Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Nc1cc(Br)c2cn[nH]c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(Br)c2cn[nH]c2c1
Yield: 61.5 %

Procedure:
4-Bromo-1H-indazol-6-amine (500 mg, 2.36 mmol) was treated with methanesulfonyl chloride (130 μl, 1.68 mmol) and triethylamine (49 μl, 3.55 mmol) according to the method described in Preparation 15b. The residue was purified using SP1® Purification System to give 300 mg (49% yield) of the title compound. Purity 80%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:53])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C:27]2[N:28]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([NH:40][CH2:41][C:42]4[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=4)=[O:39])=[CH:34][CH:33]=3)[S:30][CH:31]=2)[C:16](=[O:25])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:9]=1.Cl>CO>[CH2:48]([C:45]1[CH:44]=[CH:43][C:42]([CH2:41][NH:40][C:38]([C:35]2[CH:34]=[CH:33][C:32]([C:29]3[S:30][CH:31]=[C:27]([CH2:26][N:15]([CH2:14][C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([OH:53])=[O:4])=[CH:9][CH:10]=4)[C:16](=[O:25])/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:28]=3)=[CH:37][CH:36]=2)=[O:39])=[CH:47][CH:46]=1)[CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCc1ccc(CNC(=O)c2ccc(-c3nc(CN(Cc4ccc(OCC(=O)OC)cc4)C(=O)/C=C/c4ccccc4)cs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCc1ccc(CNC(=O)c2ccc(-c3nc(CN(Cc4ccc(OCC(=O)O)cc4)C(=O)/C=C/c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
1N aqueous NaOH (0.5 mL) was added to a solution of methyl[4-({{[2-(4-{[(4-pentylbenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}[(2E)-3-phenylprop-2-enoyl]amino}methyl)phenoxy]acetate (163 mg, 0.23 mmol) in MeOH (5 mL). The reaction mixture was stirred at RT for 2 hours, then poured into 1N aqueous HCl (25 mL). The resulting precipitate was filtered, washed with water (3×) and dried under reduced pressure to give 120 mg (75%) of the title compound as a white solid. M+(ESI): 688.1; M−(ESI): 686.5. HPLC, Rt: 5.3 min (purity: 100%). 1H NMR (CDCl3) δ: 7.97-7.79 (m, 5H), 7.50-7.01 (m, 13H), 6.84 (m, 2H), 6.57 (m, 1H), 4.88 (brs, 2H), 4.75 (brs, 2H), 4.60 (m, 4H), 2.60 (t, J=7.7 Hz, 2H), 1.61 (m, 2H), 1.33 (m, 4H), 0.90 (t, J=6.4 Hz, 3H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12]>ClC1C=CC=CC=1>[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[N:12]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1C
Reactant: Nc1ccccc1
Solvent: Clc1ccccc1
Product: Cc1ccc(N(c2ccccc2)c2ccccc2)cc1C

Procedure:
An improved process for producing triarylamines directly from an aniline is to react an arylchloride with an aniline compound in the presence of a suitable catalyst. For example, 3,4-dimethylaniline can be rapidly reacted with chlorobenzene to form 3,4-dimethyl-N,N-diphenylaniline using palladium acetate ligated with 2,4,6-trioxa-1,3,5,7-tetramethyl-8-phosphaadamantane, which is manufactured as Cytop-216 (Cytec Industries), and sodium t-pentoxide base. This reaction proceeds rapidly, in about 4 to 8 hours to produce the desired triarylamine.
Reaction SMILES: CN([CH:4]=[C:5]([C:10]1[S:14][C:13]([CH:15]([CH3:17])[CH3:16])=[N:12][C:11]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([O:8][CH3:9])=[O:7])C.Cl.[O:27]1CCCC1>>[OH:27][CH:4]=[C:5]([C:10]1[S:14][C:13]([CH:15]([CH3:17])[CH3:16])=[N:12][C:11]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: C1CCOC1
Reactant: COC(=O)C(=CN(C)C)c1sc(C(C)C)nc1/C=C/c1ccccc1
Agent: Cl
Product: COC(=O)C(=CO)c1sc(C(C)C)nc1/C=C/c1ccccc1
Reaction time: 5 h

Procedure:
2 g of the enamine of Step F, 20 ml of tetrahydrofuran and 5 ml of a 2N hydrochloric acid solution were mixed together under nitrogen and left for 5 hours at 20° to 21° C. The tetrahydrofuran was evaporated off and the product was used as is for the following step.
Reaction SMILES: [CH2:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:6](=[O:8])[C@H:5]([CH3:9])[O:4]1)[CH3:2].[BrH:16].BrBr>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:6](=[O:8])[C@H:5]([CH3:9])[O:4]1)[CH3:2]
Reactant: Br
Reactant: CCC1(c2ccccc2)OC(=O)[C@H](C)O1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C1(c2ccccc2)OC(=O)[C@H](C)O1

Procedure:
To a solution of 2-ethyl-2-phenyl-5(S)-methyl-1,3-dioxolane-4-one (1 mmol) and hydrogen bromide (0.1 mmol) in carbon tetrachloride (3 ml), bromine (1 mmol) was added and the temperature was kept at 15° C.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].Cl.[CH3:20]O>>[C:1]([O:18][CH3:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: O=C(O)CCCCCCC(=O)Nc1ccccc1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCCC(=O)Nc1ccccc1
Temperature: 50 °C

Procedure:
Suberanilic acid (Compound 3, 249.3 g, 1.0 mole) and methanol (0.4-0.5 L) are combined and heated to 45-55° C. The pH is adjusted to ≦2 using hydrochloric acid, and the batch temperature is maintained at 45-55° C. until the reaction is complete. The reaction is quenched with deionized water (0.1-0.2 L). The batch is cooled to 25-30° C. and seeded to induce crystallization, and then cooled to 0-10° C. The batch is filtered, and the cake washed with a 50:50 (v/v) methanol/water solution (0.28-0.34 L) at 0-10° C. The wet cake is dried at a maximum of 46° C. under vacuum to yield methyl suberanilate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Br:8])=[C:6]([CH3:9])[NH:5][C:4](=[O:10])[N:3]=1.C(N(CC)CC)C.Cl[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[O:20]([CH2:19][N:3]1[C:2]([CH3:1])=[C:7]([Br:8])[C:6]([CH3:9])=[N:5][C:4]1=[O:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCOc1ccccc1
Reactant: Cc1nc(=O)[nH]c(C)c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(=O)n(COc2ccccc2)c(C)c1Br
Temperature: 40 °C

Procedure:
A mixture of 4,6-dimethyl-5-bromopyrimidin-2-one (4.7 mmol) and triethylamine (4.7 mmol) in dichloromethane (60 ml) was heated at 40° C. for dissolution. The solution was then cooled to room temperature and (chloromethoxy)benzene [see Preparation 2] (4.7 mmol) in dichloromethane (15 ml) was added. The resultant mixture was stirred at room temperature for 11/2 h, the solvent distilled off, the mixture triturated with water, the remaining solid extracted with chloroform, the dried (MgSO4) chloroform solution evaporated, the residue triturated with a little ether, the residue redissolved in chloroform and the solution chromatographed on a column of alumina, activity III, using chloroform, Yield 0.35 g (24%), m.p. 120° C. (CCl4). (Found C50.32; H4.15. Calc. for C13H13BrN2O2 : C50.50; H4.25) 1H NMR (CDCl3): δ 2.50 and 2.68 (4-Me and 6-Me), 6.03 (CH2), 6.8- 7.4 (Ph), MS [70 eV, m/z (% rel. int)]. 310/308 (6/7,M), 217(97), 215(100), 174(15), 172(12), 136(20), 135(19), 108(23) 94(19).
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:21]2[CH:5]=[N:4][N:3]=[C:2]2[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Product: Fc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 4-fluorobenzylamine (0.5 ml) as described above; yield: 0.085 g (29.0%);
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)(=O)[CH3:2].[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][NH2:27]>CO.C(O)(=O)C>[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][N:27]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)[CH3:2]
Reactant: Cn1c(NN)nc2ccccc21
Reactant: CC(=O)c1cccc(-c2ccccc2)n1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2n1C)c1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-acetyl-6-phenylpyridine (0.50 g, 2.53 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.41 g, 2.53 mmol) in 10 ml of methanol is stirred at room temperature for 12 hours after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in a refrigerator at approximately 5° C. The precipitate is filtered, washed several times with water, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.51 g (59% of theory).
Reaction SMILES: Br[CH:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=3)[NH:5][C:4]=2[C:3]1=[O:17].[Li+].[Br-]>CN(C=O)C>[OH:17][C:3]1[CH:2]=[CH:14][CH:13]=[C:12]2[C:4]=1[NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:15]#[N:16])=[CH:10][C:11]2=1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CCC(Br)C3=O
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c3c(O)cccc3c2c1
Temperature: 150 °C
Yield: 38.4 %

Procedure:
2-Bromo-1-oxo-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (0.1 g, 0.5 mmol) was dissolved in DMF (5 mL) and LiBr (49 mg, 0.5 mmol) followed by Li2CO3 (42 mg, 0.5 mmol) were added. The reaction mixture was heated to 150° C. for 3 h, poured into ice cold water and extracted with EtOAc (3×30 mL). The combined organic extracts were concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to furnish the title compound as a white solid (0.04 g, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 11.71 (s, 1H), 10.03 (s, 1H), 8.61 (s, 1H), 7.70-7.66 (m, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[CH:8]2)=[O:4].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:10][C:9]=2[CH3:14])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(C)c(Cc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A methylene chloride (15 ml) solution of 5-(methoxycarbonyl)-2-methylindole (0.567 g) and 4-benzyloxybenzaldehyde (0.700 g) is dropwise added to a methylene chloride (15 ml) solution of trifluoroacetic acid (0.513 g) and triethylsilane (1.047 g) in an ice-water bath, over a period of 15 minutes. This is stirred for 30 minutes in the ice-water bath, and an aqueous solution of 2 M sodium hydroxide is added thereto to stop the reaction. The organic layer is washed with a saturated saline solution, dried and concentrated. The resulting residue is purified through silica gel column chromatography (eluent: ethyl acetate/hexane=3/7) to obtain 3-(4-benzyloxybenzyl)-5-(methoxycarbonyl)-2-methylindole (62) (0.510 g).
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:3][CH2:4][NH2:5]
Reactant: CN(CCNC(=O)OC(C)(C)C)c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN)c1ccccn1

Procedure:
tert-Butyl 2-[methyl(pyridin-2-yl)amino]ethylcarbamate was stirred with DCM (0.5 ml) and TFA (0.5 ml) for 30 min. The volatiles were removed under reduced pressure to yield the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29](Cl)(=[O:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:31])[CH3:30])=[C:3]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:4]=2)[CH2:9][CH2:10]1)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Yield: 50.8 %

Procedure:
A solution of (4-(4-amino-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (0.7 g, 1.9 mmol), acetyl chloride (0.13 ml, 1.9 mmol) and potassium carbonate (0.31 g, 2.3 mmol) in 20 ml THF was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. N-(4-(4-benzoylpiperazin-1-yl)-2-(phenylamino)phenyl)acetamide (0.40 g, 51%) was obtained after flash column chromatograph (ethyl acetate). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.15 (s, 3H), 3.03-3.95 (m, 8H), 5.93 (s, 1H), 6.66 (dd, J=2.6, 8.8 Hz, 1H), 6.92 (m, 4H), 7.26 (m, 2H), 7.44 (s, 1H), 7.46 (m, 5H), 7.53 (d, J=8.8 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 24.5, 50.2, 110.8, 112.6, 117.3, 121.0, 123.9, 125.3, 127.6, 129.0, 129.9, 130.0, 130.1, 130.3, 136.0, 137.0, 144.6, 150.0, 169.6, 170.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[F:18][C:17]1([F:19])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12][C@@:11]21[C:4]1[C:5](=[CH:6][CH:7]=[C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:3]=1)[O:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10]2
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Reactant: OB(O)c1cncnc1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cncnc4)cc32)C(F)(F)COC1
Yield: 12 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with pyrimidin-5-ylboronic acid yielded the title compound (12% yield). MS (ISP): m/z=423.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:20])[O:18][CH3:19]>O1CCCC1>[CH3:19][O:18][C:17](=[O:20])[NH:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: COC(=O)Cl
Reactant: NCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)NCCc1ccccc1Br

Procedure:
5 g of 2-(2-bromophenyl)ethanamine and 10 g of potassium carbonate in 30 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at a temperature close to 10° C. 2.5 cm3 of methyl chlorocarbonate in solution in 10 cm3 of tetrahydrofuran are poured into the reaction mixture. After returning to a temperature close to 20° C., the reaction mixture is heated for 2 h at the reflux of the solvent. The potassium carbonate is filtered and washed with tetrahydrofuran. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). 3.43 g of methyl[2-(2-bromophenyl)ethyl]carbamate are obtained in the form of a colorless thick oil
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][C:26]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:27][CH:28]=1.[ClH:38].O1CCOCC1>CC(N(C)C)=O>[ClH:19].[ClH:38].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][C:23]3[CH:24]=[N:25][C:26]([NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:27][CH:28]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnc(NC(=O)c2ccccc2)nc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc2c(Nc3cnc(NC(=O)c4ccccc4)nc3)ncnc2cc1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (760 mg, 2.53 mmol) and N-(5-amino-pyrimidin-2-yl)-benzamide (542 mg, 2.53 mmol) in DMA was added 4N HCl in dioxane (822 μl, 3.29 mmol) and the reaction heated at 50° C. for 4 hours under nitrogen. The reaction was cooled and filtered. The precipitate was washed with Et2O and dried under reduced pressure to provide the title compound as a light tan brown solid (706 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.Cl.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:33])[CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:33])[CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:7]([C:5]3[N:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:9])[CH2:31][CH2:32]2)=[CH:21][CH:20]=1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Product: Cc1cc(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)n(-c2ccccc2)n1
Yield: 78.5 %

Procedure:
The title compound was prepared in a similar manner as described in Example 1.2, using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (30.3 mg), and 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg) as starting materials, to afford the title compound (31.9 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.60-2.67 (m, 2H), 2.69 (bs., 2H), 3.81 (s, 2H), 3.89 (bs, 2H), 4.16 (bs, 2H), 6.62 (s, 1H), 7.13 (t, J=8.46 Hz, 2H), 7.38-7.54 (m, 5H), 7.99-8.09 (m, 2H). Exact mass calculated for C23H23FN4O2: 406.2. Found: LCMS m/z=407.5 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=1)[CH2:30][CH2:29]2)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)nc2)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N3CCc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-1-carboxylate and 5-(methyl-sulfonyl)indoline; MS: 473.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][N:4]=1.[OH-].[NH4+].[CH:18](O)=[O:19]>>[CH:18]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][N:4]=1)=[O:19]
Reactant: COC(=O)CCCc1ccnc(CN)c1
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)CCCc1ccnc(CNC=O)c1
Temperature: 25 °C

Procedure:
2-Aminomethyl-4-(3-methoxycarbonylpropyl)pyridine (0.11 g) is heated at 90° in 0.5 ml of 97% formic acid for 18 hours. The reaction is cooled to room temperature, made basic with ammonium hydroxide solution and extracted with methylene chloride (4×20 ml). The organic extracts are dried over sodium sulfate and evaporated to yield 2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)pyridine; IR (CH2Cl2) 1735, 1685 cm-1.
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:14]([Cl:27])[CH:13]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[C:23]([O:22][C:20]([CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([OH:28])=[O:8])=[CH:13][C:14]=1[Cl:27])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)O)cc1Cl

Procedure:
A solution of 3-(4-tert-Butoxycarbonylmethoxy-3-chloro-phenyl)-propionic acid benzyl ester (step 2) (6.35 g, 15.7 mmol) in THF (60 ml) was added to a suspension of palladium on activated carbon (10% wt, 0.84 g, 0.78 mmol) in THF (35 ml) under an inert atmosphere. The resultant mixture was placed under an atmosphere of hydrogen (0.35 bar) for 3 h. The reaction mixture was filtered through Celite® (filter material) and washed through with THF (100 ml). The filtrate was concentrated in vacuo to afford the title compound as a yellow oil; 1H NMR (400 MHz, DMSO-d6) δ 12.15 (1H, s), 7.31 (1H, d), 7.12 (1H, dd), 6.91 (1H, d), 4.74 (2H, s), 2.75 (2H, t), 2.51 (2H, t), 1.38 (9H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Reactant: C1CCNCC1
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(N5CCCCC5)ccc4C3=O)cc2F)C1

Procedure:
Trifluoromethanesulfonic acid 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ester was reacted with piperidine by method N. The product with the molecular weight of 436.58 (C26H33FN40) was obtained in this way; MS (ESI): 437 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[S:26][CH:27]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1cc(Cl)cs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Cl)cs4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 5.5 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-chlorothiophen-2-yl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (400 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (12 mg) as a white solid.