Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.O.CCOC(C)=O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(Cl)(Cl)Cl.ClCCl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:37]2[CH:36]=[N:35][C:34]([N:31]3[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:15]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2ccn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)cc3c2ccn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (0.10 g, 0.240 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (0.087 g, 0.288 mmol) and potassium phosphate (tribasic) (0.153 g, 0.721 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was degassed with N2 for 10 min, at which time PdCl2(dppf)-CH2Cl2 (0.029 g, 0.036 mmol) was added. The reaction was sealed and heated at 100° C. for 2 h. The reaction was then allowed to cool to RT and sat overnight, at which time it was diluted with EtOAc, filtered through Celite, washed with EtOAc, and concentrated in vacuo. Purification of the residue by column chromatography (12 g Isco GOLD silica column; Gradient B: 5-90%; A: dichloromethane, B: 10% chloroform containing 2 M ammonia in methanol) gave N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide (94 mg, 0.180 mmol, 74.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J=6.57 Hz, 6H) 2.12 (s, 3H) 2.17-2.28 (m, 6H) 2.38-2.46 (m, 4H) 3.49-3.57 (m, 4H) 4.37 (d, J=5.05 Hz, 2H) 4.86-4.98 (m, 1H) 5.88 (s, 1H) 6.87 (d, J=3.03 Hz, 1H) 6.93 (d, J=8.84 Hz, 1H) 7.58 (d, J=3.28 Hz, 1H) 7.65 (d, J=1.26 Hz, 1H) 7.87 (s, 1H) 7.98 (dd, J=8.97, 2.65 Hz, 1H) 8.28 (t, J=5.05 Hz, 1H) 8.57 (d, J=2.27 Hz, 1H) 11.55 (s, 1H). MS (ES) [M+H]+ 513.3.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:38])[N:9]=[C:10]([S:36][CH3:37])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[CH:28]=[C:27]([OH:34])[C:26]=1[F:35])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH2:47][O:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][O:50]1>O>[CH3:6][O:7][C:8](=[O:38])[N:9]=[C:10]([S:36][CH3:37])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[CH:28]=[C:27]([O:34][CH2:46][CH2:47][O:48][CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[C:26]=1[F:35])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: BrCCOC1CCCCO1
Reactant: CCOc1cc(O)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(OCCOC2CCCCO2)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 2 ml of a DMF solution containing 75 mg of {2-(5-ethoxy-2-fluoro-3-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester, 100 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting mixture was stirred at room temperature for 10 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give {2-{5-ethoxy-2-fluoro-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (51 mg) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[C:8]([C:18](OCC)=[O:19])[N:7]=1)=O)C.[Cl-].[Cl-].[Ca+2]>C1COCC1>[N:12]1([C:10]2[CH:11]=[C:6]([CH2:4][OH:3])[N:7]=[C:8]([CH2:18][OH:19])[CH:9]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cc(N2CCNCC2)cc(C(=O)OCC)n1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OCc1cc(N2CCNCC2)cc(CO)n1

Procedure:
Diethyl-4-piperazinyl-2,6-pyridinedicarboxylate is dissolved in THF and treated with NaBH, and CaCl2 as per the procedure of Example 51 to give the title compound.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]([OH:6])=O.[CH2:7]([C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([C@H:14]1[CH2:18][N:17]([C:4](=[O:6])[CH2:3][OH:2])[C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CO
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CO
Yield: 33.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-hydroxyacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 120, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (9.1 mg, 33.8%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.55-7.59 (m, 2H), 7.28-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.94-7.02 (m, 4H), 4.50-4.52 (m, 1H), 4.02 (s, 2H), 3.50-3.59 (m, 1H), 3.15 (m, 1H), 2.63-2.73 (m, 3H), 1.89-1.93 (m, 2H). MS (EI) for C26H25FN2O4. found 449.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([C:11](=[O:32])[NH:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:34]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([C:11](=[O:32])[NH:12][C:13]1[CH:18]=[C:17]([Br:19])[C:16]([Cl:34])=[C:15]([C:20]#[C:21][Si:22]([CH:23]([CH3:24])[CH3:25])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[N:14]=1)[CH3:10])[CH3:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C(=O)Nc1cc(Br)cc(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C(=O)Nc1cc(Br)c(Cl)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of (1-{4-Bromo-6-[(triisopropylsilanyl)-ethynyl]-pyridin-2-ylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester C1 (50 mg, 930 μmol), N-chlorosuccinimide (12 mg, 0.90 mmol) and ACN (1 ml) is stirred at 50° C. for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 11 mg (21%). HPLC-MS: M+H=574/572; tR=2.04 min (METHOD—1).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1.P(Br)(Br)([Br:30])=O>C(#N)C>[Br:30][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccccc3C)cc2c1O
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccccc3C)cc2c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of butyl 1,4-dihydroxy-6-(o-tolyloxy)isoquinoline-3-carboxylate (1.5 g, 4.2 mmol) and POBr3 (4.9 g, 16.8 mmol) in acetonitrile (32 mL) was heated to reflux for 90 minutes. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in CHCl3 (200 mL) and to the solution were added NaHCO3 (10 g) and H2O (13 mL). The resulting mixture was stirred vigorously at room temperature for 30 minutes before dried over MgSO4. The mixture was then filtered and the filtrate was concentrated in vacuo and then purified by flash chromatography (0-10% EtOAc/CH2Cl2) to give the title compound in 0.9 g. 1H NMR (CDCl3, 200 MHz): δ=11.74 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.52-7.44 (m, 2H), 7.34-7.15 (m, 3H), 7.03 (d, 1H, J=8.8 Hz), 4.46 (t, 2H, J=7.2 Hz)), 2.20 (s, 3H), 1.92-1.77 (m, 2H), 1.56-1.38 (m, 2H), 0.98 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:4].Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.COCCOC>C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([CH3:15])[CH3:1])=[CH:7][CH:8]=1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)C(=O)Nc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)C(=O)Nc1ccc(-c2ncccn2)cc1
Yield: 29.1 %

Procedure:
A mixture of 4-((2,2-dimethylpropanoyl)amino)phenylboronic acid (2.0 g, 9 mmol), 2-chloropyrimidine (0.8 g, 7 mmol), Pd(PPh3)2Cl2 (100 mg, 2 mol %) 1,2-dimethoxyethane (40 ml) and Na2CO3 (2M, 7 ml, 14 mmol) were refluxed under N2 for 5 h. The mixture was diluted with 10% Na2CO3 (20 ml) and extracted with EtOAc (3×50 ml). The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The crude product was recrystallised from MeOH/water (1:1) yielding 0.52 g (85%) of N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide as colorless crystals.
Reaction SMILES: OC1N=C2C=C(OCC3SC=C(C(C)C)N=3)C=CN2C(=O)C=1/C=C/C(OC(C)(C)C)=O.[C:32]([C:36]1[N:37]=[C:38]([NH:41][C:42]([C:44]2[CH:72]=[CH:71][N:47]3[C:48](=[O:70])[C:49](/[CH:61]=[CH:62]/[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[C:50]([N:52]4[CH2:57][CH2:56][CH2:55][C@@H:54]([O:58]C=O)[CH2:53]4)[N:51]=[C:46]3[CH:45]=2)=[O:43])[S:39][CH:40]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[N:37]=[C:38]([NH:41][C:42]([C:44]2[CH:72]=[CH:71][N:47]3[C:48](=[O:70])[C:49](/[CH:61]=[CH:62]/[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[C:50]([N:52]4[CH2:57][CH2:56][CH2:55][C@@H:54]([OH:58])[CH2:53]4)[N:51]=[C:46]3[CH:45]=2)=[O:43])[S:39][CH:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCC[C@@H](OC=O)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Agent: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCC[C@@H](O)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Yield: 69.2 %

Procedure:
Reactions were performed in the same manner as in Example 1, (K) by using tert-butyl (E)-3-{8-({[4-(tert-butyl)-1,3-thiazol-2-yl]amino}carbonyl)-2-[(3R)-3-formyloxyhexahydro-1-pyridinyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (559 mg, 0.961 mmol) to obtain 368 mg (69%) of the title compound as an orange oily substance.
Reaction SMILES: Cl[Si](Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](=O)[NH:32][CH:33]3[CH2:35][CH2:34]3)[CH:26]=1)[CH2:19][C:18]2([CH3:38])[CH3:37])=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[N:32]([CH:33]4[CH2:34][CH2:35]4)[N:8]=[N:7][N:6]=3)[CH:26]=1)[CH2:19][C:18]2([CH3:37])[CH3:38])=[O:14])[CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)NC3CC3)c1)N2
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3nnnn3C3CC3)c1)N2
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a stirred solution of tetrachlorosilane (5.3 mL, 46.3 mmol), sodium azide (5.6 g, 87 mmol) in dry acetonitrile (20 mL) was added 2-(3-cyclopropylcarbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.3 g, 3.3 mmol) at room temperature. Then the mixture solution was stirred at room temperature for over night. LC/MS showed that reaction finished completely. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (150 mL×2), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) afforded 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (908.2 mg, 66%) as a white solid: MS (ESI) M+1=418.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[CH3:12][O:13][C:14](=[O:25])[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][N:18]=[C:17](Cl)[CH:16]=1.CCOC(C)=O>C1COCC1.O>[CH3:12][O:13][C:14](=[O:25])[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][N:18]=[C:17]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:16]=1
Reactant: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2,4 difluorophenol (Aldrich Chemical Co.) (2.68 mL, 1.1 eq) in THF (60 mL) at 0° C. was added sodium hydride (60% in oil) (1.123 g, 1.1 eq), and the resulting mixture was stirred from 0° C. to room temperature over 1 hour. This solution was then added to compound (1A) (5.79 g, 26.7 mmol), and the resulting mixture was heated at reflux for 2 hours. TLC analysis confirmed that the reaction was complete, and the mixture was cooled to room temperature. EtOAc (300 mL) and water (100 mL) were added, the resulting mixture was partitioned, and the layers were separated. The organic layer was washed with water (3×100 mL) and brine (1×100 mL). Then the EtOAc layer was dried over magnesium sulfate, filtered, concentrated, and pumped to give the titled compound (1B) as an off-white powder (7.99 g, M+=310, Mp=90.2–91.4° C.)
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:13]3=[N:14][C:15]([OH:18])=[CH:16][CH:17]=[C:12]3[N:11]=[CH:10]2)=[C:4]([CH3:19])[CH:3]=1>CO.[OH-].[Pd+2].[OH-]>[Cl:8][C:7]1[CH:2]=[CH:3][C:4]([CH3:19])=[C:5]([N:9]2[C:13]3=[N:14][C:15]([OH:18])=[CH:16][CH:17]=[C:12]3[N:11]=[CH:10]2)[CH:6]=1
Reactant: Cc1cc(Br)c(Cl)cc1-n1cnc2ccc(O)nc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Cl)cc1-n1cnc2ccc(O)nc21
Reaction time: 12 h

Procedure:
To a solution of 3-(4-bromo-5-chloro-2-methylphenyl)-3H-imidazo[4,5-b]pyridin-5-ol (320 mg, 0.95 mmol) in MeOH (8.0 mL) was added palladium hydroxide (20% on carbon, 65 mg). The mixture was placed in a Parr shaker under H2 (30 psi) for 12 h, filtered through Celite® and concentrated. The mixture was purified by preparative HPLC to give the title compound as a white solid. LCMS m/z=260.1, [M+H]+.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]1[CH2:21][O:20][C:11]2([CH2:16][CH2:15][CH:14]([C:17]([O-:19])=O)[CH2:13][CH2:12]2)[O:10]1.[Na+].C(N(CC)CC)C.Cl.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][NH2:41])=[CH:36][CH:35]=1)[CH3:32]>O1CCCC1.O>[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][NH:41][C:17]([CH:14]2[CH2:13][CH2:12][C:11]3([O:10][CH2:9][CH2:21][O:20]3)[CH2:16][CH2:15]2)=[O:19])=[CH:36][CH:35]=1)[CH3:32]
Reactant: CCOc1ccc(NN)cc1
Reactant: O=C([O-])C1CCC2(CC1)OCCO2
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccc(NNC(=O)C2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At -40° C., 1.65 ml of isobutyl chloroformate are added to a mixture of 2.63 g of sodium 4,4-ethylenedioxycyclohexanoate in 20 ml of tetrahydrofuran followed by 1.8 ml of triethylamine. The reaction mixture is stirred for 2 hours at 0° C., then at -20° C., 2.4 g of 4-ethoxyphenylhydrazine hydrochloride are added; the reaction mixture is stirred for 2 hours at 0° C. then 100 ml of water are added and it is extracted with ethyl acetate. The organic phases are washed successively with water, with a solution of potassium bisulfate (pH=2), with a saturated potassium carbonate solution, dried over magnesium sulfate and evaporated off. The expected product is obtained after crystallisation from diethyl ether; M.p.=158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[C:25]([C:27]1([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])[CH2:29][CH2:28]1)#[N:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:25]([C:27]1([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]5[CH2:22][CH2:21]5)=[O:19])[N:16]=4)[N:13]=3)[CH:23]=2)=[O:34])[CH2:28][CH2:29]1)#[N:26]
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 78.6 %

Procedure:
Using N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol), 3-(1-cyanocyclopropyl)benzoic acid (91 mg, 0.49 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) and N,N-dimethylformamide (7.0 mL) as starting materials and in the same manner as in Example 318, the title compound (178 mg, 75%) was obtained as a white powder.
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:36]2C(=O)C[CH2:39][CH2:38][C:37]=2[OH:43])[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:24])=[C:17]([F:44])[CH:16]=1)#[N:14].C(N(CC)C(C)C)(C)C.O>ClCCl>[C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:36]2[C:37](=[O:43])[CH2:38][CH2:39][CH2:12][C:11]=2[O:8][CH2:9][CH3:10])[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])=[C:17]([F:44])[CH:16]=1)#[N:14]
Reactant: CC[O+](CC)CC
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CCCC2=O)c(F)c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2F)C(=O)CCC1

Procedure:
Triethyloxonium tetrafluoroborate (1.60 g, 8.42 mmol) is added to a solution of 1-((4-cyano-2-fluorophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 40 1.80 g, 4.02 mmol) and N,N-diisopropylethylamine (1.60 mL, 9.2 mmol) in dichloromethane (15 mL), and the mixture is stirred at room temperature for 20 min Water is added, and the phases are separated. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 1.82 g; ESI mass spectrum [M+H]+=476, Retention time HPLC: 1.11 min (Z018_S04).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(OC)OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COC(OC)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 100.1 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 4′-dimethoxymethylbiphenyl-4-carboxylate (1.89 g), which is the product of Reference example 11(a), and aqueous sodium hydroxide (1N, 9.90 ml) and the reaction mixture was treated to afford the desired compound (1.80 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:19][C:2]2[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]3=[N:10][CH:11]=[CH:12][C:3]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Reactant: NC1CCCCC1
Product: CSc1nc(NC2CCCCC2)c2ccnc-2[nH]1

Procedure:
To 100 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]-pyrimidine was added 2 ml of cyclohexylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford white crystals of product, yield 67 mg (51%), m.p. 189°-190°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:15]([O:17][C:18]1[CH:22]=[C:21]([N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)=[CH:31][C:26]=3[N:25]=[CH:24]2)[S:20][C:19]=1[C:38]([NH2:40])=[O:39])[CH3:16].C=O.[C:43](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:43])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:15]([O:17][C:18]1[CH:22]=[C:21]([N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)=[CH:31][C:26]=3[N:25]=[CH:24]2)[S:20][C:19]=1[C:38]([NH2:40])=[O:39])[CH3:16]
Reactant: CC(=O)O
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCNCC2)c1Cl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCN(C)CC2)c1Cl
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (Example 47, 230 mg, 0.40 mmol) in DCM (4 mL) and MeOH (2 mL) was added formaldehyde (0.033 mL, 1.2 mmol) and acetic acid (0.046 mL, 0.80 mmol) followed by sodium triacetoxy borohydride (0.17 g, 0.80 mmol). The solution was stirred for 1 h. The solution was diluted with DCM (20 mL) and washed with sat'd NaHCO3 solution (10 mL). The organic layers were dried (MgSO4), filtered and the solvent removed on a rotovap. The residue was dissolved in DCM and loaded onto a 4 g ISCO chromatography column and eluted with a gradient of 100:0 to 30:70 DCM : (80:20:2 DCM:MeOH:ammonium hydroxide) over 20 min. The appropriate fractions were combined and the solvent removed to provide 0.20 g of the title compound as a white solid (85 %). 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=1.1 Hz, 2H), 7.30-7.22 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.74 (bs, 1H), 6.64 (s, 1H), 5.91 (q, J=6.4 Hz, 1H), 4.45-4.38 (m, 1H), 3.97 (s, 3H), 2.71-2.61 (m, 2H), 2.47-2.27 (m, 2H), 2.29 (s, 3H), 2.05-1.87 (m, 4H), 1.77 (d, J=6.4 Hz, 3H). MS (ESI): 591 [M+H]+.