Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[C:18]([NH:22][C@H:23]([C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:24]([CH3:26])[CH3:25])[CH:19]=[N:20][CH:21]=4)=[CH:14][N:13](COCC[Si](C)(C)C)[C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O.C(N)CN.[OH-].[Na+]>C(Cl)Cl.CS(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[C:18]([NH:22][C@H:23]([C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])[CH:24]([CH3:26])[CH3:25])[CH:19]=[N:20][CH:21]=4)=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(-c4cnn(C)c4)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](Nc1cncc(-c2c[nH]c3ncc(-c4cnn(C)c4)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 18 h

Procedure:
To a solution N2-{5-[5-(1-methyl-1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl}-N-(2,2,2-trifluoroethyl)valinamide 8-1a (190 mg, 0.316 mmol) from step 1 in DCM (2 mL) was added TFA (2.4 mL, 31.6 mmol) and the resultant mixture was stirred for 2 h. The mixture was concentrated in vacuo, resuspended in MeOH (1 mL) and to this was added ethylenediamine (0.043 mL, 0.632 mmol) and sodium hydroxide (10 M aq) (0.221 mL, 2.21 mmol). After 18 h, the reaction was transferred to vial with an additional 1 mL of dimethylsulfoxide and this solution was purified by mass triggered reverse phase HLPC. The fractions containing product 8-1 were basified with NaHCO3, dried over MgSO4, filtered and concentrated.
Reaction SMILES: [C:1]([C:5]1([CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([O:3]C)=[O:2].[OH-].[Li+]>CO.O>[C:1]([C:5]1([CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Yield: 99 %

Procedure:
Dissolve 2-carbomethoxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (2.5 g, 8.6 mmol) in methanol (50 mL) and add 1N lithium hydroxide (15 mL, 15 mmol). Stir at reflux for 12 hours and at room temperature for an additional 12 hours. Dilute with water (10 mL) and concentrate in vacuo to 20 mL. Wash with ethyl ether and acidify the aqueous phase with 2N hydrochloric acid. Extract with methylene chloride (2×25 mL), dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as a crystalline solid (2.37 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Cl)c1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 3-Chlorophenyl isocyanate (0.03 mL, 0.26 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (1 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 32 (54 mg, 56% yield) as a yellow solid. LC-MS (M+H=361, obsd.=361).
Reaction SMILES: C(N(CC)CC)C.C(O[C@@H:12]1[C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH2:16][CH3:17])[C:14](=[O:33])[CH2:13]1)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH:21]([OH:32])[CH2:20]3)(=O)C.O>CCO>[OH:32][CH:21]1[C:22]2[C@H:27]([CH2:26][CH2:25][C:24](=[O:31])[CH:23]=2)[C@@H:28]2[C@H:19]([C@H:18]3[C@@:15]([CH2:30][CH2:29]2)([CH2:16][CH3:17])[C:14](=[O:33])[CH:13]=[CH:12]3)[CH2:20]1
Reactant: CC[C@]12CC[C@H]3[C@@H](CC(O)C4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[C@]12CC[C@H]3[C@@H](CC(O)C4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 25 °C
Yield: 33.3 %

Procedure:
Triethylamine (0.5 ml, 3.6 mmol) was added to a suspension of 15α-acetoxy-6-hydroxy-18-methyl-estr-4-en-3,17-dione (0.5 g, 1.4 mmol) in EtOH (3 ml). The mixture was heated under reflux for 2 h, cooled to room temperature and then water (30 ml) was added. The mixture was extracted with ethyl acetate (30 ml), the organic layer was washed with water (50 ml), dried and the solvent removed. The crude product was purified by flash chromatography on silica gel eluting with diisopropyl ether/ethyl acetate (7/3) to afford pure 6-hydroxy-18-methyl-estra-4,15-dien-3,17-dione (0.14 g, yield: 34%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:14])=[C:4]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[N:6][CH:7]=1.[CH2:15](OC(OCC)OCC)C>>[Cl:1][C:2]1[C:3]2[N:14]=[CH:15][N:8]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(Cl)cnnc1NC1CCCC1
Product: Clc1cnnc2c1ncn2C1CCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 5-chloro-N-3-cyclopentylpyridazine-3,4-diamine (Preparation 12, 1.2 g, 5.64 mmol) and triethylorthoformate (10 mL) were heated to reflux for 1.5 hours. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo and triturated with EtOAc (20 mL). The solid was filtered and the filtrate was reduced to dryness. The crude material was purified by silica gel column chromatography eluting with EtOAc to afford the title compound as a yellow solid in 51% yield, 902 mg.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]1([O:15][CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:8][C:12]1[CH:13]=[CH:14][C:9]([O:15][CH3:16])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1
Agent: [Zr+4]
Agent: [Cl-]
Product: COc1ccc(Br)cc1
Yield: 98 %

Procedure:
Bromination using NBS has been found to be applicable for use with a wide range of aromatic starting materials or substrates, as is summarized in Table 1. For example, anisole can be brominated by use of 1 equivalent of NBS in the presence of 5 mol % of ZrCl4 at −78° C. to afford p-bromoanisole in 98% yield as sole product (Table 1, Entry 1). However, in the absence of ZrCl4 the halogenation does not proceed, even at room temperature (Table 1, Entry 1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[CH3:14].[OH-:15].[Na+]>CSC.C(OCC)(=O)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][OH:15])[CH:4]=2)[N:9]=1
Reactant: Cc1cc(Cl)nc2ccc(CBr)cc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CSC
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2ccc(CO)cc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-methylquinoline (0.39 g) in dimethyl sulfide (5 mL) was added 1 M aqueous sodium hydroxide (5 mL) at room temperature, and the mixture was stirred at 70° C. for 1 h. After cooled to room temperature, the reaction solution was diluted with ethyl acetate. The organic layer was washed with saturated brine, the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=3:1−ethyl acetate/hexane/chloroform=1:3:1−ethyl acetate) to obtain (2-chloro-4-methylquinolin-6-yl)methanol (0.14 g).
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH2:4].[PH3:5]>C1(C)C=CC=CC=1>[CH2:4]([P:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:3][CH2:2][CH3:1]
Reactant: C=CCC
Reactant: P
Solvent: Cc1ccccc1
Product: CCCCP(CCCC)CCCC
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A 90 liter-autoclave was charged with 9.6 kg (170 mol) butene-1 and 1.75 kg (51 mol) PH3 in the sequential order indicated. Next, the autoclave was heated to 80° C. and the addition of the toluene/ABIN-solution was started. 12 l toluene in which 170 g ABIN (2 mol %, based on PH3) was dissolved was pumped over a period of 2.5 hours into the reactor so that the temperature of the reaction mixture did not exceed 100° C. After a reaction period of 71/2 hours, the whole was allowed to cool and the crude product (18.3 kg) was given into a barrel scavenged with nitrogen.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])=[CH:6][CH:7]=1
Reactant: NCCCc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
A mixture of 3-(4-bromophenyl)-propylamine (6.21 g, 29 mmol), 2-bromomethyl-benzoic acid methyl ester (6.57 g, 29 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 1.5 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(4-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (7.24 g, 88%). GC/MS gave: m/z (rel.int.) 331 (M+, 9), 329 (M+, 9), 147 (100), 146 (54) 119 (34), and 91 (33). 1H NMR (300 MHz, CDCl3): δ 1.97 (dt, 2H), 2.64 (t, 2H), 3.66 (t, 2H), 4.35 (s, 2H), 7.08 (dd, 2H), 7.38 (dd, 2H), 7.46 (m, 2H), 7.51 (dt, 1H), 7.85 (d, 1H). 13C NMR (300 MHz, CDCl3): δ 29.9, 32.5, 41.9, 49.9, 119.7, 122.7, 123.6, 128.0, 130.2 (2C), 131.2, 131.4 (2C) 132.9, 140.3, 141.1, 168.5.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Yield: 98.2 %

Procedure:
A mixture of (1-ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine (40 mg, 0.112 mmol) and 4 mg of 10% Pd/C in 10 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through Celite® and the filtrate was concentrated to dryness to give a light berown crystals which was purified through silica gel column chromatography using 1:1 chloroform:hexane as eluent to give the title compound as golden crystals (36 mg, 97%), mp 105-107° C. 1H NMR (CDCl3) δ6.88 (s, 2H), 6.11 (s, 1H), 4.00 (brs, 1H), 3.28 (m, 1H), 3.10 (brs, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 2.10 (s, 6H), 1.45-1.75 (m, 4H), 0.98 (t, 6H) ppm. The corresponding HCl salt was prepared as white solid, mp 174-178° C., 1H NMR(D2O) δ7.09 (s, 2H), 6.63 (s, 11H), 3.65 (m, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.11 (s, 6H), 1.45-1.80 (m, 4H), 0.91 (t, 6H) ppm.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(O)C>[C:15]([O:14][C:12](=[O:13])[CH2:11][NH:4][CH:1]1[CH2:3][CH2:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1CC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Cyclopropylamine (19.5 g, 0.342 mol) was placed in a pressure bottle and ethanol (100 ml.) was added. The resulting solution was cooled in an ice bath and sodium bicarbonate (8.5 g, 0.101 mol) and t-butyl bromoacetate (15.5 g, 0.0795 mol) was added. The flask was stoppered and the contents of the flask were stirred for 30 minutes with external cooling (ice bath) and then at room temperature overnight. Most of the solvent was removed on a rotary evaporator and water was added to the residue. The product was extracted several times with chloroform. The combined chloroform extract was washed with water, dried over sodium sulfate, filtered and evaporated to yield the product as a pale yellow oil (12.5 g, 92%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:9][O:10][C:11](=[O:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][C:15]=1[I:22].Cl[CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH3:41]>CS(C)=O.CCOCC>[CH3:9][O:10][C:11](=[O:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:21])[CH2:25][C:26]2[S:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[N:28][C:27]=2[CH3:41])=[CH:16][C:15]=1[I:22]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CNc1ccc(OCC(=O)OC)c(I)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1I
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.3 %

Procedure:
A suspension of potassium carbonate (45 mg, 0.33 mmol), sodium iodide (45 mg, 0.30 mmol) and of (2-iodo-4-methylamino-phenoxy)-acetic acid methyl ester (73 mg, 0.35 mmol) in DMSO (4 ml) was treated with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (96 mg, 0.30 mmol, WO02/28433) in 3 portions over 1.5 h. The reaction mixture was stirred for total 2.5 h at RT, taken up in ether and washed with KHSO4-solution (10%). The organic phase was washed with NaCl (10%), dried (Na2SO4) and evaporated. Purification by flash chromatography (SiO2, n-heptane/AcOEt=4/1) gave 151 mg of pure (2-iodo-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester, MS: 577.2 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH:10]([C:21]([NH2:23])=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1>[OH-].[OH-].[Pd+2].CO>[NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([C:21]([NH2:23])=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CN(c2cccc(N)c2)CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C1CN(c2cccc(N)c2)CCN1

Procedure:
To methanol add 4-(3-aminophenyl)-1-(phenylmethyl)-2-piperazinecarboxamide and Pd(OH)2. Place the reaction on a Parr hydrogenator at 50 psi of H2 and shake. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction, remove the catalyst by suction filtration through celite. Remove solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:21])([CH3:20])[CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH3:21])([CH3:20])[CH2:10][C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)CC(C)(C)Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(CC(=O)NCC(=O)O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of ethyl 2-(3-(4-chlorophenylamino)-3-methylbutanamido)acetate (1.34 g, 4.49 mmol) in THF (20 mL), was added aq. sodium hydroxide (10 mL, 4.49 mmol). The mixture was stirred at rt overnight. The reaction was quenched with 1N HCl, extracted into EtOAc, and the combined organic extracts were dried over Na2SO4 and concentrated to give 2-(3-(4-chlorophenylamino)-3-methylbutanamido)acetic acid (1.2 g, 99% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]([OH:34])=[O:11]
Reactant: COc1c(C)c(Cc2cccc(C=O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Yield: 98.1 %

Procedure:
To a solution of 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (1.87 g, 4.28 mmol) in acetonitrile (12.0 ml) were added an aqueous solution (7.0 ml) of sodium dihydrogen phosphate (4.01 g, 33.42 mmol), an aqueous solution (7.0 ml) of sodium hypochlorite (1.74 g, 19.33 mmol) and an aqueous hydrogen peroxide (1.89 ml, 30%) and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (1.90 g, 4.20 mmol, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C@H:12]([OH:15])[CH2:13]O)[CH2:6][CH2:5]2.N1C=CC=CC=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C@H:12]1[CH2:13][O:15]1)[CH2:6][CH2:5]2
Reactant: OC[C@@H](O)[C@@H]1CCc2cc(F)ccc2O1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Fc1ccc2c(c1)CC[C@@H]([C@H]1CO1)O2
Temperature: 1 °C
Yield: 12.2 %

Procedure:
(R)-1-((S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethane-1,2-diol (0.27 g, 1.27 mmol) was dissolved in dichloromethane (10 ml) under nitrogen atmosphere and pyridine (510 μl) added under stirring. The reaction mixture was then cooled to 1° C. and tosyl chloride (0.24 g, 1.27 mmol) in dichloromethane (3 ml) was added over a period of 2.5 h. The reaction was quenched with saturated ammonium chloride (1 ml) and further diluted with dichloromethane (10 ml) and demi water (10 ml). The aqueous layer was separated and further extracted with dichloromethane (15 ml). The collected organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to furnish a colourless oil. Said oil was dissolved in methanol (3 ml) and dichloromethane (6 ml) under stirring in nitrogen atmosphere and potassium carbonate (0.32 g, 2.35 mmol) added. The reaction mixture was left to stir for 15 h at 25° C. The reaction was then diluted with water (10 ml) and dichloromethane (10 ml). The separated aqueous layer was further extracted with dichloromethane (20 ml). The collected organic layers were dried over magnesium sulfate and concentrated in vacuo to furnish crude (S)-6-fluoro-3,4-dihydro-2-((R)-oxiran-2-yl)-2H-chromene as a yellow oil. Separation via chomatography on silica, using heptane:ethyl acetate 9:1 as eluent, furnished 30 mg of (S)-6-fluoro-3,4-dihydro-2-((R)-oxiran-2-yl)-2H-chromene as a colourless oil (12% yield).
Reaction SMILES: C[N+]1([O-])CCOCC1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[C:22]([CH2:23][OH:24])=[CH:21][C:20]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[C:19]([F:33])[C:18]=2[F:34])[CH2:11]1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:16][C@H:14]1[O:15][C@@H:10]([CH3:9])[CH2:11][N:12]([C:17]2[C:18]([F:34])=[C:19]([F:33])[C:20]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:21][C:22]=2[CH:23]=[O:24])[CH2:13]1
Reactant: C[C@@H]1CN(c2c(CO)cc(C(=O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc(C(=O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
NMO (295 mg, 0.0025 mmol) and TPAP (44 mg, 0.0001 mmol) were added to a stirred solution of {4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluoro-5-(hydroxymethyl)phenyl}(phenyl)methanone (Intermediate 23, 450 mg, 0.001 mmol) in anhydrous CH2Cl2:CH3CN (1:1, 10 mL) at 0° C., and the mixture was stirred for 12 hours with warming to room temperature. The solvents were removed and the residue was purified over a silica gel chromatography column using ethyl acetate-pet. ether gradient, providing the title compound. Yield: 340 mg, (76%)
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:31]=[C:30]([CH2:32][S:33][C:34]2[C:39]([C:40]([OH:42])=O)=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=[CH:28][N:27]=1.[NH2:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[CH:45]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:51][C:46]1[CH:45]=[C:44]([NH:43][C:40]([C:39]2[C:34]([S:33][CH2:32][C:30]3[CH:29]=[CH:28][N:27]=[C:26]([F:25])[CH:31]=3)=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:42])[CH:49]=[C:48]([CH3:50])[CH:47]=1
Reactant: O=C(O)c1cccnc1SCc1ccnc(F)c1
Reactant: Cc1cc(C)cc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(F)c2)c1
Yield: 44 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.0 g, 7.9 mmol) was added to a solution of 2-(2-fluoropyridin-4-ylmethylthio)pyridine-3-carboxylic acid (Reference compound No. 2-1, 1.5 g, 5.7 mmol), 3,5-xylidine (0.90 g, 7.4 mmol) and N,N-diisopropylethylamine (2.0 mL, 11 mmol) in N,N-dimethylformamide (20 mL) at room temperature, and the mixture was stirred for 12 hours. Ethyl acetate (30 mL) was added to the reaction mixture, the whole was washed with brine (50 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 0.91 g of the title reference compound as a colorless solid. (Yield 44%)
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.