Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:10](=O)[CH2:11][C:12]1[N:17]=[C:16]([NH:18][CH3:19])[CH:15]=[CH:14][CH:13]=1)C.C1C[O:24]CC1>>[CH3:19][NH:18][C:16]1[N:17]=[C:12]([CH:11]([OH:24])[CH3:10])[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1cccc(NC)n1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNc1cccc(C(C)O)n1
Temperature: 0 °C

Procedure:
To a mechanically stirred solution of LiAlH4 in THF (1.0 M, 20 mL, 20.4 mmol) was added dropwise a solution of ethyl-2-(methylamino)-6-pyridylacetate (0.38 g, 2 mmol) in THF (10 mL). After the addition was completed, the reaction mixture was warmed to 0° C. and quenched with 10% NaOH solution. The solids were removed by filtration, and the filtrate was concentrated in vacuum. The residue was dissolved in CH2Cl2 and the solution was dried (MgSO4) and concentrated. Reconcentration from toluene (3×) gave the title compound as a colorless oil: MS (ES) m/e 153 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17].Cl.[NH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51]CC)=[O:50]>>[F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31]([NH:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[O:32])=[CH:37][CH:38]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])[C:7]=1[CH3:17]
Reactant: CCOC(=O)CCCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)NCCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 120D and ethyl 4-aminobutyrate hydrochloride was processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.96 (s, 1 H), 7.83 (t, 1 H), 6.88-7.32 (m, 11 H), 6.68 (m, 1 H), 6.49 (m, 2 H), 4.08 (s, 2 H), 4.05 (s, 2 H), 3.91 (t, 2 H), 3.03 (dd, 2 H), 2.90 (s, 3 H), 2.33 (s, 3 H), 2.19 (t, 4 H), 2.07 (s, 1 H), 1.89 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z 696 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1
Reactant: COc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Cc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To [6-Methoxy-5-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine (31, 0.0340 g, 0.0598 mmol) was added tetrahydrofuran (5 mL) followed by tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 66 μL, 0.0658 mmol). The reaction was allowed to stir at room temperature for 2 hours, then poured into 1:1 water:saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and the volatiles were removed by rotary evaporation. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane followed by 1% methanol in dichloromethane and finally 3% methanol in dichloromethane. This provided 20 mg of the desired compound as a white solid (P-0012, 0.048 mmol, 81%). MS (ESI) [M+H+]+=413.2.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C([Li:23])CCC>C1C=CC=CC=1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([Li:23])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: CCCCCc1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: [Li]c1ccc(CCCCC)cc1
Temperature: 25 °C

Procedure:
18.35g (0.081mol) of 4-pentylbromobenzene was dissolved in 30ml of benzene and the solution was stirred at room temperature in a stream of nitrogen. To the resulting solution was added drop-wise 50ml (0.081mol) of hexane solution including 15% butyllithium for 30 minutes and the solution was stirred for 2 hours. Then the produced precipitate gathered by the filtration in a stream of nitrogen was dried under reduced pressure to yield 9.2g of 4-pentylphenyllithium.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH:16]12[CH2:21][CH:20]1[CH2:19][NH:18][CH2:17]2>>[CH:16]12[CH2:21][CH:20]1[CH2:19][N:18]([C:13]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:15])[CH2:17]2
Reactant: C1NCC2CC12
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CC4CC4C3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 3-azabicyclo[3.1.0]hexane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][N:23]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: c1ccc2c(c1)CCNC2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc4C3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (130 mg, 0.38 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), 1,2,3,4-tetrahydroisoquinoline (101.1 mg, 0.76 mmol, 2.00 equiv), potassium carbonate (157.3 mg, 1.14 mmol, 3.00 equiv). The resulting solution was stirred for overnight at 100° C. The reaction was then quenched by the addition of water. The resulting solids were collected by filtration. This resulted in 110 mg (70%) of methyl 3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][C:22]=1[F:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33]N1C(=O)CCC1=O>CC#N.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:33])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([C:28]([F:30])([F:31])[F:29])=[CH:23][C:22]=1[F:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)cc1F
Temperature: 70 °C

Procedure:
To a yellow homogeneous solution of 8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.400 g; 3.047 mmol) in anhydrous MeCN (50 ml) was added dropwise, at rt, a solution of N-chlorosuccinimide (0.407 g; 3.047 mmol; 1 eq.) in anhydrous MeCN (25 ml). The resulting solution was then heated to 70° C., under nitrogen, for 3 h30. Concentration to dryness afforded a yellow oily residue which was dissolved in EA (150 ml), and this organic layer was successively washed with aq. sat. NaHCO3 (2×50 ml), and brine (50 ml), and was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) gave the expected 1-chloro-8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.711 g; 47%). LC-MS: tR=1.10 min.; [M+H]+=493.93 g/mol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:19]1[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C(Cl)CCCCCBr
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (1.3 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in fluorobenzene (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure to give 2.47 g of 6-bromo-1-(4-fluorophenyl)-1-hexanone.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27]>C(O)C.O1CCOCC1>[N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[NH:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][S:27]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)C1CSC(c2ccc(-c3ccc(-n4ccc5ccccc54)cc3)cc2)N1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 4′-Indol-1-yl-biphenyl-4-carbaldehyde (500 mg, 1.68 mmol) and L-cysteine (150 mg, 1.26 mmol) in ethanol (5 mL) and dioxan (5 mL) was stirred at 50° C. for 16 hours, cooled to room temperature and concentrated in vacuo. Trituration with diethyl ether gave the title compound as a beige solid (302 mg, 45%): mp. 135-137° C. (dec). Rf 0.10 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 7.82 (4H, m, Ar—H), 7.65 (6H, m, Ar—H), 7.52 (1H, d, J=8 Hz, Ar—H), 7.10-7.24 (2H, m, Ar—H), 6.74 (1H, s, Ar—H), 5.77 and 5.58 (both 0.5H, s, H-2, 1:1 diastereomers), 4.21 and 3.92 (both 0.5H, m, H-4, 1:1 diastereomers), 3.10-3.38 (2H, m, 2×H-5); ESI-LCMS e/z calcd for C24H20N2O2S: 400.500, found 401 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:12]2[CH:23]=[N:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:11]2[NH:10][C:9]=1[CH3:31])=[O:7])[CH3:4]>O.C(O)C>[C:26]([C:25]1[N:24]=[CH:23][N:12]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:9]([CH3:31])[NH:10][C:11]=12)([OH:28])=[O:27]
Reactant: CCOC(=O)C1=C(C)Nc2c(C(=O)OCC)ncn2C1c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2c(C(=O)O)ncn2C1c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 10 h
Yield: 34.4 %

Procedure:
0.17 g of potassium hydroxide in 1.7 ml of water is added to a solution of 1.0 g of 3,8-diethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo[1,5-a]pyrimidine in 20 ml of ethanol, and gradually heated followed by stirring at 70° C. for 10 hours. The ethanol is distilled off under reduced pressure, chloroform is added to the resulting oil and extracted with potassium carbonate solution. The water layer is washed with chloroform and adjusted to pH 5-6 with acetic acid. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 0.32 g of 8-carboxy-3-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo[1,5-a]pyrimidine, melting at 222° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1>>[N:12]1([S:9]([CH3:11])(=[O:10])=[N:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CS(=O)Nc1ccc(Br)cc1
Reactant: C1CNC1
Product: CS(=O)(=Nc1ccc(Br)cc1)N1CCC1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and azetidine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=289, 291 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a light yellow solid (271 mg).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].CCN(CC)CC.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[NH2:1]/[C:2](/[CH3:6])=[C:3](\[C:24]1[CH2:25][CH2:26][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH:23]=1)/[C:4]#[N:5]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C/C(N)=C/C#N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C(N)=C(\C#N)C1=CCN(Cc2ccccc2)CC1
Yield: 65.8 %

Procedure:
A solution of β-aminocrotononitrile (12 g, 147 mmol) and NEt3 (37 mL, 266 mmol) in CH2Cl2 (150 mL) was cooled with an ice bath to 0°. TiCl4 (7.9 mL, 72 mmol) in CH2Cl2 (100 mL) was added slowly with stirring followed by N-benzyl-4-piperidone (21.4 mL, 120 mmol) in one portion. The mixture was stirred for 24 h at ambient temperature and the volatiles were removed under reduced pressure. Ethly ether (400 mL) was added, and the resulting mixture was stirred vigorously until the residue was ground to a fine powder. The powder was filtered off and washed with ethyl ether (400 mL) and evaporation of the solvent afforded (E)-3-amino-2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-but-2-enenitrile as an oil (20 g, 70%), which was used without further purification.
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>C(N(CC)CC)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][CH2:6][NH:5][C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:10][CH:11]=1
Reactant: NCCNc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCCNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Chloroform (1000 ml) was added to N-(2-aminoethyl)-p-chloroaniline (116.67 g) and the mixture was dissolved. Triethylamine (83.02 g) and 2-chloro-3-nitropyridine (108.40 g) were added to the resultant solution on ice in this order and stirred for 2 hours at room temperature. Subsequently, the resultant mixture was refluxed for one hour, cooled, washed with water (500 ml×2), and the aqueous layer was extracted with chloroform (500 ml). The aqueous layer was combined with the chloroform layer, washed with saturated brine, and dehydrated over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure. The thus-obtained crystalline residue was purified by silica gel chromatography (elution solvent=chloroform:methanol=100:5), to thereby obtain the target compound in the form of colorless crystals (195.97 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.[ClH:18].[Cl:19][CH2:20][CH2:21][N:22]1[CH2:28][CH:27]2[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]2)[CH2:23]1.C(N(CC)CC)C>C(O)C>[ClH:19].[ClH:18].[CH:27]12[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]1)[CH2:23][N:22]([CH2:21][CH2:20][N:12]1[CH2:13][CH2:14][C:9]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:28]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 51.4 %

Procedure:
A mixture of 8-methoxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.31 g, 0.01 mole), 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (2.49 g, 0.01 mole) and triethylamine (3.03 g) in absolute ethanol (50 ml) is refluxed for 24 hours. The reaction mixture is filtered. Hydrogen chloride gas is bubbled through the filtrate. The product is filtered off, washed with ethanol and sucked dry. Recrystallization from methanol gave the product (2.34 g), mp 265°-270° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:23]>C(#N)C>[Cl:23][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(Cc3ccncc3)n[nH]c(=O)c2c1
Solvent: CC#N
Product: COc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A suspension of 7-methoxy-4-pyridin-4-ylmethyl-2H-phthalazin-1-one (11.4 g, 42.65 mmoles), prepared as described in example 130, and POCl3 (7.95 ml, 85.30 mmoles) in acetonitrile (110 ml) was refluxed for 1.5 hours. Further POCl3 (40 ml) was added and the reflux was kept on overnight. The mixture was dried, dissolved in water, neutralised with NaHCO3, extracted with CH2Cl2 and dried. The residue was chromatographed (eluent: CH2Cl2/CH3OH 97:3) to give 2.9 g of the title compound (yield: 23.8%).
Reaction SMILES: [C:1]([C:3]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:4]=[CH:5][I:6])#[CH:2].C([Mg]Br)C.[CH3:21][Si:22]([CH3:25])([CH3:24])Cl.[Cl-].[NH4+]>C1COCC1>[I:6][CH:5]=[CH:4][C:3]([C:1]#[C:2][Si:22]([CH3:25])([CH3:24])[CH3:21])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(C=CI)(CCCCC)O[Si](C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(C#C[Si](C)(C)C)(C=CI)O[Si](C)(C)C

Procedure:
A solution of 3.3 g. of dl-3-ethynyl-1-iodo-3-trimethylsilyloxy-1-octene in 10 ml. of THF is treated at 0° C. under N2 with 3 ml. of 3M ethyl magnesium bromide and stirred at 25° C. for 1/2 hour. The mixture is then treated at 0° C. with 3.5 ml. of trimethylchlorosilane and stirred at 25° C. for an additional 21/2 hours. The whole mixture is added to aqueous ammonium chloride solution and extracted with ether. After washing with brine and drying over magnesium sulfate, the extract is evaporated. Distillation of the residue gives the title product, as an oil, 2.5 g. b.p. 79°-81° C. (0.025 mm).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[C:21]([O:30][CH3:31])(=[O:29])/[CH:22]=[CH:23]/[CH2:24][C:25]([O:27][CH3:28])=[O:26].C1CCN2C(=NCCC2)CC1>CC#N>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:22][C:21]([O:30][CH3:31])=[O:29])[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: COC(=O)/C=C/CC(=O)OC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(CC(=O)OC)n1cc(-c2nc(-c3cnn(C)c3)cc3nccn23)cn1
Temperature: 55 °C
Yield: 77.8 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation K; 0.165 g, 0.622 mmol) was suspended in CH3CN (5 mL) and (E)-dimethyl pent-2-enedioate (0.295 g, 1.87 mmol) was added followed by DBU (0.0947 g, 0.622 mmol). The reaction was warmed to 55° C. and heated for 9 hours. The reaction was then cooled and concentrated. The residue was purified on silica gel (1-4% methanol in DCM) to afford dimethyl 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedioate (205 mg, 78% yield). MS (apci) m/z=424.2 (M+H).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[NH2:21][C:22]1[C:23]2[C:31](=[O:32])[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:21][C:22]1[C:23]2[C:31](=[O:32])[CH:30]=[CH:29][N:28]([CH:2]([C:4]3[O:5][C:6](=[O:20])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[C:24]=2[N:25]=[CH:26][N:27]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1ccc(=O)c2c(N)ncnc21
Yield: 52 %

Procedure:
3-(1-Bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 50 mg, 0.15 mmol), 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (37 mg, 0.23 mmol), potassium carbonate (31.5 mg, 0.23 mmol) were reacted in DMF (0.5 ml) at 80° C. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (32 mg, 51%).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[C@@H:3]([OH:10])[C@@H:2]1O>O>[OH:10][C@@H:3]1[C@@H:4]([OH:9])[C@H:5]([OH:8])[C:6](=[O:7])[CH:1]=[CH:2]1
Reactant: O=C1C[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Yield: 50 %

Procedure:
0.5 g of 2-deoxy-scyllo-inosose synthesized according to the method described in WO 2006/112000 and 100 mg of silica gel (Merck Kieselgel 60) were added to 1 mL of water, and the resulting mixture was heated at 150 degrees centigrade for 2 hours. After the completion of the reaction, a quantitative analysis was carried out using HPLC and as a result, (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one was obtained at a yield of 50%. At this time, 15% of the raw material of 2-deoxy-scyllo-inosose was collected.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[NH:12][C:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10].[CH3:20][NH:21][CH2:22][C:23]([OH:25])=[O:24].O>N#N>[C:23]([CH2:22][N:21]([CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[NH:12][C:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10])([OH:25])=[O:24]
Reactant: CNCC(=O)O
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCCBr)C(=O)O
Agent: N#N
Solvent: O
Product: CN(CCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O)CC(=O)O

Procedure:
3.32 g. of Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid, 1.0 g. of CH3NHCH2CO2H, 3.5 g. of Na2Co3 and 30 ml of water were heated at 80° C. in N2 for 1.5 hours. After purification, 1.0 g. of product was obtained, calc. for C17H28N2O5.2H2O:C, 54,24; H, 8.57; N, 7.44; found: C, 54.40; H,8.34; N, 7.16.