Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][OH:17].[OH-].[Na+]>O>[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][O:17][CH2:1][CH2:2][OH:3]
Reactant: CON=C1C(=NO)Oc2ccccc21
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 5 °C
Yield: 60.5 %

Procedure:
At 20° C., 264.3 g (6.0 mol) of ethylene oxide are passed into a solution of 192.2 g (1.0 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime in 2 l of water over a period of 85 minutes. The solution is cooled to 5° C. and 70 g (1.06 mol) of sodium hydroxide pellets are added, on which the temperature increases to 10° C. The mixture is stirred without further cooling for another 165 minutes and the precipitate that has formed is filtered off with suction, washed with 500 ml of ice-water a little at a time and dried at 40° C. in a vacuum drying cabinet. 143.0 g (61% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) are obtained as a mixture of two stereoisomers.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13](=[O:25])[C:14]1[CH:19]=[CH:18][C:17]([CH:20](Br)[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1>CN(C)C=O>[CH3:11][O:12][C:13](=[O:25])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1
Reactant: CCCC(Br)c1ccc(C(=O)OC)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1ccc(C(=O)OC)cc1)n1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 43.2 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 113 mg, 1.00 mmol) was dissolved in anhydrous N,N-dimethylformamide (2.5 mL) and a 60% dispersion of sodium hydride in mineral oil (40 mg, 1.00 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and 4-(1-bromo-butyl)-benzoic acid methyl ester (261 mg, 0.97 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with ethyl acetate (100 mL), washed with water (2×25 mL), saturated aqueous brine solution (2×10 mL), dried over magnesium sulfate and concentrated in vacuo to give an oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 4-[1-(3-nitro-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (127 mg, 42%) as a white waxy solid: ESI-LRMS m/e calcd for C15H17N3O4 [M+] 303.1, found 304.5 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate (10 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.4 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Benzylbromide (8.0 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-4-nitro-1H-pyrrole-2-carboxylate (14.3 g, yield 97%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 73° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:10]1=[O:26].CI.Cl[CH2:30]CCl>C(Cl)Cl.[Ag]=O>[CH3:30][O:1][CH2:2][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)[C:10]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(CO)C(=O)OC1)C2=O
Reactant: ClCCCl
Agent: O=[Ag]
Solvent: ClCCl
Solvent: CI
Product: COCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 25 °C

Procedure:
tert-butyl 2-(4-(hydroxymethyl)-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.42 g, 1.15 mmol), silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were taken up in DCM (5 mL) and stirred over night at room temperature under nitrogen. Additional silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were added to the mixture with DCE (8 mL) and the resulting mixture was heated at 54° C. overnight. The reaction mixture was filtered through CELITE® to remove silver oxide, concentrated, and purified by silica gel column chromatography (40 g RediSep Gold column) using (20-80) % EtOAc/DCM as mobile phase to afford the title compound.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)=[O:8].[Si:29](OS(C(F)(F)F)(=O)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C)C=O>[CH3:33][C:32]([Si:29]([CH3:31])([CH3:30])[O:26][C@@H:24]1[CH2:25][C:20]2[C@@:21]([CH3:27])([C@@H:16]3[C@@H:17]([CH2:18][CH:19]=2)[C@H:12]2[C@@:13]([CH3:28])([C@@H:9]([C:7](=[O:8])[CH3:6])[CH2:10][CH2:11]2)[CH2:14][CH2:15]3)[CH2:22][CH2:23]1)([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Imidazole (ImH) can be added to a solution of pregnenolone (compound 3, see Scheme 1) in anhydrous dimethylformamide (DMF). Tert-butyldimethylsilyltrifluoromethanesulfonate can then be added to the solution. The reaction product can be purified to obtain compound 4, 1-((3S,8S,9S,10R,13S,14S,17S)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3-[(1,1-dimethylethyl)dimethylsilyloxy]-10,13-dimethyl-1H-cyclopenta[α]phenanthren-17-yl) ethanone, as shown in Scheme 2.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:36])[F:37])=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1C(F)(F)F)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-trifluoromethylphenyl isocyanate (0.169 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 148 mg (42.1%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[NH3:10].O>C1(C)C=CC=CC=1>[C:5](=[O:6])([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])[NH2:10]
Reactant: N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)OCC(Cl)(Cl)Cl

Procedure:
Me-PRX (150 g) is dissolved in toluene (450 ml) at room temperature. The mixture is then heated to reflux. At reflux, 2,2,2-trichloroethyl-chloroformate (120 ml) is added dropwise for about 2.5 hours. After about 3 hours at reflux, the reaction mixture is cooled, and ammonia 20% (300 ml) and water (300 ml) is added. The organic phase is separated and washed with water (500 ml), followed by brine (500 ml). The organic phase is then separated, dried over MgSO4, filtered. Toluene is then removed under reduced pressure to give 280.2 g of the 2,2,2-trichloroethyl carbamate of paroxetine. The carbamate is then hydrolyzed according to procedures set forth, for example, in Examples 5-7 to give paroxetine base. Paroxetine base may then be converted into the desired polymorphic form of, e.g., the hydrochloride acid addition salt such as the hemihydrate, anhydrate or solvate form as disclosed herein.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[CH2:13]([O:17][CH2:18][CH2:19]O)[CH2:14][CH2:15][CH3:16].[OH-].[K+]>>[CH2:13]([O:17][CH2:18][CH2:19][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[C:1]([OH:12])=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOCCO
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCOCCc1cccc(C(=O)O)c1C(=O)O
Temperature: 90 °C

Procedure:
148.1 of anhydrous phthalic acid and the molar equivalent 118.2 n of 2-butoxyethanol were added to a 500 ml glass round-bottomed flask equipped with stirring blades, thermometer and Dimroth condenser, heated while slowly stirring, and after the generated heat at about 90° C. wore off, raised to a temperature of 130° C., which was maintained for 1 hour. The mixture was subsequently cooled to 60° C. The acid value (number of mg of KOH necessary to neutralize 1 g of a sample) of the reaction solution was 226.0. Since the acid value for the case where the reaction is 100% complete is 210.7, the reaction rate was computed to be 93%.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:7]1[CH2:8][CH2:9][N:4]([CH3:3])[CH:5]([CH2:10][OH:11])[CH2:6]1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CN1CCNCC1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCN(C)C(CO)C1

Procedure:
A mixture of (1-methyl-2-piperazinyl)methanol dihydrochloride (500 mg, 2.46 mmol), ethyl bromoacetate (410 mg, 2.46 mmol), K2CO3 (1.02 g, 7.38 mmol) and MeCN (15 mL) were heated to reflux for 18 h. After cooling, the mixture was filtered and concentrated in vacuo. The title compound was isolated as a colourless oil (525 mg, 98%) and used without further purification. 1H NMR (300 MHz, CDCl3): 1.25 (3H, t, J 7.0), 2.35 (3H, s), 2.35-2.59 (4H, m), 2.76-2.90 (3H, m), 3.19 (2H, m), 3.44 (1H, dd, J 11.3, 2.0), 3.87 (1H, dd, J 11.3, 4.0), 4.15 (2H, q, J 7.1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(Cl)(=O)C.C(N(CC)CC)C>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:14])[CH3:13])[CH2:6][CH2:5]2
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N1CCc2cc(O)ccc2C1

Procedure:
5.0 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline are converted into the bisacetyl compound using acetic anhydride or acetyl chloride/triethylamine, and, without purification, this compound is heated under reflux for 6 hours with 10 ml of diethylamine in 50 ml of ethanol. The mixture is evaporated in vacuo in a rotary evaporator, and the residue is chromatographed on silica gel using ethyl acetate/methanol in the ratio 9:1. A yellow oil which crystallizes on trituration with diethyl ether is obtained. Yield: 5.2 g (78% of theory), melting point: 129°-130°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=2[NH2:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:22]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C(O)(C)C.[Pd]>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:30]2[NH:20][C:16]3=[N:17][CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:15]3[N:21]=2)=[CH:32][CH:33]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(N)c2N)CC1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)ccnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
4-(2,3-Diamino-pyridin-4-yl)-piperazine-1-carboxylic acid t-butyl ester (6) (368 mg, 1.3 mmol) was dissolved in isopropanol (9 ml) with Pd/C 10% (100 mg) and para-t-butyl benzaldehyde (324 mg, 2 mmol). The mixture was heated to 80° C. for 18 hours. MS showed the disappearance of the diamine starting material. The solvent was filtered through CELITE to remove the palladium, and the solvent was removed under vacuum. The residue was dissolved in NMP (4 ml), TFA (12 ml) was added and the reaction mixture was allowed to stir under nitrogen for 12 hours. MS showed the formation of the title product, and the TFA was removed under vacuum. The crude product-NMP mixture was purified by HPLC Method E to yield the title product 7 (320 mg (74%), 0.96 mmol). 1H NMR (DMSO-d6): δ 13.35 (bs, 1H), 8.75 (bs, 1H), 8.11 (dd, J=7.3 Hz, 2.1 Hz, 2H), 8.01 (d, J=6.2 Hz, 1H), 7.55 (dd, J=7.3 Hz, 2.1 Hz, 2H), 6.60 (d, J=6.2 Hz, 1H), 4.14 (m, 4H), 3.26 (m, 4H), 1.33 (s, 9H). MS (ESI-POS): [M+H]+=336.
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.NC1C=CC(S(N)(=O)=O)=CC=1.C[O:37][C:38]1[CH:39]=[C:40]([C:44]2[C:45]3[CH2:58][CH2:57][N:56]([C:59]4[CH:64]=[CH:63][C:62]([S:65]([NH2:68])(=[O:67])=[O:66])=[CH:61][CH:60]=4)[C:46]=3[N:47]=[C:48]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[N:49]=2)[CH:41]=[CH:42][CH:43]=1>>[OH:37][C:38]1[CH:39]=[C:40]([C:44]2[C:45]3[CH2:58][CH2:57][N:56]([C:59]4[CH:64]=[CH:63][C:62]([S:65]([NH2:68])(=[O:67])=[O:66])=[CH:61][CH:60]=4)[C:46]=3[N:47]=[C:48]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[N:49]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(S(N)(=O)=O)cc2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)cc1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 4-aminobenzene sulfonamide, 4-(3-methoxy-phenyl)-7-(4-aminosulfonylphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)=[C:28]=S.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH2:31][NH2:32])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(C)n1c(NCCN)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21
Reaction time: 1 h
Yield: 5.4 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (70 mg) and 1,1-dimethylethyl (2-isothiocyanatoethyl)carbamate (50 mg). The crude product isolated was treated with TFA (2 ml) in DCM (10 ml), the mixture stirred for 1 h, then evaporated in vacuo. The residue was dissolved in DMSO (1 ml) and purified by MDAP (HpH) to give the title compound as a beige solid (4.5 mg, 4%).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]1[CH:18]=[CH:17][C:11](OCC(O)=O)=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[F:7][C:8]1[CH:18]=[CH:17][C:11]([O:3][CH2:2][C:1]([Cl:6])=[O:5])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COc1ccc(F)cc1
Reaction time: 22 h
Yield: 100.1 %

Procedure:
Oxalyl chloride (60 mL, 686 mmol) and dimethylformamide (DMF) (8 drops, cat.) were added to a stirred suspension of 2-(4-fluorophenoxy)ethanoic acid (97.3 g, 572 mmol) in dichloromethane (500 mL). After 22 hours, the mixture was concentrated under vacuum to obtain 108 g of 2-(4-fluorophenoxy)ethanoic acid chloride, a compound of formula (Y), as a yellow oil in quantitative yield; 1H NMR (CDCl3) δ 4.90 (s, 2H), 6.84 (m, 2H), 6.99 (m, 2H) ppm.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[NH:5][C:6](=[O:8])[CH:7]=1.[CH3:15][C:16]1[CH:17]=[C:18]([SH:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1>C(O)C.C(N(CC)CC)C>[CH3:15][C:16]1[CH:17]=[C:18]([S:23][C:2]2[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[NH:5][C:6](=[O:8])[CH:7]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: CCOC(=O)c1c(Cl)cc(=O)[nH]c1C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(Sc2cc(C)cc(C)c2)cc(=O)[nH]c1C

Procedure:
A mixture of the intermediate 13 (1.2 g; 5.6 mmol) in ethanol (15 ml), triethylamine (1.5 ml) and 3,5-dimethylthiophenol (1.45 ml; 11 mmol) was heated under reflux for 16 hours. After evaporation under reduced pressure, diethylether (50 ml) was added and the precipitate was filtered off. The intermediate 14 was obtained (1.42 g; 80%) as a colorless solid m.p.=233–235° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:25][C:26](=[O:37])[CH:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH3:28])[C:16]1=[O:38])[C:11]([O:13]C)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:39][NH2:40]>O1CCCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:25][C:26](=[O:37])[CH:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH3:28])[C:16]1=[O:38])[C:11]([NH:40][CH3:39])=[O:13])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CN
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 70 °C

Procedure:
A mixture of (2R)-methyl 3-(tert-butyldimethylsilyloxy)-2-(5-(2-(3,4-dichlorophenyl)propanamido)-1-oxoisoquinolin-2(1H)-yl)propanoate (200 mg, 0.0003 mol), 5 mL of methylamine and tetrahydrofuran (2M) was heated in a sealed tube to 70° C. overnight. The reaction was only partially complete. The solvent was removed and the residue purified by flash chromatography to obtain the product as a light yellow oil. MS m/z=577.4 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:49]([C:51]1[N:52]=[C:53]([C:64]([O-])=[O:65])[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=1)#[N:50].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:22][C:18]1([CH3:21])[CH2:19][CH2:20][C:15]([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[CH3:23])[CH:13]=[CH:12][C:11]=2[NH:14][C:64]([C:53]2[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=[C:51]([C:49]#[N:50])[N:52]=2)=[O:65])=[CH:16][CH2:17]1
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 215 mg (0.638 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 446 mg (0.957 mmol) of PyBroP, 214 mg (0.701 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) and 333 μL (1.91 mmol) of DIEA and stirred at RT for 18 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 355 mg (95%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C29H43N5O4SSi, 586.3 (M+H). found 585.9.
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.Cl.[C:14]([C:18]1[O:22][N:21]=[C:20]([NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)=[O:25])[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.CCOC(C)=O>[C:14]([C:18]1[O:22][N:21]=[C:20]([NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:11][CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)=[O:25])[CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Reactant: O=CC1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2CC2CCOCC2)no1
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (0.19 g, 3.02 mmol) and tetrahydro-pyran-4-carbaldehyde (0.26 g, 2.26 mmol) is added to a solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (prepared according to Method T, step 6) (0.4 g, 1.51 mmol) in DMF (5.0 mL). After stirring for four hours, the reaction mixture is diluted with EtOAc and washed twice with water. The organic phase is dried over anhydrous Na2SO4 and after removal of the solvent under reduced pressure, the crude is purified by prep TLC to afford the title compound; m/z 364 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:15]([C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[O:12][CH3:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1-c1nc2cc(F)c(F)cc2[nH]1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-methoxy-benzoic acid (CAS Reg. No. 579-75-9). Brown solid (41%). MS (Turbo Spray): m/z=261.2 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:23][C:24]([C:26]1[NH:27]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)[CH:30]=1)=O.N[C@H](CO)C>>[OH:23][CH2:24][C@@H:26]([NH:27][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH3:30]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Agent: C[C@H](N)CO
Product: CCCCc1noc(C)c1COc1cc(C(=O)N[C@@H](C)CO)[nH]n1
Yield: 6 %

Procedure:
As described for example 6, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using L-alaninol instead of ethanolamine, to the title compound (7 mg, 6%) which was obtained as a colorless oil. MS: m/e=337.4 [M+H]+.