Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[N:20]([CH2:27][CH3:28])[N:19]=2)=[CH:14][CH:13]=1)=[O:11].CI.[C:31]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:27]([N:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]([C:2]3[N:1]([CH3:31])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:11])=[CH:17][CH:16]=2)=[N:19]1)[CH3:28]
Reactant: O=C([O-])[O-]
Reactant: CCn1nc(-c2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)c2ncccc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(C(=O)c3nc4ccccc4n3C)cc2)c2ncccc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A suspension of 1H-benzimidazol-2-yl[4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl]methanone (147 mg), MeI (0.037 mL), and K2CO3 (111 mg) in DMF (1.5 ml) was stirred overnight at 40° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give the title compound (139 mg).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=2)[N:3]=1.[NH2:27][C:28]1[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=1>>[CH3:10][O:9][CH2:8][C:6]1[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=2)[N:3]=[C:2]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:7]=1
Reactant: COCc1cc(O)nc(N2CCCC2c2cc(-c3cccnc3)no2)n1
Reactant: Cc1cc(N)n[nH]1
Product: COCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3cccnc3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-methoxymethyl-2-[2-{3-(pyrid-3-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 35(a)) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C1(C)C=CC(S(O[CH2:21][C@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:21][C@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OC[C@H]2COC(C)(C)O2)cc(C)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of 4-bromo-3,5-dimethyl-phenol (500 mg, 2.49 mmol), (R)-(−)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (856 mg, 2.99 mmol) and K2CO3 (1.03 g, 7.45 mmol) in dimethylformamide (5 ml) was stirred at 100° C. for two hours. The reaction mixture was diluted with AcOEt, and the organic layer was then washed with water (×2), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (AcOEt-hexane) to give (S)-4-(4-bromo-3,5-dimethyl-phenoxymethyl)-2,2-dimethyl-[1,3]dioxolane as a colorless solid (749 mg, 95%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.CN(C)C=O.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccccn1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.5 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (41 mg, 0.20 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (0.3 mL) and N,N-dimethylformamide (0.03 mL) were added and the solution was allowed to stir for 10 minutes at room temperature. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in anhydrous pyridine (1 mL). This solution was then slowly added to a solution of pyridin-2-amine (19 mg, 0.20 mmol) in anhydrous pyridine (1 mL). The resulting mixture was allowed to stir for 15 hours at 110° C. The crude product was then filtered, evaporated to dryness, dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product (5.9 mg, 0.021 mmol, 10%). ESI-MS m/z calc. 282.1. found 283.1 (M+1)+. Retention time 2.13 minutes.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:24][C:25]([F:38])([F:37])[C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:21])([F:22])[C:17]([F:19])([F:20])[F:18])=[C:9]([C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:30][C:26]([C:25]([F:38])([F:24])[F:37])=[CH:27][N:28]=3)[CH2:32][CH2:33]2)=[O:12])[CH:13]=1)(=[O:4])=[O:3]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 68 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid (Example A30) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a brown solid (yield 68%). MS (m/e): 568.2 (M+H+, 100%).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[O:28][CH2:27][C:13]2([C:29]3[CH:34]=[C:33]([Br:35])[C:32]([F:36])=[CH:31][C:30]=3[F:37])[N:14]=[C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:16][CH2:17][CH:12]2[CH2:11]1)C1C=CC=CC=1.Br([O-])(=O)=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[Br:35][C:33]1[C:32]([F:36])=[CH:31][C:30]([F:37])=[C:29]([C@:13]23[CH2:27][O:28][C@@H:10]([CH2:9][OH:8])[CH2:11][C@H:12]2[CH2:17][S:16][C:15]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:14]3)[CH:34]=1
Reactant: O=C(NC1=NC2(c3cc(Br)c(F)cc3F)CO[C@@H](COCc3ccccc3)CC2CS1)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1

Procedure:
A solution of C9 (3.22 g, 5.48 mmol) in ethyl acetate (100 mL) was treated with a solution of sodium bromate (4.14 g, 27.4 mmol) in water (66 mL). To the well stirred biphasic system was added a solution of sodium dithionite (4.77 g, 27.4 mmol) in water (134 mL) drop-wise over 30 minutes. The reaction mixture was stirred for 90 minutes and then diluted with ethyl acetate (500 mL). The organic layer was removed and the aqueous was extracted with ethyl acetate (3×100 mL). The combined organics were then washed with an aqueous solution of sodium thiosulfate pentahydrate (3×300 mL), brine (300 mL), and then dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a white solid. Yield: 1.77 g, 3.57 mmol, 65%. LCMS m/z 499.1 [M+H+], Br isotopic pattern. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 8.11 (d, J=6.5 Hz, 2H), 7.64 (t, J=7.9 Hz, 1H), 7.53-7.57 (m, 1H), 7.44-7.48 (m, 2H), 7.24 (dd, J=12, 8.3 Hz, 1H), 4.09 (dd, J=11.6, 1.9 Hz, 1H), 3.9 (d, J=11.9 Hz, 1H), 3.72-3.77 (m, 1H), 3.58 (d, J=5.1 Hz, 2H), 3.11-3.19 (m, 1H), 2.97 (dd, J=13.3, 4.1 Hz, 1H), 2.75 (dd, J=13.1, 2.7 Hz, 1H), 1.84 (q, J=11.6 Hz, 1H), 1.66-1.71 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH3:16])=[O:14].CC(N(C)C)=O>O1CCOCC1>[C:13]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)([O:15][CH3:16])=[O:14]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 65 °C

Procedure:
To suspension of the 4-aminomethylbenzoic acid (10 g, 66.2 mmol) in 1,4-dioxane (100 mL) were added methyl chloroformate (5.4 mL, 69.5 mmol) and dimethyl acetamide (3.4 mL). The reaction mixture was then heated to 65° C. overnight. Reaction mixture was evaporated to dryness and the residue was triturated with water. The solids were filtered and dried to give pure product as white solid. 1H NMR (600 MHz, DMSO) δ 12.84 (bs, 1H), 7.85 (d, J=7.8 Hz, 2H), 7.73 (t, J=6 Hz, 1H), 7.32 (d, J=7.8 Hz, 2H), 4.20 (bd, J=6 Hz, 2H), 3.52 (s, 3H); MS: (MH+), (MH+).
Reaction SMILES: [S:1]1[C:5]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.Cl.Cl.[NH2:24][CH:25]1[CH2:32][CH:31]2[N:33]([CH3:34])[CH:27]([CH2:28][CH2:29][CH2:30]2)[CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:34][N:33]1[CH:27]2[CH2:28][CH2:29][CH2:30][CH:31]1[CH2:32][CH:25]([NH:24][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:5]4[S:1][C:2]5[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=5[CH:4]=4)=[N:10][C:9]=13)=[O:17])[CH2:26]2
Reactant: O=C(O)c1cccc2oc(-c3cc4ccccc4s3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cc5ccccc5s4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.4 %

Procedure:
A mixture of 2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxylic acid (128 mg, 0.43 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (118 mg, 0.52 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (164 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.63 mL, 2.2 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzo[b]thiophen-2-yl benzoxazole-4-carboxamide (49 mg, 61%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.97 (d, J=7.0 Hz, 1H), 8.38-8.19 (m, 2H), 7.95 (dd, J=7.5, 1.5 Hz, 2H), 7.71 (dd, J=8.0, 1.0 Hz, 1H), 7.51-7.46 (m, 3H), 4.63-4.55 (m, 1H), 3.14 (d, J=10.0 Hz, 2H), 2.70-2.62 (m, 2H), 2.56 (s, 3H), 2.08-2.00 (m, 2H), 1.66-1.52 (m, 4H), 1.28-1.22 (m, 2H); MS (ESI+) m/z 432 (M+H); HPLC>99% (AUC), tR=14.59 min.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3]Cl.[C:9]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:25]C(OC(C)(C)C)=O)[CH2:17][C@:18]([CH2:23][OH:24])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1.CCN(CC)CC>CC(C)=O>[CH2:6]([O:5][C:1]([O:2][CH2:3][O:21][C:19](=[O:20])[C@@:18]([CH2:23][OH:24])([CH3:22])[CH2:17][C@H:16]([NH2:25])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:11]=1)=[O:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: CCOC(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloromethyl ethyl carbonate (54 mg, 387 nmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:9]=2[CH:10]=1
Reactant: CN1CCc2[nH]c3cc(F)cc(F)c3c2C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3c(F)cc(F)cc3n2CCc2ccc(C(F)(F)F)nc2)C1

Procedure:
The title compound is prepared from a mixture of 7,9-difluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[C:13]([CH3:14])=[N:12][S:11][C:9]=2[N:10]=1)[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:6]1[C:7](=[O:15])[C:8]2[C:13]([CH3:14])=[N:12][S:11][C:9]=2[N:10]=[C:5]1[CH2:1][CH:2]([CH3:4])[CH3:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1nsc2nc(CC(C)C)[nH]c(=O)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nsc2nc(CC(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 26) (1.31 g, 5.8 mmol) in 20 mL of anhydrous DMF was added 1.38 g (10 mmol) of anhydrous K2CO3 followed by benzyl bromide (1.18 g, 6.9 mmol) and the mixture was stirred at room temperature overnight. The TLC of the reaction mixture showed the complete disappearance of the SM. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried (Na2SO4) and concentrated. The TLC and the 1H NMR showed the presence of two products N alkylated as well as O-alkylated products in a ratio of 7:3. The products were separated by column (silica gel, 116 g) chromatography using 10% EtOAc in hexanes. 5-Benzyl-6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one was isolated as white crystalline solid (1.3 g, 70%). m/z 314 (MH+), 1H NMR (300 MHz) δ 0.94 (d, 6H), 2.23-2.37 (m, 1H), 2.64 (d, 2H), 2.82 (s, 3H), 5.38 (s, 2H), 7.10-7.38 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2F)[N:3]=1.[Cl:29]C1N=CC(C(F)(F)F)=C(Cl)N=1.C(OP(CC1C=CC(N)=C(Cl)C=1)(=O)OCC)C>>[Cl:29][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(F)c1)OCC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: CCOP(=O)(Cc1ccc(N)c(Cl)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(Cl)c1)OCC
Yield: 30 %

Procedure:
Prepared analogously to Compound 22C using 2,6-Dichloro-5-trifluoromethylpyrimidine (2.2 g, 10.3 mmol) and (4-amino-3-chlorobenzyl)phosphonic acid diethyl ester (Compound 24D, 2.2 g, 7.94 mmol) to afford 1.1 g of the title compound (30%). 1H NMR (400 MHz, CDCl3): δ=1.22-1.26 (m, 6H), 3.1 (d, J=22 Hz, 2H), 3.99-4.08 (m, 4H), 7.23 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.83 (brs, 1H), 8.3 (d, J=8.2 Hz, 1H), 8.57 (s, 1H).
Reaction SMILES: [C:1]([O:9][C@:10]1([CH3:35])[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:13][C@H:11]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC([O:42][CH3:43])N(C)C.CO>CN(C)C=O.ClCCl>[C:43]([O:12][C@@H:11]1[O:13][C@H:14]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@:10]1([CH3:35])[O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 21 °C
Reaction time: 12 h
Yield: 68.6 %

Procedure:
To a suspension of compound 3 (19 g, 0.0738 mol) in anhydrous N,N-dimethylformamide (150 ml) was added N,N-dimethylformamide dimethyl acetal (98 ml, 0.7385 mol) and the mixture was stirred at 20-22° C. After one hour TLC (silica gel, 30% methanol in dichloromethane, Rf for compound 3: 0.21 and for product 4: 0.55) indicated that reaction was complete. Solvent and reagent were removed under reduced pressure (temperature was kept below 40° C.). Ethanol (50 ml) was added to the obtained oily residue and the solvent was removed under reduced pressure. This process was repeated twice and crude product solidified. The crude product was stirred with 190 ml of ethanol at 20° C. for one hour and kept at 5° C. for 12 hours. Solids were collected by filtration and filter cake washed with 30 ml of cold ethanol and 30 ml of cold tert-butyl-methyl ether. Drying the solid under vacuum gave 14.7 g (64%) of compound (4) as a first crop. TLC (silica gel, 30% methanol in dichloromethane, Rf for product (4): 0.55) and (silica gel, 10% methanol in dichloromethane, Rf for product (4): 0.1) showed only a single spot for compound (4) Mother liquor from the ethanol purification was evaporated to dryness and the residue was stirred with ethanol (80 ml) at 20° C. for one hour and kept at 5° C. for 12 hours. Solids were collected by filtration and filter cake washed with 15 ml of cold ethanol and 15 ml of cold tert-butyl-methyl ether. After drying the solid under vacuum, 3.5 g (15%) was obtained as a second crop. TLC (silica gel, 30% methanol in dichloromethane, Rf for product (4): 0.55) and (silica gel, 10% methanol in dichloromethane, Rf for product (4): 0.1) showed only a single spot for compound (4); m.p. 201-209° C.; 1H NMR (DMSO-d6) δ ppm 8.62 (s, 1H, N═CH), 8.17 (d, 1H, H-6, J5-6=7.3 Hz), 5.91 (m, 2H, H-1′, H-5), 5.16 (t, 1H, OH-5′, D2O exchangeable), 5.06 (s, 1H, OH-2′, D2O exchangeable), 3.8-3.5 (m, 4H, H-3′, H-4′, H-5′ and H-5″), 3.15 and 3.02 (2s, 6H, N(CH3)2), 0.92 (s, 3H, CH3); FAB>0 (GT) 625 (2M+H)+, 313 (M+H)+, 167 (B+2H)+; FAB<0, (GT) m/z 419 (M+T−H)−, 403 (M+G−H)−, 311 (M−H)−, 165 (B)−.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[C:16]1([CH2:19][C:20](=[O:34])[C:21]([NH:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[C:29](=[O:30])[O:28][CH2:27]3)=[O:22])[CH2:18][CH2:17]1.[Cl-].[NH4+]>C1COCC1>[C:1]([C:20]([OH:34])([CH2:19][C:16]1([C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=2[F:5])[CH2:18][CH2:17]1)[C:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=[O:30])[O:28][CH2:27]2)=[O:22])#[CH:2]
Reactant: O=C(CC1(c2cc(C(F)(F)F)ccc2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)(CC1(c2cc(C(F)(F)F)ccc2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethinyl magnesium bromide (6 ml, 0.5 M in tetrahydrofuran) was added to an ice-cold solution that consists of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide (632 mg) in THF (4 ml). The reaction solution under argon was allowed to come to room temperature within 3 hours. Then, the reaction mixture was poured into ice-cold, saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate. The crude product that is obtained was chromatographed on silica gel. 2.2 g of product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.[CH2:24](N(CC)CC)C.IC.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:5][CH:6]1[CH2:7][CH:8]2[N:13]([CH2:14][C:15]3[N:19]([CH3:24])[N:18]=[N:17][N:16]=3)[CH:11]([CH2:10][CH2:9]2)[CH2:12]1
Reactant: Clc1ccc(OC2CC3CCC(C2)N3Cc2nnn[nH]2)cc1Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnnc1CN1C2CCC1CC(Oc1ccc(Cl)c(Cl)c1)C2

Procedure:
3-(3,4-Dichloro-phenoxy)-8-(1H-tetrazol-5-ylmethyl)-8-aza-bicyclo[3.2.1]octane (5 g) in 50 ml of N,N-dimethylformamide was added 3 ml of triethylamine and stirred under a nitrogen atmosphere. Iodomethane (2 ml) was added drop wise. The reaction mixture was stirred at room temperature overnight and poured into 100 ml of water. The mixture was extracted with diethyl ether, which was dried with magnesium sulphate and evaporated to an oil, the oil was triturated in dry diethyl ether. Yield 0.55 g (11%) Mp. 119-120° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[CH3:49][O:48][CH2:47][CH2:46][CH2:45][N:40]1[C:39]2[CH:50]=[C:35]([CH2:34][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[CH3:25])=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]3)[CH:36]=[CH:37][C:38]=2[O:43][CH2:42][C:41]1=[O:44]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: Cc1ccccc1OCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4C)cc3)cc21

Procedure:
Analogously to Method D, 1.04 g of tert-butyl 3-hydroxy-4-[4-(3-o-tolyloxypropoxy)phenyl]piperidine-1-carboxylate and 0.700 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [OH:1][C:2]1([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:6][CH2:5][CH2:4][CH2:3]1>C(Cl)Cl>[OH:1][C:2]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCC(c2c[nH]c3ccc(C=CC4(O)CCCC4)cc23)CC1
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(CCC4(O)CCCC4)cc23)CC1

Procedure:
Obtained from the title compound of Example 44, by analogy with Example 43. Rf 0.40 (SS 7). Found: C,73.55; H,8.90; N,8.12. C21H30N2O; 0.25 CH2Cl2 requires C,73.44; H,8.85; N,8.06%.