Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[OH:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.[O:32]1CC[CH2:34][CH2:33]1>C(N(CC)CC)C>[C:33]([O:26][C@H:10]1[C@@H:9]([NH:8][C:6](=[O:7])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=2[O:30][CH3:31])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:11]1)(=[O:32])[CH3:34]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1O
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7.5 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-piperidinyl]-2-methoxybenzamide in 68 parts of tetrahydrofuran were added dropwise 2.02 parts of N,N-diethylethanamine. After cooling to 0° C., there was dried dropwise a solution of 1.4 parts of acetyl chloride in 9 parts of tetrahydrofurane at a temperature below 0° C. Upon completion, stirring was continued for a while while cooling in an ice-bath. The reaction mixture was allowed to reach slowly room temperature and stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further separated by HPLC using a mixture of trichloromethane, hexane and methanol (48:48:4 by volume) as eluent. The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was suspended in petroleumether. The product was filtered off and dried, yielding 1.7 parts of cis-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-piperidinol acetate (ester); mp. 58.8° C. (compound 232).
Reaction SMILES: [CH2:1]([S:6]([OH:9])(=O)=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[Na].S(Cl)([Cl:13])=O>>[CH2:1]([S:6]([Cl:13])(=[O:9])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCS(=O)(=O)O
Agent: [Na]
Product: CCCCCS(=O)(=O)Cl
Temperature: 60 °C
Yield: 61 %

Procedure:
1-Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was charged into a 250 ml round bottom flask (allow headroom). Thionyl chloride (20 mL) is added; gas evolves, and a while solid forms. The mixture is heated at 60° C. for 3 hours. The solvents are removed in vacuo; toluene is added and removed in vacuo to remove residue of SOCl2. The residue is partitioned between CH2Cl2 and ice water; the organic layer is dried over Na2SO4. The crude product is purified by distillation (bp 54-56° C. @ 0.5 mm Hg) to give a clear oil, 61% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH:10]2[O:14][CH2:15][C:16]([O:19][CH3:20])([O:17][CH3:18])[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C[O:33][CH2:32]C1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:32][OH:33])[CH:10]2[O:14][CH2:15][C:16]([O:17][CH3:18])([O:19][CH3:20])[CH:9]12)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC1(OC)COC2C(=O)CN(C(=O)OC(C)(C)C)C21
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: COC1(OC)COC2C(CO)CN(C(=O)OC(C)(C)C)C21
Yield: 86 %

Procedure:
The olefin 1e (524 mg, 1.84 mmol) was dissolved in dry THF (70 mL), 9-BBN-H (0.5 M in THF) (7.34 mL, 3.67 mmol) was added and the solution was stirred over night. The solvent was removed by rotary evaporation and redissolved in THF (20 mL). MeOH (10 mL) was slowly added to the solution and when the gas evolution had ceased, H2O (20 mL) was added to the solution followed by NaBO3. The solution was filtered after it had been stirred for 18 hrs and the filtrate was diluted with EtOAc (70 mL) and washed with brine (2*50 mL). The organic phase was dried with Na2SO4, filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (heptane: ethyl acetate 2:1) which gave the title compound (477 mg, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH2:15][CH2:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: c1ccc(COc2cccc3c2NCC3)cc1
Reaction time: 4 h
Yield: 87.3 %

Procedure:
A magnetically stirred solution of 7-benzyloxyindole (16.0 g, 71.66 mmol) in glacial acetic acid (200 ml) at 10° C. under nitrogen was treated with sodium cyanoborohydride (10.0 g, 0.159 mol) in portions via a powder funnel maintaining an addition temperature of below 17° C. Resulting white suspension was stirred below 20° C. for 4 h and quenched with water (300 ml). Evaporation in vacuo gave a colourless oil which was diluted with ethyl acetate (300 ml) treated with 2M sodium hydroxide (400 ml) and stirred vigorously for 16 h. The organic layer was separated, the aqueous was extracted with ethyl acetate (3×100 ml), the combined organic phases were washed with aqueous 2M NaOH(aq) (200 ml) brine (2×200 ml), dried (Na2SO4) and evaporation of the solvent gave the crude product as an oily white solid. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 1:9) provided the title compound (14.1 g, 89%) as white crystals. Crystallised from ethyl acetate and light petroleum (b.p. 40-60° C.) as colourless plates (m.p. 58-60° C.). (Found: C, 80.04; H, 6.58; N; 6.19. C15H15NO requires C, 79.97; H, 6.71; N, 6.22%); Vmax (nujol)/cm-1 3332, 30338, 1885, 1618, 1591; δH (270 MHz) 3.02 (2H, 2×2-H, 3J2,3 =8.4 Hz); 3.51 (2H, 2×3-H, 3J3,2 =8.6 Hz); 3.80 (1H, bs, N--H); 5.02 (2H, s, CH2Ph); 6.65 (2H, m, 4-H, 5-H); 6.80 (1H, m, 6-H); 7.33 (5H, m, Ph). δC (67.8 MHz) 30.3 (2-C); 47.62 (3-C); 70.1 (OCH2Ph); 110.8 (6-C); 117.5 (5-C); 118.9 (4-C); 130.4 (3a-C); 137.2 (7a-C); 140.9 (benzyl ipso-C); 144.4 (7-C). Remaining signals lie between 127.3-128.4 ppm; m/z 225.2 (17.24, M+), 134.1 (100), 116.1 (14.06), 91.1 (29.15).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].[CH2:34]1[CH2:55][O:54][CH:36]([CH2:37][CH:38]2[CH:45]([O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[CH2:44][CH:43]3[CH:39]2[CH2:40][CH:41](O)[O:42]3)[O:35]1>C1COCC1>[CH2:34]1[CH2:55][O:54][CH:36]([CH2:37][C@H:38]2[C@H:45]([O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[CH2:44][C@H:43]([OH:42])[C@@H:39]2[CH2:40]/[CH:41]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[O:35]1
Reactant: OC1CC2C(CC(OC3CCCCO3)C2CC2OCCO2)O1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CC2OCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Reaction time: 8 h

Procedure:
(4-Carboxybutyl)triphenylphosphonium bromide (22.03 g) and potassium t-butoxide (1-M, 99.4 ml) were treated in THF (100 ml) to give a ylide, to which was added the previously obtained lactol (58) at 0° C., and the mixture was kept at room temperature overnight. The reaction was worked up in the usual manner to give the carboxylic acid
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[CH:34][C:35](B4OC(C)(C)C(C)(C)O4)=[C:30]3[CH:29]=[CH:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:7][C:5]1[S:6][C:2]([C:35]2[CH:34]=[CH:33][N:32]=[C:31]3[N:27]([S:24]([C:21]4[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=4)(=[O:25])=[O:26])[CH:28]=[CH:29][C:30]=23)=[C:3]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c(Br)s1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4sc(C)nc4-c4ccc([N+](=O)[O-])cc4)ccnc32)cc1

Procedure:
Following the procedure described for Intermediate 6 with 5-bromo-2-methyl-4-(4-nitrophenyl)-1,3-thiazole and [(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine provided title compound. ESMS [M+H]+: 491.2
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([Cl:21])=[C:5]([C:7]2[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[NH:12][C:10](=[O:11])[CH:9]([OH:20])[N:8]=2)[CH:6]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:22][N:12]1[C:10](=[O:11])[CH:9]([OH:20])[N:8]=[C:7]([C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[Cl:21])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]1=2
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(O)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
To a stirring solution of lorazepam (3.21 g, 1.0×10-2 mol) in anhydrous dimethylformamide (100 ml) was added anhydrous powdered potassium carbonate (1.52 g, 1.1×10-2 mol) followed by iodomethane (0.69 ml, 1.1×10-2 mol). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under vacuum, the residue was treated with water (100 ml) and was stirred at room temperature for 2 hours. The resulting fine light yellow solid was collected by filtration and was dried under vacuum to afford 3.3 g (98%) of lormetazepam as a pale yellow solid: m.p. 201°-203° C.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:13]([C:20]1[C:21]([CH3:37])=[N:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([C:31](N(OC)C)=[O:32])=[CH:25][CH:24]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1C=CN=C1>C1COCC1>[CH2:13]([C:20]1[C:21]([CH3:37])=[N:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([C:31]([C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1)=[O:32])=[CH:25][CH:24]=2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cn1cncc1I
Reactant: CON(C)C(=O)c1ccc2nc(C)c(Cc3ccccc3)c(C)c2c1
Agent: CC(C)[Mg]Cl
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: Cc1nc2ccc(C(=O)c3cncn3C)cc2c(C)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A translucent solution of 5-iodo-1-methyl-1H-imidazole (197 mg, 0.946 mmol) in THF (1.5 mL) was stirred at 0° C. while iPrMgCl (2.01 M in THF, 0.43 mL, 0.864 mmol) was added dropwise under argon. The ice bath was immediately removed and the white mixture was stirred at room temperature for 15 minutes, and was then added rapidly dropwise to a solution of 3-benzyl-N-methoxy-N,2,4-trimethylquinoline-6-carboxamide (71.9 mg, 0.215 mmol, Intermediate 34: step c) in THF (0.5 mL) at room temperature. The resulting milky opaque mixture was stirred at room temperature for 1.5 hours, and was then quenched with 1 M aqueous NaHCO3 (6 mL) and extracted with EtOAc (2×6 mL). The combined organic layers were shown by LCMS to be a mixture of title compound and starting material, so the material was concentrated from THF (3×) and re-subjected to the above conditions but with reaction at 50° C. for 2 hours. The reaction was then worked up as described above, and the residue was flash chromatographed with a heptane to 100% EtOAc gradient to provide a 1:4 mol ratio of the title compound and N-methylimidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:6]([N+:31]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:12]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:13][CH2:14][CH2:15][CH:16]2[C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[C:6]([NH2:31])[CH:5]=1
Reactant: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(N)c1
Yield: 69 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.829 g, 3.10 mmol), 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.26 g, 4.61 mmol), KI (115 mg, 0.69 mmol), and DIPEA (1.20 mL, 6.89 mmol) in DMF (16 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 1.40 g (98%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester as a tan solid. To a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester (1.40 g, 3.03 mmol) in MeOH (15 mL) and EtOAc (15 mL) was added palladium (50% wet with water), 10 wt. % on activated carbon (0.30 g). The resultant mixture was hydrogenated at 30 psi on a Parr shaker for 3 hours. The mixture was vacuum filtered through celite and the cake was washed with MeOH and EtOAc. The solvent was removed from the filtrate under reduced pressure and the thus obtained oil was purified by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.90 g (69%) of 3-amino-4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][C:12]([CH3:14])=O>S(=O)(=O)(O)O>[CH3:11][C:12]1([CH3:14])[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: CC(C)=O
Reactant: NC(=O)c1ccccc1O
Agent: O=S(=O)(O)O
Product: CC1(C)NC(=O)c2ccccc2O1
Yield: 47 %

Procedure:
A solution of salicylamide (4.14 g, 30.2 mmol) and conc. sulfuric acid (3 drops) in acetone (40 mL) was refluxed for 5 h. The reaction was concentrated and the residue taken up in ethyl acetate. The organic solution was washed with 1 N NaOH (2×), 1 N HCl (2×), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2,2-dimethyl-4-keto-1,3-benzoxazine (2.50 g, 47%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 7.92 (d, 1H), 7.60 (bs, 1H), 7.47 (m, 1H), 7.06 (m, 1H), 6.92 (d, 1H), 1.65 (s, 6H).
Reaction SMILES: Cl.[C:2](=[NH:9])([O:6][CH2:7][CH3:8])[CH:3]([CH3:5])[CH3:4].N1C(C)=CC(C)=CC=1C.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20]([N:9]=[C:2]([O:6][CH2:7][CH3:8])[CH:3]([CH3:5])[CH3:4])=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)C(C)C
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)N=C(OCC)C(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
Ethyl isobutyrimidate hydrochloride (1.8 g, 11.9 mmol) was suspended in hexanes (29.7 mL) and cooled to 0° C. 2,4,6-Collidine (4.1 mL, 30.9 mmol) and ethyl chloroformate (1.9 g, 17.8 mmol) were sequentially added and the mixture was allowed to warm to RT and stirred for 12 h. Organic solvent was removed in vacuo. The residue was suspended in EtOAc (50 mL) and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylisobutyrimidate (2.2 g, 99%) as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 4.09 (q, J=7.1 Hz, 2H), 4.03 (q, J=7.1 Hz, 2H), 2.65-2.64 (m, 1H), 1.20 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H), 1.07 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:2][N:3]2[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2)=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)NN1CC=CCC1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.012 g) in dry methylene chloride (40 ml) was added a solution of 3-fluorophenyl isocyanate (1.37 g) in dry methylene chloride under ice-bath cooling. After stirring for one hour, the reaction mixture was evaporated to dryness. The residue was extracted with ethyl acetate (100 ml). The extract was washed with water, evaporated to dryness and recystallized from ethyl acetate to give N-[[(3-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.43 g). mp: 136.5°-138.5° C.
Reaction SMILES: [O:1]([CH2:13][CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>C([O-])(=O)C>[O:1]([CH2:13][CH3:14])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Product: CCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 27.3 %

Procedure:
Ethyl D-glucopyranoside (30 g, prepared as described in example 10) with an anomeric ratio α:β=1:1 was dissolved in 0.05M acetate buffer (400 ml, pH 4.5) at 30° C. β-glucosidase (50 mg from almonds, Sigma) was added and the mixture was stirred for a week. The solution was evaporated in vacuo and purified by chromatography to give the product as a crystalline solid (8.2 g, 55%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:20]1[N:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[C:39]([C:42]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:43])=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:22][CH:21]=1>O1CCCC1>[CH2:1]([O:8][C:20]1[N:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[C:39]([C:42]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:43])=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(Cl)nc1)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(OCc3ccccc3)nc1)C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 29.3 %

Procedure:
To a solution of benzylalcohol (0.025 mL, 0.241 mmol) in dry tetrahydrofuran (5 mL) at 0° C. under nitrogen was added a 1.0 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.26 mL, 0.26 mmol) and the reaction mixture stirred at 0° C. for 20 minutes. A solution of 10-[(6-chloropyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 117 (0.100 g, 0.219 mmol) in dry tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at room temperature for 72 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL) and then diluted with ethyl acetate (10 mL). The organic phase was separated, washed with water (10 mL) and brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a white foam that was triturated with diethyl ether to afford the title compound (0.034 g, 30%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([S:15][C:16]#[N:17])[C:12]([N+:18]([O-])=O)=[CH:11][N:10]=2)=[CH:6][C:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:4]([F:29])[CH:3]=1>C(O)(=O)C>[NH2:17][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:7]3[C:2]([Cl:1])=[CH:3][C:4]([F:29])=[C:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=3)[N:10]=[CH:11][C:12]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(Cl)cc1F
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(Nc2ncc3nc(N)sc3n2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To a solution of the above-mentioned crude product of tert-butyl {4-chloro-2-fluoro-5-[(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate in acetic acid (20 mL) was added reduced iron (697 mg, 12.5 mmol), and the mixture was stirred at 80° C. for 30 min. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (487 mg, 6%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+:20].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][C:14](=[O:16])[NH:20][C:10](=[O:11])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)CC(=O)N1
Temperature: 160 °C
Yield: 86.6 %

Procedure:
A suspension of 2,2′-(benzylazanediyl)diacetic acid (5.0 g, 22.4 mmol) and ammonium formate (4.2 g, 67.2 mmol) in N,N-dimethylformamide (75 mL) was stirred to reflux (160° C.) for 2 days. After cooling to room temperature, the reaction mixture was diluted by successive addition of ethyl acetate (150 mL) and a saturated solution of sodium hydrogen carbonate (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL) and the combined organic phases were washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give the title product as a yellow liquid (3.96 g, 87%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[S:26][C:16]=3[N:17]=2)=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH3:17])[C:3]=12.[N:18]1([CH2:23][CH2:24]O)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][CH2:23][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:15]=[C:16]([CH3:17])[C:3]=12
Reactant: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Reactant: OCCN1CCCC1
Product: Cc1nn(CCN2CCCC2)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound XIIId was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(pyrrolidin-1-yl)ethanol following the general procedure for the Mitsunobu reaction described in Example 20.