Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH:10](=[O:14])[CH:11]([CH3:13])[CH3:12]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: Br[Mg]c1ccc(Br)cc1
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(Br)cc1

Procedure:
A solution of 4-bromophenylmagnesium bromide in ether was treated with isobutyraldehyde to give 1-(4-bromophenyl)-2-methylpropan-1-ol, b.p. 152°-154°C./15mm. This was dehydrated with polyphosphoric acid at 20°C., to give 1-bromo-4-(2-methyl-1-propenyl)benzene, b.p. 110°-112°C./6mm, which was hydrogenated in an ether/ethanol solvent containing 50% hydrobromic acid (2% by volume of solvent) over platinum oxide to give the desired product, b.p. 120°-122°C./22mm.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:14]([F:17])([F:16])[F:15])=[N:9]2)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:14]([F:17])([F:15])[F:16])=[N:9]2
Reactant: O=[N+]([O-])c1cccc2nc(C(F)(F)F)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cccc2nc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
390 mg (1.61 mmol) of 5-nitro-2-(trifluoromethyl)quinoline is dissolved in 13 ml of methanol. After the addition of 39 mg of palladium on carbon and 19 mg of potassium carbonate, the reaction mixture is allowed to stir for 20 hours at room temperature under hydrogen atmosphere. It is then filtered on Celite and washed with ethyl acetate. After the solvent is removed in a vacuum and after chromatography on silica gel with hexane-ethyl acetate (0-100%), 250 mg (73% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:33]1([C:39](=[S:41])[NH2:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:41][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:40][C:9]=2[C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)N1CCOCC1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (20 g, 57 mmol) (Intermediate 20) in DMA (300 mL), NBS (10.2 g, 57 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then morpholine-4-carbothioamide (9.2 g, 63 mmol) was added at 0° C. The mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound (20 g, 83.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.20-8.27 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 7.20-7.26 (m, 1H), 7.08-7.12 (m, 1H), 6.92-6.98 (br, 1H), 6.62 (d, J=5.5 Hz, 1H), 5.90-6.03 (m, 1H), 5.25-5.41 (m, 2H), 5.65-5.70 (m, 2H), 3.57-3.63 (m, 4H), 3.77-3.86 (m, 4H). m/z (ES+): 476 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].C(N(CC)CC)C.[CH2:34]([N:36]([CH2:40][CH3:41])[C:37](Cl)=[O:38])[CH3:35].Cl>O1CCCC1>[CH2:34]([N:36]([CH2:40][CH3:41])[C:37]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])=[O:38])[CH3:35]
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)ON=C(C)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran are placed in a reaction vessel, to which 0.16 g of N,N-diethylcarbamoyl chloride is slowly added dropwise with stirring under ice cooling. After completion of the addition, the reaction mixture is further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-(N, N-diethylcarbamoyl)oxime.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[CH2:25]([O:27][CH:28](O)[C:29]([F:32])([F:31])[F:30])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:25]([O:27][CH:28]([NH:24][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=4)[S:17][C:10]=23)=[C:2]([F:1])[CH:3]=1)[C:29]([F:32])([F:31])[F:30])[CH3:26]
Reactant: CCOC(O)C(F)(F)F
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Yield: 68.7 %

Procedure:
A mixture of 12 (Scheme 3) (500 mg, 1.47 mmol), trifluoroacetaldehyde ethyl hemiacetal (0.35 mL, 2.94 mmol) and 4-toluenesulfonic acid monohydrate (280 mg, 1.47 mmol) in ethanol (25 mL) was heated to reflux for 48 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane 5:95 to 8:92) to afford title compound 318 (470 mg, 1.01 mmol, 68% yield). NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (d, J=5.5 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.72 (d, J=0.8 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.08-7.02 (m, 2H), 3.86 (dd, J=9.2, 2.0 Hz, 1H), 6.52 (d, J=5.5 Hz, 1H), 5.68 (qd, J=10.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.76-3.59 (m, 2H), 1.15 (t, J=7.0 Hz, 3H). LRMS (M+1) 467.0 (100%).
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]2[S:15][C:16]([CH3:24])([C:20]([F:23])([F:22])[F:21])[C:17](=[O:19])[N:18]=2)[CH3:12])=[CH:7][CH:6]=1>CN(C=O)C>[CH3:24][C:16]1([C:20]([F:23])([F:22])[F:21])[S:15][C:14]([NH:13][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]#[N:2])=[CH:6][CH:7]=2)[CH3:12])=[N:18][C:17]1=[O:19]
Reactant: N#C[Cu]
Reactant: C[C@H](NC1=NC(=O)C(C)(C(F)(F)F)S1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: C[C@H](NC1=NC(=O)C(C)(C(F)(F)F)S1)c1ccc(C#N)cc1
Temperature: 150 °C

Procedure:
CuCN (140 mg, 1.6 mmol) and 2-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-5-(trifluoromethyl)thiazol-4(5H)-one (150 mg, 0.39 mmol) and 2 mL of DMF were combined in a sealed tube and heated to 150° C. for 12 h. The residue was purified by column chromatography (10 to 60% EA/Hex, 40 g) to give 4-((S)-1-(5-methyl-4-oxo-5-(trifluoromethyl)-4,5-dihydrothiazol-2-ylamino)ethyl)benzonitrile as a slightly yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14](Cl)(Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)Cl.Cl>C1(C)C(C)=CC=CC=1>[ClH:13].[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClC(Cl)(Cl)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a stirred suspension of ethyl 4-aminobenzoate (165.0 g; 1.0 mole) in xylene (465 mL) was added α,α,α-trichlorotoluene (100.7 g; 0.52 mole). The mixture was allowed to reflux for 18 h, then was cooled to 0° C. and filtered. The resultant precipitate was washed with ice-cold xylene (2×70 mL), triturated with hot toluene and dried to yield the salt (89.8 g; 39.7%) as white crystals: mp 214.0°-215.5° C. 1H-NMR (CDCl3) 8.0-6.9 (m, 14H), 4.3 (q, 4H, J=7 Hz), 1.4 (t, 6H, J=7 Hz); IR (CHCl3) 1715, 1600; MS (m/e) 416 (M+ -HCl), 252 (base).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][F:27]>>[F:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:9])=[CH:4][CH:3]=1
Reactant: FCCCCCBr
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(OCCCCCF)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except the reaction mixture is stirred at room temperature overnight starting from (4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 1-bromo-5-fluoropentane. MS (ES+) 363.3
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O:34][CH2:35][C:36](O)=[O:37])(C)(C)C.N=C=N>C(Cl)Cl>[OH:37][CH2:36][C:35]([N:27]1[CH2:28][CH2:29][N:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:15][CH:16]=[N:17]3)=[CH:22][CH:21]=2)[CH2:25][CH2:26]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNCC4)ccc23)CC1
Reactant: CC(C)(C)OCC(=O)O
Agent: N=C=N
Solvent: ClCCl
Product: O=C(CO)N1CCN(c2ccc3c(C4CCNCC4)ncnc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(7-Piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 45, was added to a mixture of t-butoxyacetic acid (0.15 mmol) and PS-carbodiimide (0.2 mmol) in anhydrous DCM (2 mL). The mixture was shaken at rt overnight. It was then filtered and the resin washed with DCM. The combined filtrate and washings were concentrated in vacuo. To this was then added 3M HCl/MeOH (2 mL) and stirred at rt for 2 h and then concentrated in vacuo.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[C:12]=[S:13]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:12]([NH:11][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=3)[N:21]=2)=[CH:18][CH:19]=1)=[S:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: N[C@H](CO)c1ccccc1
Product: OC[C@@H](NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccccc1

Procedure:
The title compound was prepared with (S)-2-amino-2-phenylethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.300 g, 73%): mp 125-128° C.; 1H NMR (400 MHz, CD3OD) δ 9.14 (s, 1H), 8.13 (d, J=8.3 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.43-7.35 (m, 4H), 7.30-7.27 (m, 1H), 5.64 (s, 1H), 3.94-3.86 (m, 2H) (NH, OH not observed); ESIMS m/z 500 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Nc1ccc(I)c(Cl)c1)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)c(Cl)c3)cn2)CC1
Temperature: 95 °C

Procedure:
A solution of 6-Chloro-N-(3-chloro-4-iodo-phenyl)-nicotinamide (100 mg, 0.26 mmol), ethyl isonipecotate (60 mg, 0.38 mmol), diisopropyl ethyl amine (0.14 mL, 0.77 mmol) and a catalytic amount of DMAP in dioxane, in a sealed tube was heated at 85° C. for 19 h. Followed addition of another portion of ethyl isonipecotate (60 mg, 0.38 mmol) and the mixture was heated at 95° C. for 24 h. The mixture was then cooled, the solvent was evaporated and the residue was purified with a silica gel column and 20-40% EtOAc in hexanes to afford the product. HRMS m/z calcd for C20H21N3O3ClI [M+H]+: 514.0389. Found: 514.0387.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([I:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([I:33])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(I)cc(C(=O)Cl)cc1C#N
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(I)cc(C(=O)N2CSc3ccccc32)cc1C#N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (317 mg) and 37% formalin (0.21 mL) in the same manner as in Example 1 was dissolved in dichloromethane (6 mL), and triethylamine (0.70 mL) and 3-cyano-5-iodo-4-methoxybenzoyl chloride (527 mg) were added to the solution, and then the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (435 mg) as a yellow oily substance.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[C:14]2[CH3:21].O.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:12]1[C:11]([O:10][CH3:9])=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([CH3:21])=[CH:15][CH:16]=[N:17]2
Reactant: COc1ccc2nccc(C)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2nccc(C)c2c1Br
Reaction time: 1 h

Procedure:
N-bromosuccinimide (0.57 g, 3.2 mmol) is added at RT to a mixture of 6-methoxy-4-methylquinoline (0.5 g, 2.9 mmol) in conc. sulfuric acid (5 ml). The mixture is stirred for 1 h and poured onto ice-water. The water phase is made basic with an aqueous solution of sodium hydroxide (1 mol/l) and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 256 mg (35%). HPLC-MS: M+H=252/254; tR=1.09 min (METHOD—1).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (10 g, 64.04 mmol), 4-dimethylaminopyridine (9.49 g, 158.0 mmol) in dry CH2Cl2 (190 ml) was cooled to 0° C. and acetic anhydride (7.35 ml, 77.9 mmol) added dropwise in 15 min. The reaction mixture was stirred overnight at room temperature, diluted with CH2Cl2 (500 ml) and washed with 2 N HCl solution (80 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from MeOH, giving 5-acetyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 1 (8.6 g, 68%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:22])[CH3:21])[CH:12]=2)=[O:7])CCC.[NH2:24][CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:21])[CH3:22])[CH:12]=2)=[O:7]
Reactant: NCCO
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(OC(C)C)ccc2c1O
Product: CC(C)Oc1ccc2c(O)c(C(=O)NCCO)nc(Cl)c2c1

Procedure:
Synthesized from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-amino-ethanol in analogy to example B-5; MS-(−)-ion: M−1=323.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(C(F)(F)F)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 109 from tert-butyl (±)cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (63 mg, 0.16 mmol) and 2-chloro-4-(trifluoromethyl)phenylboronic acid (69 mg, 0.32 mmol), after chromatographic purification (35.9 mg, 46%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.69 (s, 1H), 7.51 (bd, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.1 Hz), 7.04 (s, 1H), 6.97 (s, 1H), 3.60-3.75 (m, 1H), 3.48-60 (m, 1H), 3.15-3.35 (m, 4H), 2.65-2.80 (m, 4H), 2.10-2.20 (m, 2H), 1.85-2.00 (m, 2H), 1.46 (s, 9H) ppm. MS (CI, NH3): 493 (base, M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:10]1[O:14][N:13]=[C:12]([NH2:15])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:3](=[O:4])[CH2:2][Cl:1])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1cc(N)no1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)CCl)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 132.4 %

Procedure:
Chloroacetic acid chloride (0.93 ml; II.42 mmol) is dropped slowly into a stirred solution of 5-t-Butyl-3-amino isoxazole (1.5 g; 7.67 mmol) in pyridine (1.09 ml; 13.49 mmol) and dichloromethane (20 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid, twice with an aqueous solution of NaHCO3 and with water. The reaction mixture is then dried over Na2SO4, filtered and evaporated to yield 2.2 g (98%) brownish solid of 10.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:20][CH2:21]Br)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[K])(C)(C)C.O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCBr)C1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C2CCN(Cc3ccccc3)CC2)CC1
Yield: 73.2 %

Procedure:
13 ml of diisopropylamine was dissolved in a solvent mixture of tetrahydrofuran (140 ml) with HMPA (15 ml) in a nitrogen atmosphere and cooled to −78° C. Into the obtained solution was dropped 42 ml of a 2.5 M solution of n-butyllithium in hexane and the resulting mixture was stirred at 0° C. for 30 minutes. After cooling to −78° C. again, 15 ml of a solution of 5.8 g of ethyl (1-benzylpiperidin-4-yl)acetate in tetrahydrofuran was dropped thereinto. The reaction mixture was stirred at 0° C. for 1 hour. Then 1,2-dibromoethane was dropped thereinto at −78° C. again. The reaction mixture was stirred at 0° C. for 30 minutes and then brought back to room temperature. Next, it was distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.40 g of ethyl 2-(1-benzyl-4-piperidyl)-4-bromobutanoate as a colorless oily substance. A solution of 1.40 g of ethyl 2-(1-benzyl-4-piperidyl)-4-bromobutanoate in tetrahydrofuran (20 ml) was stirred at room temperature and 1.0 g of t-butoxypotassium was added thereto. The reaction mixture was distributed into water and ethyl acetate. The organic layer was extracted and washed with water. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 800 mg of the title compound as a colorless oily substance.
Reaction SMILES: [OH:1][C@H:2]([CH2:35][OH:36])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[N:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].C(N(CC)CC)C.[CH:44]([Si:47](Cl)([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])([CH3:46])[CH3:45]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:1][C@H:2]([CH2:35][O:36][Si:47]([CH:51]([CH3:53])[CH3:52])([CH:48]([CH3:50])[CH3:49])[CH:44]([CH3:46])[CH3:45])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[N:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Reaction time: 14 h
Yield: 64.4 %

Procedure:
N-[(2S)-2,3-Dihydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (666 mg, 1.28 mmol) synthesized in Example (101a) was dissolved in methylene chloride (20 mL), and triethylamine (0.89 mL, 6.40 mmol), triisopropylsilyl chloride (410 μL, 1.92 mmol) and 4-dimethylaminopyridine (234 mg, 1.92 mmol) were added, followed by stirring for 14 hours under nitrogen atmosphere. The reaction solution was diluted with methylene chloride (50 mL), washed with water and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-60%) to afford the desired product (558 mg, 64%) as a white solid.