Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:10](CC)CC)C.[P:15]([Cl:19])([Cl:18])([Cl:17])=[O:16]>>[P:15]([Cl:19])([Cl:18])([Cl:17])=[O:16].[N:10]1[C:5]([CH3:6])=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:7]
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc(C)n1

Procedure:
Intermediate 1(b) may then be cyclized to the 6-chloro-purine intermediate 1(c) by treatment with a condensation agent using analogous procedures and conditions described in U.S. Pat. No.4,728,644, incorporated herein by reference. In a preferred method, intermediate 1(b) can be refluxed in a weak acid (e.g., acetic acid) or sulfuric acid in an appropriate solvent (e.g., isopropyl alcohol, toluene) to provide the hydroxy purine intermediate 1(d) followed by refluxing in phosphorous oxychloride, toluene in the presence of phosphorous oxychloride and triethylamine, or 2,6-lutidine in phosphorous oxychloride to give intermediate 1(c). In another preferred method, 1(b) may be directly converted to 1(c) by refluxing in phosphorous oxychloride; an appropriate co-solvent (e.g., toluene) and/or base (e.g., pyridine, triethylamine) may be added to aid in the condensation.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(=O)([O-])[O-].[Na+].[Na+].F[C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26].O>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-naphthol (7 g) in 50 ml dimethylformamide was added sodium carbonate (10 g), followed by 3-fluoro-4-nitropyridine-N-oxide. After stirring three hours at ambient temperature the reaction mixture was stirred with water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, dried (anhy. MgSO4), filtered and concentrated to a solid. This solid was triturated with ether, collected and dried to give a solid, 11.6 g, m.p. 130°-133° C. A three gram portion was recrystallized from ethanol to give crystals, 2.8 g, m.p. 131°-133° C.
Reaction SMILES: [CH:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[OH-].[Na+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1.O>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]1[CH2:11][C:12]([OH:14])=[O:13])(=[O:28])=[O:29]
Reactant: O=C(O)CC1NCCc2ccccc21
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.91 g of (1,2,3,4-tetrahydro-1-isoquinolyl)acetic acid (Preparation 2.18) are suspended in 25 ml of dioxane, 10 ml of 1N NaOH are added, followed by portionwise addition of 2.3 g of 2-naphthalenesulphonyl chloride, and the mixture is maintained at pH=10.5-12 by addition of 1N NaOH. The mixture is kept stirring at a constant pH for 2 hours at RT. The reaction medium is diluted with 100 ml of water and is then washed twice with EtOAc and brought to pH=1.2 by addition of 6N HCl in the presence of EtOAc. This mixture is extracted with EtOAc, washed with saturated NaCl solution, dried over Na2SO4 and evaporated to dryness. The expected product crystallizes from heptane, and is drained, washed with heptane and then dried to give 3.14 g, m.p.=132° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[S:20][CH:19]=[N:18][C:17]=3[CH3:21])=[O:15])[C@H:11]([C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:27]12[CH2:33][C@H:30]([NH:31][CH2:32]1)[CH2:29][O:28]2.C(N(CC)CC)C>O>[CH3:21][C:17]1[N:18]=[CH:19][S:20][C:16]=1[C:14](=[O:15])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:31]3[CH2:32][C@@H:27]4[CH2:33][C@H:30]3[CH2:29][O:28]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:22]([F:25])([F:24])[F:23]
Reactant: Cc1ncsc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ncsc1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 130 °C
Yield: 51.6 %

Procedure:
170 mg (0.511 mmol) of (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 70.42 mg (0.52 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 151 μl (1.08 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 3 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11]2.[N-:18]=[N+]=[N-].[Na+]>C1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[NH:18][CH2:12][CH2:11]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCNC2=O
Temperature: 60 °C

Procedure:
Sulfuric acid (82.6 mL) was carefully added, at 0° C., to 5-methoxy-1-indanone (25 g, 154 mmol) in benzene (400 mL) followed by sodium azide (18 g, 277.4 mmol). The resulting mixture was heated at 60° C. for 24 h. After cooling at room temperature, the benzene was evaporated and the resulting mixture was diluted with water and extracted with dichloromethane. After drying of the organic layer with MgSO4, filtration and evaporation the product was obtained as a white solid after purification by chromatography (SiO2, ethyl acetate/n-hexane 1:1 to 4:1 v:v gradient) (13.2 g, 49%). MS: m/e=177.2 (M+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:10](=[O:13])[CH2:11][CH3:12])[OH:9].[H-].[Na+].[CH3:16]I>CN(C)C=O.O>[CH3:16][O:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CI
Reactant: CCC(=O)N(O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N(OC)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 25 to 30° C., a solution of 22.7 g (0.127 mol) (Example 6a) of N-(2-methylphenyl)-N-propionyl-hydroxylamine in 50 ml of dimethylformamide is dripped into a stirred mixture of 3.4 g (0.14 mol) of NaH in 150 ml of dimethylformamide. After completion of gas evolution (15 mins) 18.4 g (0.13 mol) of methyl iodide is added and the mixture is stirred overnight at room temperature. The reaction mixture is then diluted with water and the aqueous phase is extracted three times with methyl tert-butyl ether. The combined organic phases are extracted with water, dried over MgSO4 and evaporated down. The residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 18 g (0.081 mol{circumflex over (=)}64%) of the title compound as a yellow oil.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH2:16]([O:18][CH:19]([O:31][CH2:32][CH3:33])[CH2:20][NH:21][C:22](=[NH:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH3:17]>>[CH2:16]([O:18][CH:19]([O:31][CH2:32][CH3:33])[CH2:20][N:21]1[C:11](=[O:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:30]=[C:22]1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH3:17]
Reactant: CCOC(CNC(=N)c1ccc(F)cc1)OCC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc(-c2ccc(F)cc2)n(CC(OCC)OCC)c1=O

Procedure:
This compound was prepared from diethyl ethoxymethylenemalonate and N-(2,2-diethoxyethyl)-4-fluorobenzamidine by a procedure similar to that described in Example 1.b. to obtain ethyl 1-(2,2-diethoxyethyl)-2-(4-fluorophenyl)pyrimidin-6(1H)-one-5-carboxylate as an oil; MS: m/z=379(M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([NH2:26])[CH:14]=[C:15]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:16]=1.CS(O)(=O)=O>O1CCOCC1.C([O-])(O)=O.[Na+]>[F:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH:26][C:13]2[CH:14]=[C:15]([B:17]3[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18]3)[CH:16]=[C:11]([CH3:10])[CH:12]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nc(Cl)ncc1F
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(F)c(C)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
To a solution of 2-chloro-5-fluoro-4-methyl-pyrimidine (4.00 g, 27.3 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (8.27 g, 35.5 mmol) in dioxane (40.7 mL) was added methanesulfonic acid (1.77 ml, 27.3 mmol) dropwise during which the reaction exothermed 15.7° C. Subsequently the reaction mixture was heated to 100° C. and allowed to stir over the weekend. The mixture was cooled to room temperature and was diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic extracts were washed with brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography provided (5-fluoro-4-methyl-pyrimidin-2-yl)-[3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine (5.87 g, 17.1 mmol) MS ESI: [M+H]+ m/z 344.1. 1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 838 (d, J=1.6, 1H), 7.81-7.62 (m, 2H), 7.07 (s, 1H), 2.36 (d, J=2.3, 3H), 2.26 (s, 3H), 1.27 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][C:47]=1[CH3:48]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]6)=[O:50])[CH:45]=[CH:46][C:47]=5[CH3:48])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1ccc(C(=O)N2CCN(C)CC2)cc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)N4CCN(C)CC4)ccc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (3-bromo-4-methyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (160 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methyl-phenyl]-(4-methyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-130) as a pale yellow oil (84 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:11](=[O:20])[NH:12][CH2:13][CH:14]=[C:15]([CH2:16][C:17](O)=[O:18])[C:5]2=1.C(N(CC)CC)C.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:11](=[O:20])[NH:12][CH2:13][CH:14]=[C:15]([CH2:16][C:17]([N:42]=[N+:43]=[N-:44])=[O:18])[C:5]2=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=NC(=O)CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice-cold solution of (7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid (0.99 g, 3.6 mmol) and triethylamine (0.36 g, 3.6 mmol) in dry DMF (10 mL) was added in dropwise a solution of diphenylphosphoryl azide (0.99 g, 3.6 mmol), in DMF (5 mL) over a period of 2 h. After removal of the cooling bath, the mixture was stirred at room temperature for 12 h. It was poured into ice and the precipitate therefore formed was collected by vacuum filtration, which appeared to be the title compound (0.10 g). Extract the rest part of the mixture with ethyl acetate (20 mL×2). The organic layers were combined, washed with saturated aqueous NaHCO3, brine, and dried over anhydrous Na2SO4. It was concentrated and the oil obtained was treated with diethyl ether to give additional title compound as a solid precipitate (0.23 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9]
Reactant: NCCCCO
Reactant: CCOC(=O)C(F)(F)F
Product: O=C(NCCCCO)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl trifluoroacetate (3.3 mL; 28 mmol) was added dropwise to cooled (0° C.) 4-amino-1-butanol (2.0 g; 22.4 mmol). The mixture was stirred for 2 h at 0° C. and evaporated. The clear liquid was dried on the high vacuum. The product was obtained in a yield of 4.1 g (99%). 1H-NMR (500 MHz, CDCl3): δ=1.61-1.67 ppm (m, 2H), 1.68-1.74 ppm (m, 2H), 2.31 (bs, 1H), 3.38 ppm (dt, 2H), 3.72 ppm (t, 2H), 7.40 ppm (bs, 1H); 13C-NMR (500 MHz, CDCl3): δ=26.02, 29.70, 40.01, 62.48, 116.20 ppm (q, J=1144.0 Hz), 157.66 ppm (q, J=146.5 Hz). HRMS [+Scan]; calculated m/z for C6H11NO2F3 186.0747; observed mass: 186.0741.
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:28]([O:32][C:33](Cl)=[O:34])[CH2:29][CH2:30][CH3:31]>ClCCl>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:33]([O:32][CH2:28][CH2:29][CH2:30][CH3:31])=[O:34])[C:6]1=[O:14])[CH3:18]
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1C(=O)[C@H](O[Si](CC)(CC)CC)[C@@H]1c1ccco1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
(3R,4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.58 g, 2.17 mmol) in 30 mL of dichloromethane was stirred with diisopropylethyl amine (0.4 mL, 2.30 mmol) and butylchloroformate (0.3 mL, 2.36 mmol) in addition to a catalytic amount of DMAP (N,N-dimethylaminopyridine). The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 3:1 hexane/ethyl acetate) to give 523 mg of product (Y: 65%); IR(KBr) 1820, 1734, 1318, 1018, 734 cm-1 ; 1H NMR (CDCl3,300 MHz) δ7.38 (m, 1H), 6.35 (m, 2H), 5.09 (ABq, J=15.5, 5.6 Hz, 2H), 4.14 (m, 2H), 1.56 (m, 2H), 1.28 (s, 2H), 0.87 (t, J=8.7 Hz, 3H), 0.82 (t, J=7.9, 9H), 0.50 (m, 6H); 13C NMR (CDCl3,75.5 Hz) δ165.4, 149.1, 147.6, 142.9, 110.5, 109.9, 77.7, 66.6, 55.9, 30.5, 18.8, 13.6, 6.3, 4.3; DCIMS M+H calcd for C18H29NO5Si: 368, Found: 368.
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([Cl:27])[CH:21]=[CH:22][CH:23]=2)[N:18]=1.[CH3:28][CH:29]=[O:30]>C1COCC1.CCCCCC>[Cl:16][C:17]1[C:26]([CH:29]([OH:30])[CH3:28])=[CH:25][C:24]2[C:19](=[C:20]([Cl:27])[CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: CC=O
Reactant: Clc1ccc2cccc(Cl)c2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1cc2cccc(Cl)c2nc1Cl
Reaction time: 0.75 h

Procedure:
To a cold solution of diisopropylamine (6.6 mL, 1.1 eq) in THF (100 mL) was added dropwise a solution of BunLi (1.1 eq, 2.5 M, 18.7 mL) in hexane at −20° C. The resulted LDA solution was kept in 0° C. for 30 min and cooled to −78° C. before addition of a solution of 2,8-dichloroquinoline (8.4 g, 42.4 mmol) in THF (44 mL) dropwise. The temperature was controlled below −72° C. by adjusting of adding rate (15 min). After 45 min, MeCHO (3.6 mL, 1.5 eq) was added dropwise. After 30 min, the reaction was quenched with NH4Cl and partitioned between EtOAc (150 mL) and water (100 mL). The combined organics were washed with water, brine, dried over Na2SO4 Removal of solvent gave colorless oil which was purified by column chromatography on silica gel (DCM/Hexane, 3/2) to give an oil. Hexane was added (80 mL) and the mixture was left over night. Filtration gave a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 5.40 (q, J=8.0 Hz, 1H), 1.63 (d, J=8.0 Hz, 31-1). Mass Spectrum (ESI) m/e=242 (M+1).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C@H:11]12[CH2:17][C@H:14]([NH:15][CH2:16]1)[CH2:13][N:12]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[OH-].[Na+]>O1CCOCC1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:15]1[CH2:16][C@@H:11]2[CH2:17][C@H:14]1[CH2:13][N:12]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nc2ccccc2s1

Procedure:
2-Chlorobenzothiazole (2.57 g; 15.1 mmol) tert-butyl(1S,4S)-(−)-2,5-diazabicyclo-[2.2.1]heptane-2-carboxylate (2.0 g; 10.1 mmol) and dioxane (10 ml) was stirred at reflux for 19 days. Aqueous sodium hydroxide (50 ml; 1 M) was added. The mixture was extracted with ethyl acetate (2×50 ml). Chromatography on silica gel with a mixture of ethyl acetate and petroleum (1:3), gave the title compound as free base (oil). Yield 1.7 g (57%).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:24]=1[C:25](Cl)=[O:26].C(OCC)(=O)C.C(O)C>C(OCC)(=O)C.O.C(OCC)(=O)C>[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:24]=1[C:25]([N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:26]
Reactant: COc1cc(OC)c(C(=O)Cl)cc1OC
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc1OC
Reaction time: 18 h

Procedure:
Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (1.8 mmol) and sodium carbonate (0.76 g, 7.2 mmol) in ethyl acetate/water (10 mL/10 mL). With stirring, add a solution of 2,4,5-trimethoxybenzoyl chloride (1.1 g, 1.8 mmol) in ethyl acetate (1 mL). After 18 hours, separate the layers and extract the aqueous layer twice with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 9/1 ethyl acetate/ethanol to give the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: COc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 70.2 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 230 mg of 5-methoxyisoindoline, 300 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 300 mg of the target compound.
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][C:14](=O)[N:13](CC2C=CC=CC=2)[CH:12]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]1=O)C1C=CC=CC=1.Cl>CO.C(OCC)(=O)C.[C].[Pd]>[ClH:1].[ClH:1].[CH:24]([CH:12]1[CH2:11][NH:10][CH2:15][CH2:14][NH:13]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1C(C(c2ccccc2)c2ccccc2)N(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(C(c2ccccc2)C2CNCCN2)cc1
Yield: 205 %

Procedure:
A solution of 1,4-dibenzyl-3-benzhydryl-2,5-piperazinedione dihydrochloride (840 mg) in methanol (10 ml) was hydrogenated over 10% palladium-carbon (50% wet, 84 mg) at room temperature under atmospheric pressure for 5 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give an oil, which was treated with 4N hydrogen chloride in ethyl acetate solution to give 2-benzhydrylpiperazine dihydrochloride (525 mg) as a colorless powder.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[NH3:18]>>[S:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:13]2)(=[O:16])(=[O:15])[NH2:18]
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: N
Product: CC(=O)NC1Cc2ccc(S(N)(=O)=O)cc2C1

Procedure:
was prepared from 2-Acetylamino-indan-5-sulfonyl chloride and an excess of ammonia.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:16]1[NH:17][C:18]([Cl:22])=[C:19](Br)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(Cl)C(=O)C1>C(#N)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:16]1[NH:20][CH:19]=[C:18]([Cl:22])[N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc(Br)c(Cl)[nH]1
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc(Cl)c[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
[(S)-1-(4-Bromo-5-chloro-1H-imidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester: To a suspension of 141C (5.0 g, 17 mmol) in acetonitrile (400 mL) at 0° C. was added NCS (2.3 g, 17 mmol). The reaction mixture was stirred at 0° C. for 1 h, then at rt for 1 h followed by 50° C. overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated. The crude was purified by flash column chromatography to give [(S)-1-(4-chloro-1H-imidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as white solid (2 g, 36%). LCMS m/z 321 (M+H)+. To a solution of this intermediate (2 g, 6.20 mmol) in chloroform was added NBS (1.2 g, 6.8 mmol) and the reaction mixture was stirred at rt for 20 min. The reaction was quenched with water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by crystallization from hexane to give 141D as an off-white solid (1.7 g, 71%). LC/MS m/z 400 (M+H)+. 1HNMR (CDCl3, 400 MHz) δ 7.28 (m, 3H), 7.12 (d, 2H), 5.33 (d, 1H), 4.81 (d, 1H), 3.27 (dd, 2H), 1.3 (s, 9H).