Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][Cl:16])[C:9](=[O:17])[CH2:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[N+:25]([O-])([OH:27])=[O:26]>>[N+:25]([C:4]1[C:3]([O:2][CH3:1])=[CH:18][C:7]2[CH2:8][C:9](=[O:17])[N:10]([CH2:13][CH2:14][CH2:15][Cl:16])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:27])=[O:26]
Reactant: COc1ccc2c(c1)CC(=O)N(CCCCl)CC2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CCCCl)C(=O)C2

Procedure:
Here, 1-(8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)3chloro-propane (28.5 g, 0.016 mol) is stirred into concentrated nitric acid (350 ml) for half an hour at 20°-25° C. The solution is poured onto ice water, neutralized with potassium carbonate and extracted twice with methylene chloride. The extract is dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue is purified over a silica gel column with ethyl acetate as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].C1C=CC=CC=1>O>[C:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)N1CCN(C(C)c2ccc(-c3ccc(Cl)cc3)cc2)CC1

Procedure:
With constant stirring, reflux a solution of 25.1g of 4'-chloro-4-(1-chloroethyl)[1,1']biphenyl, 51g of 1-acetyl piperazine and 400 ml of anhydrous benzene for 24 hours. Add 200 ml of water to the reaction mixture, separate the organic phase, water-wash (5 times with 200 mls of water). Dry (over sodium sulfate), concentrate (in vacuo) and recrystallize the resulting residue from ethyl acetate to obtain the desired product.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:15]=2)[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:2]1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>[Pd].C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:18][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:17][C:16]3=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cc2c(cc1C=Cc1ccccn1)OCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cc3c(cc2CCc2ccccn2)OCO3)cc1
Reaction time: 0.5 h

Procedure:
2-(4,5-Methylenedioxy-2-nitrostyryl)pyridine (10.8 g., 0.04 mole) is hydrogenated on a Parr apparatus in 200 ml. of ehtanol with 2.0 g. of 10% palladium on carbon as catalyst. After the reduction is complete, the mixture is filtered and the solvent evaporated. The residue consisting of 2-(4,5-methylenedioxy-2-aminophenethyl)pyridine is immediately dissolved in pyridine (100 ml.) and anisoyl chloride (7.5 g., 0.044 mole) added. The solution is stirred for 30 min. A basic workup according to the procedure of Example 25 affords 10 g. of 4-methoxy-4',5'-methylenedioxy-2'-[2-(2-pyridyl)ethyl]benzanilide obtained analytically pure by crystallization from ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[C:8][Si](C)(C)C)=[CH:5][N:4]=[C:3]1[C:13]([OH:16])([CH3:15])[CH3:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:13]([OH:16])([CH3:14])[CH3:15])=[N:4][CH:5]=1)#[CH:8]
Reactant: Cn1c(C#C[Si](C)(C)C)cnc1C(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cnc(C(C)(C)O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To 2-(1-Methyl-5-trimethylsilanylethynyl-1H-imidazol-2-yl)-propan-2-ol (100 mg, 0.42 mmol) in 5 mL of THF was added 1M TBAF in THF (1.3 mL, 1.3 mmol). The reaction was stirred at rt overnight, and then was diluted with 50 mL of water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine and dried with MgSO4, filtered, and concentrated to provide 58 mg of 2-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-propan-2-ol.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:19]1([CH2:24][CH2:25][OH:26])[CH:23]=[CH:22][N:21]=[N:20]1.Cl>CN(C1C=CN=CC=1)C.ClCCl>[N:19]1([CH2:24][CH2:25][O:26][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCn1ccnn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Temperature: -4 °C
Reaction time: 8 h

Procedure:
A solution of 12.9 g (66.3 mmol) p-toluenesulfonic acid chloride, 2.03 g (16.6 mmol) 4-(N,N-dimethylamino)-pyridine and 11.2 ml (80.2 mmol) triethylamine in 150 ml dichloromethane was cooled to −10° C. A solution of 7.50 g (66.3 mmol) 2-(1H-[1,2,3]triazol-1-yl)-ethanol in 150 ml dichloromethane was added dropwise and the mixture stirred overnight at −4° C. 170 ml Ice and 170 ml dichloromethane were added and stirring continued for 10 min. followed by addition of 3.9 ml conc. HCl. The organic phase was separated, washed with sat. NaHCO3-solution and brine, dried over Na2SO4 and solvents distilled off. Yield 15.3 g (86%) orange crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24]Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][O:23][CH2:22][CH2:21][O:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: O=C(OCCOCCl)c1ccccc1
Product: O=C(OCCOCn1cnc2c(Cl)nc(Cl)nc21)c1ccccc1
Yield: 41 %

Procedure:
Following the procedure of Example 1, 2,6-dichloro-purine was condensed with 1-benzoyloxy-2-chloromethoxyethane to give a 41% yield of 2,6-dichloro-9-(2-benzoyloxy ethoxymethyl)purine, m.p. 121°-125° C. This was treated according to the procedure of Example 2 to give simultaneous ammonolysis of the 6-chloro and benzoyloxy groups yielding 2-chloro-9-(hydroxyethoxymethyl)adenine, in 94% yield, m.p. 188°-190° C. after recrystallization from isopropanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[N:3]=1.[F-:25].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[N:3]=1
Reactant: [F-]
Reactant: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(Cl)c2cc1F
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(F)c2cc1F
Temperature: 140 °C
Yield: 78.8 %

Procedure:
To a solution of 1-chloro-7-fluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinoline (1 g, 2.89 mmol) in DMSO (6 mL), was added CsF (0.879 g, 5.78 mmol) and the mixture was heated to 140° C. for 4 hrs. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using 50% DCM/Hexanes. The product fractions were collected and the solvent removed under vacuum to give 1,7-difluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinoline (750 mg, 79% yield). MS: MS m/z 330.1 (M++1).
Reaction SMILES: [C:1]1([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[CH2:21]([O:20][C:18]([C:17](=[C:31]1[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]1=[O:30])[C:15]1[N:16]=[C:12]([NH:11][C:10]([NH:9][C:1]2[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:8])=[O:24])[S:13][CH:14]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2c(C)cccc2C)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2c(C)cccc2C)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared using 1.74 g of ethyl 2-[3-(2,6-xylyl)ureido]thiazol-4-ylglyoxylate, 0.96 g of rhodanine-3-acetic acid, O.5 g of ammonium chloride. 0.5 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NC1CCCC1
Solvent: CO
Product: Nc1nc(Cl)cc(NC2CCCC2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
In a 25 mL sealable tube under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol), cyclopentylamine (0.75 mL, 7.62 mmol) and CH3OH (10 mL). The vial was sealed and the reaction mixture was stirred for 16 hours at 50° C. The reaction was concentrated, and the resulting oil was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (605 mg, 93%) as an orange oil. LC-MS (ES) m/z=213 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=3)[C:8](=[O:9])[C:7]2=[CH:22][CH:23]=1)([O-])=O.CC(O)=O>O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=3)[C:8](=[O:9])[C:7]2=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)C(=O)N(c1ccc(C(=O)O)cc1)C2=O
Reaction time: 8 h
Yield: 41.9 %

Procedure:
4-nitro-N-(p-carboxyphenyl)phthalimide (145) (0.2 g, 0.6 mmol) partially dissolved in 30 ml of 1,4-dioxane and 2 ml HOAc was added to a three necked round bottom flask equipped with a rubber septum, a gas inlet adapter and an adapter tightly fitted with a balloon. After the reaction vessel was purged three times with N2, 0.02 g of 10% Pd on activated charcoal was added. The reaction vessel was then flushed three times with H2. The heterogenous mixture was vigorously stirred under a hydrogen atmosphere overnight. The catalyst was removed by filtration through a celite pad and the filtrate concentrated under vacuum to give a bright yellow solid. The crude material which contained unreacted nitro compound was resubjected to the above procedure. Resulting crude material was triturated with hot 1,4-dioxane and undissolved material removed by filtration. The filtrate was diluted with water. The ensuing solid was filtered through a Buchner funnel and washed three times with 1 ml water. The product was dried in air for a short time and then in vacuo for 48-72 hours to afford 0.071 g (39%) 165 as a dark yellow solid: mp=270-271° C.; Rf0.88 (A): Rf0.80 (C): Rf0.49 (D): IR (cm−1): 3366 (NH), 3193 (NH), 2750-3200 (OH), 3075 (C═CH), 2669 (C—H), 1767 (C═O), 1752 (C═O), 1701 (bs, C═O), 1637 (C═C), 1607 (C═C), 1514 (C═C), 1482 (C═C), 1370 (C—N), 1220 (C—O), 740 (C═CH); MS m/z (rel intensity) 282 (16), 281 (100), 237 (71) 120 (43).
Reaction SMILES: [NH:1]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>C(O)CCC.C(O)C.[Pd]>[NH:1]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCCCO
Solvent: CCO
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h
Yield: 94.4 %

Procedure:
Substance [2] (76.98 g, 145 mM) was dissolved in n-butanol (20 ml) and ethanol (300 ml). 5% Pd/C (15 g) was added thereto and catalytic hydrogenation was allowed to proceed for 3 hours. After removing the catalyst, the mother liquor was concentrated in vacuo. Diethyl ether (300 ml) was added to the residue, which was then extracted successively with 500 ml and 200 ml of 5% aqueous sodium bicarbonate. The extract was adjusted to pH 4 by adding 1 N HCl with ice cooling to precipitate the product continuously, which was extracted with ethyl acetate and washed twice with water. After drying with anhydrous sodium sulfate, the solution was concentrated in vacuo. The residue was solidified by adding ether-hexane. Recrystallization was effected with ethyl acetate-ether-hexane to obtain the substance [3] (60.33 g, yield: 94.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.CCOC(C)=O>C(#N)C>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:3][C:2]=1[NH2:1])([O-:10])=[O:9]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1cc(OCc2ccc3ccccc3n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-4-nitrophenol (5.0 g, 32 mmol) in acetonitrile (162 mL) was added 4N NaOH (16.2 mL, 4 N) followed by 2-(chloromethyl)quinoline hydrochloride (7.6 g, 34 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction was then heated to 80° C. for 4 h. The reaction mixture was cooled to RT and concentrated to dryness. Water was added to the residue to give a dark orange solid that was isolated by filtration. Trituration using EtOAc then afforded the title compound. MS (ESI): mass calcd. for C16H13N3O3, 295.10; m/z found, 296.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J=8.5, 1H), 8.02 (dd, J=10.0, 9.2, 2H), 7.83-7.75 (m, 1H), 7.68 (d, J=8.5, 1H), 7.66-7.60 (m, 1H), 7.55 (d, J=3.0, 1H), 7.32 (dd, J=9.2, 3.0, 1H), 7.28 (s, 2H), 7.03 (d, J=9.3, 1H), 5.34 (s, 2H).
Reaction SMILES: C([O:3][C:4]([NH:6][N:7]([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9])=O)C.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:10]([N:7]1[C:8]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:9][C:4]([OH:3])=[N:6]1)([CH3:12])[CH3:11]
Reactant: C1CCNC1
Reactant: CCOC(=O)NN(C#N)C(C)C
Product: CC(C)n1nc(O)nc1N1CCCC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
26,6 g (0,15 mole) of 2-isopropyl-2-cyanohydrazinecarboxylic acid ethyl ester is added dropwise to 100 ml of pyrrolidine. The temperature raises to 30° C during the dropwise addition. The whole mixture is then stirred for 12 hours at room temperature and subsequently for 1 hour at 70° C. Then excess pyrrolidine is distilled off in vacuo. To the crystalline residue ethyl acetate is added and the crystals are filtered with suction. There is obtained 21,6 g (70% of theory) of 1-isopropyl-3-hydroxy-5-pyrrolidino-1,2,4-triazole, mp. 123°-125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[C:4]([F:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([O:29][CH3:30])=[O:28])O1>>[F:13][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:7]=[CH:6][C:5]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)c(F)c2)c1

Procedure:
According to General Method 1A, 8.0 g (30.9 mmol) of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene and 20.13 g (77.22 mmol) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate were reacted. Yield: 8.02 g (69% of theory)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:27][N:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)=[CH:30][C:29]1=[O:40]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:37]4[CH2:36][CH2:35][CH:34]([C:31]5[CH:32]=[CH:33][N:28]([CH3:27])[C:29](=[O:40])[CH:30]=5)[CH2:39][CH2:38]4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: Cn1ccc(C2=CCNCC2)cc1=O
Agent: Cl
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCC(c6ccn(C)c(=O)c6)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-2(1H)-one hydrochloride. LCMS (M+H)+: m/z=515.3.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[N:37]1.CN(C)C=O>C(OCC)(=O)C>[N:36]1([CH2:35][N:8]2[C:9](=[O:26])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]2[CH3:27])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[N:37]1
Reactant: ClCn1nnc2ccccc21
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cn2nnc3ccccc32)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-(chloromethyl)-1H-1,2,3-benzotriazole (0.62 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=1.CCCCCC>CCO>[Br:19][C:20]1[CH:21]=[N:22][C:23]([N:12]2[CH2:13][CH2:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11]2)=[N:24][CH:25]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Solvent: CCO
Solvent: CCCCCC
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncc(Br)cn2)CC1
Temperature: 70 °C
Yield: 51.6 %

Procedure:
To a solution of methyl 4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (0.11 g, 0.42 mmol) in EtOH (5 mL) was added 5-bromo-2-chloropyrimidine (0.09 g, 0.46 mmol) at rt and the reaction mixture heated up to 70° C. for 1 h. After completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 20% EtOAc:hexane to obtain the desired product as a yellow solid (0.09 g, 52% yield). MS: 415.17 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:11][S:12]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7])(=[O:14])=[O:13]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1ccc(O)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
55 g of p-Hydroxybenzoic acid (I) (Aldrich) was added in small portions to 545 g of chlorosulfonic acid (Aldrich) while stirring at room temperature. After 18 hours the reaction mixture was poured in a thin stream upon crushed ice (5 liters). The product was filtered and the precipitate dissolved in ethyl acetate. The solution was then washed with brine, dried with magnesium sulfate, filtered and evaporated to yield 65 g of 3-chlorosulfonyl-4-hydroxybenzoic acid (II), m.p. 181°-182° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:28]4[C:23](=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:26][CH:27]=4)[N:22]=[CH:21][C:20]=3[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:14]=2)=[CH:7][CH:6]=1.[CH2:41]=O>>[CH2:33]([C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[C:15]1[CH:14]=[C:13]([N:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:2])=[O:40])=[CH:10][CH:9]=3)[CH3:41])[CH:18]=[CH:17][CH:16]=1)=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C=O
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Product: CN(Cc1ccc(CC(=O)O)cc1)c1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from (4-{[3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamino]-methyl}-phenyl)-acetic acid methyl ester and formaldehyde according to the procedure of Example 66. MS (ES) m/z 541.3.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH3:7][N:8]=[C:9]=[O:10].O>CN(C=O)C>[CH3:7][NH:8][C:9](=[O:10])[NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1
Reactant: Nc1nnn[nH]1
Reactant: CN=C=O
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1nnn[nH]1
Temperature: 100 °C
Yield: 89.8 %

Procedure:
5-Aminotetrazole (5.5 g, 0.065 mole) was dissolved in 75 ml of DMF. On the addition of methylisocyanate (5 g) the temperature began to slowly rise to 40° C. with the formation of a white solid. The solution was heated for 90 minutes at 100° C. and on cooling, poured into cold water. The resulting white solid was filtered, water washed and dried to give 8.3 g of product which softened at 264°-267° C. but was not melted completely at 305° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]=3[N:22]([CH3:25])[C:23]=2[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(Cl)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 30.3 %

Procedure:
4-(5-Chloropyridin-2-yl)pyridin-2(1H)-one (111 mg, 0.537 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (80 mg, 30%) as a green solid: 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.5, 2.4 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 7.36 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 6.98 (dd, J=7.1, 1.8 Hz, 1H), 4.65 (br s, 2H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.83 (br s, 2H), 1.50 (s, 9H).