Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][N:38]([CH3:44])[C@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:41]4[CH2:42][CH2:43][C@H:39]([N:38]([CH3:44])[CH3:37])[CH2:40]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C(F)(F)F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.76 (s, 1H), 3.83 (t, 1H), 3.75 (m, 2H), 3.46 (m, 2H), 3.26 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 2.12 (m, 2H), 1.85-1.72 (m, 4H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 499 [M+H]
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.[ClH:16].[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21].CCN=C=NCCCN(C)C.Cl.C1[CH:43]=[CH:44][C:45]2N(O)N=[N:48][C:46]=2C=1.CN1CCOCC1>CN(C=O)C.O>[ClH:16].[CH3:17][O:18][C:19](=[O:29])[C@@H:20]([NH:21][C:13]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH2:43][CH2:44][CH2:45][CH2:46][NH2:48])[CH:4]=1)=[O:15])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cccc(O)c2cc1O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cccc(OCCCCN)c2cc1O
Yield: 46.8 %

Procedure:
A solution of 3,5-dihydroxy-2-naphthoic acid (4.08 g), L-phenylalanine methyl ester hydrochloride (4.74 g), WSC.HCl (4.22 g), HOBT (2.97 g) and N-methylmorpholine (2.41 ml) in DMF (200 ml) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1 v/v) to give the title compound (4.42 g, yield 61%).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]([CH3:10])[N:4]=1.[OH-:12].[Na+].OO>O>[F:11][CH:2]([F:1])[C:3]1[C:7]([C:8]([OH:12])=[O:9])=[CH:6][N:5]([CH3:10])[N:4]=1
Reactant: Cn1cc(C=O)c(C(F)F)n1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cn1cc(C(=O)O)c(C(F)F)n1
Temperature: 42.5 °C
Yield: 83 %

Procedure:
A 3-neck 250 ml round bottomed flask was fitted with a magnetic stirrer and thermometer. Water (130 g), the product of example 1 (compound of formula IX) (6.50 g) and aqueous sodium hydroxide (8.17 g) were charged to the reactor, and the resulting solution heated to 40-45° C. A 35% hydrogen peroxide solution (39 g) was added over 1 hr, and the mixture then stirred at 40-45° C. for 0.5 hr [83% yield of desired product (compound of formula XI)−quantitative HPLC]. The pH of the reaction mass was adjusted to 2.5 by addition of 36% aqueous hydrochloric acid solution. The resulting precipitate was isolated by filtration and washed with water. Drying (60° C., 10 mbar) gave the desired product (XI) as pale yellow, free-flowing powder [69% yield of desired product−quantitative HPLC].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=CC=2)[CH:4]=[CH:3][C:2]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)O[C:14]1C=CC=C[CH:15]=1.[CH2:34]([NH2:47])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>O>[CH2:36]([C:35]1[CH:7]=[CH:6][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:10]=2)[C:34]=1[NH2:47])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCN
Reactant: Oc1ccc2ccccc2c1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCCCCCCCCCCCCc1ccc2ccccc2c1N
Yield: 97 %

Procedure:
288 parts of β-naphthol, 9 parts of triphenyl phosphite and 418 parts of tridecylamine are heated to 175° C, whilst stirring. The elimination of water commences at this temperature and has ended after 10 hours, when the internal temperature is 230° C and 36 parts of water have been removed. Excess β-naphthol and amine are distilled off in vacuo. 2-Tridecyl-naphthylamine is then distilled at a boiling point of 225° C/3 mm Hg. 630 parts of end product are obtained, corresponding to a yield of 97% of theory.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21](Cl)[CH:20]=3)[C:17]([C:26]([O-])=[O:27])=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].CN(C)CCCN=C=NCC.O[N:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2N=N1>ClCCl>[C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:37])[CH:20]=3)[C:17]([C:26]([N:50]3[CH2:55][CH2:56][CH2:57][CH2:58][CH2:53][CH2:54]3)=[O:27])=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: On1nnc2ccccc21
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)OCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)N2CCCCCC2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
152 mg (0.303 mmol) of mono(3,3-diphenylpropane-1-yl)4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 45.0 mg (0.454 mmol) of hexamethyleneimine were dissolved in 20 ml of dichloromethane. 87.1 mg (0.454 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 46.4 mg (0.303 mmol) of 1-hydroxybenzotriazole were added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:23])[CH2:10][CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COc1ccccc1C1CC(O)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1C1CC(OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2-(2-methoxyphenyl)-4-hydroxypiperidine (910 mg, 2.94 mmol) in DMF (10 mL) at 0° C. was added methyl iodide (0.92 mL, 14.8 mmol) and NaH (236 mg, 5.9 mmol) and the resulting suspension was stirred at room temperature for 2 hours. The reaction mixutre was quenched with H2O at 0° C., EtOAc was added, and the aqueous layer was extracted with EtOAc (×4). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to provide the title compound as a colorless oil (898 mg). 1H NMR (CDCl3, 400 MHz) δ:3.82 (3H, s, OMe), 3.10 (3H, s, OMe), and 1.22 (9H, s, Bu-t).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[NH2:13][N:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:13][N:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH2:15]1
Reactant: NN1C=Cc2ccccc2C1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: NN1C=CC2=C(CCCC2)C1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-aminoisoquinoline to the title compound except platinum oxide was used as the catalyst. The product was triturated with EtOH to give a white solid. The analysis of the product was found to be consistent with the proposed structure. 1H NMR (D2O): δ7.35 (d, J=6 Hz, 1H); 6.55 (d, J=6 Hz, 1H); 2.6-2.5 (m, 2H); 2.20-2.10 (m, 2H); 1.75 (s, 3H); 1.70-1.50 (m, 4H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH-].[NH4+:8].[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([C:23]3([C:27]([OH:29])=O)[CH2:26][CH2:25][CH2:24]3)[NH:16][CH2:15][CH2:14][C:13]2=1>O1CCCC1.CN1CCOCC1>[NH2:8][C:27]([C:23]1([CH:17]2[C:18]3[NH:19][C:20]4[C:12](=[CH:11][C:10]([Cl:9])=[CH:22][CH:21]=4)[C:13]=3[CH2:14][CH2:15][N:16]2[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:26][CH2:25][CH2:24]1)=[O:29]
Reactant: O=C(O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: [NH4+]
Reactant: CCOC(=O)Cl
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2c([nH]c3ccc(Cl)cc23)C1C1(C(N)=O)CCC1

Procedure:
0.3 ml of ethyl chloroformate, and then 0.2 ml of a 28% ammonium hydroxide solution, are added at −10° C. to a solution of 1 g of the compound of Example 32 in 50 ml of tetrahydrofuran and 0.5 ml of N-methylmorpholine. After reaction for 12 hours, the solvent is distilled off; the residue is then taken up in a water/dichloromethane mixture. The expected product is isolated by decanting, drying and concentrating under reduced pressure.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:43])([CH3:42])[C:35](=O)[CH:36]=[CH:37]N(C)C)=[CH:30][CH:29]=1.[CH2:44](N(CC)CC)C>CN1CCCC1=O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:35]2[C:36]([CH3:44])=[CH:37][N:26]=[C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)[N:25]=2)([CH3:43])[CH3:42])=[CH:30][CH:29]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCN(CC)CC
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc(C)c(C(C)(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Reaction time: 2.5 h

Procedure:
The title compound was prepared in analogous manner as described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate, 4-(4-chloro-phenyl)-1-dimethylamino-4-methyl-pent-1-en-3-one, and triethylamine using 1-methyl-2-pyrrolidone as solvent. The reaction was performed in a microwave at 200° C. for 2.5 h. The title compound was isolated as a yellow solid in 52% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([NH2:12])=[CH:10][N:11]=2)[CH:2]=1.[Cl:13]N1C(=O)CCC1=O>O1CCOCC1>[ClH:13].[Cl:13][C:10]1[N:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[S:8][C:9]=1[NH2:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cnc(-c2cccnc2)s1
Solvent: C1COCCO1
Product: Cl
Product: Nc1sc(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 170.3 %

Procedure:
To a dry 250 ml round bottom flask equipped with magnetic stirrer, was charged 6.3 g (35.5 mmoles) of 2-(pyridin-3-yl)-1,3-thiazol-5-amine, and 100 mLs of anhydrous 1,4-dioxane. The solution was cooled to ˜0° C. and 4.75 g (35.5 mmoles) of N-chlorosuccinimide was added portionwise at a rate that maintained the temperature below 10° C. The reaction mixture was stirred at 5-10° C. for 20 minutes, and then filtered through a small pad of diatomaceous earth. The filtrate was diluted with 50 mLs of diethyl ether, and acidified with 10 mLs of 4.0 M HCl in 1,4-dioxane. The resulting solid was collected by vacuum filtration, washed with ethyl ether (100 mLs) and methylene chloride (500 mLs), and then dried in vacuuo at 40° C. to afford 7.5 g (85%) of an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=2.1 Hz, 1H), 8.76 (dt, J=9.5, 4.7 Hz, 1H), 8.66 (ddd, J=8.3, 2.0, 1.3 Hz, 1H), 7.97 (dt, J=15.6, 7.8 Hz, 1H).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([S:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1/[CH:18]=[CH:19]/[C:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]([CH3:31])[CH2:23][CH2:22][N:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32]([NH:35][CH2:36][C:37](O)=[O:38])(=[O:34])[CH3:33].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:1].[ClH:1].[C:32]([NH:35][CH2:36][C:37]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([S:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:12](/[CH:18]=[CH:19]/[C:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]([CH3:31])[CH2:23][CH2:22][N:21]=2)[CH:13]=1)=[O:38])(=[O:34])[CH3:33]
Reactant: CC(=O)NCC(=O)O
Reactant: CN1CCN=C(/C=C/c2cc(N)ccc2SCc2ccccc2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)Nc1ccc(SCc2ccccc2)c(/C=C/C2=NCCN(C)c3ccccc32)c1
Reaction time: 4 h
Yield: 30.7 %

Procedure:
To a mixture of 58 mg (0.114 mmol) of (E)-4-benzylthio-3-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]aniline dihydrochloride (prepared as described in Example 82), 20 mg (0.171 mmol) of N-acetylglycine and 1-hydroxy-7-azabenzotriazole in 5 ml of dimethylformamide was added 44 mg (0.228 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 4 hours. The solvent was removed and the residue was purified by column chromatography eluting with 5-20% methanol/dichloromethane and treated with 0.10 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated and the residue was recrystallised from acetone/methanol/diethyl ether to give 10 mg of (E)-2-acetamido-4′-benzylthio-3′-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]acetanilide dihydrochloride as a yellow solid; MS: m/e 499 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(=O)c2cc(C(C)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a suspension of 0.102 g of 6-acetyl-2-butyl-4(1H)quinazolinone in 10.0 ml of ethanol is added 0.015 g of sodium borohydride. The reaction mixture is stirred for 1.5 hours at room temperature and then diluted with 50 ml of water. The aqueous layer is extracted with 5:1 chloroform-methanol and the combined organics dried over magnesium sulfate, filtered and concentrated in vacuo to yield 0.103 g of the desired product. CI MASS SPEC 247(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.[CH2:21]([NH2:23])[CH3:22].[CH2:24]([NH2:27])[CH:25]=[CH2:26]>O>[CH2:24]([NH:27][C:9]1[N:8]=[C:7]([NH:23][CH2:21][CH3:22])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1)[CH:25]=[CH2:26]
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: C=CCN
Reactant: CCN
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: C=CCNc1nc(NCC)c2cc([N+](=O)[O-])ccc2n1
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To 311 mg (1.50 mmol) of 6-nitroquinazoline-2,4 (1H,3H)-dione was added 12.80 g (83.47 mmol) of phosphorus oxychloride to effect reaction in the same manner as in Example 10. Next, to the reaction mixture was added dropwise 151 mg (3.00 mmol) of a 70% aqueous ethylamine solution under ice cooling, and the resulting mixture was stirred under ice cooling for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. The solvent was distilled off to obtain 2-chloro-4-ethylamino-6-niroquinazoline. To the compound thus obtained was added 761 mg (13.33 mmol) of allylamine, and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 180 mg (yield: 44.1%) of the title compound.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH2:12]([C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)=[O:15])[CH3:13].O>C(O)C>[CH3:13][CH:12]1[CH:2]2[N:3]([CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[C:14]1=[O:15]
Reactant: CCC(=O)C1=CCCCC1
Reactant: C1=NCCc2ccccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1C(=O)C2CCCCC2N2CCc3ccccc3C12

Procedure:
A mixture of 16.75 g (0.1 mole) of 3,4-dihydroisoquinoline hydrochloride and 28.0 g of (0.2 mole) of 1-cyclohexen-1-yl ethyl ketone in 28 ml of ethanol is refluxed for 52 hours then poured into 300 ml of water and extracted with ether. The aqueous layer is separated and made basic by slowly adding ammonium hydroxide solution with stirring. Stirring is continued until a solid is formed after which the liquid is decanted. The solid is washed with water, dissolved in methylene chloride, dried over sodium sulfate and concentrated to an oil. The oil is dissolved in refluxing hexane, filtered, concentrated and cooled to give a solid which is recrystallized from hexane-benzene to give 2,3,4,4a,6,7,11b,12,13,13a-decahydro-12-methyl-1H-dibenzo[a,f]quinolizin-13-one, M.P. 144.5°-147.5°C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH:18]1([C:21]2[C:22]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:20][CH2:19]1>>[ClH:17].[CH:18]1([C:21]2[C:22]([N:30]3[CH2:31][CH2:32][N:33]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:3]5[C@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:16][CH:15]=4)=[O:14])[CH2:34][CH2:35]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:19][CH2:20]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 152.5 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (221 mg) described in Preparation Example 37 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (487 mg) described in Preparation Example 50, the title compound (736 mg) was obtained.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1)[CH3:21]>C(Cl)Cl.CO>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:17](=[O:19])[CH2:16][C:13]3[CH:12]=[CH:11][C:10]([N:3]4[C:4]5=[N:5][CH:6]=[CH:7][CH:8]=[C:9]5[N:1]=[CH:2]4)=[CH:15][CH:14]=3)=[CH:31][C:30]=2[C:36]([F:39])([F:37])[F:38])[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 523.0 [M+H]+; single peak at tR=3.00 min (System 1); Rf=0.12 (CH2Cl2/MeOH+1% NH3aq, 95:5).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>O.O1CCCC1>[ClH:24].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:3][C:4]2[CH:5]=[C:6]([NH:10][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[NH:12])[CH:7]=[CH:8][CH:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1cccc(NC(=O)c2ccc(Cl)cc2)c1)N1CCCC1
Temperature: 0 °C
Reaction time: 65 h

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. A solution of 4chlorobenzoyl chloride, 0.96 g, 0.0053 moles, in 10 ml of tetrahydrofuran was added. A white solid developed after stirring for 65 hours, and was filtered. The filtered product was then taken up in 20 ml of isopropanol and 1 ml of concentrated hydrochloric acid was added. The mix was then brought to a volume of 500 ml with ether and crystals developed. The crystals were filtered and washed with 20 ml of ether (twice) and the product was dried in a vacuum oven, yielding N-(3-(((4-chlorophenyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.15 g, m.p. 247-250° C.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[IH:19]>>[I:19][C:12]1[CH:17]=[C:16]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[N:15]=[CH:14][N:13]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: Fc1ncccc1-c1cc(I)ncn1

Procedure:
The compound was prepared according to Example 1 using 2-fluoropyridine-3-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[S:15])[NH2:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O>C(O)(C)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:14]=[C:13]([C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)[S:15][CH:19]=2)=[CH:23][CH:24]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCCCCCCOc1ccc(C(N)=S)cc1
Solvent: CC(C)O
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Yield: 41.6 %

Procedure:
To a stirring mixture of 4-(heptyloxy)benzothioamide (1.30 g, 5.17 mmol) in isopropanol (20 mL) was added 2-bromo-1-(4-bromophenyl)ethanone (1.44 g, 5.17 mmol). The precipitate was collected by filtration and washed with EtOH (2×5 mL). The filter cake was slurried with NaHCO3 (2×20 mL), water (2×20 mL) then EtOH (2×5 mL) and dried to afford 926 mg (41%) of 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole as a pale yellow powder. LCMS-ESI (m/z) calculated for C22H24BrNOS: 429.1; found 430.0 [M+H]+, tR=3.41 min. (Method 4).