Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15].[C:19]([O:25][CH2:26][C:27]([CH3:39])([CH3:38])[CH2:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30])(=[O:24])[CH2:20][C:21]([CH3:23])=O>CC(O)C>[CH3:23][C:21]1[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:4]([C:3]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:20]=1[C:19]([O:25][CH2:26][C:27]([CH3:39])([CH3:38])[CH2:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30])=[O:24]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1c(F)cccc1Cl
Yield: 6.3 %

Procedure:
A mixture of 170 mg of 2-chloro-6-fluorobenzaldehyde, 137 mg of methyl 3-aminocrotonate and 345 mg of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate in 2 ml of 2-propanol was reacted and then purified in the same way as in Example 8 to yield 36 mg of the desired compound (168).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:38].O>[Pd].O1CCOCC1>[Na+:38].[OH:32][CH:30]([CH:17]1[C:16](=[O:33])[N:15]2[CH:18]1[CH:19]([CH3:29])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH2:27][OH:28])[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:31]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(CO)C3)C(C)C12
Yield: 46.2 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.170 g of product from Example 78, 0.0328 g of sodium bicarbonate, 2 ml of water, 11.3 ml of dioxane, and 0.070 g of 10% palladium/carbon to give 0.060 g of the desired compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[CH:16]([OH:21])[N:15]([CH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1)[CH:14]2[OH:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[CH:16]([OH:21])[N:15]([C@@H:22]1[CH2:26][CH2:25][C@H:24]([O:27][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:23]1)[CH:14]2[OH:28]
Reactant: OC1CCC(N2C(O)c3cc(Cl)c(Cl)cc3C2O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CC[C@@H](N2C(O)c3cc(Cl)c(Cl)cc3C2O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a flask was added DCM (40 mL), DIPEA (2.0 mL, 11.48 mmol), c is 5,6-dichloro-2-(3-hydroxy-cyclopentyl)-2,3-dihydro-1H-isoindole-1,3-diol 1.071 g, 3.57 mmol) and methanesulfonyl chloride (0.6 mL, 7.72 mmol) and the mixture stirred overnight at RT. The mixture was concentrated in vacuo, EtOAc (100 mL) and H2O (100 mL) added, filtered off insolubles, separated and extracted the aqueous layer with EtOAc (50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give cis methanesulfonic acid 3-(5,6-dichloro-1,3-dihydroxy-1,3-dihydro-isoindol-2-yl)-cyclopentyl ester as a tan solid (1.5 g, impure as >100% yield).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:9])=[C:5]1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])=[CH2:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:9])=[C:5]1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: C=C(C)C1CCC(C)=C1CCC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCC1=C(C)CCC1C(C)C
Yield: 99 %

Procedure:
4 g of 3-isopropenyl-1-methyl-2-(3-oxobutyl)-cyclopent-1-ene were hydrogenated in 50 ml of ethyl acetate in the presence of 400 mg of palladium on calcium carbonate (5%). After the uptake of one equivalent of hydrogen, the solution was filtered over Celite, concentrated and distilled under a high vacuum. There were obtained 4 g of 3-isopropyl-1-methyl-2-(3-oxobutyl)-cyclopent-1-ene; boiling point 0.005 about 70° C; nD20 = 1.4709; IRfilm : νmax = 1/25, 1390/70 and 1170cm-1. The compound has a woody, floral note.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][CH:38]=1)[C:23]([C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24].C(N(CC)CC)C.C(#N)C>O1CCOCC1>[CH2:30]([O:29][C:27]([C:26]1[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=1[C:23]([C:22]1[CH:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:38]=[CH:37][CH:36]=1)=[O:24])=[O:28])[CH3:31]
Reactant: CCOC(=O)c1ccccc1C(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1ccccc1C(=O)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 14.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (5.1 g) is added, at a temperature between 70° and 78° C., to a solution of ethyl 2-(3'-aminobenzoyl)benzoate (4.6 g) and triethylamine (3.45 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 70° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 45 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with a saturated aqueous sodium bicarbonate solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (9 g) is thereby obtained, which is chromatographed on an 8 cm diameter column containing silica (0.02-0.045 mm; 640 g). Elution is carried out with ethyl acetate at a pressure of 0.45 bar (45 kPa), collecting 300 cm fractions. The first 12 fractions are discarded. The following 6 fractions are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (5.1 g) is thereby obtained, which is dissolved in boiling acetonitrile (30 cc). The solution obtained is filtered in the heated state. The filtrate obtained is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed 3 times with acetonitrile cooled to a temperature in the vicinity of 4° C. (30 cc in total) and 3 times with diethyl ether (90 cc in total) and the dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-ethoxycarbonylbenzoyl)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (1.2 g) in the form of cream-coloured crystals, m.p. 150° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[CH:40]=[C:39](F)[C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:27]([O:37][CH3:38])=[CH:26][N:25]=3)=[N:16]2)=[C:12]([F:42])[CH:11]=1.O>CN(C=O)C>[Br:9][C:10]1[CH:40]=[C:39]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:27]([O:37][CH3:38])=[CH:26][N:25]=3)=[N:16]2)=[C:12]([F:42])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3F)c3ccccc23)nc1Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3OCC(F)(F)F)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
38.2 mg of 2,2,2-trifluoroethanol (0.382 mmol, 2 eq.) were dissolved in 1.5 ml of dry DMF under nitrogen atmosphere. 16.8 mg of 60% sodium hydrid in paraffin oil (0.42 mmol, 2.2 eq.) were added. The suspension was stirred at room temperature for 15 minutes. 100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-12-1, 0.191 mmol, 1 eq.) were added. The reaction mixture was stirred at room temperature for 18 hours. Water was added dropwise. The suspension was filtered off. The precipitate was dried at 50° C. under vacuo. The precipitate was purified by preparative HPLC to yield 34 mg (0.05 mmol, 28%) of the analytically pure target compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O>[N+:14]([C:5]1[CH:4]=[CH:3][C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Reactant: C1COCCN1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1N1CCCCC1
Temperature: 125 °C
Reaction time: 84 h
Yield: 89.3 %

Procedure:
A mixture of 150 mg (0.623 mmol) 1-(5-chloro-2-nitro-phenyl)-piperidine (as prepared in the previous step) and 272 μL (3.12 mmol) of morpholine were heated with stirring under Ar at 125° C. for 84 h. After cooling to rt, the mixture was poured into water (40 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL) and then dried (Na2SO4) Concentration afforded 162 mg (89%) of the title compound as an orange resin: Mass spectrum (ESI, m/z): Calcd. for C15H21N3O3, 292.2 (M+H), found 292.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[C:42]1([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([N:51]2[CH2:52][CH2:53][N:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:49][CH2:50]2)=[O:40])=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N4CCN(c5ccccc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-phenylpiperazine (83 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (130 mg, yield 79%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH3:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[I:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:21]3[CH:22]=[C:18]([I:17])[N:19]=[CH:20]3)[N:7]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidine (example A.47) (3.5 g, 13.8 mmol) and commercially available 4-iodo-imidazole (2.95 g, 15.2 mmol) according to the general procedure IVa. Obtained as an off-white solid (2.67 g, 92%). MS (ISP) 485.1 [(M+H)+]; mp 223° C.
Reaction SMILES: F[B-](F)(F)F.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7].[FH:17].[FH:18].F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:6]([CH:10]1[CH2:15][CH2:14][C:13]([F:18])([F:17])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: F
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C1CCC(F)(F)CC1
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (593 mg, 2.6 mmol) in dichloromethane (10 mL) at room temperature is added 4-tert-butylcyclohexanone (200 mg, 1.3 mmol) and triethylamine trihydrofluoride (266 μl, 1.3 mmol). The reaction mixture is stirred for 4 hours, then an aqueous solution of sodium bicarbonate (5%) is added and stirring is continued for 30 minutes. The organic phase is isolated and dried with magnesium sulphate. The solution is diluted with pentane (10 mL) and the solution is passed through a pad of silica gel with pentane elution. Solvent are evaporated in vacuo to provide 4-t-butyl-1,1-difluorocyclohexane (120 mg, 53%) as a clear liquid, admixed with 3% of the corresponding vinyl fluoride. Major compound: 1H NMR (CDCl3) 2.09-1.95 (m, 2H), 1.76-1.67 (m, 2H), 1.65-1.51 (m, 2H), 1.30-1.15 (m, 2H), 1.02-0.97 (s, 1H), 0.80 (s, 9H); 19F NMR (CDCl3)-91.9 (d, J=232.6 Hz, 1F), −103.5 (dm, J=232.6 Hz, 1F).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[CH:6]1([S:9]([C:12]2[CH:17]=[CH:16][C:15](/[C:18](=[CH:22]\[CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)/[C:19](O)=[O:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:8][CH2:7]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:6]1([S:9]([C:12]2[CH:13]=[CH:14][C:15](/[C:18](=[CH:22]\[CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)/[C:19]([N:4]([O:3][CH3:2])[CH3:5])=[O:20])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH2:8][CH2:7]1
Reactant: O=C(O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.9 %

Procedure:
To a solution of N-methoxymethanamine hydrochloride (350 mg) in N,N-dimethylformamide (10 mL) was added triethylamine (500 μL), and the mixture was stirred at room temperature for 30 min. (2E)-2-[4-(Cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propan-2-enoic acid (1.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (860 mg) and 1-hydroxybenzotriazole (600 mg) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated to give a crude product (1.15 g) of the title compound as colorless crystals. MS: 380 (MH+).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].N1[CH:24]=[CH:23]C=CC=1.C(Cl)(=[O:28])CC.C(Cl)Cl>O.O1CCOCC1>[O:28]=[C:3]([CH2:23][CH3:24])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: c1ccncc1
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCC(=O)Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
According to the method of Production Example 1, a mixed solution of methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (6.30 g), pyridine (3.2 ml), propionyl chloride (3.26 g) and methylene chloride (60 ml) is heated under reflux for 11 hours, and then heated under reflux with 1,4-dioxane in water for 16 hours to obtain methyl 4-(2-oxobutyl)-3-nitrobenzoate (5.63 g).
Reaction SMILES: [CH3:1][N:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1.[I:11][CH2:12][CH2:13][CH2:14][CH3:15]>CO>[I-:11].[CH2:12]([N+:2]1([CH3:1])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCI
Reactant: CN1CCC2CCCCC21
Solvent: CO
Product: CCCC[N+]1(C)CCC2CCCCC21
Product: [I-]
Yield: 87060.4 %

Procedure:
20 g (0.14 mmol) of 1-methyl-octahydroindole was mixed with 53 g (0.29 mmol) of 1-iodobutane in 300 mL of methanol. The reaction mixture was heated at reflux for 72 hours. Then, an additional 0.5 mol equivalent of 1-iodobutane was added and the reaction mixture was heated for an additional 12 hours. The reaction mixture was cooled and the solvent removed on a rotary evaporator to give an off-white powder which was used without further purification. The quaternization afforded 39.4 g (86% yield) of 1-butyl-1-methyl-octahydroindolium iodide. The obtained 1-butyl-1-methyl-octahydroindolium iodide (18.15 g) was dissolved in 56 g of deionized water. To this solution, 70 g of BIO-RAD AG® 1-X8 ion exchange resin was added and the slurry was gently stirred at room temperature overnight. The solution was filtered and the filtrate analyzed for hydroxide content by titration of a small aliquot with dilute HCl. The exchange afforded 1-butyl-1-methyl-octahydroindolium hydroxide in 87% yield.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=O)[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:28]>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([Cl:28])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Yield: 98.5 %

Procedure:
2-(biphenyl-4-ylmethyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (25 mg, 0.075 mmol) is refluxed in POCl3 (10 mL) for 60 hours, and the mixture is evaporated to dryness. The residue is purified by silica gel flash chromatography to give 26 mg product as white solids (Yield: 98.5%). 1H NMR (400 MHz, CDCl3) 153.68 (s, 3H), 5.45 (s, 2H), 7.39 (m, 3H), 7.43 (m, 2H), 7.59 (m, 4H), 8.01 (s, 1H). MS (FAB) m/z 351.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2].ClC(Cl)C.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CO>[Br:23][CH:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CO
Solvent: CC(Cl)Cl
Product: CC(Br)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To the solution dissolved 15.0 g of 2-ethylanthraquinone (63 mmol; produced by Wako Pure Chemical Industries, Ltd.) into 100 mL of dichloroethane, 11.3 g of N-bromosuccinimide (NBS) (63.5 mmol; produced by Wako Pure Chemical Industries, Ltd.) and 1.0 g of 2,2′-azobis(isobutyronitrile) (AIBN) (6.1 mmol; produced by Wako Pure Chemical Industries, Ltd.) were added, then, the solution was reacted by stirring for 2 hours at 60° C. After completing reaction, the reaction solution was condensed, and 120 mL of methanol was poured into the condensed residue, and after the resultant crystal was filtered, the resultant crystal was dried to obtain 18.0 g of 2-(1-bromo-1-ethyl)anthraquinone (yield: 90%) as pale yellow crystal. Measurement results of 1H-NMR are shown as the follows:
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C>[C:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=C(NC1CCN(c2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: Nc1ccc(C(=O)NC2CCN(c3ccccc3)C2)cc1

Procedure:
A suspension of 10 g. of 1-phenyl-3-(4-nitrobenzamido)pyrrolidine in 250 ml. of 95% ethanol containing 5% palladium on charcoal was shaken in a Paar hydrogenator in three atmospheres of hydrogen at room temperature. The reduction mixture was filtered and the filtrate concentrated to give 3.8 g. of crystalline product which melted at 213-216° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11](O)=[O:12]>C1C=CC=CC=1>[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([Cl:3])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
15 ml of thionyl chloride were added to a solution of 5.22 g (0.0216 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid [(XII), R1 =--OCHF2, R3' =H, X=X'=F] (prepared as described in Preparation 1, 2 or 3) in 300 ml of benzene, and the mixture was heated under reflux for 3 hours. At the end of this time, benzene and excess thionyl chloride were removed by distillation under reduced pressure, to give 3-difluoromethoxy-2,4,5-trifluorobenzoyl chloride [(XIII), R1 =--OCHF2, R3' =H, X=X'=F].
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH2:7]N)[C:3]([OH:5])=[O:4].[CH2:9]([O:16][C:17]([NH:19][C:20]([N:32]1C=CC=N1)=[N:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]([N:19]([CH2:7][CH2:6][C@H:2]([OH:1])[C:3]([OH:5])=[O:4])[C:20]([NH2:32])=[N:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: NCC[C@H](O)C(=O)O
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)OCc1ccccc1)N(CC[C@H](O)C(=O)O)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2(S)-hydroxy-4-amino-butyric acid (0.059 g, 0.50 mmol) in DMF (2 ml) was added N,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.26 g, 0.70 mmol) followed by DIPEA (0.87 mL, 4.99 mmol) and the reaction was heated to 80° C. and stirred overnight. The crude mixture was purified on a 2-inch reverse-phase HPLC column (Method 2) to yield N,N′-bis-Cbz-2(S)-hydroxy-4-guanidino-butyric acid: MS: m/z (M+H)+ calcd. 430.15. found 430.1.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[O:67][C:68]2[CH:74]=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=1>>[O:67]1[C:68]2[CH:74]=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=[C:66]1[S:65][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:51][CH2:52][CH2:53][CH2:54]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][CH2:47][CH2:48]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Sc1nc2ccccc2o1
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, to thereby yield the title compound as a pale yellow solid.