Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:12]=[CH:11][C:10]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:17]([NH:16][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([C:20]([O:22][CH3:23])=[O:21])=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)c1ccc(CNC(C)=O)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CNC(C)=O)cc1S(N)(=O)=O
Yield: 76.2 %

Procedure:
A solution of 2.09 g (6.1 mmol) of N-tert-butyl-5-acetamidomethyl-2-methoxycarbonylbenzenesulfonamide in 25 ml of trifluoroacetic acid is stirred at room temperature for 14 h and then evaporated to dryness. Crystallization of the residue from ethyl acetate yields 1.33 g (76%) of 5-acetamidomethyl-2-methoxycarbonylbenzenesulfonamide of mp. 173-175° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:11]1([CH2:17][C:18]2[N:22]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: c1c[nH]c(CN2CCOCC2)n1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1-n1ccnc1CN1CCOCC1

Procedure:
Combine 10 g of 2-fluoronitrobenzene, 13 g of 2-((4-morpholinyl)methyl)-imidazole, 18 mL of N,N-diisopropyl ethylamine, and 150 mL of acetonitrile, and heat at reflux for 48 hr. Remove the solvent under vacuum, and dissolve the residue in 500 mL of 2N H2SO4. Wash the aqueous portion with 400 mL of ether, basify with K2CO3, and extract with two 400 mL portions of CH2Cl2. Combine extracts, dry over MgSO4, charcoal treat and remove the solvent under vacuum to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]([CH3:20])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12]I>>[CH3:10][C:11]([CH3:20])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCC(C)(C)CI
Product: CCCCCCC(C)(C)COc1ccccc1C=O

Procedure:
2-Hydroxybenzaldehyde was condensed with 2,2-dimethyl-1-iodo octane to yield 2-(2,2-dimethyl octyloxy)benzaldehyde which was reduced to 2-(2,2-dimethyl, octyloxy)benzyl alcohol and then converted to [[2-(2,2-dimethyloctyloxy)phenyl]methyl]triphenylphosphonium bromide as in Example 1. Condensation of this phosphonium bromide with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 followed by hydrolysis, as in Example 5, gave the (All-E)-3,7-Dimethyl-9-[2-[(2,2-dimethyl-octyl)oxy]phenyl]-2,4,5,8-non-atetraenoic acid mp 113°-117° (from dichloromethane/hexane mixture).
Reaction SMILES: CO[CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13]C)=O)=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1.CC(O)=O.CS(O)(=O)=O.[NH2:32][C@H:33](CO)[CH3:34]>CC#N>[CH3:34][C@@H:33]1[N:32]2[C:11](=[O:13])[C:10]3[N:5]([CH:6]=[C:7]([C:18]([OH:20])=[O:19])[C:8](=[O:17])[C:9]=3[O:15][CH3:16])[CH2:4][C@H:3]2[O:21][CH2:22]1
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Reactant: C[C@H](N)CO
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1c2n(cc(C(=O)O)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Temperature: 61.5 °C
Reaction time: 15 h

Procedure:
1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid (22.54 g) was dissolved in 220 mL of CH3CN. HOAc (20 mL) and CH3SO3H (1.4 mL) were added at room temperature and the mixture was heated to 58-65° C. for 19.5 h. Alaninol (7.511 g) in CH3CN (15 mL) was added slowly and the resultant mixture was stirred at 64° C. for 18.5 h. The mixture was concentrated, and the residue was redissolved in CH2Cl2 (170 mL). HCl (1 N, 170 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (170 mL×2) and the organic layers were combined and concentrated. MeOH (50 mL) was added and the resultant mixture was again concentrated. MeOH (80 mL) was added and the resultant mixture was heated at reflux for 4 h, gradually cooled to 20° C. and held at 20° C. for 15 h. The product was collected by filtration and dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]1[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(Cl)c1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A stirred mixture of 20.0 g (0.12 mole) of 2-chloro-4-nitroaniline and 17.9 g (0.14 mole) of 2,5-dimethoxytetrahydrofuran in 30 ml of glacial acetic acid was heated at reflux for three hours. The mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether. The extract was washed with a saturated aqueous potassium carbonate solution then dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to leave a solid. The solid was purified by recrystallization from methylcyclohexane to yield 22.5 g of 1-(2-chloro-4-nitrophenyl)pyrrole (mp 54°-55° C.).
Reaction SMILES: [NH:1]([C:31]([O:33]CC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH2:3][C:4](=[O:14])[O:5]C(C1C=CC=CC=1)=O.[NH:41]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42]C(O)=O>CO.Cl.[Pd].[C]>[NH:41]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][C:31]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:16])[CH2:3][C:4](=[O:14])[OH:5])=[O:33]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(=O)OC(=O)c1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)OC(C)(C)C
Yield: 73.4 %

Procedure:
4.81 g (0.009 mole) of Z-Asp(OBz)-Tyr-OMe [m.p. 126°-127° C. [α]D24 =-4.8° (C=1, methanol). Anal. Calcd. (%) for C29H30N2O8 : C, 65.16; H, 5.66; N, 5.24. Found (%): C, 65.14; H, 5.71; N, 5.18] was dissolved in a mixture of 150 ml of methanol and 9 ml of 1N HCl and hydrogenated over 0.9 g of a 10% Pd-carbon catalyst at room temperature for 6 hours. Then the catalyst was filtered off, and the filtrate was distilled in vacuo to dryness. The resulting dipeptide was condensed with a mixed anhydride which had been prepared from 1.89 g of Boc-Gly-OH in the same manner as in (1) of Example 2. The product was recrystallized from ethyl acetate-ether, giving 3.09 g of Boc-Gly-Asp-Tyr-OMe; yield 71.8%, m.p. 97°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Product: COCCNc1ccc([N+](=O)[O-])cc1Cl

Procedure:
0.3 mol (56.2 g) of 3,4-dichloronitrobenzene in 170 ml of 2-methoxyethylamine is heated to reflux for 3 hours.
Reaction SMILES: C(N[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)C.[CH:30]([O:33]C1N=C(C(O)=O)C=C(C)N=1)([CH3:32])[CH3:31]>>[CH:30]([O:33][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)([CH3:32])[CH3:31]
Reactant: Cc1cc(C(=O)O)nc(OC(C)C)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)nc(OC(C)C)n1

Procedure:
rac-3-{4-[5-(2-Isopropoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-isopropoxy-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.86 min*; [M+H]+=415.09.
Reaction SMILES: [N:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[C:10]1=[O:15]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1C(=O)N1CCOCC1
Product: CN(C)C=C1CCCC(C(=O)N2CCOCC2)C1=O

Procedure:
2-(Morpholine-4-carbonyl)-cyclohexanone (17 mg, 0.08 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (16 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 267.5 (100) [(M+H)+].
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:10])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[I-:11].[Na+].COC(C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:11][CH2:2][O:3][C:4](=[O:10])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCC(CC)C(=O)OCCl
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CCC(CC)C(=O)OCI

Procedure:
2-Ethyl butyric acid chloromethyl ester (700 g) was dissolved in acetone (3 L). To this solution was added sodium iodide (1.0 kg). The resulting reaction mixture was heated at reflux until reaction completion (2 h (hours), monitored by GC). The solution was then cooled to ambient temperature where tert-butyl methyl ether (7 L) and 5% aqueous sodium thiosulfate (4 L) were added. The phases were separated and the organic phase was washed with aqueous sodium thiosulfate (4 L), low pyrogen water (4 L) and 10% sodium chloride solution (4 L). The organic layer was dried over magnesium sulfate (350 g), filtered, and the filter cake was washed with tert-butyl methyl ether (2×0.7 L). The filtrate was evaporated to a small volume (ca. 2 L) to give 2-ethyl butyric acid iodomethyl ester, as a solution in tert-butyl methyl ether.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:3]1.[H][H]>C(O)C.[Pd]>[NH2:12][C:9]1[CH:8]=[N:7][C:6]([N:4]2[CH2:5][C:2]([F:15])([F:1])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CC(F)(F)C2)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CC(F)(F)C2)nc1

Procedure:
A suspension of 0.34 g (1.58 mmol) of 2-(3,3-difluoroazetidin-1-yl)-5-nitropyridine, prepared in the preceding stage, and 8 mg of Pd/C at 10% in 10 mL of ethanol is stirred vigorously at 20° C. under 5 atm of hydrogen for 4 hours. After this time, the mixture is filtered on a Celite pad, then concentrated at reduced pressure. The resultant product is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. We thus obtain 0.188 g of the expected product in the form of a red powder, which is used as it is in the rest of the synthesis.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc3ccccc3cc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cc3ccccc3cc2c1
Temperature: 25 °C
Yield: 109.2 %

Procedure:
2-Methylanthracene (5.00 g, 26.25 mmol, 1 eq), N-bromosuccinimide (4.70 g, 26.25 mmol, 1 eq), benzoyl peroxide (1.0 g) and carbon tetrachloride (250 mL) were mixed and refluxed for 6 hours. The mixture was cooled to room temperature, and the succinimide precipitate filtered. The filtrate was evaporated to dryness and the residue taken up in ethyl acetate (250 mL) and washed with 1 N NaOH (3×200 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to yield 7.77 g of a light brown solid which was used without purification in the next step. NMR (DMSO-d6): δ 4.90 (s, 2H, CH2Br). ##STR55##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:22]O)[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:22][Br:25])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@@H](CBr)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
A solution of tert-butyl(4S)-4-{[(benzyloxy)carbonyl]amino}-5-hydroxypentanoate (5.0 g, 15.5 mmol) in dichloromethane (50 ml) was cooled to 0° C. and carbontetrabromide (6.15 g, 18.5 mmol) was added thereto. At the same temperature triphenylphosphine (5.68 g, 21.7 mmol) was divided to five portions and they were added to the reaction mixture for every 2 minutes and the mixture was stirred for 30 minutes. The solvent was removed in vacuo. To the residue was added diethyl ether and mixture was stirred. After removal of the resulting crystall by filtration, the filtrate was condensed in vacuo and the residue was purified with silica gel chromatography to give tert-butyl(4S)-4-{[(benzyloxy)carbonyl]amino}-5-bromopentanoate (4.5 g, 80%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]([NH:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.1 %

Procedure:
Into a DCM solution (50 mL) of tert-butylamine (5.9 mL, 56.5 mmol) and triethylamine (7.16 mL, 51.3 mmol) at 0° C. was slowly added a DCM solution (20 mL) of 4-fluoro-benzenesulfonyl chloride (10 g, 51.3 mmol), and the reaction stirred at RT for 19 h. The reaction was concentrated and the resulting solid recrystalized from ether/hexanes to get the product (9.5 g, 80%) as white crystals. MS: APCI (AP+): 230.1 (M)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][SH:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28]OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CCO>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][S:8][CH3:7])[CH2:18][CH2:17]1)=[O:15])([CH3:11])([CH3:10])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2COS(C)(=O)=O)CC1
Reactant: CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CSCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Potassium t-butoxide (159 mg, 1,42 mmol) in 15 mL of abs. EtOH was saturated with methyl mercaptan gas. To this mixture was added 1-t-butoxycarbonyl-4-(2-(methanesulfonyloxymethyl)phenyl)-piperazine (0.94 mmol, which was generated according to the procedure described in Step C of Example 9). The resulting mixture was refluxed for 50 min and concentrated. The residue was purified by preparative TLC (20% EtOAc in Hex) to give the title compound (157 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:9]1([C:15]#[C:16][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(I)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (320 mg, 0.45 mmol) was dissolved in 50 ml THF and 2-amino-5-iodopyrdine (2.0 g, 9.1 mmol) and phenylacetylene (2.0 ml, 18.2 mmol) were added at room temperature. Et3N (3.8 ml, 27 3 mmol), triphenylphosphine (72 mg, 0.27 mmol) and copper(I)iodide (52 mg, 0.27 mmol) were added and the mixture was stirred for 2 hours at 65° C. The reaction mixture was cooled and extracted once with saturated NaHCO3 solution and three times with ethyl acetate. The organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. The crude product was suspended in 5 ml of dichloromethane, stirred for 15 minutes and filtered. The crystals were washed with a small volume of dichloromethane and dried for 1 hour at 50° C. and <20 mbar. The desired compound was obtained as a light yellow solid (1.1 g, 63%), MS: m/e=195.3 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH:71]1[N:75]=[C:74]([NH2:76])[S:73][CH:72]=1>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:76][C:74]2[S:73][CH:72]=[CH:71][N:75]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:39]
Reactant: Nc1nccs1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3nccs3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2-aminothiozole (8.26 mg, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (15.6 mg, 46%). LC-MS m/z 622 (M+H)+.
Reaction SMILES: [O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=O)[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].O.[NH2:26][NH2:27]>C(O)C>[O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:26][NH2:27])=[O:23])[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: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 92 %

Procedure:
Compoud 1 (1 g) was dissolved in a mixture of ethanol (5 ml) and 85% hydrazine hydrate (2 ml). After 24 h the solvent was evaporated and residual traces of hydrazine removed by co-evaporation with toluene to give 8-hydrazinocarbonyloctyl β-D-galactopyranoside as a white solid which was recrystallized from ethanol, mp 194°, [α]D18 -2.16° (c 1.1, water), 92% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[C:11]([Cu])#[N:12]>CN(C=O)C.O>[F:10][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:11]#[N:12]
Reactant: COc1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-methoxybenzene (30.0 g, 146 mmol) and CuCN (15.6 g, 174 mmol) in dry DMF (45 mL) was stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure gave 20.0 g (91%) of the subtitle compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.36 (dd, J=10.8 Hz, 2.0 Hz, 1H), 7.02 (dd, J=8.8 Hz, 8.4 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23]
Reactant: Cc1n[nH]c(=O)c(-c2cc(F)ccc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2cc(F)ccc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
2.86 g of 5-(4-chlorophenyl)-4-(2,5-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 6.5 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:1, to obtain 2.89 g of 3-chloro-5-(4-chlorophenyl)-4-(2,5-difluorophenyl)-6-methyl pyridazine (hereinafter, referred to as compound (xiii) of the present invention).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1[NH2:8].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=O)=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:24]=1>>[CH2:9]([N:6]1[C:7]2[N:8]=[C:40]([CH2:39][C:36]3[CH:35]=[CH:34][C:33]([S:30]([NH:29][C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)(=[O:31])=[O:32])=[CH:38][CH:37]=3)[NH:1][C:2]=2[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Reactant: O=C(O)Cc1ccc(S(=O)(=O)Nc2cccnc2)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(S(=O)(=O)Nc4cccnc4)cc3)nc21

Procedure:
Prepared from 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (30.6 mg, 0.1 mmol) and [4-(pyridin-3-ylsulfamoyl)-phenyl]-acetic acid. 4-[3-Butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-N-pyridin-3-yl-benzenesulfonamide was obtained as a colorless solid; 1H NMR (DMSO-d6, 300 MHz) δH 13.50 (s, 1H), 10.54 (s, 1H), 8.23 (d, J=14.3 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.55–7.40 (m, 3H), 7.35–6.95 (m, 5H), 5.08 (s, 2H), 4.13 (s, 2H), 3.92 (t, J=7.3 Hz, 2H), 1.59 (t, J=7.1 Hz, 2H), 1.23 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.5 Hz, 3H); FAB-HRMS m/e calculated for C28H27FN6O4S (M+H)+ 563.1877, found 563.1860.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]([C:22]([OH:24])=O)[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:25]>C(O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]([C:22]([NH2:25])=[O:24])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: Cn1c2c(c3cc(OCc4ccccc4)ccc31)CC(C(=O)O)C2
Solvent: CCO
Product: Cn1c2c(c3cc(OCc4ccccc4)ccc31)CC(C(N)=O)C2
Temperature: 100 °C

Procedure:
In a sealed tube was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-4-methylcyclopent[b]indole-2-carboxylic acid ecid ethyl ester (5.0 g, 0.014 mole) in 25 ml of absolute ethanol, followed by ammonia (30% aqueous solution, 10ml, 0.17 mole). After heating at 100° C. for five days, the mixture was cooled and the resultant tan precipitate collected and dried to give 3.0 g, m.p. 145°-148° C.