MTBE (50 mL) and washed with water (2×25 mL) and brine (25 ml). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a white powder (510 mg, 89%). HPLC (Method A), Rt: 1.9 min (purity: 99.9%). UPLC/MS, M−(ESI): 196.0.