Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:4]1[OH:16].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.C([O-])([O-])=O.[Na+].[Na+]>CCC(C)=O>[O:23]=[C:22]1[NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH:4]2[O:16]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C(O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CNC(=O)OC2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a mixture of rac-(3R*,4R*)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (3.39 g, 14.72 mmol; prepared according to Tetrahedron (2008), 64, 2456-2464) in MEK (40 mL) heated to 60° C. was added CDI (3.58 g, 22.08 mmol, 1.5 eq). The mixture was stirred for 3 h. Na2CO3 (5% aq., 4 mL) was added. The reaction proceeded at rt for 70 min. The two layers were decanted and the aq. layer was extracted with EA (10 mL). The combined org. layers were washed with brine (8 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (DCM to DCM/MeOH 9:1) to afford the title compound as a white solid (2.59 g).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)c(C)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: Cc1ccc(-c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)c(C)c1

Procedure:
The product of Example 159A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68 (s, 1H), 8.37-8.40 (m, 1H), 7.85-7.97 (m, 2H), 7.34-7.45 (m, 4H), 7.25-7.31 (m, 1H), 7.19-7.24 (m, 2H), 7.14-7.18 (m, 1H), 3.69 (s, 2H), 2.37 (s, 3H), 2.04 (s, 3H); MS (APCI+) M/Z 418 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2Cl.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:18]=1[F:25])[CH3:15]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:14][CH3:15])=[C:18]([F:25])[CH:19]=1)[CH3:24]
Reactant: CCOc1ccc(NC)cc1F
Reactant: Cc1nc(Cl)c2cc(Br)ccc2n1
Solvent: CC(C)O
Product: CCOc1ccc(N(C)c2nc(C)nc3ccc(Br)cc23)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A mixture of 0.21 g (0.82 mmol) of 6-bromo-4-chloro-2-methyl-quinazoline and 0.16 g (0.89 mmol) of (4-ethoxy-3-fluoro-phenyl)-methyl-amine in i-PrOH (20 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected and washed with Et2O to give 0.1 g of the title compound as the HCl salt. 1H NMR (DMSO-d6) δ 8.32-6.8 (6H), 4.23 (q, 2H), 3.72 (s, 3H), 2.73 (s, 3H), 1.39 (t, 3H); LC-MS (ESI+; 391 ([M+H]+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:24][CH2:23][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:17][C@H:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)[C:11]=3[CH2:10]2)=[CH:5][C:4]=1[C:25]([F:28])([F:27])[F:26].[CH3:29][N:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[N:31]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:24][CH2:23][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:35]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)=[O:36])[CH2:19]4)[C:11]=3[CH2:10]2)=[CH:5][C:4]=1[C:25]([F:28])([F:26])[F:27]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Reactant: Cn1cc(C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5cnn(C)c5)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (44 mg, 0.11 mmol), 1-methyl-1H-pyrazole-4-carboxylic acid (15 mg, 0.12 mmol), benztriazol-1-ol (19 mg, 0.12 mmol) in CH2Cl2 (1.0 mL) was added EDC (34 mg, 0.18 mmol) and the resulting mixture was stirred at rt for 18 h. Partitioned between CH2Cl2 (10 mL) and sat. NaHCO3(aq) (2.0 mL) and the organic layer separated by filtering through a phase separation tube. Concentrated in vacuo and purified by flash chromatography through Biotage® amino silica gel eluting with cyclohexane/EtOAc, 100/0 to 0/100 to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanone as a white lyophilized powder (44 mg, 75% yield). 1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 2.26-2.45 (m, 2H) 3.04-3.10 (m, 2H) 3.49-3.57 (m, 2H) 3.89-4.00 (m, 7H) 4.01 (s, 3H) 4.10-4.18 (m, 2H) 5.78-5.83 (m, 1H) 7.60-7.62 (m, 1H) 7.76-7.89 (m, 2H) 8.04-8.07 (m, 1H) 8.61-8.66 (m, 1H) MS: [M+H]+=504.2, Rt(3)=1.59 min. Example 55 was prepared using procedures analogous to those used in example 54 using appropriate starting materials.
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][C:21]([CH3:31])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=2)[N:18]=1.[K][S:33][C:34](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[S:35][K]>>[N+:28]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[CH3:31])[N:18]=[C:17]1[S:33][C:34](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[S:35][C:26]1=[N:25]2)([O-:30])=[O:29]
Reactant: Cc1cc2nc(Cl)c(Cl)nc2cc1[N+](=O)[O-]
Reactant: N#CC(C#N)=C(S[K])S[K]
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: Cc1cc2nc3c(nc2cc1[N+](=O)[O-])SC(=C(C#N)C#N)S3
Yield: 71 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 1.5 g of 2,3-dichloro-6-nitro-7-methylquinoxaline and 1.5 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a dark yellow powder weighing 1.35 g with a calculated overall yield of 71 percent and has a melting point of 283° to 284° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1([O:19][CH2:18][CH2:17][O:16]1)[CH2:14][Br:15])[C:10]([OH:12])=O.[NH2:20][CH:21]1[C:31](=[O:32])[N:23]2[C:24]([C:28]([OH:30])=[O:29])=[CH:25][CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1([O:19][CH2:18][CH2:17][O:16]1)[CH2:14][Br:15])[C:10]([NH:20][CH:21]1[C:31](=[O:32])[N:23]2[C:24]([C:28]([OH:30])=[O:29])=[CH:25][CH2:26][S:27][C@H:22]12)=[O:12]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CON=C(C(=O)O)C1(CBr)OCCO1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1(CBr)OCCO1
Yield: 100 %

Procedure:
Phosphorus oxychloride (0.54 ml.), N,N-dimethylformamide (438 mg.), 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyric acid (syn isomer, 1.6 g.), 7-amino-3-cephem-4-carboxylic acid (1 g.), trimethylsilylacetamide (3.3 g.) and dry ethyl acetate (21 ml.) were treated in a similar manner to that of Example 11 (1) to give 7-(2-methoxyimino-3,3-ethylenedioxy-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 2.25 g.)
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:35]1[CH:36]=[CH:37][C:38](=[O:42])[N:39]([CH3:41])[CH:40]=1>>[CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:35]3[CH:36]=[CH:37][C:38](=[O:42])[N:39]([CH3:41])[CH:40]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Product: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 76. Mass spectrum (ESI+): m/z=433 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3ccccc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (160 mg, 0.490 mmol) and phenol were reacted as starting materials at 120° C. for 22 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless needles (133.1 mg, 70.7%). Melting point: 198.8-199.5° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O.CC[O:22][CH2:23][CH3:24].[C:25](OC(=O)C)(=O)[CH3:26]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:23](=[O:22])[CH:24]=[C:25]([CH3:26])[O:16][C:14]=3[CH3:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CC(=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)o1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-chlorophenoxy)phenylpropan-2-one (26 g) in acetic anhydride (100 ml) was added, over 5 min, to a vigorously stirred mixture of polyphosphoric acid (200 g) and acetic anhydride (100 ml) at 80°. After stirring for 30 min the mixture was poured into water (1 liter) and extracted with toluene (2×500 ml). The combined extracts were washed with water then satd. aq. sodium bicarbonate, dried over magnesium sulphate and evaporated to give an oil. Trituration with ether gave a yellow solid, which was recrystallised from carbon tetrachloride to afford the title compound (14.64 g), m.p. 150°-152°, NMR δH (CDCl3) 6.95-7.4 (8H, m), 6.2 (1H, s), 2.3 (3H, s), 2.2 (3H, s).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[O:18]([C:25]1[CH:33]=[CH:32][C:28](C(Cl)=O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:34]([NH:41][CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]([CH3:42])[C:15]([C@@H:9]1[CH2:10][C:11](=[CH:13][Cl:14])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:17])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)[C@@H]1CC(=CCl)CN1C(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and N-benzyl-N-methylamine the title compound was obtained in 61% purity by LC/MS. MS(ESI+): m/z=461.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:16]2[N:15]=[C:14]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:7].[OH:25][C:26]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>CS(C)=O.C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:16]2[N:15]=[C:14]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH2:28][C:27]4[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:26]=4[OH:25])[CH2:23][CH2:24]3)[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COCCNC(=O)c1cccc2[nH]c(NCC3CCNCC3)nc12
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COCCNC(=O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)ccc4O)CC3)nc12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
After dissolving 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid (2-methoxy-ethyl)-amide (20 mg, 0.049 mmol) in dimethylsulfoxide-acetic acid (10:1, 0.50 ml), 2-hydroxy-5-chlorobenzaldehyde (23 mg, 0.15 mmol) and sodium triacetoxyborohydride (31 mg, 0.15 mg) were added and the mixture was stirred at 50° C. for 2 days. Methanol (1 ml) was added to the reaction mixture, and after stirring for 1 minute, the mixture was purified by SCX solid phase extraction (Bond Elute SCX500MG). The product was further purified by preparative HPLC to obtain 2-{[1-(5-chloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid (2-methoxy-ethyl)-amide. The compound was identified by LC-MS.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5](OC)=[N:4]1)[CH3:2].[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH2:1]([CH:3]1[NH:4][C:5](=[NH:13])[CH2:6][CH2:7][CH2:8][CH2:9]1)[CH3:2]
Reactant: CCC1CCCCC(OC)=N1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: CCC1CCCCC(=N)N1
Product: Cl
Yield: 84.5 %

Procedure:
The product of EXAMPLE 57 (802 mg, 5.2 mmol) in 15 mL of MeOH was reacted, with ammonium chloride (225 mg, 4.2 mmol) by the method of EXAMPLE 27 to yield 627 mg (82%) of the title material.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6](O)[CH2:5][CH2:4][CH2:3]1.[CH3:9][NH2:10].Cl.[C-:12]#[N:13].[Na+]>O1CCOCC1.O>[OH:7][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([NH:13][CH3:12])[C:9]#[N:10]
Reactant: CN
Reactant: CC1CCCC(O)O1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(C#N)CCCC(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 6-methyltetrahydro-2H-pyran-2-ol (42 g, 350 mmol) was dissolved in dioxane (300 mL) and treated with methylamine (40% in water, 32 mL, 350 mmol) followed by methylamine.HCl (19 g, 280 mmol) and then sodium cyanide (17 g, 350 mmol) followed by water (50 mL). After stirring at room temperature overnight, the organic phase was decanted off and concentrated. The residue was dissolved in ethyl acetate. Water was added to the initial aqueous suspension (which had been left behind) until dissolution was complete, after which both phases were combined and extracted. The organic phase thus obtained was concentrated. The aqueous phase was extracted twice more with fresh ethyl acetate and the extracts concentrated. The combined residue was dissolved in ether and filtered to remove the remaining solids. Concentration gave the product as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 3.81 (m, 1H), 3.46 (t, J=7 Hz, 1H), 2.53 (s, 3H), 1.76 (m, 2H), 1.34-1.65 (m, 4H), 1.19 (d, J=6.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][C:14]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=3[F:35])=[O:26])=[C:20]([F:36])[CH:19]=2)[CH:9]=1)=[O:7].C(N(CC)C(C)C)(C)C.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].O>CN(C=O)C>[F:36][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[NH:24][C:25]([NH:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[F:35])=[O:26])[O:17][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:7])[S:16][C:15]=12
Reactant: COC(=O)CBr
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN)sc34)cc2F)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (125 mg, 0.24 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) in 10 ml of anhydrous DMF was added methyl bromoacetate (36 mg, 0.24 mmol). The mixture was stirred at room temperature for 50 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 5˜8% of MeOH in CHCl3 to afford methyl ({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate as light beige solid. Yield: 54 mg, 38%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)c1ccc(OCCCCBr)cc1
Product: CCN(CC)CCCCOc1ccc(N(C)C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
In analogy to example 17.1, reaction of [4-(4-Bromo-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester with diethylamine yielded [4-(4-Diethylamino-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester, MS: 405 (MH+).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=[C:16]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CS(C)=O>[F:28][C:2]([F:1])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=[C:16]([NH:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:24][CH2:25]4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (180 mg, 0.46 mmol) and DIPEA (178 mg, 1.38 mol) in DMSO (2.0 mL) was added dropwise MeSO2Cl (53 mg, 0.46 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed most of starting material was converted. The mixture was partitioned between brine (100 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-91 (57.1 mg, 26.4%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10].S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([O:11][CH2:17][CH2:3][CH2:2][CH2:20][CH3:19])=[O:10]
Reactant: CC(Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCCOC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionic acid is dissolved in tetrahydrofuran, to this is added thionyl chloride while stirring, then, the mixture is heated while stirring under reflux condition. Then, the solution is allowed to cool, concentrated, then, dissolved in tetrahydrofuran (hereinafter, referred to as Solution A). Tetrahydrofuran is added to 1-pentyl alcohol, and Solution A is added to this, then, pyridine is added. The mixture is stirred at room temperature, then, 2% aqueous hydrochloric acid is poured into the reaction solution, and extracted with ethyl acetate. The organic layer is washed with saturated saline, and dried over magnesium sulfate, then, concentrated. The residue is subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain pentyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [compound 3-189 of the present invention].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([I:1])[C:10]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)=[C:9]([I:12])[CH:8]=1
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Reactant: BrCc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1cccc(Br)c1)c1cc(I)c(OCc2cccc(Br)c2)c(I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.8 %

Procedure:
A suspension of 3,5-diiodo-4-hydroxybenzoic acid (0.39 g, 1.0 mmol), 3-bromobenzyl bromide (0.62 g, 2.5 mmol), and cesium carbonate (0.98 g, 3.0 mmol) in 10 mL DMF was stirred for 15 hours at room temperature. The mixture was then poured into 1 M HCl (100 mL) and a white precipitate formed. The precipitate was isolated by vacuum filtration and was recrystallized from hot isopropanol/chloroform, yielding the title compound as bright white crystals (610 mg, 84%); 1H NMR (CDCl3) δ 8.48 (s, 2H), 7.80 (br. s, 1H), 7.58-7.49 (m, 4H), 7.38-7.28 (m, 3H), 5.31 (s, 2H), 5.01 (s, 2H).
Reaction SMILES: OC[C:3]1[CH:16]=[N:15][C:6]2[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C[CH2:26][N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C.Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2CCNCC=2)=[CH:38][CH:37]=1>C(#N)CC>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH2:30][CH2:28][N:27]([CH2:26][N:10]3[C:9](=[O:11])[CH2:8][N:7]([CH:12]([CH3:13])[CH3:14])[C:6]4[N:15]=[CH:16][CH:3]=[CH:4][C:5]3=4)[CH2:31][CH:33]=2)=[CH:38][CH:37]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CC(C)N1CC(=O)Nc2cc(CO)cnc21
Reactant: CCN(C(C)C)C(C)C
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Product: CC(C)N1CC(=O)N(CN2CC=C(c3ccc(Cl)cc3)CC2)c2cccnc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.452 mmol) was taken up as a suspension in propiononitrile (1 mL). Next was added (cyanomethyl)trimethylphosphonium iodide (132 mg, 0.542 mmol) followed by DIPEA (0.237 mL, 1.356 mmol). To the stirred white suspension was then added the 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (114 mg, 0.50 mmol). The reaction was heated to 90° C. and stirred overnight. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (46.9 mg, 26%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.50 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.40-7.46 (m, 2H), 7.34-7.39 (m, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.18 (br. s., 1H), 4.76-4.87 (m, 1H), 3.81 (s, 2H), 3.40 (s, 2H), 3.01 (d, J=2.8 Hz, 2H), 2.60 (t, J=5.6 Hz, 2H), 2.43 (br. s., 2H), 1.12 (d, J=6.8 Hz, 6H). [M+H] calc'd for C22H25ClN4O, 397. found, 397.