Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[O:19][CH:10]([C:11]3[C:16]2=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)[CH2:9]1)=O)(C)(C)C.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1>COCCO.C([O-])(O)=O.[Na+]>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:20][C:14]2[CH:13]=[CH:12][C:11]3[CH:10]4[O:19][CH:17]([CH2:18][NH:8][CH2:9]4)[C:16]=3[CH:15]=2)=[N:23][CH:24]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2OC(C1)c1cc(N)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CNCC3O2)ncc1Cl
Temperature: 120 °C
Yield: 9.7 %

Procedure:
4-Amino-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene-10-carboxylic acid tert-butyl ester (220 mg, 0.80 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (236 mg, 0.80 mmol) were combined in 2-methoxyethanol (3 mL) and heated at 120° C. for 6 h. The reaction was then was diluted with saturated aqueous NaHCO3 (3 mL), extracted with CH2Cl2 (3×5 mL), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-30% MeOH in EtOAc) to obtain 2-[5-Chloro-2-(12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a tan solid (34 mg, 10%). 1HNMR (400 MHz, CDCl3) δ 11.0 (bs, 1H), 8.6 (d, 1H, J=8.3 Hz), 8.0 (s, 1H), 7.6 (s, 1H), 7.5 (d, 1H, J=7.8 Hz), 7.4 (m, 2H), 7.3 (d, 1H, J=7.8 Hz), 7.1 (d, 1H, J=8.1 Hz), 7.0 (appt t, 1H, J=7.6 Hz), 6.5 (bs, 1H), 5.0 (s, 1H), 4.9 (s, 1H), 3.3 (t, 2H, J=13.5 Hz), 3.0 (d, 3H, J=4.8 Hz), 2.9 (bs, 1H), 2.6 (t, 2H, J=13.5 Hz); MS (m/e) 437 (M+1); mp 164-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[NH2:20][CH2:21][CH2:22][OH:23].O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:20][CH2:21][CH2:22][OH:23])[N:14]=1)=[O:8]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Reactant: NCCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CNCCO)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Fluorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate 7) was taken up in tetrahydrofuran and an excess of the 2-amino-ethanol (20 equiv.) was added. The reaction was allowed to stir overnight at room temperature. The reaction was poured into water and extracted with EtOAc, partitioned with brine, dried over Na2SO4, filtered, and volatiles were removed in vacuo. The resulting solid was triturated with EtOAc, followed by diethyl ether to give the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OP(O)(O)=O.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]2[C:36](=O)[CH2:35][N:34]([CH3:38])[C:33]2=[O:39])=[CH:23][CH:22]=1>O>[Cl:20][C:21]1[CH:41]=[CH:40][C:24]2[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[C:33](=[O:39])[N:34]([CH3:38])[CH2:35][C:36]=3[C:23]=2[CH:22]=1
Reactant: CN1CC(=O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CN1CC2=C(C1=O)c1ccccc1Oc1ccc(Cl)cc12
Reaction time: 8 h
Yield: 57.9 %

Procedure:
P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%.1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m,1H), 7.2-7.4 (m, 6H), 8.2 (dd,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:32](I)[CH3:33].O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][O:16][CH2:32][CH3:33])=[NH:14])=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCONC(=N)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
P1.2) A solution of 790 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine in 20 ml of dimethylformamide is added dropwise in the course of 15 minutes at 0-5° C. to 80 mg of sodium hydride 55% in 10 ml of dimethylformamide. After 3 hours' stirring at 0-5° C., 256 mg of ethyl iodide are added. After being stirred for 16 hours at room temperature the reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-ethoxy-benzamidine is obtained.
Reaction SMILES: [OH:1][C@H:2]([C@@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:35]([O:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.OS([O-])(=O)=O.[K+]>O1CCOCC1.O>[OH:1][C@H:2]([C@@H:20]([NH:28][C:43]([O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:44])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Under a nitrogen atmosphere, 220 mg (0.57 mmol) of 1-[2(S)-hydroxy-3(S)-amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[tert-butoxycarbonyl]-hydrazine (=H-[PheNNPhe]-Boc, Example 30b) in 15 ml of dioxane/water 1:1 and 408 mg (2.9 mmol) of K2CO3 are reacted with 120 mg (0.69 mmol) of chloroformic acid benzyl ester for 16 h at RT. KHSO4 solution is added, the mixture is extracted with 3 portions of ethyl acetate, and the organic phases are washed with water and brine, dried with Na2SO4 and concentrated by evaporation. Digestion from hexane yields the pure title compound: TLC Rf (I)=0.52; tRet (V)=17.1 min; FAB-MS (M+H)+ =520.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH2:16]([OH:19])[CH2:17][OH:18].[C:20]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([NH:30][C@H:31]([C:35]([O:18][CH2:17][CH2:16][OH:19])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a mixture of DCC (11.4 g, 55 mmol), DMAP (0.611 g, 5 mmol) and ethyleneglycol (55.8 mL, 1 mol) in CH2Cl2 (300 mL) at 0° C., was added dropwise a solution of N-CBz-L-valine (12.6 g, 50 mmol) in CH2Cl2 (100 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 5→10% MeOH in CH2Cl2), to give 12.0 g 2-(N-CBz-L-valyloxy)-ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[O:28]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH3:29]>>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:28][CH3:29])=[CH:31][CH:32]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CNCCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Yield: 57.8 %

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.5 g) as starting compound and 4-methoxylbenzaldehyde (0.56 g) were reacted and treated in the same manner as in Example 121 to give 1.13 g of 4-amino-5-chloro-N-((1-(6-(4-methoxybenzylamino)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:7][C:8]1[C:13]([CH:14]=O)=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6].Cl>CO>[CH2:3]([O:7][C:8]1[C:13]([CH2:14][NH:2][CH3:1])=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CN
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Agent: Cl
Solvent: CO
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CNC
Reaction time: 4 h

Procedure:
Methylamine (2.0M in methanol, 1 ml) was added to a stirring mixture of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carboxaldehyde [Example 30] (150 mg, 0.35 mMol) and molecular sieves (3A, 1.0 g) in 50 ml methanol. After stirring for 4 hours, the mixture was cooled by an ice bath and 5 ml 5% HCl was added. The mixture was concentrated to an oil containing the molecular sieves. Water (50 ml) and 5 ml 5% NaHCO3 were added and the product was extracted into ethyl acetate (2×50 ml). The ethyl acetate extracts were combined, dried over Na2SO4, filtered and concentrated to a solid. The titled material was purified by silica gel chromatography to give a solid: m.p. (DSC) 113.98° C. Anal. Calc'd. C24H27N2O3SF: C, 65.14; H. 6.15; N, 6.33. Found: C, 64.81; H, 6.15; N, 6.17.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@@H:5]1[N:14]2[C:15]([C@@:17]([NH:20][C:21]([C@@H:23]3[CH:38]=[C:37]4[C@@H:26]([CH2:27][C:28]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][C:35]=64)[NH:30][CH:29]=5)[N:25]([CH3:39])[CH2:24]3)=[O:22])([CH3:19])[O:18][C@@:13]2([OH:40])[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:6]1=[O:7])=[O:16])[CH3:3].[CH3:41][S:42]([OH:45])(=[O:44])=[O:43].C(OCC)C>C(O)C>[CH3:3][CH:2]([CH2:4][C@@H:5]1[N:14]2[C:15]([C@@:17]([NH:20][C:21]([C@@H:23]3[CH:38]=[C:37]4[C@H:26]([CH2:27][C:28]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][C:35]=64)[NH:30][CH:29]=5)[N:25]([CH3:39])[CH2:24]3)=[O:22])([CH3:19])[O:18][C@@:13]2([OH:40])[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:6]1=[O:7])=[O:16])[CH3:1].[CH3:41][S:42]([OH:45])(=[O:44])=[O:43]
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C)(NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)C(=O)N12
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C)(NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@@H]4N(C)C3)C(=O)N12

Procedure:
Ergosinine (5.48 g; 10 mmoles) was dissolved in absolute ethanol (60 ml), containing methanesulfonic acid (0.72 ml; 11 mmoles). The clear solution was poured into absolute diethylether (600 ml). The precipitated salt was filtered off and dried in vacuo. Ergosinine methanesulfonate (6.05 g; 98.7% of the theory) with a melting point of 190°-192° C. was obtained.
Reaction SMILES: [Cl-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH3:25][N:26]1[C:32](=[O:33])[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]2[CH:38]=[N:39][C:40]([CH:41]=O)=[C:28]2[CH2:27]1>O1CCCC1>[Cl:2]/[CH:3]=[CH:41]\[C:40]1[N:39]=[CH:38][N:29]2[C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32](=[O:33])[N:26]([CH3:25])[CH2:27][C:28]=12
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1Cc2c(C=O)ncn2-c2ccccc2C1=O
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(/C=C\Cl)ncn2-c2ccccc2C1=O
Temperature: 25 °C

Procedure:
13.50 g of an equimolar mixture of chloromethyltriphenylphosphonium chloride and sodium amide were stirred for 15 minutes with 50 ml of tetrahydrofuran, whereby the temperature rose to 42°. 6.2 g (25.7 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde were then added portionwise thereto, the mixture was stirred at room temperature for a further hour, filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1) there was obtained 3-[(Z)-2-chlorovinyl]-4,5-dihydro-5-methyl-6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 197°-199°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:4]2[C:3]3[C:8](=[N:9][CH:10]=[CH:11][C:2]=3[NH:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=3)[NH:7][C:6](=[O:12])[C:5]=2[CH:13]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccc(Cl)cc12
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4cc(Cl)ccc4c23)cc1)c1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 1,8-dichloro-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-aminophenyl)benzamide to provide 275. LC-MS (M+H=442, obsd.=442).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[C:10]([F:15])[C:9]=1[F:16])(=[O:3])[CH3:2].Cl[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:11]=[C:10]([F:15])[C:9]=1[F:16])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cc(F)c1F
Reactant: Clc1ccccn1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccccn2)cc(F)c1F

Procedure:
By carrying out the operation analogously to example 58, starting from 5-bromo-2,3-difluorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 2-chloropyridine, the expected compound is obtained in the form of a crude product used without further purification in the deacetylation stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([Cl:18])=[C:6]([O:8][C:9]2[C:14]([F:15])=[C:13]([CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])[CH:7]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([Cl:18])=[C:6]([O:8][C:9]2[C:14]([F:15])=[C:13]([CH2:16][Br:27])[CH:12]=[CH:11][C:10]=2[Cl:17])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(Br)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Yield: 62.4 %

Procedure:
2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (13.25 g, 36.0 mmol) and NBS (6.41 g, 36.0 mmol) were combined in carbon tetrachloride (150 mL) with a catalytic amount of AIBN (0.296 g, 1.800 mmol) and stirred at reflux for 16 h. The reaction mixture was washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by chromatography on 330 g silica gel eluted with 0 to 10% Et2O in hexanes to give the desired product, 2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-(bromomethyl)-1-chloro-3-fluorobenzene (10.04 g, 22.47 mmol, 62.4% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.53-7.67 (m, 3H), 6.78 (s, 1H), 4.75 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][OH:31].[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][O:31][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCO)c(F)cc(F)c3o2)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reaction time: 0.83 h
Yield: 98.8 %

Procedure:
2.98 g (6.65 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-hydroxypropylamino)-4H-1-benzopyran-4-one was dissolved in 100 mL of pyridine, 1.1 mL (14 mmol) of methanesulfonyl chloride was added under ice-cooling and the mixture was stirred for 50 minutes. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 3.46 g of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one (yield: 99%).
Reaction SMILES: [CH2:1]([N:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:19]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)(O)[CH:20]=[CH2:21])=[C:16]([OH:18])[CH:17]=1)[CH:2]=[CH2:3].O>CC1C=CC=CC=1C>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]2[C:15]([C:19]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:20][CH2:21][O:18]2)=[CH:14][CH:13]=1)[CH3:30])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(O)(C=C)c2ccc(Br)cc2)c(O)c1
Solvent: O
Solvent: Cc1ccccc1C
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)OCC=C2c1ccc(Br)cc1
Yield: 72 %

Procedure:
A solution of 0.26 g of (RS)-5-[6-(allyl-methyl-amino)-hexyloxy]-2-[1-(4-bromo-phenyl)-1-hydroxy-allyl]-phenol in 50 ml of o-xylene is boiled at 170° C. on a water separator for 2 hrs., evaporated and the residue is purified over silica gel with methylene chloride/methanol 95:5. There is obtained 0.18 g of allyl-[6-[4-(4-bromo-phenyl)-2H-chromen-7-yloxy]-hexyl]-methyl-amine, MS: m/e 456 (M+H+, 1 Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C(O)=O>C(O)C.O>[Br:15][C:12]1[CH:13]=[N:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cn1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cn1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2-[bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine 10 (216 kg crude, 460 mol, assuming quantitative yield in previous step) in anhydrous ethanol (1692 L) was slowly added a solution of sodium hydroxide (55.2 kg, 1380 mol) in water (344 L) while maintaining the temperature at 0-20° C. The mixture was stirred at that temperature until the content of 2-[bis(tert-butoxycarbonyl)-amino]-5-bromopyrimidine (10) was ≦0.5% by HPLC. The reaction mixture was cooled to 0-5° C. and the pH was adjusted to 7 by addition of oxalic acid (86.0 kg, 955 mol) while maintaining the temperature below 5° C. The mixture was then distilled under vacuum to a volume of 500-600 L while controlling the temperature below 50° C. Water (800 kg) was added and the mixture was stirred for 1 h. The solid was collected by filtration and stirred with water (2×500 L). The resulting solid was collected by filtration and dried under reduced pressure at 50° C. to afford tert-butyl 5-bromopyrimidin-2-ylcarbamate 11 (107 kg, 85% yield over two steps). 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 2H), 8.12 (s, 1H), 1.55 (s, 9H). LCMS (ESI) m/z [M+H-Boc] 176
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: CS(=O)(=O)Nc1ccc(OCCCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(OCCCI)cc1
Yield: 96.7 %

Procedure:
A solution of N-[4-(3-chloro-1-propyloxy)phenyl]methanesulfonamide (1.03 g, 3.90 mmol) and sodium iodide (1.75 g, 11.70 mmol) in acetone (15 mL) was heated under reflux for 18 hours. The mixture was concentrated, taken up in EtOAc, and washed with brine, 10% aqueous sodium bisulfite, and brine. The organic phase was dried (MgSO4) and concentrated to give 1.34 g (96%) of product as an off-white solid m.p. 109°-111° C.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1>C1COCC1.C(Cl)Cl>[CH2:1]([S:8][C:16]1[CH:15]=[C:14]([Cl:19])[N:13]=[C:12]([NH2:11])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1nc(Cl)cc(SCc2ccccc2)n1
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Benzylmercaptan (0.14 g, 1.11 mmol) was treated with NaH (60% in mineral oil, 67 mg, 1.66 mmol) in dry THF (15 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (0.2 g, 1.22 mmol) was added and the mixture was stirred overnight. The mixture was diluted with methylenechloride, washed with water, then brine, dried over MgSO4, and concentrated to give 0.11 g of 4-(benzylthio)-6-chloropyrimidin-2-amine.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])[C:3]([OH:5])=O.CCN=C=NCCCN(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34].CCOC(C)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][O:33][N:32]([CH3:31])[C:3](=[O:5])[C:2]([CH3:1])([CH3:18])[CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10]
Reactant: CNOC
Reactant: CC(C)[Si](OCC(C)(C)C(=O)O)(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 2,2-dimethyl-3-triisopropylsilanyloxy-propionic acid in anhydrous dichloromethane (13 ml) was slowly treated with EDCI (1.03 g, 5.38 mmol) followed by N,O -dimethylhydroxylamine hydrochloride (525 mg, 5.4 mmol), DMAP (55 mg, 0.045 mmol), and TEA (0.75 ml, 5.38 mmol). After stirring overnight at room temperature the reaction mixture was partitioned between DCM/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a greenish oil. Silica gel chromatography using 10-60% EtOAc in hexanes as eluant provided 1.13 mg (79%) of N-methoxy-2,2,N-trimethyl-3-triisopropylsilanyloxy-propionamide as a colorless oil. M+H=318.