Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CCOCC>[ClH:16].[Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ncccc2Br)cc1
Reactant: Clc1ccccn1
Solvent: CCOCC
Product: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Product: Cl
Temperature: 160 °C

Procedure:
A mixture of 4-(3-bromopyridin-2-yloxy)aniline (50.01 g, 188.6 mmol) and 2-chloropyridine (22.50 ml, 238.8 mmol, Aldrich) was sealed neat in a 350 mL screw-cap flask and heated at 160° C. for 3.5 h. The reaction was cooled to room temperature and stirred over Et2O overnight. The solid was filtered, washed with Et2O and dried in vacuo to give a gray amorphous solid. MS (ESI, pos. ion) m/z: 341.9, 343.9 [M+1]. PDE10 IC50 (uM) 0.96.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>>[F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate, to give the desired product as a light yellow oil (62%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:14]S(O)(=O)=O>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH:11]=[O:14]
Reactant: O=S(=O)(O)O
Reactant: COc1c(C)ccc([N+](=O)[O-])c1Cl
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1c(C=O)ccc([N+](=O)[O-])c1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2-methoxy-4-nitrotoluene (1.0 g, 5.0 mmol) in acetic acid (10 mL) and acetic anhydride (10 mL) was cooled to 5° C. and treated with 1 mL conc. H2SO4. Chromium trioxide (1.4 g, 14 mmol) was added in portions over 10 minutes while the reaction temperature was maintained at 0-5° C. After 30 minutes at this temperature, the mixture was poured onto ice-water (20 g) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine, dried (sodium sulfate) and concentrated. The crude bis-acetate was combined with water (10 mL), ethanol (10 mL) and concentrated sulfuric acid (1 mL) and heated to reflux for 40 minutes. Upon cooling, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The crude mixture was chromatographed (10% ethyl acetate/hexanes) to give 3-chloro-2-methoxy-4-nitrobenzaldehyde (400 mg, 1.9 mmol): LC/MS (m/z=215).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:12][C:11](=[O:14])[C:10]3[C:16](=[CH:17][CH:18]=[C:19]([NH:15][C:4](=[O:3])[CH3:5])[CH:9]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2

Procedure:
A mixture of 24.8 g of 4-methoxyacetanilide, 37.3 mL of acetyl chloride and 250 mL of CH2Cl2 was refluxed until the insoluble solid was dissolved, and then cooled to 0° C. 70.0 g of AlCl3 was gradually added thereto, and then the mixture was heated under reflux for 5 hours. The reaction mixture was poured into 500 mL of water with ice, and stirred for 30 minutes. The resulting precipitate was collected through filtration, washed with water and dried under vacuum to obtain 23.5 g of 5-acetylamino-2-hydroxyacetophenone. 9.96 g of N-Boc-piperidin-4-one, 4.17 mL of pyrrolidine and 75 mL of MeOH were added to 9.66 g of the product, and heated under reflux for 13 hours. The reaction mixture was concentrated, cold MeOH was added to the residue, and the insoluble solid was taken out through filtration and dried under vacuum to obtain 16.3 g of N-{1′-[(tert-butoxy)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}acetamide. TFA (43 mL) cooled at 0° C. was gradually added to 16.1 g of the product, and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and TFA still remaining therein was removed through codistillation with toluene added thereto, and 50 mL of Et2O was added to the residue. The resulting insoluble solid was taken out through filtration, washed with Et2O/EtOAc (1/2), and dried under vacuum to obtain N-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}acetamide TFA salt.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:27][CH:28]=2)O1>>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:27]3[CH:26]=[C:25]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=[CH:23][CH:28]=3)=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)c1
Yield: 44 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.28 g, 1.04 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (165 mg, 44%) as a yellow powder: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.53 (1H, td, J 8 and 1), 7.59-7.68 (3H, m), 7.70-7.75 (2H, m), 7.80-7.85 (2H, m), 8.14 (1H, s), 9.20 (1H, d, J 7); m/z (ES+) 365 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([OH:8])=O.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:43][CH2:44][CH:45]([C:47]1[CH:52]=[C:51](OC)[C:50](OC)=[C:49](OC)[CH:48]=1)[OH:46]>ClCCl>[OH:46][CH:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:44][NH:43][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: COc1cc(C(O)CN)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)cc(C(=O)NCC(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
A suspension of 3,5-dimethoxybenzoic acid (1.00 g, 5.49 mmol) in dichloromethane (50 mL) at 0° C. was treated with HOBt hydrate (0.742 g, 5.49 mmol), stirred for 15 minutes, treated with EDCI (1.05 g, 5.49 mmol) in one portion, stirred for an additional 25 minutes, treated with triethylamine (1.84 g; 2.53 mL, 1.9 mmol) and the acetate salt of 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol (1.58 g, 005.49 mmol), stirred for 18 hours while warming to room temperature, and concentrated. The concentrate was partitioned between ethyl acetate (400 mL) and water (200 mL), and the organic extract was washed sequentially with 10% KHSO4 (200 mL), water (100 mL), NaHCO3 (200 mL), and water (100 mL), dried (MgSO4), filtered, and concentrated to provide 1.56 g of the desired product as a white foamy semi-solid.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([CH2:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:16]12[CH2:22][CH:19]([CH2:20][CH2:21]1)[CH:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH:17]2.Cl.[Cl-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:6]([NH:5][S:2]([N:17]1[CH:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]2[CH2:22][CH:16]1[CH2:21][CH2:20]2)(=[O:4])=[O:3])([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C1NC2CCC1C2
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1C2CCC(C2)N1S(=O)(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a stirred solution of 16.61 ml (191.31 mmol) of chlorosulfonyl isocyanate in methylene chloride was added phenylmethanol (19.92 ml, 191.31 mmol) at 0° C. After stirring the above solution for 2 hours at this temperature, a solution of 30.84 g (182.2 mmol) of ethyl 2-azabicyclo[2,2,1]heptan-3-carboxylate in methylene chloride containing triethylamine (42.92 ml) was added at 0° C. and the resulting mixture was stirred overnight allowing the mixture to warm to room temperature. The reaction mixture was poured into 500 ml of 10% aq. HCl solution, saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with methylene chloride, the combined organic layer was concentrated in vacuo and purified by flash chromatography (30% ethyl acetate in hexane) to yield 40.75 g (58.5%) of ethyl N-(carbobenzyloxyaminosulfonyl)-2-azabicyclo [2,2,1]-heptan-3-carboxylate (Formula XIV: R=Ethyl; R1 =H; R2 and R3 together = ##STR18## as an oil.
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=O)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CCO.O>[CH2:1]([C:5]12[CH2:18][C:19](=[O:21])[CH:20]=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCC12CCc3cc(OC)ccc3C1=CC(=O)C2

Procedure:
A solution of crude 2-butyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone (888 mg, ˜3 mmol) in EtOH (15 mL) was treated with freshly prepared 2N KOH in EtOH (1.5 mL, 3 mmol). The resulting solution was placed under a N2 atmosphere and heated at reflux for 17 hours. After cooling, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7 cm) silica gel column, eluting with 1000 mL portions of 19:1 and 10:1 hexane-EtOAc. The product-containing fractions were evaporated under vacuum to provide 3a-butyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:15]([C:23]([C:38]([O-:40])=[O:39])([OH:37])[C:24]([C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:28])[C:25]([O-:27])=[O:26])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[C:29]([C:24]([C:25]([OH:27])=[O:26])([OH:28])[C:23]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:37])[C:38]([OH:40])=[O:39])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:1][C@@H:2]1[C@@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: O=C([O-])C(O)(C(=O)c1ccccc1)C(O)(C(=O)[O-])C(=O)c1ccccc1
Reactant: CC1CNCCC1OC(=O)C(C)(C)C
Solvent: CCOC(C)=O
Product: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Product: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1

Procedure:
2,2-Dimethyl-propionic acid (3RS,4RS)-3-methyl-piperidin-4-yl ester (5) (9.6 g, 48 mmol) is dissolved in 50 ml of ethyl acetate. A solution of (−)-dibenzoyltartrate (8.6 g, 24 mmol) in ethyl acetate is added drop wise. The precipitate is filtrated off and washed with cold ethyl acetate to yield colourless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24]>>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Product: COCC1COc2cc3ncnc(Nc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3cc2O1
Yield: 47.1 %

Procedure:
The titled compound (8 mg, 50%) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (10 mg, 0.037 mmol) and 3,5-bis(trifluoromethyl)aniline (17 mg, 0.075 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7](=O)[CH2:6][CH2:5][CH2:4][C:3]1=2.[C:16](O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)CCC>[CH3:1][C:2]1([CH3:15])[C:3]2[CH2:4][CH2:5][C:6]3[CH:16]=[N:21][CH:20]=[N:22][C:7]=3[C:8]=2[C:9]([CH3:13])([CH3:12])[CH2:10][CH2:11]1
Reactant: CC1(C)CCC(C)(C)C2=C1CCCC2=O
Reactant: CC(=O)O
Reactant: N=CN
Solvent: CCCCO
Product: CC1(C)CCC(C)(C)C2=C1CCc1cncnc12
Temperature: 130 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A 100 mL reaction flask is charged with 5,5,8,8-tetramethyl-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (prepared as described in U.S. Pat. Nos. 3,927,083 and 2,912,462) (10 g, 0.048 mol), formamidine acetate (25 g, 0.24 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 7,7,10,10-tetramethyl-5,6,7,8,9,10-hexahydro-benzo[h]quinazoline (˜5 g) is obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[N:9]([CH3:27])[C:10](=[O:26])[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]([NH:16][CH3:17])=[O:15])[N:13]=1.[CH3:28][C:29]1[CH:30]=[C:31]([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][CH:34]=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH3:17][NH:16][C:14]([C:12]1[N:13]=[C:8]([NH:7][S:36]([CH2:35][C:31]2[CH:30]=[C:29]([CH3:28])[CH:34]=[CH:33][CH:32]=2)(=[O:38])=[O:37])[N:9]([CH3:27])[C:10](=[O:26])[C:11]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15]
Reactant: Cc1cccc(CS(=O)(=O)Cl)c1
Reactant: CNC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(NS(=O)(=O)Cc2cccc(C)c2)n(C)c(=O)c1OCc1ccccc1
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
Potassium tert-butoxide (75.9 mg, 676 μmol) was added to a solution of 2-amino-5-(benzyloxy)-N,1-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (150 mg, 520 μmol) in THF (15.0 ml) and DMF (3 ml). The resulting mixture was stirred for 10 min and then cooled with an ice-bath. To this mixture was slowly added a solution of (3-methylphenyl)methanesulfonyl chloride (140 mg, 684 μmol) in THF (1 ml). The reaction mixture was stirred at room temperature overnight. A further solution of (3-methylphenyl)methanesulfonyl chloride (140 mg, 684 μmol) in THF (1 ml) was added and then the mixture was stirred at room temperature for 48 hours. The resulting mixture was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine. The organic layers were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (silica gel, 0% to 2% MeOH in DCM) provided the desired product as a light yellow solid (0.070 g; 29%). LCMS: m/z=457 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]#[N:7].[C:8]([C@@H:11]([NH:20][C@H:21]([C:33]([OH:35])=O)[CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(=O)C(F)(F)F)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:10])N.[OH-:36].[Na+].[OH-:38].[NH4+:39]>C(O)C.O>[N:6]#[N:7].[C:8]([C@@H:11]([NH:20][C@H:21]([C:33]([N:39]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:8]([OH:10])=[O:38])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([OH:10])=[O:36]
Reactant: NC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Reactant: [OH-]
Reactant: [NH4+]
Agent: N#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To 10 ml of 6NB sulfuric acid was added 1 g of N2 -(1(S)-carbamyl-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysine followed by stirring for 15 hours at 80° C., after cooling the mixture to 0° C., 50 ml of water was added thereto, and after adjusting the pH thereof to 5.5 with an aqueous solution of 2N sodium hydroxide and then adjusting the pH to 7.5 with 1 N ammonium hydroxide, the volatile matters were distilled off. To the residue formed was added to 10 ml of ethanol, insoluble inorganic salts were filtered away, and after concentrated the filtrate under reduced pressure, the residual solids were purified by LH-20 chromatography (methanol) to provide 632 mg of N2 -(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline as solids. The properties of the product coincided with those described in Journal of Pharmaceutical Science, 74, 352(1985).
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][C:7]2[C:8]3[CH:9]=[N:10][NH:11][C:12]=3[CH:13]=[CH:14][C:6]=2[CH2:5]1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]2=[O:50])[CH2:36][CH2:35]1>ClCCl>[CH2:19]([N:16]1[C:17](=[O:18])[C@H:4]([CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH:37]([N:40]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:42][C:41]3=[O:50])[CH2:38][CH2:39]2)[CH2:5][C:6]2[CH:14]=[CH:13][C:12]3[NH:11][N:10]=[CH:9][C:8]=3[C:7]=2[CH2:15]1)[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CCO)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CCN2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
(S)-7-(2-hydroxyethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (15 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL). Thionyl chloride (100 μL) was added to the mixture. Reaction stirred at room temperature for 2 hours. Thionyl chloride (500 μL) was added to the mixture. Reaction stirred at room temperature for 2 hours and then was warmed to reflux for 2 hours. Reaction mixture was concentrated in vacuo. Residue was dissolved in acetonitrile (1 mL). Potassium carbonate (25 mg, 0.18 mmol) was added to the mixture followed by 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (16 mg, 0.07 mmol). Reaction was heated at reflux for 2 hours. Preparatory HPLC purification afforded the title compound as white solid in 25% yield. High resolution MS m/e (M+H)+=529.3282.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:14][C@H:13]([CH2:15][OH:16])[CH2:12]2)=[C:4]([O:17]CC2C=CC=CC=2)[N:3]=1.Cl.CN(C)C=O>CO.O>[NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[N:6]=[CH:7][N:8]([C@H:11]3[CH2:14][C@@H:13]([CH2:15][OH:16])[CH2:12]3)[C:9]=2[N:10]=1
Reactant: Nc1nc(OCc2ccccc2)c2ncn([C@H]3C[C@@H](CO)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2[C@H]2C[C@@H](CO)C2)c(=O)[nH]1
Reaction time: 2 h

Procedure:
To a solution of the above preparation of (cis)-3-[2-amino-6-(phenylmethoxy)-9H-purin-9-yl]-cyclobutanemethanol (330 mg) in 5.2 ml of methanol was added 2.6 ml of 3N HCl. The mixture was stirred under nitrogen at 40° for 2 hours and concentrated in vacuo to a solid, which was suspended in water. The pH was adjusted to 7.0 using 1N KOH, and the water was removed in vacuo leaving a solid. Chromatography of this solid on 80 ml of CHP-20P resin (Mitsubishi Chemical Industries) water and then 5% dimethylformamide in water gave 140 mg of (cis)-2-amino-1,9-dihydro-9-[3-(hydroxymethyl)cyclobutyl]-6H-purin-6-one as a solid having m.p. 275°-278° (dec.).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:12]=[C:11]([CH:13]2[CH2:15][O:14]2)[C:10]2[C:5](=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.B(F)(F)F.C([O-])(O)=[O:27].[Na+].[CH3:31][CH2:32]OCC>>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:12]=[C:11]([CH:13]([CH2:15][O:14][CH2:31][CH3:32])[OH:27])[C:10]2[C:5](=[C:6]([C:16]([F:17])([F:18])[F:19])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C([O-])O
Reactant: FC(F)(F)c1cc(C2CO2)c2cccc(C(F)(F)F)c2n1
Reactant: CCOCC
Agent: FB(F)F
Agent: [Na+]
Product: CCOCC(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of (2,8-bis(trifluoromethyl)-4-quinolinyl)oxirane (208 mg, 0.68 mmol) in ether (3 mL) was treated with BF3.etherate (0.2 mL), stirred at room temperature for 2 h, poured into dilute NaHCO3 (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were dried (MgSO4), concentrated in vacuo and the residue purified by flash chromatography [SiO2; heptane-EtOAc (2:1)] to give the title compound (196 mg, 82%) as a yellow oil: IR νmax (Nujol)/cm−1 3700-3200, 3087, 2982, 2879, 1606, 1586, 1431, 1372, 1311, 1191, 1144, 1109, 769; NMR δH (400 MHz, CDCl3) 1.26 (3H, t, J 7.0 Hz), 3.24-3.31 (1H, br s), 3.48 (1H, dd, J 8.4, 9.6 Hz), 3.54-3.69 (2H, m), 3.84 (1H, dd, J 9.6, 3.2 Hz), 5.70 (1H, dd, J 8.4, 3.2 Hz), 7.75 (1H, t, J 7.9 Hz), 8.13 (1H, s), 8.17 (1H, d, J 7.5 Hz), 8.28 (1H, d, J 9.1 Hz); M/Z 354 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[SH2:9].[K].C[O-].[Na+].CO.[Cl:16][C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][N:20]2[CH:26]=1>CO>[Cl:16][C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][C:22]([S:9][CH2:2][CH2:3][CH2:4][S:5](=[O:7])(=[O:6])[NH2:8])=[N:21][N:20]2[CH:26]=1
Reactant: NS(=O)(=O)CCCCl
Reactant: Clc1cn2nc(Cl)ccc2n1
Reactant: S
Agent: C[O-]
Agent: [K]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)CCCSc1ccc2nc(Cl)cn2n1
Temperature: 70 °C

Procedure:
To a solution of 1.57 g of 3-chloro-1-propanesulfonamide in 20 ml of methanol was added 20 ml of 2N-potassium hydrogensulfide, followed by heating at 70° C. for 50 minutes. Further, 1.48 g of 28% sodium methoxide-methanol solution and 1.32 g of 2,6-dichloroimidazo[1,2-b]pyridazine [Japanese Unexamined Patent Publication No. SHO 64(1989)-38092] were added to the reaction mixture, and refluxed at 100° C. for 3 hours. The mixture was concentrated under reduced pressure. Then, the residue to which was 20 ml of water was added was adjusted to pH 7.0 with 1N-hydrochloric acid. The precipitated crystals were collected by filtration and subjected to a silica gel column chromatography, eluting with chloroform and methanol (50:1). The corresponding combined fractions were concentrated, and the residue was recrystallized to obtain 1.1 g of the title compound.