Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)C)N=C(C3C=NC(N)=NC=3)C=12.[NH2:37][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([CH:48]([C:50]3[O:51][C:52](=[O:67])[C:53]4[C:58]([C:59]=3[CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH3:49])[N:45]=[C:46](I)[C:39]=12.[F:68][C:69]1[CH:70]=[C:71](B(O)O)[CH:72]=[C:73]([OH:75])[CH:74]=1>>[NH2:37][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([CH:48]([C:50]3[O:51][C:52](=[O:67])[C:53]4[C:58]([C:59]=3[CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH3:49])[N:45]=[C:46]([C:71]3[CH:72]=[C:73]([OH:75])[CH:74]=[C:69]([F:68])[CH:70]=3)[C:39]=12
Reactant: CC(c1oc(=O)c2ccccc2c1Cc1ccccc1)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(N)nc2)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1Cc1ccccc1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 29.8 %

Procedure:
The title compound was made in a similar way as that of the compound of example 51 from 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-benzyl-1H-isochromen-1-one (Intermediate D15, 45 mg, 0.086 mmol), (3-fluoro-5-hydroxyphenyl)boronic acid (26.8 mg, 0.172 mmol), to give the title compound (13 mg, 19.8%) as brown pale solid.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Si:12](OC(CCC)CC(OCC)=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCCC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Reactant: CCCCC(O)C(=O)OCC
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Yield: 74 %

Procedure:
Ethyl 2-((tert-butyldimethylsilyl)oxy)hexanoate 5 (2.54 g) was prepared in 74% yield using ethyl 2-hydroxyhexanoate 4 according to the procedures described for compound 2 in above (See Schemes 1 and 2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([Cl:25])=[N:20][N:19]=[C:18]3Cl)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].[O:29]1CCOCC1.Cl>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([Cl:25])=[N:20][NH:19][C:18]3=[O:29])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccc(-c2ccco2)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(-c2ccco2)c1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide (400 mg, 1.041 mmol), 2N NaOH (5.2 mL, 10.41 mmol) and dioxane (5 mL) was heated to 50° C. for 5 h. The reaction was diluted with water, acidified with conc. HCl to pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide (43 mg) as a pale yellow solid, 1H NMR (400 MHz, d6-DMSO) δ: 6.76 (m, 1H), 7.08 (d, 1H), 7.58 (t, 1H), 7.64 (m, 1H), 7.90 (m, 2H), 8.30 (d, 1H), 8.34 (s, 1H), 8.70 (dd, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 13.19 (s, 1H) ppm; m/z (M+1) 365.90; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide (40 mg) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ: 6.62 (m, 1H), 6.92 (d, 1H), 7.44 (t, 1H), 7.50 (m, 1H), 7.74 (m, 1H), 7.78 (s, 1H), 8.17 (m, 1H), 8.45 (m, 2H), 8.52 (s, 1H), 10.80 (s, 1H), 13.01 (s, 1H) ppm; m/z (M+1) 365.97.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[CH3:2].Cl[C:18]1[N:19]=[N:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:5]([CH:10]=1)[CH2:4][N:3]([C:18]1[N:19]=[N:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)[CH2:1][CH3:2]
Reactant: C=C(C)COc1ccc(Cl)cc1CNCC
Reactant: NS(=O)(=O)c1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(S(N)(=O)=O)nn1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A mixture of N-ethyl-5-chloro-2-(2-methylprop-2-en-1-yloxy)benzylamine (2.76 g, 10 mmol), 3-chloro-pyridazine-6-sulphonamide [Archiv der Pharmazie (1966) 299, 646-650 and EP patent no 96,004] (1.5 g, 7.8 mmol) and ethyl di-isopropylamine (10 ml, 57 mM) in DMF (50 ml) was stirred at 130° C. for 16 hours under a reflux condenser. The solvent was evaporated at reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and evaporated to give a brown gum (2.5 g). The brown gum was purified by chromatography on silica, eluting with a gradient of 0→20% ethyl acetate in dichloromethane to give the title compound as a yellow solid (600 mg).
Reaction SMILES: C1(O[C:8](=O)[C:9]2[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=[C:11]([Br:20])[C:10]=2[CH3:21])C=CC=CC=1.[NH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH2:34])(=[O:33])=[O:32].BrCl>>[Br:20][C:11]1[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]([OH:15])=[C:9]([C:8]2[NH:34][S:31](=[O:33])(=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[N:23]=2)[C:10]=1[CH3:21]
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Oc1ccccc1
Agent: ClBr
Product: Cc1c(Br)cc(C(C)(C)C)c(O)c1C1=Nc2cc(Cl)ccc2S(=O)(=O)N1

Procedure:
From 3-bromo-5-tert-butyl-6-hydroxy-2-methyl-benzoic acid phenyl ester and 2-amino-4-chlorobenzenesulfonamide; obtained as white crystals following column chromatography (silica gel/EtOAc-heptane-CH2Cl2 1:6:3); mp 270-271° C. (decomp., ebullition); 1H NMR (DMSO): δ 12.58 (s, 1H, NH), 9.64 (s, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.55 (dd, J˜8.3, 1.9 Hz, 1H), 7.48 (s, 1H), 7.34 (d, J=1.9 Hz, 1H), 2.20 (s, 3H), 1.37 (s, 9H); LC-MS: m/z 457/459/461 (M+H; BrCl isotope pattern), 935/937/939/941 (2M+Na; Br2Cl2 isotope pattern); Rt=2.24 min.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.[C:17]([O:22][CH3:23])(=[O:21])/[CH:18]=[CH:19]/[CH3:20]>C(O)(C)(C)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:20][CH:19]=[CH:18][C:17]([O:22][CH3:23])=[O:21])[CH:14]=[CH:15][CH:16]=1
Reactant: C/C=C/C(=O)OC
Reactant: COc1cccc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C=CC=Cc1cccc(OC)c1
Temperature: 65 °C

Procedure:
A mixture of potassium tert-butoxide (52 g) and tert-butanol (170 ml) was treated dropwise with a mixture of 3-methoxybenzaldehyde (30 g) and methyl crotonate (35 ml). The temperature of the reaction mixture rose to 80° C. during the addition and was then maintained for a further 3 hours at 65° C. The reaction mixture was cooled to room temperature, poured into ice/water and washed with diethyl ether. The aqueous phase was acidified with concentrated HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated under reduced pressure to yield an orange oil. Yield 53.2 g. Used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>ClCCl>[O:22]=[C:3]1[C:2]([NH:1][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:7][CH:6]=[CH:5][N:4]1[CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:20])[CH3:21])[C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])=[O:10]
Reactant: CC(C)C(NC(=O)Cn1cccc(N)c1=O)C(O)C(F)(F)F
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1cccc(NC(=O)Nc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 8 h
Yield: 92 %

Procedure:
2-(3-Amino-2-oxo-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.43 g) and phenylisocyanate (0.175 g) were combined in dichloromethane (5 mL) and allowed to stir overnight. The mixture was poured into ethyl acetate, washed (saturated aqueous sodium bicarbonate, brine), evaporated, and purified using chromatography, eluting with ethyl acetate:dichloromethane (gradient, 0:100, 50:50, 100:0), to give the urea (0.54 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(4-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 0.0060 mol) in CH2Cl2 (19.0 mL), trifluoro acetic acid (3.46 g, 0.0303 mol) was added at 0° C. and the mixture was allowed to stir at RT overnight. CH2Cl2 and TFA were removed under reduced pressure and the crude product was filtered and washed with diethyl ether (2×20 mL) to obtain 4-(4-trifluoromethyl-phenyl)-piperidine trifluoro acetic acid salt with (1.58 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH:15]([OH:16])[CH:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:28][SiH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH:25]=[CH2:26])[O:12]1.CN(C1C=CC=CN=1)C.[C:55]1([O:61][C:62](Cl)=[S:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(#N)C>[C:55]1([O:61][C:62](=[S:63])[O:16][CH:15]2[CH:14]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:28][SiH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])([CH:25]=[CH2:26])[O:12][CH:11]2[N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH2:1])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2cnc3c(N)ncnc32)C(O)C1OCc1ccccc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2cnc3c(N)ncnc32)C(OC(=S)Oc2ccccc2)C1OCc1ccccc1
Yield: 82 %

Procedure:
A flask was charged with 2-(6-Amino-purin-9-yl)-4-benzyloxy-5-(tert-butyl-diphenyl-silanyloxymethyl)-5-vinyl-tetrahydro-furan-3-ol, acetonitrile, dimethylamino pyridine (DMAP), and PhOCSCl. The reaction was stirred, extracted, and the solvent was evaporated to provide the titled compound in 82% yield.
Reaction SMILES: [CH2:1]([O:5][CH:6]([CH3:12])[C:7](N(C)C)=[O:8])[CH2:2][CH2:3][CH3:4].[CH2:13]([O:17][CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH2:14][CH2:15][CH3:16].CNC.C([C@H:29]1[CH2:34][CH2:33][C@H:32](C2C=CC([Mg]Br)=CC=2)[CH2:31][CH2:30]1)CC>C1COCC1>[CH2:13]([O:17][CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH2:14][CH2:15][CH3:16].[CH2:1]([O:5][CH:6]([C:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:8])[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(C)C(=O)N(C)C
Reactant: CCC[C@H]1CC[C@H](c2ccc([Mg]Br)cc2)CC1
Agent: CCCCOC(C)C(=O)O
Agent: CNC
Solvent: C1CCOC1
Product: CCCCOC(C)C(=O)c1ccccc1

Procedure:
To (R) 2-butoxy-N,N-dimethylpropanamide prepared from (R) 2-butoxypropionic acid and dimethylamine, a solution of 4-(trans-4'-propylcyclohexyl)phenylmagnesium bromide in THF is dropped. They are reacted and purified in the same manner as in Example 3 (1) to obtain (R) 4-trans-4'-propylcyclohexyl)phenyl (1-butoxyethyl) ketone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:29][O:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:16][C:14]([F:17])([F:15])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:34]1[CH2:35][CH2:36][CH:31]([O:30][CH3:29])[CH2:32][CH2:33]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reactant: COC1CCNCC1
Product: COC1CCN(c2ccc3nc(C)c(C(=O)C(F)(F)F)c(-c4ccc(S(C)(=O)=O)cc4)c3c2)CC1
Yield: 14 %

Procedure:
The title compound was prepared from 1-[6-bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 4-methoxy-piperidine according to the procedure of example 25. Yield: 14%; MS: m/z=507 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:3][C:4]([OH:6])=O.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:3][C:4]([NH:26][CH2:25][CH2:23][OH:24])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)O
Reactant: NCCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)NCCO
Yield: 92 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid and 1.8 ml of ethanolamine were used as starting materials. 6.4 g (yield 92%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:33])[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c1ccccc1n2-c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2-c1ccccc1
Yield: 80.4 %

Procedure:
A mixture of 4-hydroxy-9-phenyl-9H-b-carboline-3-carboxylic acid ethyl ester (399 mg, 1.20 mmol), NBS (227 mg, 1.26 mmol) and BzOOBz (15 mg, 0.06 mmol) in carbontetrachloride (10 mL) was refluxed for 90 min. Then the reaction was cooled, the mixture was then filtered through a Celite plug, followed by the concentration of filtrate to give the desired product (397 mg). The title compound: ESI MS (m/z): 411 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:28]2[CH2:29][C:30](=[O:31])[N:26]([CH3:25])[C:27]2=[O:32])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Reactant: CN1C(=O)CNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Yield: 35.1 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (817 mg) described in Preparation Example 167 and 3-methylimidazolidine-2,4-dione (339 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Preparation Example 241, the title compound (310 mg) was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:16][CH2:17][CH3:18])(=O)[CH3:2].ClC1C=CC=CN=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:41]([O:43][CH2:44][CH3:45])#[CH:42]>C(Cl)Cl>[CH2:41]([O:43][C:44]1[C:15]2[C:5](=[C:6]([O:16][CH2:17][CH3:18])[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=2)[N:4]=[C:1]([CH3:2])[CH:45]=1)[CH3:42]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(OCC)c1
Reactant: C#COCC
Agent: Clc1ccccn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCC)c2nc(C)cc(OCC)c2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 8.2 %

Procedure:
To a nitrogen flushed vial were added ethyl 4-(acetylamino)-3-ethoxybenzoate (100 mg, 0.40 mmol), 2-chloropyridine (90 mg, 0.80 mmol) and CH2Cl2 (2 mL). Triflic anhydride (0.40 mmol) was added via a syringe at −78° C. The reaction mixture was stirred at −78° C. for 5 minutes. Ethyl ethynyl ether (0.174 mL, 40% in hexanes, 0.80 mmol) was added. The resulting reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 1 hour. The reaction was quenched by addition of Na2CO3 (5 mL, sat'd.), water (20 mL) and EtOAc (20 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified on a silica gel column eluting with a gradient of 10-20% EtOAc/hexanes to give the title intermediate (10 mg) as a light brown sticky material.
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])[CH3:3].Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([CH:23]2[CH2:24][CH2:25]2)=[O:22])[CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)SC1CCNC/C1=C\c1ccccc1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-benzylidene-piperidine hydrochloride and 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (713 mg) in N,N-dimethylformamide (10 ml) was added potassium carbonate (256 mg) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:17) as the eluent to afford the title compound (531 mg, yield: 68%) as a yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([CH2:28]OS(C)(=O)=O)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:34])([CH3:3])[CH3:2].[CH3:35][NH2:36]>>[CH3:35][NH:36][CH2:28][C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:34])=[N:15][C:16]=2[CH:27]=1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(COS(C)(=O)=O)ccc21
Reactant: CN
Product: CNCc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
A mixture of methanesulfonic acid 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl ester (10 mg, 0.02 mmol) and methylamine (1M in THF, 0.5 mL) was stirred at ambient temperature for 12 h then the solvent evaporated. The residue was purified by prep-HPLC (gradient 10%-100% B) to give 8.1 mg (94%) of 1-[5-methylaminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one as a colorless gum.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[OH:19][C@@H:20]1[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.[H-].[Na+].O>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:19][C@@H:20]2[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CO1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Temperature: 60 °C

Procedure:
To a stirred solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1, step ii) (0.25 g) and 1,1-dimethylethyl (S)-4-hydroxyisoxazolidine-2-carboxylate (0.16 g) in dry THF (5 mL) was added 60% Sodium hydride (0.034 g) over 5 min. The reaction mixture was stirred and heated at 60° C. for 7 days, H2O was added and the solvents were partially evaporated. The residue was extracted with EtOAc which was washed with H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with Et2O/iso-hexane (1:9) to give the subtitle compound as a gum. Yield: 0.15 g.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15]([NH:22][C:23](=O)[CH3:24])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.C(OCC)(=O)C>O1CCOCC1>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15]([NH:22][C:23](=[S:35])[CH3:24])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(NC(C)=O)cc3c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(NC(C)=S)cc3c12
Yield: 53.7 %

Procedure:
2741 mg of 6-acetylamino-4-ethyl-β-carboline-3-carboxylic acid isopropyl ester is heated to 70° C. in 110 ml of dioxane with 3915 mg of Lawesson's reagent while being stirred. After cooling, it is mixed with 100 ml of ethyl acetate and washed with saturated sodium chloride solution. The organic phases are dried and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with toluene+methanol=8+2. 1541 mg of 4-ethyl-6-thioacetylamino-β-carboline-3-carboxylic acid isopropyl ester with a melting point of 158-160° C. is obtained from the desired fractions.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: OCc1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 4-fluorobenzyl alcohol (85.7 mg; 0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 550.3 (M+H); Rt: 2.00 min.