Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>>[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([S:2]([N:1]=[C:23]=[O:24])(=[O:3])=[O:4])[CH:14]=1)[CH3:17]
Reactant: CCCCN=C=O
Reactant: CCOc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Agent: O=C(Cl)Cl
Product: CCOc1ccc(C(=O)OC)c(S(=O)(=O)N=C=O)c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of methyl 2-(aminosulfonyl)-4-ethoxybenzoate (7.56 g. 29.2 mmol). n-butyl isocyanate (3.29 mL. 29.2 mmol). and 1.4-diaza[2.2.2]bicyclooctane (0.13 g 1.2 mmol) in mixed xylenes was heated at reflux for 10 minutes. Phosgene was then added at such a rate that the internal temperature stayed at 133° C. or above. When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporation gave methyl 4-ethoxy-2-(isocyanatosulfonyl)benzoate as a cloudy yellow oil (8.2 g). This was used immediately without further purification or characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:39][C:37]2[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3cnccc23)CC1
Reactant: Cc1ccc(F)cc1O
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccncc2n1-c1ccccc1

Procedure:
The crude title compound was prepared from the compound of example 16, step 5, (100 mg, 227 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(OC)=NN=NC=1OC.CN1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:44]([O:51][C:52](=[O:56])[CH2:53][CH2:54][NH2:55])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([O:51][C:52](=[O:56])[CH2:53][CH2:54][NH:55][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Agent: COc1nnnc(OC)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCC(=O)NCCC(=O)OCc1ccccc1

Procedure:
4-(t-Butoxycarbonylamino)butyric acid in THF was activated with chlorodimethoxytriazine and N-methylmorpholine and reacted with β-alanine benzyl ester p-toluenesulphonate in the presence of N-methylmorpholine to give N-[4-(1-t-butoxyformamido)butyryl]-β-alanine benzyl ester, m.p. 54°-55° C.
Reaction SMILES: ClC1C=CC(CC(O)=O)=CC=1OC1C=C[C:16]([S:19](C)(=[O:21])=[O:20])=[CH:15]C=1C#N.N[C:26]1[CH:27]=[CH:28][C:29]([Cl:34])=[C:30]([CH:33]=1)[C:31]#[N:32].C(SSCC)C>>[Cl:34][C:29]1[CH:28]=[CH:27][C:26]([S:19]([CH2:16][CH3:15])(=[O:21])=[O:20])=[CH:33][C:30]=1[C:31]#[N:32]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(C#N)c1
Reactant: N#Cc1cc(N)ccc1Cl
Solvent: CCSSCC
Product: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1

Procedure:
The subtitle compound was prepared by the methods of example 2 steps (i) and (ii) using 5-amino-2-chlorobenzonitrile and diethyldisulfide.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]3[OH:31])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:33][C:34]1[CH:35]=[CH:36][C:37]2[O:42][CH2:41][C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=2[CH:49]=1>>[CH:1]1([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH:19]3[O:31][CH2:33][C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=4[CH:49]=3)=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC3CCCCC3)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOC4CCCCC4)cc3)cc21

Procedure:
Analogously to Method D, 0.470 g of tert-butyl 4-[4-(3-cyclohexyloxypropoxy)phenyl]-3-hydroxypiperidine-1-carboxylate and 0.324 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.46 (1:1 EtOAc-heptane); Rt=6.20.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([S:13]([C:16]([C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[CH3:31])[N:22]=[C:21]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[N:20]=1)([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH3:12].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:11]([S:13]([C:16]([C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[CH3:31])[N:22]=[C:21]([C:32]2[CH:33]=[CH:34][C:35]([NH:36][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:37][CH:38]=2)[N:20]=1)([CH3:17])[CH3:18])(=[O:14])=[O:15])[CH3:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCS(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Phenyl chloroformate (0.373 mL, 2.97 mmol) was added dropwise to 4-[4-(2-ethylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.20 g, 2.97 mmol) and sodium bicarbonate (0.374 g, 4.45 mmol) in dioxane (25 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a white solid (1.40 g).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CCOCC.[C:10]([N:14]1[C:19](=[O:20])[C:18](Cl)=[C:17]([Cl:22])[CH:16]=[N:15]1)([CH3:13])([CH3:12])[CH3:11].ClC1C=NNC(=O)C=1Cl>C1(C)C=CC=CC=1>[CH2:1]([C:18]1[C:19](=[O:20])[N:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:15]=[CH:16][C:17]=1[Cl:22])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CC[Mg]Br
Agent: O=c1[nH]ncc(Cl)c1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Into a four-necked flask of 1 liter, 43 g of ethylmagnesium bromide (3 mol/liter of an ether solution) and 200 ml of dehydrated toluene were charged. While thoroughly stirring the mixture at room temperature, 22.1 g (0.1 mol) of 2-t-butyl-4,5-dichloro-3(2H)pyridazinone was added in three portions. The reaction temperature was raised to a level of about 60° C., and the stirring was continued for about 30 minutes. The disappearance of the starting dichloropyridazinone was confirmed by thin layer chromatography (developer; hexane:acetone =20:1, v/v), whereupon the reaction was terminated. After the addition of about 300 ml of chilled water, the mixture was stirred vigorously, and transferred to a separating funnel, and then the aqueous layer was removed. The organic layer was washed with about 200 ml of water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The pale brown oily substance thereby obtained was purified by silica gel column chromatography (developer; benzene) to obtain pale yellow crystals. 1.45 g (yield: 67.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([OH:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([Br:24])[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:13]([C:14](=[O:23])[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[C:12]([Br:24])[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
3-Benzyloxy-5-bromo-4-[hydroxyl(4-methoxyphenyl)-methyl]-1-isopropyl-1H-pyrazole (0.6 g) was dissolved in dichloromethane (10 mL), and manganese dioxide was added to the stirred solution at room temperature. The mixture was stirred at 50° C. for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.4 g).
Reaction SMILES: C[CH:2]([CH3:19])[CH2:3][CH2:4][C:5]([CH2:15][CH2:16][CH2:17]O)([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:6]([OH:8])=[O:7].[CH2:20](OC(=O)CCCCC([O:32][CH2:33][CH2:34][CH:35]([CH3:37])[OH:36])=O)CCC.C(O)(=O)CCCCC(O)=O.C(O)CC(O)C>C(O)CCC>[CH2:15]([C:5]([CH2:4][CH2:3][CH2:2][CH3:19])([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:6]([OH:8])=[O:7])[CH2:16][CH2:17][CH3:20].[CH2:33]([OH:32])[CH2:34][CH:35]([OH:36])[CH3:37]
Reactant: CC(C)CCC(CCCO)(CCCC(=O)O)C(=O)O
Reactant: CCCCOC(=O)CCCCC(=O)OCCC(C)O
Agent: CC(O)CCO
Agent: O=C(O)CCCCC(=O)O
Solvent: CCCCO
Product: CCCCC(CCCC)(CCCC(=O)O)C(=O)O
Temperature: 160 °C
Yield: 75.8 %

Procedure:
The ester-alcohol can be obtained in the method of the present invention by not carrying out the alcohol removing ester-interchange reaction, or as an unreacted fraction in the ester-interchange reaction which distills between the bis compound and the starting diester. On the other hand, it can be obtained as an intermediate of direct alcohol removing ester-interchange reaction between the diester and the diol. Adipic acid 3-methyl-3-hydroxypropyl butyl ester (3-methyl-3-hydroxypropyl butyl adipate), an ester alcohol prepared from adipic acid, 1,3-butanediol, and butanol may be purified after dehydrating esterification as in Example 1, and catalyst removing treatment and then distillation. The boiling point is 155° to 160° C./0.2 mmHg. Using a mixture of 82.8 g of this product and 405 g of dibutyl adipate (mol ratio is 1:5.2) to which 0.5 g of butyl titanate was added, reaction was carried out under a reduced pressure of 20 mmHg and heating at 160° C. for 12 hours with stirring while removing 21.5 g (97%) of resulting butanol, and after completion of the reaction, catalyst removing alkali washing and water washing as well as distillation was carried out to obtain 342 g of DBA and 5.2 g of unreacted ester-alcohol and 94.9 g (75.8%) of 1,3-butanediol bis-butyl adipate having a boiling point of 235° to 245° C./0.8 mmHg and 7.6 g (8.4%) of a residual material which was considered to be an oligomer of n=2.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:45][C:44]2[CH:46]=[CH:47][CH:48]=[C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][N:33]=3)[CH:43]=2)=[O:19])[N:7]([C:20]2[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ncccc1-n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccnc4C)c3)c2cc1OC
Yield: 20 %

Procedure:
Phenyl 3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.3 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.30 mmol) (prepared as described in Example 113A) using the procedure in Example 115C to afford 1-(3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (33 mg, 0.06 mmol, 20%). 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.60 (d, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 7.80 (d, 1H), 7.54 (s, 2H), 7.45-7.32 (m, 3H), 7.12 (d, 1H), 6.91 (d, 1H), 6.35 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 2.20 (s, 3H) 1.25 (s, 9H); LC-MS (ESI) m/z 554 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]3[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:21][C:22]1[CH:23]=[C:24]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:20]=[CH:19][C:11]3[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:10]=3[CH:9]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Brc1cccc(I)c1
Reactant: c1ccc(Nc2ccc3oc4ccccc4c3c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1cccc(N(c2ccccc2)c2ccc3oc4ccccc4c3c2)c1
Yield: 70 %

Procedure:
N-phenyldibenzo[b,d]furan-2-amine (5.0 g, 19.3 mmol), and 1-bromo-3-iodobenzene (10.9 g, 38.6 mmol) were mixed in 100 mL of toluene. The solution was bubbled with nitrogen for 15 min. Pd(OAc)2 (0.22 g, 1.0 mmol), triphenylphosphine (0.51 g, 1.9 mmol) and sodium t-butoxide (2.2 g, 23.1 mmol) were then added. The mixture was refluxed overnight under nitrogen. After cooling, the reaction mixture was filtered through celite/silica pad and the filtrate was concentrated under vacuum. The residue was then purified by column chromatography using DCM:hexane (1:1, v/v) as the eluent. 5.6 g (71%) of a yellow solid was obtained as the product.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:18]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)=[O:19])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH2:2][CH3:3].Cl.[NH2:30][OH:31]>CCO.N1C=CC=CC=1>[CH2:1]([C:4]1[C:5]([C:18]([C:20]2[CH:28]=[CH:27][C:23]([C:24](=[N:30][OH:31])[OH:25])=[CH:22][CH:21]=2)=[O:19])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCCc1cc2c(cc1C(=O)c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCc1cc2c(cc1C(=O)c1ccc(C(O)=NO)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthyl)carbonyl]benzoic acid (101) (12.6 mmol) in EtOH (10 mL) and pyridine (15.3 mL) was treated with hydroxylamine hydrochloride (4.38 g, 63 mmol), and the mixture was heated at reflux. After 6 h, the mixture was cooled to room temperature and the ethanol was removed in vacuo. The residue was taken-up in water and the aqueous layer was adjusted to pH=4-5 with 1 M aqueous HCl. The aqueous solution was extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated to give a foamy white solid. Recrystallization (CH2Cl2/ether/hexanes) gave 4-[(3-n-propyl,5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (104), as white crystals (85%): mp 255-257°C.; 1H-NMR (400 MHz, CDCl3) δ8.19 (½ABq, J=8.3 Hz, 2H, ArH), 7.89 (½ABq, J=8.3 Hz, 2H, ArH), 7.23 (s, 1H, ArH), 7.20 (s, 1H, ArH), 2.65 (m, 2H, CH2), 1.70 (m, 4H, 2CH2), 1.56 (m, 2H, CH2), 1.32 (s, 6H, 2CH3) 1.20 (s, 6H, 2CH3), 0.88 (t, J=7.3 Hz, 3H, CH3).
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:34])[N:29]=3)[CH:23]=2)[CH2:17][C@@H:16]1[CH3:35])=[O:14])([CH3:11])([CH3:10])[CH3:9].NCCC1C=CC(O)=CC=1>>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:34])[N:29]=3)[CH:23]=2)[CH2:17][C@H:16]1[CH3:35])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[C@H]1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Agent: NCCc1ccc(O)cc1
Solvent: Oc1ccccc1
Product: C[C@@H]1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C

Procedure:
442-{4-[3-(3-S-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol: Intermediate 128 4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester was coupled with tyramine following procedure F then deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 404. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.6 (s, 1H) 8.4 (m, 2H) 7.9 (s, 1H) 7.6 (d, 2H) 7.1 (s, 2H) 6.7 (a, 2H) 4.6 (S, 2H) 3.9 (s, 2H) 3.6 (m, 7H) 2.9 (s, 2H) 1.4 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][C:19](S(C)(=O)=O)=[N:20][CH:21]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[N:27]1[C:28]([CH2:36][OH:37])=[CH:29][N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=12.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([O:37][CH2:36][C:28]4[N:27]=[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]5[CH:29]=4)=[N:20][CH:21]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: OCc1cn2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2cn3ccccc3n2)nc1
Temperature: 67 °C
Yield: 23.3 %

Procedure:
A mixture of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide (120mg, 0.32mmol), imidazo[1,2-a]pyridine-2-methanol (48mg, 0.32 mmol) and potassium carbonate (44 mg, 0.32 mmol) in THF (5 mL) was heated to 67° C. for 3.5 h. The mixture was cooled to room temperature and partitioned between DCM and water and the layers separated. The aqueous layer was extracted with DCM and the combined organic extracts dried (MgSO4), filtered and concentrated at reduced pressure to give a yellow oil. This material was purified by silica column chromatography, eluting with a gradient of 0 to 8% methanol in DCM to give the title compound as a white solid (33 mg, 23%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 2.27 (s, 3H), 2.83 (m, 1H), 5.70 (s, 2H), 7.26 (t, 1H), 7.35 (d, 1H), 7.66 (m, 2H), 7.78 (d, 1H), 7.83 (d, 1H), 8.30 (s, 1H), 8.38 (d, 1H), 8.75 (d, 1H), 9.17 (s, 2H), 10.16 (s, 1H); Mass Spectrum: M−H− 441, M+H+ 443.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[N+:22]([C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([O-])=O.O.CCOC(C)=O>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(CNC(=O)OC(C)(C)C)c4)nc(Cl)nc32)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 99.1 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.585 mmol), tert-butyl 3-nitrobenzylcarbamate (137 mg, 0.617 mmol) and TEA (0.200 mL, 1.44 mmol) in nBuOH (5 mL) was stirred at 110° C. for 20 h. Water and EtOAc were added. The organic phase was washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzylcarbamate (306 mg).
Reaction SMILES: [Cl:1][C:2](=[C:8]([Cl:10])[Cl:9])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]=1[NH:20][C:21](=[O:24])[O:22][CH3:23]>O1CCCC1.N12CCN(CC1)CC2>[Cl:1][C:2](=[C:8]([Cl:10])[Cl:9])[C:3]([NH:5][C:6]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][C:21](=[O:24])[O:22][CH3:23])=[O:7])=[O:4]
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Reactant: O=C=NC(=O)C(Cl)=C(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COC(=O)Nc1nc2ccccc2n1C(=O)NC(=O)C(Cl)=C(Cl)Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.9 %

Procedure:
13.5 g of trichloroacryloyl-isocyanate were added dropwise to 10 g of methyl 2-benzimidazolyl-carbamate and 0.1 g of 1,4-diazabicyclo (2,2,2) octane in 160 ml of tetrahydrofuran and the mixture was stirred for 17 hours at room temperature and was vacuum filtered. The crystals obtained were washed with petroleum ether and dried under reduced pressure to obtain 18.2 g of methyl 1-trichloroacryloylcarbamoyl-2-benzimidazolyl-carbamate as a solid melting at 231°C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:5].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:2][CH2:3][C:4]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C(=O)CN)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)cc1
Yield: 53 %

Procedure:
In the same manner as in Reference Example 6, ethyl 4-(2-amino-1-oxoethyl)benzoate hydrochloride and 4-trifluoromethylbenzoyl chloride were condensed to obtain ethyl 4-[2-(4-trifluoromethylbenzoylamino)-1-oxoethyl]benzoate. Yield: 53%. NMR (CDCl3) δ 1.43 (3H, t, J=7 Hz), 4.43 (2H, q, J=7 Hz), 5.01 (2H, d, J=4 Hz), 7.31 (1H, brs), 7.75 (2H, d, J=8 Hz), 7.95-8.25 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:12]([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ncccc1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
In a 50 mL round-bottom flask fitted with magnetic stirrer were placed 3-hydroxypyridine-2-carboxylic acid methyl ester (3.5 g, 22.80 mmol), K2CO3 (3.46 g, 25.0 mmol), Mel (4.87 g, 34.3 mmol) and DMF (20 mL). The reaction mixture was stirred for 18 h at rt under nitrogen. The reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography using 30% EtOAc in hexane to give 2.1 g of 3-methoxypyridine-2-carboxylic acid methyl ester (54%).