Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]1=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:6]([CH2:5][CH2:4][CH2:3][NH:2][C:32](=[O:34])[CH3:33])[C:7](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Reaction time: 2 h

Procedure:
N-[3-(3-Aminopropyl)-4-(4-bromophenyl)-thiazol-2(3H)-ylidene]aniline hydrochloride (730 mg) obtained in Example 132 and triethylamine (0.77 ml) were dissolved in N,N-dimethylformamide (5 ml), and thereto were added dropwise acetic anhydride in an ice bath under nitrogen atmosphere. The mixture was stirred at the same temperature for 2 hours, and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl alcohol to give the title compound (580 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([CH3:10])[CH3:9])[N:5]=[C:4]([NH:12][CH:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[N:1][C:2]2[N:7]=[C:6]([C:8]([F:11])([CH3:9])[CH3:10])[N:5]=[C:4]([NH:12][CH:13]([CH:23]3[CH2:24][CH2:25]3)[CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(F)c1nc(N)nc(NC(CCCc2ccccc2)C2CC2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(F)c1nc(N=Cc2ccc(Cl)cc2)nc(NC(CCCc2ccccc2)C2CC2)n1

Procedure:
A mixture of 2.5 g (7.28 mmol) of 2-amino-4-(1-fluoro-1-methylethyl)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazine, 1.08 g (7.70 mmol) of p-chlorobenzaldehyde and 100 mg of p-toluenesulfonic acid in 80 ml of toluene are boiled for 10 hours in a water separator. When cold, all volatile constituents are distilled. The crude product is purified by column chromatography (eluent:toluene/ethyl acetate=85:15). This gives 3.0 g (89% of theory) of 2-(4-chloro-6-benzylideneamino)-4-(1-fluoro-1-methylethyl-)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazine as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O>[CH3:1][O:2][C:3]1[C:12]([N:13]([CH3:32])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([CH3:29])[CH:25]=[C:26]([CH3:28])[CH:27]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: CI
Reactant: COc1cc2ccccc2cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ccccc2cc1N(C)C(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
To 1-[(2-methoxynaphth-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine (210 mg, 0.54 mmol) dissolved in dimethylformamide (15 ml), 60% sodium hydride (21.5 mg, 0.54 mmol) was added, stirred at room temperature for 15 minutes, and thereto methyl iodide (76.6 mg, 0.54 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[CH:16][C:14](=[O:15])[CH2:13][C:12]([O:18][CH3:19])=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 97.9 %

Procedure:
o-Nitrobenzaldehyde (7.6 g, 0.05 mole) and methyl acetoacetate (5.8 g, 0.05 mole) are dissolved in benzene (40 ml), and thereto are added piperidine (0.2 ml) and acetic acid (0.6 ml), and the mixture is refluxed for 5 hours. The produced water is removed, and when a stoichiometic amount of water is distilled off, the reaction is stopped. After completion of the reaction, the reaction mixture is washed with 5% hydrochloric acid and then with water, and the solvent is distilled off under reduced pressure to give the title compound (12.2 g, yield 98%) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([OH:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([O:19][C:17]2[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[CH:18]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Oc1cncc(Cl)c1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cnc1Oc1cncc(Cl)c1
Yield: 47.1 %

Procedure:
A mixture of 2,5-dichloronicotinic acid (Syn. Commun. 1989, 19, 553–9, 500 mg, 2.6 mmol), 3-chloro-5-hydroxypyridine (404 mg, 3.1 mmol), copper bronze (36 mg, 0.57 mmol), cuprous iodide (40 mg, 0.21 mmol) and potassium carbonate (792 mg, 5.7 mmol) in N,N-dimethylforamide (7 mL) was heated under reflux for 3 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated. The residue was diluted with water (10 mL) and the mixture was acidified with 2 N hydrochloric acid (2 mL). Precipitateed solids were collected by filtration and dried under reduced presssure at 40° C. to afford 349 mg of the title compound: 1H-NMR (CDCl3) δ 8.37 (3H, br.s), 7.96 (2H, br.s), a peak of COOH was not observed; MS (ESI) m/z 285 (M+H)+.—
Reaction SMILES: Br[CH:2]([CH2:26][CH2:27][Cl:28])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]([NH2:32])=[S:31].C(O)C>O>[NH2:32][C:30]1[S:31][C:2]([CH2:26][CH2:27][Cl:28])=[C:3]([C:5]2[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:7][CH:6]=2)[N:29]=1
Reactant: NC(N)=S
Reactant: N#Cc1ccc(OCCCCCOc2ccc(C(=O)C(Br)CCCl)cc2)cc1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(OCCCCCOc2ccc(-c3nc(N)sc3CCCl)cc2)cc1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
16.9 g (36.3 mmol) of 4-{5-[4-(2-bromo-4-chlorobutyryl)phenoxy]pentyloxy}-benzonitrile compound (9) of Preparative Example 1-4 and 5.53 g (72.6 mmol) of thiourea were added to 100 ml of ethanol, and the mixture was refluxed at 80□ for 12 hrs. The reaction solution was cooled to room temperature, added with purified water for recrystallization, and filtered under reduced pressure to obtain 3.3 g (yield: 21%) of a title compound (16).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C1COCC1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:36])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[N:26]([CH2:31][CH2:32][O:33][CH3:34])[C:25]1=[O:35])[C:18]2=[O:23]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][O:33][CH2:32][CH2:31][N:26]1[C:27](=[O:30])[CH2:28][CH2:29][CH:24]([N:17]2[C:18](=[O:23])[C:19]3[C:15](=[C:14]([NH:13][C:1](=[O:3])[CH3:2])[CH:22]=[CH:21][CH:20]=3)[C:16]2=[O:36])[C:25]1=[O:35]
Reactant: CC(=O)OC(C)=O
Reactant: COCCN1C(=O)CCC(N2C(=O)c3cccc(N)c3C2=O)C1=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCN1C(=O)CCC(N2C(=O)c3cccc(NC(C)=O)c3C2=O)C1=O

Procedure:
Acetic anhydride (0.5 mL) and DMAP (3 mg) were added to a THF solution of 4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50 mg). The reaction mixture was allowed to react for 8 hrs at room temperature. Then, DCM (15 mL) were added and solvents were removed by rotary evaporation in vacuo. The residue was washed with 0.5 N aqueous hydrochloric acid, saturated sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and filtered. Pale white solid (38 mg) was obtained after removal of solvent by rotary evaporation in vacuo. MS (m/e): 374 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+]([C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][CH:15]=1)([O-])=O>CN(C=O)C>[CH2:3]([O:10][C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a DMF suspension (200 mL) of sodium hydride (60% oilyness, 7.50 g, 0.188 mmol), benzyl alcohol (20.3 mL) was added under cooling with ice, and stirred for an hour at room temperature. Then 4-nitropyridine 1-oxide (25.5 g, 182 mmols) was added little by little under stirring, followed by an hour's stirring at room temperature. The solvent was concentrated under reduced pressure and chloroform (1 L) was added to the resulting residue. The insoluble matter was filtered using Celite (100 g). The filtrate was concentrated and to which acetone was added to provide the title compound (24.8 g, 69%).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:6][N:7]([C@H:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:28]2[C:37]([CH3:46])=[C:38]([C:42]([F:45])([F:44])[F:43])[C:39]([CH3:41])=[CH:40][C:27]1=2)[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[N:12]=1.O.NN>CO>[NH2:15][CH2:14][CH2:13][N:11]1[N:10]=[N:9][C:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:54])[F:55])[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=2)[C@H:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH:34]3[CH2:35][CH2:36]3)[C:28]3[C:37]([CH3:46])=[C:38]([C:42]([F:44])([F:45])[F:43])[C:39]([CH3:41])=[CH:40][C:27]2=3)=[N:12]1
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN)n1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
Heat the mixture of (S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-ethyl)-isoindole-1,3-dione (0.175 g, 0.224 mmol) and hydrazine hydrate (0.1 ml) in methanol (2.0 mL) at 60° C. overnight. Cool down to room temperature. Remove the precipitate by filtration and evaporate the solvent to provide the title compound (0.143 g, 98%). MS (ES+): 650 (M+H).
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:18]([O-:20])=[O:19])=[C:5]2[C:9](=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:8](=[O:17])[O:7][CH2:6]2.Cl>C(O)(=O)C>[OH:2][C:3]1[C:4]([N+:18]([O-:20])=[O:19])=[C:5]2[C:9](=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:8](=[O:17])[O:7][CH2:6]2
Reactant: COc1c(OC)c([N+](=O)[O-])c2c(c1[N+](=O)[O-])COC2=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(O)c([N+](=O)[O-])c2c(c1[N+](=O)[O-])C(=O)OC2

Procedure:
5,6-Dimethoxy-4,7-dinitro-3H-isobenzofuran-1-one (450 mg), acetic acid (15 ml) and 37% aqueous HCl (3 ml) were refluxed for 7.25 hours. The acetic acid and water were evaporated in vacuo. The residue was purified by column chromatography (toluene-ethyl acetate-methanol 8:1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20](Br)[CH2:21][CH3:22]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: CCC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1N1CCCC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To the mixture containing 2-methyl-5-nitrophenylamine and potassium carbonate (4 eq) in dimethyl formamide was added 1,2 dibromobutane (4 eq) and the resulting mixture was stirred at 70° C. for 16 hours. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and concentrated and purified on silica gel to give (2-methyl-5-nitrophenyl)pyrrolidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]3[CH2:12][S:13][CH2:14][C:10]3=[C:9]([C:15]#[N:16])[CH:8]=2)[CH:2]=1.[Br:17]N1C(=O)CCC1=O>>[Br:17][C:8]1[C:9]([C:15]#[N:16])=[C:10]2[CH2:14][S:13][CH2:12][N:11]2[C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cc(-c2cccnc2)n2c1CSC2
Product: N#Cc1c(Br)c(-c2cccnc2)n2c1CSC2
Yield: 30.7 %

Procedure:
6-Bromo-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile is prepared as in Example 9, from 5 g of 5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile and 4.1 g of N-bromosuccinimide. 2.07 g of 6-bromo-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile are thus obtained in the form of white powder melting at 190° C.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[C:16]2[CH:17]=[N:18][N:19]([CH2:20][CH3:21])[C:15]=2[N:14]=[C:13]2[C:22](=[O:31])[C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][CH2:26][C:12]=12>O1CCCC1>[Cl:10][C:11]1[C:16]2[CH:17]=[N:18][N:19]([CH2:20][CH3:21])[C:15]=2[N:14]=[C:13]2[C:22]([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)([OH:31])[C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][CH2:26][C:12]=12
Reactant: CN1CCC(Cl)CC1
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Agent: [Mg]
Solvent: C1CCOC1
Product: CCn1ncc2c(Cl)c3c(nc21)C(O)(C1CCN(C)CC1)c1ccccc1CC3

Procedure:
A Grignard reagent is prepared from 7.2 g. of magnesium turnings (0.3 mol.), 230 ml. of dry tetrahydrofuran and 40 g. of 4-chloro-1-methyl-piperidine (0.3 mol.). To this Grignard solution 31 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.1 mol.), from example 1(e), dissolved in 230 ml. of dry tetrahydrofuran is added. Reaction and work-up according to the procedure of example 15 yields 4-chloro-1-ethyl-1,5,6,11-tetrahydro-11-(1-methyl-4-piperidinyl)benzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol; m.p. 130°-132° (hexane, refrigerator).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH3:21])[CH:20]=1.Cl>CN(C=O)C>[CH3:13][C:11]1[NH:10][N:9]=[C:8]([O:7][C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH3:21])[CH:20]=2)[CH:12]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)n[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
Potassium carbonate (2.23 g, 16.1 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (3.16 g, 32.2 mmol) and 5-fluoro-2-nitrotoluene (5.00 g, 32.2 mmol) in DMF (50 ml), and the mixture was stirred at 70° C. for 3 hours. After completion of the reaction, a reaction mixture was poured into 2N hydrochloric acid (50 ml) and extracted with ethyl acetate (30 ml×2). An organic layer was washed with water (50 ml×3), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellowish solid of 5-methyl-3-(4-nitro-3-methylphenyloxy)pyrazole (2.51 g, yield: 27.8%). mp: 114-117° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.30 (d, J=0.5 Hz, 3H), 2.61 (s, 3H), 5.72 (d, J=0.5 Hz, 1H), 6.98-7.04 (m, 2H), 8.05 (d, J=9.8 Hz, 1H), 10.12 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1nc(Cl)c2c(I)c[nH]c2n1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a suspension of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.80 g, 8.92 mmol) and p-toluenesulfonyl chloride (1.65 g, 8.66 mmol) in CH2Cl2 (30 mL), triethylamine (3.0 mL, 21.6 mmol) and dimethylaminopyridine (0.047 g, 0.38 mmol) were added. The mixture was stirred at room temperature for 2 h. Water and CH2Cl2 were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (4.00 g). MS 468.2 and 470.2 (M+H)
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH:30](CS([O-])(=O)=O)([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:29]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:30]([CH3:32])[CH3:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: CC(C)CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3C(C)C)CC1
Temperature: 95 °C
Reaction time: 22 h
Yield: 47.3 %

Procedure:
To a mixture of (1,1-dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Example 2, 100 mg, 1.0 eq.) and isopropyl-methanesulfonate (67 mg, 2.0 eq.) in dimethylformamide (4 mL) was added cesium carbonate (156 mg, 2.0 eq.). The solution was stirred 22 h at 95° C. The reaction mixture was concentrated in vacuo and the residue partitioned between water and methyl-tert-butylether. The aqueous layer was extracted with methyl-tert-butylether. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and then purified on silica, eluting with cyclohexane/ethyl acetate. One fraction was isolated and dried in vacuo, to yield 52 mg (47%) of the desired product as off-white solid. MS (m/e): 462.5 (MH+, 100%)
Reaction SMILES: [C:1]([N:5]([CH3:29])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=1)=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][N:12]3[C:8]([C:6](=[O:7])[N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:29])=[CH:9][C:10]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[C:11]32)=[CH:16][C:17]=1[O:22][CH3:23])[CH3:31]
Reactant: COc1cc2c(cc1O)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)cc(-c3cccs3)c1-2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of the product of example 52 (250 mg), bromo-acetic acid ethyl ester (81 μl) and Cs2CO3 (595 mg) in DMF (10 ml) was stirred at 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature, subsequently poured into water and extracted with dichloromethane. The organic layer was washed with an aqueous HCl solution (0.5 M), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/1 (v/v)] as eluent.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[O:18]([CH2:25][CH2:26][NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[O:18]([CH2:25][CH2:26][NH:27][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccccc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound A (400 mg, 1, 63 mmol), 2-phenoxyethylamine (638 μl) and sodium hydrogencarbonate (1.37 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-phenoxyethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (66 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:5]=1[CH3:32])[CH3:2].[OH-].[Na+]>>[CH2:33]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:5]=1[CH3:32])[CH3:34]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc(N(CC)CC)c(C)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCO)cc1C
Yield: 46.1 %

Procedure:
In a manner similar to that of Example 12a, by reacting 130 mg (0.3 mmol) of ethyl 4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate (Example 15d) with 3 mL of 1N sodium hydroxide solution. 60 mg of 4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained in the form of a white solid (yield=46%, m.p.=208° C.).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[O:14])=O)C1C=CC=CC=1.[BrH:30].CCOCC>C(O)(=O)C>[BrH:30].[NH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])=[O:14]
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCC(=O)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of N-benzyloxycarbonyl derivative (2a, 3.13 g, 8.06 mmol) obtained in Preparation 1 and a solution of 30% hydrobromic acid in acetic acid is stirred for 1 hour. Excess ether is added, and the resultant precipitate is filtered off. After washing with ether, it is dried to obtain 2.50 g (92%) of hydrobromate (compound 3a).