Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F-:13].[K+].O>CN(C)C=O>[F:13][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: [F-]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1F
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
55.7 g (0.3 mol) of 2-chloro-5-nitrobenzaldehyde and 34.8 g (0.6 mol) of potassium fluoride are suspended in 250 ml of dimethylformamide and the mixture is stirred for 0.5 hours at 160° C. The mixture is then introduced into 600 ml of water and the aldehyde which has separated out is extracted with methylene chloride. The extract is separated off, dried and evaporated down. 48.9 g of 2-fluoro-5-nitrobenzaldehyde with a content of 94.8% are obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:20][C:12]3=[CH:13][C:14]([OH:19])=[C:15]([OH:18])[C:16]([OH:17])=[C:11]3[C:9](=[O:10])[CH:8]=2)=[CH:5][CH:6]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[CH3:28]O>>[OH:17][C:16]1[C:15]([OH:18])=[C:14]([OH:19])[C:13]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[C:12]2[C:11]=1[C:9](=[O:10])[CH:8]=[C:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[O:20]2
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)c(O)c(O)c12
Reactant: CN1CCNCC1
Reactant: CO
Product: CN1CCN(Cc2c(O)c(O)c(O)c3c(=O)cc(-c4ccccc4)oc23)CC1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The mixture of Baicalein (100 g), methanol 2 L, 37% formaldehyde solution (36.5 ml), 4-N-methyl-piperazin solution (45 g) was stirred under for 4 hours at 55° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 55° C. to get the product as yellow solid 113 g of purity 99.9%. m.p.: 280˜282° C. UV: λmax(alcohol) 278, 330 nm; MS: (API-ES) m/z 383.1 [M+H]+, 405.1 [M+Na]+; IR: 3400, 3050, 2925, 2861, 1637, 1570, 1509 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 2.14 (s, 3H, CH3), 2.62 (s, 8H, N—CH2), 3.44 (s, 7-OH), 3.96 (s, 2H, 8-CH2), 6.87 (s, 1H, 3-H), 7.46˜7.54 (m, 3H, Ar—H), 8.01˜8.02 (m, 2H, Ar—H), 8.11 (s, 6-OH), 12.64 (s, 1H, 5-OH).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([NH2:23])=[CH:20][CH:21]=2)[CH:16]=[N:15]1.Cl[S:25]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1)(=[O:27])=[O:26].O>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][S:25]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:35])[CH2:32][CH2:33]3)(=[O:26])=[O:27])=[CH:20][CH:21]=2)[CH:16]=[N:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Reactant: Nc1ccc2c(cnn2C2CCCCO2)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3c(cnn3C3CCCCO3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Triethylamine (0.789 ml, 5.69 mmol) was added to a solution of 1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (1.04 g, 4.79 mmol) and benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (1.5 g, 4.74 mmol) in methylene chloride (50 ml) at 0° C. and stirred at 0° C. for 30 minutes and then at room temperature for 15 hours. The reaction solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate=3/1) to obtain benzyl 4-{[(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]sulfonyl}-1-piperidinecarboxylate (1.32 g, 56%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][C:33]1[S:37][C:36]([CH:38]=[O:39])=[N:35][CH:34]=1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:38]([C:36]3[S:37][C:33]([CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)=[CH:34][N:35]=3)=[O:39])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(COC2CCCCO2)s1
Yield: 79.9 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.84 g), 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (1.32 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (0.14 g), triethylamine (0.32 mL), tetrahydrofuran (5 mL) and ethanol (10 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (2.43 g, yield 80%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 576 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]12([NH2:35])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>C(#N)C>[C:25]12([NH:35][CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]4[C:15]5[S:16][CH:17]=[CH:18][C:14]=5[O:13][N:12]=4)[CH:6]=3)[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCNC23CC4CC(CC(C4)C2)C3)cc(-c2noc3ccsc23)c1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 1-adamantanamine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a graded solvent mixture of 5% ethyl acetate in DCM to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=97%, [M+H]+=395.
Reaction SMILES: [C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][S:11][CH:12]=[C:8]2[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][S:11][CH:12]=[C:8]2[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2cscc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1Cc2cscc2C1

Procedure:
Dissolve 5-(carboethoxy)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene (6.68 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 5-(carboxy)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:19]#[N:20].[O:21]=[C:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][CH:32]=O)=[CH:30][C:25]=2[CH2:24][O:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:32][CH2:31][C:29]4[CH:28]=[CH:27][C:26]5[C:22](=[O:21])[O:23][CH2:24][C:25]=5[CH:30]=4)[CH2:14][C:13]3=[O:18])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:19]#[N:20]
Reactant: N#Cc1c(F)ccc2c1CCC2CN1CCNCC1=O
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c1CCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask containing 5-Fluoro-1-[(2-oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-4-carbonitrile (5 mg, 0.018 mmol) and a stir bar was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (16 mg, 0.091 mmol), Sodium Triacetoxyborohydride (19 mg, 0.091 mmol), and DCM (1 mL). The mixture was allowed to stir at RT for 16 hours. LC-MS indicated formation of the desired product. The solvent was removed, and the residue was redissolved in MeOH (1 mL). The sample was subjected to purification by reverse phase HPLC to afford the title compound. LC-MS (IE, m/z): 434 [M+1]+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29](Cl)[C:30](OCC)=[O:31])=[CH:24][CH:23]=1)([CH3:19])[CH2:9][C:8]2=[O:36])(=O)C.[NH2:37][C:38](N)=[S:39].S1(CCCC1)(=O)=[O:42].Cl>C(OCC)(=O)C.O.COCCO>[C:15]([C:14]1[CH:13]=[C:12]2[C:7]([C:8](=[O:36])[CH2:9][C:10]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH:29]4[S:39][C:38](=[O:42])[NH:37][C:30]4=[O:31])=[CH:26][CH:27]=3)([CH3:19])[O:11]2)=[CH:6][C:5]=1[OH:4])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3cc(OC(C)=O)c(C(C)(C)C)cc3O2)cc1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Agent: Cl
Solvent: COCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CC(=O)c2cc(O)c(C(C)(C)C)cc2O1

Procedure:
In a similar manner to Example 22, a mixture of 291 mg of ethyl 3-[4-(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 49), 64 mg of thiourea and 1 ml of sulfolane was heated. 5 ml of ethylene glycol monomethyl ether, 1 ml of concentrated hydrochloric acid and 2 ml of water were added, and the resulting mixture was further heated under reflux for 6 hours. Ethyl acetate was then added to the reaction mixture, and the resulting solution was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was removed by evaporation under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, eluted with a 5:1 by volume mixture of benzene and ethyl acetate, to give 143 mg of the desired 5-[4-(7-t-butyl-6-hydroxy-2-methyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH:14]([C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([CH3:27])=[C:18]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:17]=1[CH3:36])=[O:15]>C1COCC1.O>[OH:15][CH:14]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1)[C:16]1[C:24]2[O:23][C:22]([CH3:25])([CH3:26])[CH2:21][C:20]=2[C:19]([CH3:27])=[C:18]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:17]=1[CH3:36]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Reactant: CC(C)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2c(c(C(O)c3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of magnesium (198 mg, 8.13 mmol) and a catalytic amount of iodine was added dropwise under argon atmosphere a solution of 1-bromo-4-isopropylbenzene (1.62 g, 8.13 mmol) in THF (5 mL) under argon atmosphere at room temperature, and the reaction solution was heated until the color of iodine disappeared. To the reaction solution was added dropwise at room temperature a solution of N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 340 (860 mg, 2.71 mmol) in THF (5 mL) and the mixture was stirred for 1 hour. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to synthesize 1.15 g (yield: 97%) of the title compound. Amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-nitroaniline (10 g, 59.5 mmol, 1.0 equiv.) and trimethyl-acetaldehyde (9.73 g, 113 mmol, 1.9 equiv.) were dissolved in anhydrous DCM (100 ml). The resulting solution was treated with acetic acid (18.72 ml, 327 mmol, 5.5 equiv.), followed by sodium triacetoxyborohydride (30.3 g, 143 mmol, 2.4 equiv.). The reaction mixture was stirred at room temperature. When LCMS showed completion of the reaction, the reaction was quenched with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give N-(2,2-dimethylpropyl)-4-methoxy-2-nitroaniline (3), which was used without purification. LRMS m/z (M+H) 239.0 found, 238.1 required.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([C:33]([F:36])([F:35])[F:34])[C:27]([C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[N:26]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([C:37]([F:42])([F:43])[C:38]([F:40])([F:41])[F:39])[C:28]=2[C:33]([F:35])([F:36])[F:34])=[O:31])=[CH:13][C:6]=1[C:7](=[O:8])[NH:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
95.3 mg (0.45 mmol) of 5-amino-2-chloro-N-cyclopropylbenzamide, 3.7 mg (0.03 mmol) of N,N-dimethylpyridine-4-amine are dissolved in 2.5 ml of ethyl acetate. The solution is cooled to 0° C. using an ice bath and admixed with 158 μl (0.91 mmol) of N-ethyldiisopropylamine. 100 mg (0.30 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride are suspended in 2.5 ml of ethyl acetate and then added to the cooled reaction solution. The reaction mixture is heated for four hours at 50° C. and then stirred for 16 hours at room temperature. The reaction solution is diluted with 10.0 ml of ethyl acetate. The organic phase is washed three times with 1M hydrochloric acid, twice with 1M sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and filtered and solvent is removed under reduced pressure on a rotary evaporator. This gives 151 mg of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (97%) as white solid.
Reaction SMILES: C(O[C:6](=[O:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:28])[NH:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([CH3:27])[CH2:24]3)=[CH:19][CH:18]=2)[CH:10]=1)(C)(C)C.[ClH:30].[O:31]1[CH2:36][CH2:35]OCC1.[CH3:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl.CCOCC>[CH3:27][N:23]1[CH2:22][CH2:21][C:20]2[C:25](=[CH:26][C:17]([NH:16][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[CH2:8][NH:7][C:6]([C:39]3[CH:38]=[CH:37][C:42]([C:9]4[CH:10]=[CH:11][CH:35]=[C:36]([OH:31])[CH:8]=4)=[CH:41][CH:40]=3)=[O:29])=[O:28])=[CH:18][CH:19]=2)[CH2:24]1.[ClH:30].[ClH:30].[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][N:23]([CH3:27])[CH2:24]2)=[CH:19][CH:18]=1)=[O:28]
Reactant: C1COCCO1
Reactant: CCCCCC
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)OC(C)(C)C)c3)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Product: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-c5cccc(O)c5)cc4)c3)cc2C1

Procedure:
To a solution of [3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (6.35 g, 15.6 mmol) in anhydrous DCM (250 mL) at rt add 4M HCl in 1,4-dioxane (58.4 mL, 233.6 mmol) and stir the reaction at rt for 24 h. Dilute the solid suspension with Et2O (500 mL) and hexane (800 mL), stir vigorously for 20 min then filter and wash with Et2O then hexane to afford the desired product 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide dihydrochloride as a hydroscopic solid (5.68 g, 14.7 mmol).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][CH:20]=[CH2:21])[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][CH:20]=[CH2:21])[S:15]1)=[O:11]
Reactant: C=CCSc1nc(O)ns1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.5 ml of triethylamine and 5 ml of methyl isocyanate were added to a solution of 13.9 g of 3-hydroxy-5-allylthio-1,2,4-thiadiazole in 150 ml of tetrahydrofuran and the mixture was stirred at 20° C for 2 hours and was concentrated to dryness under reduced pressure. The residue was empasted with ethyl ether and was vacuum filtered and dried to obtain 15.9 g of 2-(N-methylcarbamoyl)-5-allylthio-1,2,4-thiadiazole-3-one melting at 110° C.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]1([NH:32][C:33]2[N:34]=[CH:35][C:36]([C:45]([OH:47])=O)=[N:37][C:38]=2[O:39][CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH3:48][O:49][C:50](=[O:57])[C:51]([NH2:56])([CH2:54][CH3:55])[CH2:52][CH3:53]>>[CH3:48][O:49][C:50](=[O:57])[C:51]([NH:56][C:45]([C:36]1[CH:35]=[N:34][C:33]([NH:32][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[C:38]([O:39][CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[N:37]=1)=[O:47])([CH2:54][CH3:55])[CH2:52][CH3:53]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: CC(C)(C)COc1nc(C(=O)O)cnc1NC1CCCCC1
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(NC2CCCCC2)c(OCC(C)(C)C)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-cyclohexylamino-6-(2,2-dimethyl-propoxy)-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 435.4 (M+H).
Reaction SMILES: [Br-].[C:2]1([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:47]([Br:54])[C:48]1C=CC=[CH:50][CH:49]=1>C1(C)C=CC=CC=1>[Br:54][CH2:47][CH2:48][CH2:49][CH2:50][CH2:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrCCCCCc1ccccc1
Reaction time: 24 h
Yield: 94 %

Procedure:
Phenylmethyl-triphenylphosphonium bromide (51 a) (PAA 59). Triphenylphosphine (2.364 g, 9.00 mmol) was added to benzyl bromide (1.348 g, 8.00 mmol) in 35 mL toluene in a 100-mL round-bottom flask. The mixture was heated to reflux under argon and stirred 24 h, then concentrated in vacuo. The resulting white amorphous solid was triturated with ether (3×20 mL) to yield 3.268 g (94%) white powder. 1H NMR (CDCl3, 300 MHz) δ 7.58-7.78 (m, 15H), 7.10-7.26 (m, 5H), 5.34-5.42 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c2ccc3ccccc3c2N1
Yield: 40.9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.050 mmol) obtained in Example 1, (3), and 4-(trifluoromethyl)benzoyl chloride (16 mg, 0.077 mmol), the title compound (10 mg, yield 41%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O>C(O)C.Cl>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:5]1[C:16]([CH3:17])=[CH:15][CH:11]=[C:12]1[CH3:14]
Reactant: CC(=O)CCC(C)=O
Reactant: NCc1ccc(F)cc1F
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)n1Cc1ccc(F)cc1F
Temperature: 80 °C

Procedure:
42.9 g (0.30 mol) of 2,4-difluorobenzylamine are dissolved in 300 ml of ethanol. 5 drops of concentrated hydrochloric acid (36%) are added to this solution. 36.0 g (0.315 mol) of acetonylacetone are then added dropwise, and the mixture is warmed to reflux. The reaction is complete (GC check) after refluxing for 4.5 hours at about 80° C. The brown solution is cooled to -30° C. and the crystals which have precipitated are filtered off and dried. 56.2 g (85% of theory) of white crystals which melt at 41°-42° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[NH2:11].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:21]Br>O>[Br:21][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([NH2:11])[N:6]=[CH:5][N:4]=2
Reactant: BrBr
Reactant: Cn1cnc2c(N)ncnc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(Br)nc2c(N)ncnc21
Reaction time: 2 h

Procedure:
Fifteen grams (0.1 mol) of 9-methyladenine of Example 1 was dissolved in 1.5 liters of buffer prepared from 30.8 g of sodium acetate, 1.4 liters of water and sufficient acetic acid to provide a pH of 4.0. To this solution was added dropwise 25 ml of bromine in 2 liters of water over a period of two hours. The reaction was stirred a further two hours and the resulting solid filtered off and rinsed with the water. The solid was air dried and warmed to about 50° in about 80 ml of methanol, stripped to a hazy suspension and filtered. The precipitate after rinsing with water and drying at 40° under vacuum overnight weighed 15.6 g. The filtrate was stripped of methanol and a further 1.6 g was collected. The combined solids were triturated in about 100 ml of acetone for three hours and then allowed to sit overnight. The resulting precipitate was filtered and washed with acetone to yield 13.3 g after drying at 40° on a vacuum pump overnight.