Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1.C(OCC)(=O)C>[CH3:17][C:11]([C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([F:1])[CH:3]=1)([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(C)c1cc(F)cc2ccoc12
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)c1cc(F)cc2ccoc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 0.17 gm (0.71 mMol) ethyl 2-(5-fluorobenzofur-7-yl)propionate (EXAMPLE 39) in 2.5 mL tetrahydrofuran was cooled to −78° C. To this solution were added 0.89 mL (0.89 mmol) lithium bis(trimethylsilyl)amide (1.0 M in hexane). After stirring at −78° C. for 1 hour, the reaction mixture was quenched by the addition of 0.13 mL (2.13 mMol) iodomethane. The reaction mixture was allowed to warm to room temperature and was diluted with ethyl acetate. This mixture was then washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organics were concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.16 gm (90%) of the desired compound.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:5]=1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17]CC1C=CC=CC=1.CO>[H][H].[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:5]=1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]
Reactant: [H][H]
Reactant: COc1ccc(CCNCC(O)c2ccccc2OCc2ccccc2)c(OC)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(CCNCC(O)c2ccccc2O)c(OC)c1OC
Yield: 84 %

Procedure:
A mixture of 5 g of α-(2,3,4-trimethoxyphenethylaminomethyl)-2-benzyloxybenzylalcohol hydrochloride, one g of 10% palladium-carbon and 50 ml of 90% aqueous methanol is shaken at room temperature in hydrogen gas atmosphere under atmospheric pressure. After hydrogen uptake is completed, insoluble materials are removed by filtration, and the filtrate is condensed. The residue thus obtained is recrystallized from a mixture of ethanol and ether. 3.4 g of α-(2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzylalcohol hydrochloride are obtained. M.p. 133°-134° C. Yield: 85%
Reaction SMILES: C([C@H]1COC(=O)N1C([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:19][N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17]1)=O)C1C=CC=CC=1.[C:35](=O)([O:38]C)[O:36][CH3:37].C[O-].[Na+]>ClCCl>[CH2:28]([N:18]1[CH2:19][C@@H:20]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C@H:16]([C:35]([O:36][CH3:37])=[O:38])[CH2:17]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of (4S)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one, from preparation 24 (2.51 g, 5.28 mmol) and dimethyl carbonate (2.22 mL, 26.4 mmol) in dichloromethane (40 mL) was added sodium methoxide (1.42 g, 26.4 mmol) at room temperature. The reaction mixture was stirred for 24 hours and diluted with dichloromethane (50 mL). The phases were separated and the organic phase was washed with water (2×40 mL), dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using ethyl acetate:pentane (5:95-20:80) as eluent to afford the desired product as a colourless oil, 1.61 g (79%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[O:10])[CH:2]=1.[BH4-].[Na+].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][OH:10])[CH:2]=1
Reactant: O=Cc1ccccc1-c1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccccc1-c1cccnc1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of 2-pyridin-3-yl-benzaldehyde (1 g, 5.46 mmole) in methanol (10 ml) was added a solution of NaBH4 (0.26 g, 6.82 mmole) in methanol (10 ml) at 0° C. and stirred for 30 min at same temperature and then refluxed for 1 h. The unreacted NaBH4 was decomposed by solution of 6N HCl. The solvent was removed under reduced pressure and the residue was dissolved in 5N NaOH (20 ml) and extracted with ethyl acetate (3×20 ml). Combined organic extracts were dried (Na2SO4), filtered and concentrated to yield 0.95 g (94%) of product. MS (ESI+) m/z 186 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>N1C=CC=CC=1.ClCCl>[NH2:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:33](=[O:34])[O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:8][CH:7]=3)=[CH:10][N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CNC(=O)OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of trans-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.119 mol) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0° C. then treated with benzyl chloroformate (22 mg, 0.131 mmol). The mixture was warmed to ambient temperature and stirred an additional 2 hours, evaporated and the residue purified by preparative reverse-phase chromatography to give trans-benzyl N-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzyl)carbamate: 1H NMR (DMSO-d6, 400 MHz) 8.13(s, 1H), 7.85(t, 1H), 7.3-7.42(m, 10H), 6.02(bs, 2H), 5.06(s, 2H), 4.54(m, 1H), 4.26(d, 2H), 1.44-2.37(m, 20H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 22.15 min.; MS:MH+ 554.3.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[CH2:16][CH2:17][OH:18].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:9]1([CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:16][CH2:17][OH:18])[CH2:3][CH2:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: OCCNC1CCN(Cc2ccccc2)CC1
Yield: 93.1 %

Procedure:
To a mixture of 4-amino-1-benzylpiperidine (2.13 g, 11.2 mmol) and 2-bromoethanol (0.15 g, 4.08 mmol) in anhydrous CH2Cl2 (20 ml) was added Hunig's base (2.6 ml, 5.7 mmol). The solution was refluxed for 24 hours. After evaporating off CH2Cl2, the crude material was purified by silica flash chromatography to afford 2-[[1-(phenylmethyl)-4-piperidinyl]amino]ethanol (0.88 g, 3.8 mmol) with 92% yield. FAB Mass [M+1]+35Cl 235.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:6]([CH:8]=1)[NH2:7].[CH2:15]([N:19]=[C:20]=[S:21])[CH2:16][CH2:17][CH3:18]>C(O)C>[CH2:15]([NH:19][C:20]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[S:21])[CH2:16][CH2:17][CH3:18]
Reactant: Nc1cc(Cl)ccc1N1CCOCC1
Reactant: CCCCN=C=S
Solvent: CCO
Product: CCCCNC(=S)Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
Reaction of 5-chloro-2-morpholinoaniline (2.8 g) (2.8 g) with n-butyl isothiocyanate (1.5 g) in ethanol (20 ml) at room temperature for 60 days yielded 1-(n-butyl)-3-(5-chloro-2-morpholinophenyl)thiourea (m.p. 150°-152° C.).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:8][O:9][CH3:10])(=O)=O.[N-:22]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].O>[NH2:22][CH2:6][C@@H:7]([NH:11][C:12](=[O:13])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][O:9][CH3:10]
Reactant: COC[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H](CN)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxypropyl methanesulfonate (37.6 g, 0.118 mol) in DMF (400 mL) was added sodium azide (23.2 g, 0.178 mol) and tetrabutylammonium iodide (0.526 g, 1.42 mmol), and then the reaction mixture was heated to 80° C. After 3 hours, the reaction mixture was cooled to ambient temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was diluted with THF/water (250 mL/50 mL), and to this mixture was added triphenylphospine (36.7 g, 0.140 mol). After 2 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (6×300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (3% methanol/DCM) to afford benzyl [(2R)-1-amino-3-methoxypropan-2-yl]carbamate. MS ESI calc'd. for C12H19N2O3 [M+H]+ 239. found 239. 1H NMR (400 MHz, CDCl3) δ 7.46-7.39 (m, 5H), 5.86 (d, J=7.2 Hz, 1H), 5.12-5.05 (m, 2H), 3.92 (bs, 1H), 3.55-3.49 (m, 2H), 3.34 (s, 3H), 2.93 (d, J=5.6 Hz, 2H), 1.91 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([C:31]2[CH:41]=[C:40]([O:42][CH3:43])[C:34]3[O:35][CH2:36][CH2:37][CH2:38][O:39][C:33]=3[C:32]=2[F:44])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]=C(C)O[N:26]=3)=[CH:21][CH:20]=2)=[N:12]1)=[O:5])[CH3:2].FC1C=C(OC)C(OC)=CC=1C(NC1C=CC(C2N=C(C)ON=2)=CC=1)C1NC(=O)N(C2C=CC=CC=2C(O)=O)N=1.FC(F)(F)C(O)=O>C(O)(=O)C>[C:4]([OH:5])(=[O:3])[CH3:6].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:29])=[CH:23][CH:24]=2)[C:31]2[CH:41]=[C:40]([O:42][CH3:43])[C:34]3[O:35][CH2:36][CH2:37][CH2:38][O:39][C:33]=3[C:32]=2[F:44])=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2F)OCCCO3)[nH]c1=O
Agent: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)c3c(c2F)OCCCO3)[nH]c1=O

Procedure:
The same procedure was carried out as in Example (1g), except that 5-(3-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(5-methyl[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester and 0.1% acetic acid were used instead of respectively 2-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)benzoic acid and 0.1% trifluoroacetic acid, to give the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH:21]=[O:22])[CH:15]=2)[N:7]=1)=[O:5])[CH3:2].[C:23]([Cu])#[N:24].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([C:23]#[N:24])=[CH:10][CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH:21]=[O:22])[CH:15]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.1 %

Procedure:
To a solution of 3-bromo-6-(4-bromo-3-formyl-phenoxy)-pyridine-2-carboxylic acid ethyl ester (23, 1.8 g, 4.19 mmol) in DMF (6 mL) was added CuCN (0.75 g, 8.38 mmol) in portions at 130° C. and heated for 4 hour. The mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The mixture was stirred for 10 minutes, filtered, and washed with ethyl acetate (2×50 mL). The filtrate was washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to yield compound 24 (0.3 g, 19%) as a white solid. 1H NMR 400 MHz (DMSO-d6) δ: 10.20 (s, 1H), 8.51 (d, J=8.6 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.55 (dd, J=8.5, 2.7 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H); MS (ES) m/z: 377 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].[CH3:11][N:12]1[C:16]([O:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20](OC3N(C)N=C(C(F)(F)F)C=3)[N:19]=2)=[CH:15][C:14]([C:37]([F:40])([F:39])[F:38])=[N:13]1>S1(CCCC1)(=O)=O.CCCCC.C(OCC)(=O)C>[CH3:11][N:12]1[C:16]([O:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])[N:19]=2)=[CH:15][C:14]([C:37]([F:40])([F:39])[F:38])=[N:13]1
Reactant: COc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: OCC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: COc1cc(OCC(F)(F)C(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 110 °C
Reaction time: 3.7 h
Yield: 99.2 %

Procedure:
To a mixture of 2,2,3,3-tetrafluoropropan-1-ol (0.29 g, 2.2 mmol) in dry sulfolane (2 ml) is added NaH (60% in oil, 0.09 g, 2.2 mmol) and 2,6-bis-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methoxypyridine (0.8 g, 1.8 mmol). After stirring at 110° C. for 3.7 h the mixture is cooled to ambient temperature. The resulting mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed 10 times with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 9/1 v/v) yields the title compound (0.72 g, 57% yield) of m.p. 73-74° C.
Reaction SMILES: Cl.[CH3:2][S:3][CH2:4][C:5]1[N:9]=[C:8]([CH2:10][N:11]2[C:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:15]=3[C:14](=[O:26])[N:13]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:12]2=[O:33])[O:7][N:6]=1.[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:13]5[C:14](=[O:26])[C:15]6[S:19][C:18]([C:20]7[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=7)=[CH:17][C:16]=6[N:11]([CH2:10][C:8]6[O:7][N:6]=[C:5]([CH2:4][S:3][CH3:2])[N:9]=6)[C:12]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CSCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CSC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-({3-[(methylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}methyl)-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (202.4 mg; compound B36), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10) and HBTU (167 mg) in DCM (8 ml) is added DIPEA (207 mg). The reaction mixture is stirred for 3 h at RT. Additional 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (80 mg; compound C10) and HBTU (84 mg) are added in order to complete the reaction. A saturated aqueous sodium bicarbonate solution (5 ml) is added and the mixture is extracted with DCM (25 ml). The phases are separated and the aqueous phase is extracted with further DCM (10 ml). The organic phases are combined and filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified two times by flash column chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] to yield the title compound as a solid.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][CH:11]([CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[CH2:12][OH:13].[C:21]([N:25]=[C:26]=[S:27])([CH3:24])([CH3:23])[CH3:22]>C(O)C>[C:21]([NH:25][C:26]([NH:10][CH:11]([CH2:12][OH:13])[CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)=[S:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: NC(CO)Cc1cnccn1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=S)NC(CO)Cc1cnccn1
Temperature: 50 °C

Procedure:
11.2 cm3 of triethylamine are added with stirring to a solution of 7.91 g of (2RS)-2-amino-3-(2-pyrazinyl)-1-propanol dihydrochloride in 80 cm3 of ethanol, followed by addition of 7.2 cm3 of tert-butyl isothiocyanate. The mixture is heated at a temperature in the region of 50° C. for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C., taken up in 100 cm3 of water and extracted with dichloromethane. The organic phases are combined, washed with 50 cm3 of water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. 7.2 g of N-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)-ethyl]thiourea are obtained in the form of a colorless paste [mass spectrum: DCI m/z=269 MH+].
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)cc1Br
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1Br
Yield: 78.8 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 260 mg of 2-bromo-4-fluoroaniline in place of the 2,4-difluoroaniline. 310 mg of N-(2-bromo-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](Cl)=[O:18].Cl.[C:21]1([C:27]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:35][CH:34]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[C@H:32]3[C@@H:28]2[CH2:29][NH:30][CH2:31]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:44]1([C:27]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:35][CH:34]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[C@H:32]3[C@@H:28]2[CH2:29][N:30]([C:17](=[O:18])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH3:8])[CH2:31]3)[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: COc1ccccc1C1=CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@@H]12
Reactant: COc1ccccc1CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1C[C@H]2C(c3ccccc3OC)=CCC(c3ccccc3)(c3ccccc3)[C@H]2C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 20 %

Procedure:
1.5 cm3 of triethylamine and then 1.6 g of (2-methoxyphenyl)-acetyl chloride are added to a solution of 1.5 g of (3aS,7aR)-4,4-diphenyl-7-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-isoindole hydrochloride in 20 cm3 of methylene chloride, cooled to 0° C. The mixture is stirred at room temperature for 15 hours; the reaction mixture is washed with twice 40 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 3.6 cm, height 25 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (75/25 by volume) and collecting fractions of 25 cm3. Fractions 14 to 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The yellow foam obtained is recrystallised from 10 cm3 of cyclohexane to give 0.38 g of (3aS,7aR)-4,4-diphenyl-2-[(2-methoxyphenyl)-acetyl]-7-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-isoindole in the form of a beige solid which melts at 142° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1[C:12]2[S:13][C:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([O-:25])=[O:24])=[CH:22][C:17]=4[S:16][C:15]=3[C:11]=2[CH:10]=[CH:9][C:8]=1[C:26]([O-:28])=[O:27]>C1COCC1>[OH:28][CH:26]([OH:27])[C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[S:16][C:17]4[CH:22]=[C:21]([CH:23]([OH:24])[OH:25])[CH:20]=[CH:19][C:18]=4[C:14]=3[S:13][C:12]=2[CH:7]=1
Reactant: O=C([O-])c1ccc2c(c1)sc1c3ccc(C(=O)[O-])cc3sc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(O)c1ccc2c(c1)sc1c3ccc(C(O)O)cc3sc21
Reaction time: 8 h
Yield: 143.5 %

Procedure:
LiAlH4(0.74 g, 19.5 mmol) was added to [1]benzothieno[3,2-b]benzothiophene 2,7-dicarboxylate (1.50 g 3.9 mmol) in THF (40 mL). The mixture was stirred overnight. Insoluble materials were removed by filtration and washed with hot DMSO. The solution was precipitated in 50 mL of 1 normal (“N”) HCl. The product was collected by filtration to obtain 1.86 g (75%) of pure 2,7-bis(dihydroxymethyl)[1]benzothieno[3,2-b]benzothiophene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31]C1C=CC(F)=CC=1C=O>>[F:31][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[O:9]1
Reactant: O=Cc1cc(F)ccc1F
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2cc(F)ccc2F)Oc2ccc(O)cc21

Procedure:
2-(2,5-Difluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.57 ml of 2,5-difluorobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (300 MHz, d6-DMSO) δ: 9.46 (s, 1H), 7.53 (m, 1H), 7.36-7.30 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 5.76 (dd, 1H, J 13.6, 2.7 Hz), 3.26 (dd, 1H, J −16.8, 13.6 Hz), 2.76 (dd, 1H, J −16.8, 2.7 Hz).