Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[S:35][C:34]([CH2:36][CH3:37])=[N:33][C:32]=1[CH3:38]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:30][C:31]1[S:35][C:34]([CH2:36][CH3:37])=[N:33][C:32]=1[CH3:38])[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)nc1
Reactant: CCc1nc(C)c(CCl)s1
Product: CCc1nc(C)c(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C)cn2)s1
Yield: 46.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.43 g) and 5-chloromethyl-2-ethyl-4-methylthiazole (0.68 g) as starting materials, 5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.92 g) was obtained.
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([O:12]CC)=[O:11])[CH2:9][C:4]=2[NH:3][CH:2]=1.[ClH:15]>>[ClH:15].[N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=[O:11])[CH2:9][C:4]=2[NH:3][CH:2]=1
Reactant: CCOC(=O)C1CCc2nc[nH]c2C1
Agent: Cl
Product: O=C(O)C1CCc2nc[nH]c2C1

Procedure:
A 0.3 g portion of this ethyl (+)-4.5,6,7-tetrahydrobenzimidazole-5-carboxylate was dissolved in 2 ml of 6N hydrochloric acid and refluxed for 1.5 hours, and then evaporated to dryness under reduced pressure to obtain 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride with the optical rotation indicated below. mp: 245°-248° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19]C(=O)C(C)(C)C)=[N:4][C:5]([NH:12]C(=O)C(C)(C)C)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+]>CO>[NH2:12][C:5]1[N:4]=[C:3]([NH2:19])[C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)nc1N
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a colorless solution of methyl 5-chloro-2,6-bis[(2,2-dimethylpropanoyl)amino]nicotinate (EXAMPLE 26, Step 2, 153.9 g, 416 mmol) in methanol (1.5 L) was added a solution of potassium tert-butoxide (185 g, 1.65 mol) in methanol (500 mL) dropwise during the period of 20 min at room temperature under nitrogen atmosphere. Dissolving potassium tert-butoxide in methanol was exothermic, so potassium tert-butoxide must be added portionwise from powder addition funnel to methanol during the period of 2 h with ice-cold water bath. After the addition was completed, the reaction solution was stirred at reflux temperature for 1 h under nitrogen atmosphere, and cooled to room temperature. The resulting suspension was evaporated and ca. 1.3 L of methanol was removed (ca. 700 mL of methanol was remained). To this mixture was added water (1.2 L) and stirred at room temperature for 1 h with water bath (internal temperature was maintained at 20° C.), then the resulting suspension was filtered through paper filter and the pale yellow solid was dried under reduced pressure at 50° C. for 12 h to give 74.3 g (368.9 mmol, 89%) of the title compound as a pale yellow crystal. Rf value: 0.28 (ethyl acetate/hexane=1:2).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]=2[C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
2-Phenylbenzofuran (7.81 g., 0.040 mol.) was acylated with 7.0 g. (0.041 mol.) of anisoyl chloride according to the procedure described in Example 10 to give 2-phenyl-3-(4'-methoxybenzoyl)benzofuran.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:24][N:23](COCC[Si](C)(C)C)[C:20]3=[N:21][CH:22]=2)=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[O:4].Cl(O)(=O)(=O)=O.O>C(O)(=O)C>[Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[O:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)CBr)c(C(=O)N(C)C)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(NC(=O)CBr)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 23 h
Yield: 68.1 %

Procedure:
300 mg of 2-(2-bromo-acetylamino)-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 5 mL of glacial acetic acid. 400 μL of 70% perchloric acid was added and the resulting solution stirred at ambient temperature for 23 h. 85 mL of water was added and the resulting precipitate filtered off and dried by suction to afford 162 mg (0.32 mmol, 68%) of 2-(2-bromo-acetylamino)-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a yellow solid. MS: m/z 508.0+510.1 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([C:12]1[C:17]([O:18]COCCOC)=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:15]=[C:14]([CH:29]=[O:30])[N:13]=1)([CH3:11])[CH3:10].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][C:9]([C:12]1[C:17]([OH:18])=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:15]=[C:14]([CH:29]=[O:30])[N:13]=1)([CH3:8])[CH3:10]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
Trifluoroacetic acid (1.05 g, 9.2 mmol) is added to a solution of 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (1.0 g, 3.1 mmol) in methylene chloride and the reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is neutralized by the addition of saturated aqueous NaHCO3 and the layers separated. The organic layer is washed with brine (50 mL), dried over MgSO4, and evaporated. Recrystallization of the residue from hexane gives pure 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (0.24 g, 33%); mp 187°-189° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-:15].[Na+]>[Ag]=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[C:12]([OH:15])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: [OH-]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Agent: O=[Ag]
Agent: [Na+]
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 57 %

Procedure:
To a stirred suspension of 1.4 g of silver oxide in 20 ml of 6% aqueous sodium hydroxide was added dropwise 2.1 g of the 2-(4-isobutylphenyl)-propionaldehyde obtained in the procedure of Example 3(i) over 10 minutes at 60°C with stirring. The mixture was further stirred at 60°C for 15 minutes and then allowed to stand. The precipitate was filtered off and washed with hot water. The filtrate and the washing liquor were combined together, and the insoluble oil was removed by extracting with ethyl ether. The remaining aqueous phase was then extracted with ethyl ether, and the ether extract was washed with water, dried and then distilled under reduced pressure to remove the ether. The crude crystalline product so obtained was recrystallised from petroleum benzine, affording 1.3 g of 2-(4-isobutylphenyl)-propionic acid, M.P. 74.8°-76.5°C. Yield 57% (based on the theoretical).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:25]#[N:26])[C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][C:24]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(C#N)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(C#N)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrile to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH:15]1[CH2:17][CH2:16]1)[O:5][C:6]1[C:7](Cl)=[N:8][C:9]([Cl:13])=[N:10][C:11]=1[Cl:12].C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH:15]1[CH2:17][CH2:16]1)[O:5][C:6]1[C:11]([Cl:12])=[N:10][C:9]([Cl:13])=[N:8][C:7]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: COC(=O)C(Oc1c(Cl)nc(Cl)nc1Cl)C1CC1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: COC(=O)C(Oc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
To a suspension of cyclopropyl-(2,4,6-trichloro-pyrimidin-5-yloxy)-acetic acid methyl ester (224 mg, 0.72 mmol) in IMS (4 mL) was added triethylamine (150 μL, 1.08 mmol) followed by morpholine (63 μL, 0.72 mmol). The yellow solution was stirred for 2.5 hours at RT before being concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-20% ethyl acetate in cyclohexane) affording Cyclopropyl-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid methyl ester as a colourless gum (233 mg, 89%). 1H NMR (CDCl3): δ 3.99 (1H, d, J=9.54 Hz), 4.03-3.83 (4H, m), 3.80-3.75 (4H, m), 3.78 (3H, s), 1.32-1.21 (1H, m), 0.70-0.57 (2H, m), 0.52-0.45 (1H, m), 0.33-0.26 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][C:11]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH2:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)(=O)C.[CH3:32][N:33](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:20]1[CH:19]=[C:18]([C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH:3]=3)[C:32]#[N:33])=[N:13][CH2:12]2)[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: Fc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrole (0.88 g) was dissolved in DMF (10 ml), and the solution was deaerated and then left to stand in an argon atmosphere. To the reaction mixture, Zn(CN)2 (0.45 g) and Pd(PPh3)4 (0.67 g) were added. The mixture was stirred for 4 hours at 90° C. The reaction mixture was returned to room temperature, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, and then dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-fluorobenzonitrile (0.25 g) at a yield of 32%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].[Cl:18][C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([N:28]=[C:29]=[O:30])=[C:21]([CH:31]([CH3:33])[CH3:32])[CH:20]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:31]([CH3:33])[CH3:32])[C:22]([NH:28][C:29]([NH:17][S:14]([C:3]2[CH:4]=[C:5]([C:8]3([CH3:13])[O:12][CH2:11][CH2:10][O:9]3)[CH:6]=[CH:7][C:2]=2[F:1])(=[O:16])=[O:15])=[O:30])=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=1
Reactant: CC(C)c1cc(Cl)cc(C(C)C)c1N=C=O
Reactant: CC1(c2ccc(F)c(S(N)(=O)=O)c2)OCCO1
Product: CC(C)c1cc(Cl)cc(C(C)C)c1NC(=O)NS(=O)(=O)c1cc(C2(C)OCCO2)ccc1F

Procedure:
3-(2-Fluoro-5-(2-methyl-[1,3]dioxolan-2-yl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 168-170° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)(C(C)(C)C)(C)C.[C:21](OC)(=[O:30])/[CH:22]=C/C1C=CC=CC=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:21]([N:12]1[CH2:13][CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]([CH2:9][OH:8])[CH2:11]1)(=[O:30])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCC1CNCC1c1ccccc1
Reactant: COC(=O)/C=C/c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CC(CO)C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
A pyridine solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidine which had been synthesized from methyl trans-cinnamate, in accordance with the technique of Ling et al. (“Tetrahedron”, 2001, vol. 57,p. 6579-6588) and the method of International Patent Publication WO 2000/59502, was mixed with acetic anhydride and stirred at room temperature for 2Hours. After completion of the reaction, this was concentrated under a reduced pressure with toluene azeotropy, and THF and 1 M THF solution of TBAF were added to the thus obtained residue and stirred overnight at room temperature. Thereafter, its work-up and purification were carried out in the standard method to obtain (1-acetyl-4-phenylpyrrolidin-3-yl)methanol. EP: 220.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([CH:33]5[CH2:35][CH2:34]5)=[O:32])[CH:25]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1)C1CC1

Procedure:
Example 118 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.12–7.88 (br, 1H), 7.48–7.14 (m, 7H), 6.85 (d, 1H, J=7.2 Hz), 5.83–5.66 (br, 1H), 3.29–3.09 (m, 4H), 2.66–2.53 (m, 2H), 2.53–2.40 (m, 1H), 2.37–2.17 (m, 2H), 1.95–1.53 (m, 7H), 1.14–0.91 (m, 6H), 0.89–0.71 (m, 2H); ESMS m/e: 480.2 (M+H)+; Anal. Calc. (HCl salt) C28H35Cl2N3O2.0.38CHCl3: C, 60.64; H, 6.34; N, 7.47. Found: C, 60.38; H, 6.57; N, 7.80.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH2:18].[C:19](OC)(OC)(OC)[CH2:20][CH2:21][CH3:22]>Cl.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:19]1[CH2:20][CH2:21][CH3:22]
Reactant: Nc1cnc2ccccc2c1NCCCCCCl
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCl
Yield: 60.5 %

Procedure:
Using the general method of Example 1 Part D, N4-(5-chloropentyl)quinoline-3,4-diamine (˜20.4 mmol) was cyclized using trimethyl orthobutyrate (3.6 g, 24.5 mmol) in the presence of pyridine hydrochloride (˜0.1 g). The crude product was purified by column chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 3.9 g of 1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a light green solid.
Reaction SMILES: Cl.CN[O:4][CH3:5].C[Al](C)C.C([C@H:17]1COC(=O)[N:18]1[C:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:28][N:27]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:26]1)=[O:24])C1C=CC=CC=1>C(Cl)Cl>[CH3:5][O:4][N:18]([CH3:17])[C:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:28][N:27]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:26]1)=[O:24]
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a suspension of N,O-dimethylhydroxylamine hydrochloride (3.61 g, 0.037 mol) in DCM (40 mL) at RT was added trimethylaluminium (2.0M solution in heptane, 18.5 ml, 0.037 mol) dropwise and stirring was continued for one hour. To this mixture was added a solution of (S)-4-benzyl-3-[(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one (9.47 g, 0.0186 mol) in DCM (50 mL) over 10 minutes. Stirring was continued for three hours. The reaction was quenched by an addition of aq. Potassium sodium tartarate solution and extracted with ethyl acetate. The separated organic layer was washed with brine and dried on Na2SO4 and concentrated under vacuo. Purification by column chromatography (SiO2, EtOAc/H, 2:3) yielded 6.58 g (90%) of the title compound as a light yellow oil. ES-MS m/e: 393.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]1CCC[CH2:27]1>>[CH3:11][CH:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:27](=[O:26])[N:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]3)[C:3]=2[CH:4]=1)[CH3:10]
Reactant: CC(C)Oc1ccc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: C1CCOC1
Product: CC(C)Oc1ccc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 50 °C
Yield: 69 %

Procedure:
A solution of 1,1-dimethylethyl 4-({2-amino-5-[(1-methylethyl)oxy]phenyl}amino)-1-piperidinecarboxylate (D48, 470 mg, 1.34 mmol) in tetrahydrofuran (5 ml) was treated with N,N′-carbonyldiimidazole (322 mg, 2.01 mmol) and heated at 50° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with Na2CO3 solution (10 ml) and extracted with ethyl acetate (2×20 ml). The combined extract was dried (MgSO4), concentrated under vacuum and the residue purified by chromatography on silica gel eluting with 5-60% ethyl acetate/60-80 petrol ether to afford the title compound as a dark orange oil (351 mg, 69%). M+−H=374.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[C:21]([CH3:36])[CH:20]=1>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH3:36])[C:22]([N:27]3[CH2:28][CH2:29][CH:30]([N:33]([CH3:35])[CH3:34])[CH2:31][CH2:32]3)=[CH:23][C:24]=2[O:25][CH3:26])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 1-(4-amino-5-methoxy-2-methylphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 30).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:12]=1[C:13](Br)=[O:14]>COC(C)(C)C>[Br:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:12]=1[C:13]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: OCc1ccccc1
Reactant: Cc1cccc(CBr)c1C(=O)Br
Solvent: COC(C)(C)C
Product: Cc1cccc(CBr)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
24.2 g (221 mmol) of benzyl alcohol are added with ice cooling to 136 g (233 mmol) of 2-bromomethyl-6-methylbenzoyl bromide solution (35% solution in heptane). Subsequently, the mixture is left to stir at RT for one hour. After addition of 500 ml of tert-butyl methyl ether, the organic solution is washed successively with 410 ml of sat. sodium hydrogencarbonate solution and four times with 300 ml each time of water. Subsequently, the solvent is removed fully under reduced pressure. 74 g of benzyl 2-bromomethyl-6-methylbenzoate are obtained as a colorless oil having a purity of 80%. The benzyl 2-bromomethyl-6-methylbenzoate prepared in this way has a molecular weight of 318.02 (C16H15BrO2); MS (ESI): 341.0 [M+Na]+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15](=[O:29])[NH:16][C@H:17]([C:22]([N:24]1[CH2:27][CH:26](O)[CH2:25]1)=[O:23])[C@@H:18]([CH3:21])[CH2:19][CH3:20])([CH3:13])([CH3:12])[CH3:11]>ClCCl.C(OCC)(=O)C>[C:10]([O:14][C:15](=[O:29])[NH:16][C@H:17]([C:22]([N:24]1[CH2:27][CH:26]([F:7])[CH2:25]1)=[O:23])[C@@H:18]([CH3:21])[CH2:19][CH3:20])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a cooled (−78° C.) solution of diethylaminosulfur trifluoride (0.46 mL, 3.5 mmol) in dichloromethane (6 mL), was added dropwise a solution of [(1S,2S)-1-(3-hydroxy-azetidine-1-carbonyl)-2-methyl-butyl]-carbamic acid tert-butyl ester (1.0 g, 3.5 mmol) in dichloromethane (4 mL). The mixture was warmed to room temperature, stirred overnight, then diluted with ethyl acetate and poured into ice/water. The layers were separated, and the organic phase washed with water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (ethyl acetate) and isolated as an oil (250 mg, 25%).
Reaction SMILES: [C:1]([NH:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:24]I.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:4]([CH3:24])[N:5]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N(NC(C)=O)C(=O)OC(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(C(=O)OC(C)(C)C)N(C)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-acetyl-1-[4-(ethoxycarbonyl)phenyl]hydrazinecarboxylate (606 mg) was dissolved in DMF (10 ml), and methyl iodide (0.14 ml) and then sodium hydride (60%, 83 mg) were added at 0° C. The mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 (volume ratio)→1:1 (volume ratio)), and further recrystallized from ethyl acetate-hexane to give the title compound (608 mg) as colorless crystals.
Reaction SMILES: C[N:2](C)/[CH:3]=[C:4](\[C:8]([F:11])([F:10])[F:9])/[C:5](=O)[CH3:6].O.[NH2:14]N>C(O)C>[CH3:6][C:5]1[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:3][NH:2][N:14]=1
Reactant: CC(=O)/C(=C/N(C)C)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]cc1C(F)(F)F
Temperature: 75 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (Z)-4-(dimethylamino)-3-(trifluoromethyl)but-3-en-2-one (compound 262.1, 2.0 g, 11.0 mmol) in ethanol (30 mL). Hydrazine hydrate (3.7 mL, 77 mmol) was added and the resulting solution was stirred overnight at 75° C., then cooled and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to obtain the title compound as a white solid (1.0 g, 61%).