Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.[F:16][C:17]([F:51])([F:50])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]3[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=3)[CH:35]=2)[N:19]=1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:46]([C:42]2[CH:41]=[C:40]([C:36]3[CH:35]=[C:34]([C:20]4[N:19]=[C:18]([C:17]([F:16])([F:50])[F:51])[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[N:21]=4)[CH:39]=[CH:38][N:37]=3)[CH:45]=[CH:44][CH:43]=2)(=[O:47])=[O:48])[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2cccc(-c3cc(-c4nc(-c5ccc(C(F)(F)F)cc5)cc(C(F)(F)F)n4)ccn3)c2)CC1
Temperature: 0 °C
Yield: 87.1 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methyl-piperazine (0.09 g, 0.9 mmol), triethylamine (0.09 ml, 0.63 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.20 g, 0.34 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.18 g, 88%). MS (ISP) 607.6 [(M+H)+]; mp 205° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 98.6 %

Procedure:
Following a procedure similar to that described in Example 74(c), but using 1.29 g of 2-butyl-4-(1-hydroxy-2-methylpropyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (b) above] in 75% v/v aqueous acetic acid, 0.83 g of the title compound was obtained as a glass.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:15][CH2:16]O>>[CH2:15]([O:8][C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9])[CH3:16]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C)s1
Yield: 85 %

Procedure:
A solution of 5-methyl-thiophene-2-carboxylic acid (25.2 g, 177 mmol) in EtOH (500 mL) is treated with conc. H2SO4 (15 mL) and heated to a gentle reflux for 72 h. The solution is partially concentrated and poured into water (500 mL) and extracted with Et2O (3×). The combined extracts are washed with aq Na2CO3, water, dried over Na2SO4, filtered and concentrated in vacuo. Vacuum distillation of the residue afforded 5-methyl-thiophene-2-carboxylic acid ethyl ester (25.6 g, 85%): bp 98-99° C./9-10 mbar; 1H NMR (CDCl3, 300 MHz) δ 7.6 (s, 1 H), 6.78 (s, 1 H), 4.30 (q, J=6.0 Hz, 2 H), 2.50 (s, 3 H), 1.34 (t, J=6.0 Hz, 3 H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:12])=[CH:10][S:11][C:5]3=[N:4][C:3]=2[C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(Br)c(=O)n12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 76.6 %

Procedure:
(S)-tert-Butyl 1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (5.46 g, 14.1 mmol) and (3-fluorophenyl)boronic acid (2.95 g, 21.1 mmol) were suspected in 1,4-dioxane (110 mL). A solution of sodium carbonate (4.47g, 42.2 mmol) in water (27 mL) was added to the mixture followed by tetrakis(triphenylphosphine)palladium(0) catalyst (0.81 g, 0.70 mmol). The reaction mixture was degassed and heated under nitrogen at 100° C. for 16 h. HPLC indicated the starting material was consumed. The reaction mixture was cooled to room temperature and water (100 mL) was added. The resultant mixture was extracted with ethyl acetate (2×100 mL). The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel using 1-50% ethyl acetate in hexane as eluent to give (S)-tert-butyl 1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (4.34 g, 10.8 mmol, 76%) as an off-white solid. LCMS calculated for C20H23FN3O3S (M+H)+: m/z 404.1; Found 404.1. 1H NMR (500 MHz, DMSO-d6) δ 7.48 (ddd, J=8.1, 7.8, 6.2 Hz, 1H), 7.18 (m, 3H), 7.05 (q, J=1.3 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 4.41 (m, 1H), 2.66 (d, J=1.3 Hz, 3H), 1.33 (s, 9H), 1.13 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:17]=1[CH:18]=[CH:19][CH:20]=O.C(O)=O.Cl>C(O)C>[ClH:1].[ClH:15].[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:20][CH:19]=[CH:18][C:17]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:16]=3[Cl:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=CC=Cc1ccc(Cl)cc1Cl
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: Clc1ccc(CN2CCN(CC=Cc3ccc(Cl)cc3Cl)CC2)cc1
Temperature: 130 °C
Yield: 81.4 %

Procedure:
N-(4-Chlorobenzyl)piperazine (4.2 g, 19.93 mmole) (which is prepared by the process as disclosed in Yoshiaki Ikeda et al., Yakugaku Zasshi, Vol. 89, 669-676, 1969) and 2,4-dichlorocinnamaldehyde (4.1 g, 20.39 mmole) (which is prepared by the process as disclosed in U.S. Pat. No. 3,094,561) are mixed and heated on an oil bath at 130° C. to melt them, and thereto is added dropwise formic acid (2.0 ml, 52.6 mmole), and the mixture is stirred under heating for 30 minutes. The reaction mixture is allowed to cool and is dissolved in ethanol (30 ml), and to the solution is added an ethanol solution (90 ml) of conc. hydrochloric acid (4.5 ml). The precipitated crystals are separated by filtration. The crystals are recrystallized from water-ethanol to give the title compound (3.8 g). The product shows the same physical properties as those of the compound prepared in Example 1-(1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH3:29])[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([Cl:27])=[CH:21][C:22]=3[Cl:26])[NH:17][C:16]2=[O:28])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2([CH3:29])[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([Cl:27])=[CH:21][C:22]=3[Cl:26])[NH:17][C:16]2=[O:28])[CH:12]=[CH:13][CH:14]=1
Reactant: CC1(c2cccc(OCc3ccccc3)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2cccc(O)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 89.2 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(3-benzyloxy-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (0.26 g, 0.60 mmol) and BBr3 (1.20 mL, 1.0 M dichloromethane solution). After normal workup, the objective compound (0.18 g, 90%) was obtained as yellow solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3+DMSO-d6) δ 1.62 (s, 3H, CH3), 6.57-6.71 (m, 3H, ArH), 6.98-7.12 (m, 3H, ArH), 9.17 (s, 1H, OH), 11.07 (s, 1H, NH); m.p. 248° C. (decomp.); MS(EI) m/e 335 [M+], 148, 91.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:28]=[C:29]([CH2:33][CH2:34][CH:35](O)[CH3:36])[CH:30]=[CH:31][CH:32]=1.[Br:40]Br>C(Cl)Cl.CCCCCC>[Br:40][CH:35]([CH3:36])[CH2:34][CH2:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:39])([F:38])[F:25])[CH:28]=1
Reactant: BrBr
Reactant: CC(O)CCc1cccc(C(F)(F)F)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(Br)CCc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
750 mg (11.0 mmol) of imidazole and 2.88 g (11.0 mmol) of triphenylphosphine were added to a solution of 2.0 g (9.2 mmol) of 4-(3-(trifluoromethyl)phenyl)butan-2-ol in DCM (10 ml). 570 μl (11.0 mmol) of bromine were added dropwise at 0° C., and stirring was carried out for 1 h at RT. The mixture was then concentrated in vacuo. CC (hexane) of the residue yielded 2.0 g (7.1 mmol, 78%) of 1-(3-bromobutyl)-3-(trifluoromethyl)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([OH:12])[CH2:7][CH2:6][CH2:5]2.[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: OC1CCCc2cc(Br)ccc21
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCCC2Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (0.68 g, 3.0 mmol) and phenol (0.38 g, 4.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added triphenylphosphine (1.04 g, 4 mmol). The reaction mixture was stirred at room temperature for 0.5 hour under nitrogen atmosphere. Then diisopropyl azodicarboxylate (0.8 g, 4 mmol) was added dropwise at 0° C., and then the reaction mixture was stirred at room temperature for 12 hours. After the reaction, it was quenched with water (100 mL), and the product was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give the pure product 6-bromo-1-phenoxy-1,2,3,4-tetrahydro naphthalene (0.73 g, 80%). 1H NMR (300 MHz, CDCl3): δ 7.32-7.20 (m, 5H), 7.00-6.97 (m, 3H), 5.27 (t, J=4.5 Hz, 1H), 2.86-2.67 (m, 2H), 2.11-1.74 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[OH:24].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C@@H:12]2[O:24][C@H:11]2[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: O=C([O-])O
Reactant: COc1ccc(C=Cc2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OC)c2)cc1OC

Procedure:
Mixture: 50.0 g 166 mmol) of 3,3',4,4'-tetramethoxystilbene, 1000 ml of dichloromethane, 1000 ml of sodium hydrogen carbonate solution, 64.0 g (185 mmol) of m-chloroperoxybenzoic acid (about 50% strength).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[Cl:10]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]([OH:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(=O)C=Cc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)C=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.25 g (0.0599 mol) of NaBH4 are added portionwise at room temperature to a suspension of 39.2 g (0.182 mol) of 4-(3,4-dichlorophenyl)-3-buten-2-one in 900 ml of ethanol and the mixture is stirred overnight at room temperature. The mixture is concentrated under vacuum, taken up in water, extracted with methylene chloride, washed with water, dried over sodium sulphate, filtered and evaporated under vacuum. The product obtained is used without subsequent purification in the following stage. Yd.: 35.2 g (89%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 2,5-dimethoxyaniline similar to Example 13 and isolated as a tan oil (116 mg, 74%). 1H NMR (CDCl3): 8.78–8.76 (m, 1H), 8.44 (d, J=7.8 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H), 7.79–7.74 (m, 1H). 7.32–7.28 (m, 2H), 6.78 (d, J=9.3 Hz, 1H), 6.60 (s, 1H), 6.53 (dd, J=3.0, 8.7 Hz, 1H), 3.77 (d, J=3.3 Hz, 6H), 2.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.CN(C)CCCN=C=NCC.ON1C(=O)CCC1=O.[NH2:57][CH2:58][CH2:59][OH:60].C(=O)([O-])O.[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:57][CH2:58][CH2:59][OH:60])=[O:33])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCO)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a solution of 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoic acid (126 mg) in N,N-dimethylformamide (1.2 mL) were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (72 mg) and 1-hydroxypyrrolidine-2,5-dione (43 mg), and the mixture was stirred at room temperature for 3 hrs. To this reaction mixture was added dropwise a solution of 2-aminoethanol (23 mg) in a mixed solvent of N,N-dimethylformamide (1.2 mL) and 10% aqueous sodium hydrogen carbonate (1.2 mL), and the mixture was stirred at room temperature for 48 hrs. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mL×3). The organic layer washed with saturated brine (25 mL×3), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (1/4) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (105 mg) as white powder crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][N:17](C(OC(C)(C)C)=O)[CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:8][C:7]=2[CH:37]=1)#[N:2].N1CCCC1.[ClH:43].Cl.Cl.N1C=C(CN2C3C=CC([C:63]4[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1>>[ClH:43].[ClH:43].[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH2:36][CH2:64][N:65]3[CH2:63][CH2:68][CH2:67][CH2:66]3)(=[O:34])=[O:35])[CH2:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: C1CCNC1
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)CCN1CCCC1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Yield: 46 %

Procedure:
Example 327 was prepared in 46% yield as a light yellow solid from Compound A of Example 250 and pyrrolidine as described for Compound B of Example 250. MS (M+H)+ =505.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][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][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(CCc3ccccc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(CCc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(2-phenylethyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH:4]1[C:12]1[N:16]2[C:17]3[CH:23]=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]=3[N:19]=[CH:20][C:15]2=[N:14][N:13]=1)[CH3:2]>O1CCOCC1.[OH-].[Na+]>[CH2:1]([CH:3]1[CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH:4]1[C:12]1[N:16]2[C:17]3[CH:23]=[CH:22][NH:21][C:18]=3[N:19]=[CH:20][C:15]2=[N:14][N:13]=1)[CH3:2]
Reactant: CCC1CC2(CC1c1nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n13)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC1CC2(CC1c1nnc3cnc4[nH]ccc4n13)OCCO2
Temperature: 60 °C
Yield: 88.1 %

Procedure:
To the solution of 1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (3.76 g, 8.04 mmol) in 1,4-dioxane (55 mL), aqueous sodium hydroxide solution (2N, 12 mL) was added and the reaction mixture was heated at about 60° C. for about 90 min. The solvent was removed and the residue partitioned between saturated solution of ammonium chloride in water and EtOAc (75 mL each). The aqueous phase was further washed with EtOAc (60 mL); the combined organic extracts were washed with brine (65 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to yield a brown solid. The solid was triturated in ether (20 mL) and the precipitate was collected by filtration and dried to yield 1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (2.22 g, 88%) as a beige solid. LC/MS (Table 1, Method a) Rt=1.71 min; MS m/z: 314 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Yield: 69.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (50 mg, 0.16 mmol), 5-aminovaleric acid (945 mg, 8.06 mmol) and NaOMe solution (12 mL, 6.05 mmol, 0.5 M in MeOH) was refluxed for 48 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 44 mg of the title compound as a light yellow solid. MS: (+) m/z 396.08 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:18])[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:18])[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](=[O:21])[CH3:20])[CH:15]=2)[CH2:10]1
Reactant: COC(=O)CC1Cc2ccccc2C1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccc(C(C)=O)cc2C1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 91 %

Procedure:
160 ml of methylene chloride was added with 52.9 g (0.388 mol) of anhydrous aluminum chloride, and further added with 40 ml of methylene chloride containing 25.03 g (0.132 mol) of methyl(indan-2-yl)acetate under ice-cooling. Subsequently, 13.1 ml (0.185 mol) of acetyl chloride was added thereto dropwise. Stirring was conducted for 40 minutes at the same temperature. The reaction mixture was poured into ice-water and the organic phase was collected. After washing and drying, the solvent was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 27.8 g of an oily product. Yield: 91%
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[O:6].[N:13]([O-])=[O:14].[Na+].CO>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:13]=[O:14])[C:5]([NH:7][C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[O:6]
Reactant: O=N[O-]
Reactant: CNCC(=O)NC(=O)NCCCl
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: CNCC(=O)NC(=O)N(CCCl)N=O
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
N-[N'-(2-Chloroethyl)carbamoyl]sarcosine amide (100 mg, 0.516 mmol.) was dissolved in a 99% formic acid (0.7 ml) under ice-cooling, to which sodium nitrite (53.4 mg, 1.5 moles per mole of the starting compound) was slowly added and the mixture was held under stirring for further 30 minutes to complete the reaction. Then, Amberlite IR-120 (H+ form), a strongly acidic cation exchange resin made and sold by Rohm & Haas Company, (1 ml) and methanol (1 ml) were added to the resulting reaction solution and the mixture was stirred for 10 minutes. After the resin was removed by filtration, the reaction solution was concentrated in vacuo to leave an oily residue. The residue was purified by column chromatography on silica gel (Wako-gel C-300) with a developer system of toluene-ethanol (3:1 by volume), where the eluate was collected in fractions and the fractions containing the main product were collected together and concentrated in vacuo to afford N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]sarcosine amide (62 mg) as a white crystalline residue.