Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=O.[I:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1>CCO>[CH:5]1([C:3]2[N:15]=[C:12]3[CH:11]=[CH:10][C:9]([I:8])=[CH:14][N:13]3[CH:2]=2)[CH2:7][CH2:6]1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)C1CC1
Solvent: CCO
Product: Ic1ccc2nc(C3CC3)cn2c1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A mixture of 2-bromo-1-cyclopropylethanone (18.0 g), 5-iodopyridin-2-amine (5.2 g) and EtOH (100 ml) was heated at reflux for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The resulting residue was diluted with DCM (200 ml), and washed with water (100 ml) and brine (100 ml). The DCM layer was dried over Na2SO4 and concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.53 g) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[CH2:10]([NH:12][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCN
Reactant: N#Cc1ccc(F)cc1
Product: CCNc1ccc(C#N)cc1

Procedure:
According to a similar manner to that in Reference Example 1, the title compound was synthesized from 4-fluorobenzonitrile and 70% aqueous ethylamine solution.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][C@@H:23]([C:36]([NH:38][C@H:39]([C:47]([N:49]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:50])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH:34]=[O:35])[CH:26]=1)=[O:21])[C@@H:17]([CH3:19])[OH:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([NH:15][C@H:16]([C:20]([NH:22][C@@H:23]([C:36]([NH:38][C@H:39]([C:47]([N:49]([CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH3:50])=[O:48])[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:37])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH:34]=[O:35])[CH:26]=1)=[O:21])[C@@H:17]([CH3:19])[OH:18])=[O:6]
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
Boc-βAla-OH (0.19 g), HCl.H-Thr-D-Trp(CHO)-Phe-NMeBzl (0.62 g) and HOBT (0.14 g) were dissolved in DMF (10 ml). To this solution was added WSC (0.18 ml) under ice cooling and the mixture was stirred for four hours at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with water, 2% sodium hydrogencarbonate solution, water, 2% hydrochloric acid, water and saturated sodium chloride solution, and dried over magnesium sulfate. The evaporated residue was crystallized from a mixed solvent of ethanol and water. Filtration and drying gave Boc-βAla-Thr-D-Trp(CHO)-Phe-NMeBzl (0.66 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a chilled solution (−10° C.) of 4-chloro-3-nitrobenzoyl chloride (0.92 g, 4.2 mmol) in anhydrous THF (20 mL) added dropwise a solution of N,N-dimethylethylenediamine (0.44 mL, 4.0 mmol) in THF (20 mL). After stirring 30 min combined with a 1:1 mixture of ice and saturated NaHCO3 (50 mL) and then extracted with EtOAc (3×80 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and chromatographed (silica gel, MeOH/DCM, 3:22) to yield the title compound (0.40 g, 37%) as a pale yellow solid. 1H-NMR (CDCl3): δ 8.28 (1H, d), 7.96 (1H, dd), 7.63 (1H, d), 6.98 (1H, br s), 3.54 (2H, m), 2.56 (2H, t), 2.30 (6H, s)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][O:24][CH2:25][CH3:26]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][O:24][CH2:25][CH3:26])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOCCBr
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2cccnc21
Yield: 101.3 %

Procedure:
This compound was prepared following the procedure described in example 24, part C, starting with 2.8 g (10 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 1.7 ml (15 mmol) of 2-bromoethylethyl ether. After standard work-up and purification, 3.5 g of 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.P(=O)(O)(O)O.[OH-].[Na+]>S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N.C(N(CC)S(C1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(S(=O)(=O)N(CC)CC)=CC=3)=CC=2C(O)=O)=CC=1)(=O)=O)C.CO>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: CCN(CC)S(=O)(=O)c1ccc(Nc2cc(C(=O)O)c(Nc3ccc(S(=O)(=O)N(CC)CC)cc3)cc2C(=O)O)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Agent: O=P(O)(O)O
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 94 °C
Reaction time: 0.08 h
Yield: 101.4 %

Procedure:
To 600 g of polyphosphoric acid (117.2%) heated at 89° C. were added 1.2 g of 2,5-di(sulfamoylanilino)terephthalic acid followed by 12.0 g of 2,5-di[4-(N,N-diethylsulfamoyl)anilino]terephthalic acid. The mixture was stirred for five minutes, after which 120 g of 2,5-di(4-methylanilino)terephthalic acid were added over a period of approximately 45 minutes, the temperature being maintained below 105° C. by adjustment of the addition rate. The reaction mixture was held at 105° C. for five hours and then cooled to 94° C. To this mixture was added 92.8 g of phosphoric acid (75%) dropwise over a period of approximately 25 minutes. The resultant melt was allowed to stir for 15 minutes at 90° C. and then poured slowly into 1120 g of methanol, the temperature being maintained below reflux using a water bath. The slurry was allowed to cool to room temperature and stand for 16 hours. After adjustment of the pH to 7.4, 74.1 g of 50% sodium hydroxide were added and the resultant slurry was heated at 90° C. for one hour. The slurry was allowed to cool to 70° C., filtered, and washed with water until alkaline free. The resultant presscake was reslurried in water and heated to 45° C. After the slurry was acidified to pH 3.4, an emulsion of 3.5 g of an anionic surfactant, 52 g of a petroleum distillate, and 120 g of water was added, and the slurry was stirred for three hours. The resultant slurry was collected by filtration and washed with water. The resultant wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 110 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:6]([O:8]C)=[O:7].Cl[CH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:20][CH:19]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:29][C:28]1[O:27][C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:25][C:24]=1[CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:3]/[N:4]=[C:5](\[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)/[C:6]([OH:8])=[O:7])=[CH:37][CH:36]=1
Reactant: COC(=O)/C(=N/O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Sodium hydride (60%, in oil, 122 mg) was added under a nitrogen atmosphere to a solution of methyl E-2-hydroxyimino-2-phenylacetate (548 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (960 mg) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v). This oil was dissolved in methanol (5 ml)-1N aqueous solution of sodium hydroxide (5 ml) and the mixture was heated under reflux for 3 hours. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-isopropyl ether to obtain E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-phenylacetic acid (948 mg, yield 70%) as colorless crystals. m.p. 142-143° C. (decomposition)
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34]>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1
Reactant: NC(CO)CO
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NC(CO)CO)nc3N(C3CCCC3)C2=O)c1

Procedure:
1-Cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(2-hydroxy-1-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.4 g (0.92 mmol) 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.25 g (2.76 mmol) serinol. The final product was purified by column chromatography (20:1 dichloromethane/methanol). This gave 0.29 g (68%) of 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(2-hydroxy-1-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp 194° C.–195° C.; MS (APCI) m/z 462.2, 463.2.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[N:6][CH:5]=[N:4]1)[CH3:2].[H-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:21][N:22]2[C:27]=1[CH:26]=[N:25][N:24]=[C:23]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34].O>CN(C)C=O>[CH2:1]([N:3]1[C:7]([CH2:8][O:9][C:20]2[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])=[C:27]3[N:22]([C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[N:24][N:25]=[CH:26]3)[N:21]=2)=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nncc3c2-c2ccccc2F)cc1
Reactant: CCn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccc1F
Reaction time: 0.5 h

Procedure:
The title compound was prepared as part of a rapid analogue library using the following methodology. To a solution of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (32 mg, 0.25 mmol) in dry N,N-dimethylformamide (5 ml) in a RADLEYS reaction carousel under nitrogen was added sodium hydride (60% wt in oil) (10 mg, 0.25 mmol) and the suspension was stirred for 30 min. A solution of 3,7-bis(2-fluorophenyl)-2-(p-toluenesulfonyloxy)pyrazolo[1,5-d][1,2,4]triazine (100 mg, 0.21 mmol) in dry N,N-dimethylformamide (2 ml) was then added and the solution was stirred under nitrogen for 1 h. A further amount (4 mg, 0.10 mmol) of sodium hydride (60% wt in oil) was added and the solution was stirred for 18 h. Water (25 ml) was added to quench the reaction and the solid which was precipitated was collected by filtration and washed with water. The solid was dissolved in dichloromethane, filtered and the filtrate was concentrated in vacuo to give a white solid (40 mg). Data for the title compound: mp=164° C.; 1H NMR (360 MHz, CDCl3) δ 1.31 (3H, t), 4.09-4.16 (2H, m), 5.56 (2H, s), 7.21-7.33, (3H, m), 7.37-7.43 (2H, m), 7.58-7.68 (2H, m), 7.82 (1H, m), 7.87 (1H, s), 9.28 (1H, s); MS (ES+) m/e 434 [MH]+; HPLC>97% purity (run on an HP1100, using a Hichrom KR100-5C18, 25 cm column, flow rate of 1 ml/min and 50% acetonitrile/pH 3 phosphate buffer as the mobile phase).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][OH:32])[CH2:27][CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC([C@H]1CC[C@@H](C2N3C=CN=C(Cl)C3=C(C3C=CC=C(OCC4C=CC=CC=4)C=3)N=2)CC1)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C@@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][OH:32])[CH2:27][CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC[C@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn32)CC1
Agent: COC(=O)[C@H]1CC[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn32)CC1
Product: OC[C@H]1CC[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn32)CC1

Procedure:
cis-{4-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol (compound of Formula II-B where Z=cyclohexyl and Q1=Ph-(3-OBn)) was prepared as described for the synthesis of trans-{4-[1-(3-benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol (compound of Formula II-B where Z=trans-1,4-cyclohexyl and Q1=Ph-(3-OBn)) except for the substitution of trans-4-[1-(3-benzyloxyphenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]cyclohexane carboxylic acid methyl ester with cis-4-[1-(3-benzyloxyphenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]cyclohexane carboxylic acid methyl ester; MS (ES) 448.2 (M+1), 450.2 (M+3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC>[Cl-].[Cl-].[Zn+2].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.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: C#CC(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)c1cc2ccc(F)cc2c(=O)o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 5-fluoro-2-iodobenzoic acid (9.04 g, 34.0 mmol), but-3-yn-2-ol (5.7 mL, 5.46 g, 78.0 mmol), ZnCl2 (4.62 g, 34.0 mmol), Pd(Ph3P)4 (1.96 g, 1.7 mmol), Et3N (14.2 mL, 10.3 g, 102.0 mmol) and DMF (50 mL) was stirred under argon at 100° C. for 2 hours. After the removal of the volatiles under vacuum, the residue was chromatographed (silica gel, ethyl acetate in hexanes, 0-50%) to provide intermediate 7-fluoro-3-(1-hydroxyethyl)-1H-isochromen-1-one as a brown oil (5.93 g, 84%). MS m/z 209.2 [M+H]+; 1H NMR (500 MHz, CDCl3-d): 6 ppm 7.91-7.96 (1H, m), 7.43-7.47 (2H, m), 6.55-6.59 (1H, m), 4.67 (1H, q, J=6.52 Hz), 1.57 (3H, d, J=6.62 Hz).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCC([O:13][C:14](=[O:17])[CH2:15][Cl:16])=O>C(Cl)(Cl)(Cl)Cl>[Cl:16][CH2:15][C:14]([O:8][CH:1]([O:17][C:14](=[O:13])[CH2:15][Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=Cc1ccccc1
Reactant: O=C(CCl)OC(=O)CCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCl)OC(OC(=O)CCl)c1ccccc1
Temperature: 35 °C

Procedure:
Benzaldehyde (10.0 g, 0.094 mol) and chloroacetic acid anhydride (16.1 g, 0.094 mol) were dissolved in carbontetrachloride (50 ml) under N2 atmosphere. Nafion NR 50 (240 mg) was added and the reaction mixture stirred at 35° C. over night. An additional amount of benzaldehyde (5.0 g) and catalyst (120 mg) was added and the reaction continued for several days. The catalyst was filtered off and the filtrate evaporated. The residue was distilled under reduced pressure (B.p. 123-125° C./0.1 mbar) giving a slightly yellow oil, which solidified upon standing. The yield was 7.9 g, 30% of the theoretical. 1H NMR (CDCl3), d (ppm) rel. to TMS: 7.75 (s, 1H, CH(OCO--)2), 7.57-7.41 (m, 2+3H, Ar-H) and 4.14 (d, 4H CH2Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH:17][O:18]C)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:17]=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCCCCCC(=COC)c1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCC(C=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
4-(1-Methoxymethylene-heptyl)-benzoic acid methyl ester (3.5 g, 12.68 mmol) is dissolved in tetrahydrofuran (50 mL) and concentrated hydrochloric acid (5 mL) is added. The system is purged of air with nitrogen and heated to reflux for 6 h. The reaction is monitored by HPLC. The reaction is allowed to cool to room temperature and then neutralized with 30% potassium hydroxide solution and bicarbonate. The two phases are separated and the aqueous extracted a second time with diethyl ether. The combined organic extracts are washed with brine, dried over sodium sulfate, and concentrated. The crude material is loaded onto a silica gel column and purified using hexanes/ethyl acetate. MS (ES): 261.2 [M+H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[N+](C1C=C2C(C=C[N+](C)=C2)=CC=1)([O-])=O.C(=O)(O)[O-].[K+].[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[C:48](Cl)=[O:49].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:57][O:56][C:52]1[CH:51]=[C:47]([CH:46]=[C:45]([O:44][CH3:43])[C:53]=1[O:54][CH3:55])[C:48]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1)=[O:49]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN1CCc2ccc(N)cc2C1
Agent: C[n+]1ccc2ccc([N+](=O)[O-])cc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Solvent: c1ccccc1
Product: COc1cc(C(=O)Nc2ccc3c(c2)CN(C)CC3)cc(OC)c1OC
Reaction time: 1 h

Procedure:
7-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (2 g), prepared from 7-nitro-2-methyl-isoquinolinium p-toluenesulfonate as described for the 5-nitro isomer in Example 4 was dissolved in dry benzene (50 ml) and 0.5 g of dry potassium bicarbonate was added. A 0.1 mole excess of 3,4,5-trimethoxybenzoyl chloride was dissolved in benzene (50 ml) and this solution was added to the solution of the tetrahydroisoquinoline. A brown precipitate formed immediately and the mixture was refluxed for 3 hours. The benzene was removed in vacuo leaving a tan residue which was suspended in 10% sodium carbonate solution to remove excess acid chloride and stirred for 1 hour. The insoluble residue was a brown oil which was extracted from the aqueous sodium carbonate with chloroform. The chloroform was dried over anhydrous magnesium sulfate and the chloroform was distilled off to leave a viscous red oil which crystallized to a white powder (2.7 g) when washed with cold ether. The white solid was recrystallized from ethanol-ether to yield the desired product as a white powder, m.p. 157.5°-158° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.Cl.C(N=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N)CC1>CN(C=O)C.O>[CH:40]1([NH:41][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[CH:27][CH:26]=2)[CH2:38][CH2:39]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.119 mmol) was taken up in DMF (0.5 mL). To the mixture was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34.1 mg, 0.178 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.2 mg, 0.178 mmol), 4-methylmorpholine (0.065 mL, 0.593 mmol) and cyclopropanamine (6.77 mg, 0.119 mmol). The reaction was stirred at room temperature overnight. To the stirred solution was added water (2 mL) and the precipitate was filtered, collected, and dried in vacuum to afford the title compound (41.2 mg, 75.0%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.57-7.76 (m, 3H), 6.80-7.02 (m, 3H), 4.50 (d, J=13.1 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.35 (br. s., 2H), 3.22 (br. s., 4H), 2.79 (td, J=7.3, 3.9 Hz, 1H), 2.60 (td, J=12.6, 2.7 Hz, 1H), 2.46 (br. s., 4H), 2.03 (d, J=12.9 Hz, 1H), 1.83 (br. s., 1H), 1.64 (d, J=12.9 Hz, 1H), 1.31-1.57 (m, 3H), 0.61-0.69 (m, 2H), 0.48-0.56 (m, 2H). [M+H] calc'd for C26H32N6O2, 461; found, 461.
Reaction SMILES: [CH3:1][O-].[Na+].CO.CC1C=CC(S([O:16][CH2:17][C@@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[O:19]2)(=O)=O)=CC=1.CO>C(O)(=O)C>[O:16]1[CH2:17][C@@H:18]1[CH2:22][CH2:21][C:20]([O:19][CH3:1])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC[C@H]1CO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
28% Sodium methoxide/MeOH solution (74.0 g, 383.35 mmol) was added to a mixture of (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (51.81 g, 191.67 mmol) and dehydrated MeOH (280 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was cooled under ice-cooling, and the mixture was neutralized with acetic acid (about 15 mL). The reaction mixture was concentrated to about half-volume under reduced pressure, and ice water (350 mL) was added thereto. Then, the mixture was extracted with a mixed solvent of ethyl acetate/diethyl ether (3:1) (×3). The organic layer was washed successively with aqueous sodium hydrogencarbonate solution, water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude methyl (S)-3-(oxiran-2-yl)propanoate (13.12 g, 101 mmol, 53%) as a colorless oil.