Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([CH:18]=[O:19])=[C:13]([O:20][CH3:21])[CH:12]=[CH:11][C:10]=3[CH2:9]2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:22][I:23]>C(#N)C>[I-:23].[CH:18]([C:14]1[C:13]([O:20][CH3:21])=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][N:8]([C:6]([N:1]1[CH:5]=[CH:4][N+:3]([CH3:22])=[CH:2]1)=[O:7])[CH2:9]2)=[O:19]
Reactant: CI
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)n1ccnc1)C2
Solvent: CC#N
Product: COc1ccc2c(c1C=O)CCN(C(=O)n1cc[n+](C)c1)C2
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 2-(imidazole-1-carbonyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde (426 mg, 1.50 mmol) and methyl iodide (475 μL, 1.05 g, 7.6 mmol) in anhydrous acetonitrile (10 mL) was stirred at room temperature for 24 h. After evaporation of the solvent the title compound (640 mg, 1.50 mmol, 100%) was obtained as a brownish foam.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>>[CH3:13][C:12]1[C:7]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][C:24]([F:33])([F:34])[F:23])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccccc1OC(F)(F)F
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccccc2OC(F)(F)F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [2-(trifluoromethoxy)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.09 (s, 3H), 2.35 (s, 3H), 4.74 (d, J=5.5 Hz, 2H), 6.81 (s, 1H), 6.98 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.0 Hz, 2H), 7.23 (d, J=7.3 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.3 Hz, 1H), 8.43 (d, J=7.5 Hz, 1H), 8.59 (d, J=3.8 Hz, 1H); MS (ESI) m/z 390.5 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.C(N(CC)CC)C.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.O.[NH2:28][NH2:29]>CS(C)=O>[F:8][C:7]1[C:2]([N:19]([CH3:18])[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:3][C:4]([CH3:10])=[N:5][C:6]=1[NH:28][NH2:29]
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: CNCc1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(NN)c(F)c(N(C)Cc2ccncc2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (0.18 g, 0.99 mmol) was dissolved in DMSO (1 mL). To this solution was added triethylamine (0.15 mL, 1.08 mmol), followed by commercially available N-methyl-1-(4-pyridinyl)methanamine (0.122 g, 1.0 mmol). The reaction was left to stir for 3 hours. Then hydrazine monohydrate was added, and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was heated to 60° C. for 90 minutes. After cooling, the reaction mixture was purified by RP-HPLC to provide 5-fluoro-6-hydrazino-N,2-dimethyl-N-(4-pyridinylmethyl)-4-pyrimidinamine (0.130 g, 49%). LCMS: (M+H)+=263.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2].[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(O)=O>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([CH2:43][O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:34])[CH:10]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]2=3)=[CH:45][CH:46]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)CCCCN(CCc1ccccc1O)C1CCCc2cc(C(=O)OCC)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=CO
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(C(C)(C)C)cc1)C1CCCc2cc(C(=O)OCC)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (1.07 mmol) of the compound from Example 4A were dissolved in 20 ml of DMF, 245 μl (1.23 mmol) of 4-tert-butylbenzyl bromide and 1.12 g (3.4 mmol) of caesium carbonate were added and the mixture was stirred at RT overnight. Water was then added to the mixture. After addition of 1.4 ml of 5 N formic acid, the mixture was extracted repeatedly with toluene and the combined organic phases were dried over sodium sulphate and concentrated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([C:21]3[C:22]([CH3:38])=[C:23]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:24]=[CH:25][CH:26]=3)[CH:16]([N+:18]([O-])=O)[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1.C([O-])(=O)C.[NH4+]>CO.O1CCCC1.CCOC(C)=O.[Zn]>[NH2:18][CH:16]([CH3:17])[CH:15]([C:21]1[C:22]([CH3:38])=[C:23]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=[CH:25][CH:26]=1)[C:10]1[C:9]2[C:13](=[CH:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[NH:12][CH:11]=1
Reactant: COCCOc1ccc2c(C(c3cccc(NC(=O)OCc4ccccc4)c3C)C(C)[N+](=O)[O-])c[nH]c2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCOc1ccc2c(C(c3cccc(NC(=O)OCc4ccccc4)c3C)C(C)N)c[nH]c2c1
Reaction time: 5 h
Yield: 91.7 %

Procedure:
A solution of benzyl 3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitropropyl)-2-methylphenylcarbamate (1.6194 g, 3.13 mmol), ammonium acetate (2.51 g, 46.9 mmol) and zinc (3.07 g, 46.9 mmol) in methanol (Ratio: 1.000, Volume: 57.9 ml) and tetrahydrofuran (Ratio: 1.000, Volume: 57.9 ml) was stirred under nitrogen. After 5 h, the reaction was diluted with EtOAc and filtered through a wad of CELITE®. The filtrate was concentrated in vacuo, and the residue was dissolved in EtOAc (75 mL) and saturated aqueous NaHCO3 (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×75 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo to give benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamate (1.3975 g, 2.87 mmol, 92% yield, mixture of 2 isomers) as a colorless oil, LC/MS (M+H)=488.30, 488.30.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[N:23][NH2:24])[C@H:19]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[C:42]4[C:37](=[N:38][CH:39]=[CH:40][CH:41]=4)[NH:36][C:35]3=[O:43])[CH2:30][CH2:29]2)=[O:27])[CH2:18][CH2:17]1.[CH:44]1([C:47](Cl)=O)[CH2:46][CH2:45]1>ClCCl>[CH:44]1([C:47]2[N:21]3[CH2:22][C@H:16]([C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=4[F:8])[CH2:17][CH2:18][C@@H:19]([NH:25][C:26]([N:28]4[CH2:29][CH2:30][CH:31]([N:34]5[C:42]6[C:37](=[N:38][CH:39]=[CH:40][CH:41]=6)[NH:36][C:35]5=[O:43])[CH2:32][CH2:33]4)=[O:27])[C:20]3=[N:23][N:24]=2)[CH2:46][CH2:45]1
Reactant: NN=C1NC[C@H](c2cccc(F)c2F)CC[C@H]1NC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3CC3)nnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 45 °C
Reaction time: 20 h
Yield: 88.1 %

Procedure:
Triethylamine (20 μL, 0.142 mmol) was added to a solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-hydrazonoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (59 mg, 0.118 mmol) and cyclopropanecarbonyl chloride (11 μL, 0.124 mmol) in dichloromethane (1 mL) and the mixture heated to 45° C. After 20 h, the reaction was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)] gave the title compound (57 mg). MS 549.2524 (M+1).
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:15]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[F:35])[CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[O:16])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:36]=[C:37]([CH3:41])[C:38](O)=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:38](=[O:39])[C:37](=[O:36])[CH3:41])[CH2:10][CH2:9]1)=[O:16]
Reactant: CC(=O)C(=O)O
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 46.4 %

Procedure:
4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one TFA salt (320 mg, 0.65 mmol), 2-oxopropanoic acid [0.3 ml (d=1.26), 4.29 mmol], DIPEA (1 ml, 6 mmol), and HATU (510 mg, 1.34 mmol) were mixed in DMF (30 ml). After the resulting reaction mixture was stirred at room temperature for 60 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:2) to afford the desired product (136 mg, 45.1%) as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:11]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])=[CH:15][CH:14]=2)=[O:13])(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A 5-liter 3-neck round bottom flask was equipped with a mechanical stirrer and nitrogen inlet. CH2Cl2 (2 liters) was placed in the reaction flask and terephthalic acid mono-t-butyl ester (127.5 g, 0.574 mol), DMAP (70.06 g, 0.574 mol), and 4-chlorobenzenesulfonamide (110.04 g, 0.574 mol) were added in that order using CH2Cl2 (400 ml) to wash down the solids. WSCDI (110.10 g, 0.574 mol) was added in portions over 10 min using CH2Cl2 (100 ml) to wash down the solid. After the reaction mixture was stirred overnight at room temperature, it was concentrated under vacuum to dryness. The residue was partioned between EtOAc and water. The EtOAc solution was washed (20% aq citric acid, satd aq NaHCO3, brine), dried (Na2SO4), and concentrated under vacuum to a white solid. After drying in a vacuum oven at 50°, the title product (227 g, 100%) was obtained in a sufficiently pure state to be used directly for the next step; TLC, Rf =0.43, MeOH:CHCl3 (15:85). (Further purification was possible by recrystallization from EtOH:water; m.p. above 300°).
Reaction SMILES: Br[CH:2]([CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])[CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)=[O:6].N1CCCC[CH2:28]1.[CH4:33]>C1C=CC=CC=1>[CH3:33][C:3]([CH3:28])([CH:2]=[CH:22][C:23]([Cl:26])([Cl:25])[Cl:24])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)=[O:6]
Reactant: C1CCNCC1
Reactant: O=C(CCC(Br)CC(Cl)(Cl)Cl)OCc1cccc(Oc2ccccc2)c1
Reactant: C
Solvent: c1ccccc1
Product: CC(C)(C=CC(Cl)(Cl)Cl)CC(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
In the manner of Example II, 22.1 g of 3-phenoxybenzyl 4-bromo-6,6,6-trichlorohexanoate was treated with 7.4 g of piperidine. Chromatography of the crude reaction product on a charcoal column using benzene as the eluent gave 13.5 g of 3-phenoxybenzyl 3,3-dimethyl-6,6,6-trichloro-4-hexenoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:2]3[N:7]=[C:6]4[NH:8][N:9]=[CH:10][C:5]4=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=4)[N:3]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: NS(=O)(=O)c1ccc(Nc2nc(Cl)nc3[nH]ncc23)cc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(Nc2nc(Nc3ccc4[nH]ncc4c3)nc3[nH]ncc23)cc1
Temperature: 120 °C
Yield: 99 %

Procedure:
Compound 4A, 1H-indazol-5-ylamine Compound 5A and TFA (94 ul, 1.1 mmol) were mixed in dry DMSO (1 ml) and heated to 120° C. for 48 hours to provide Compound 12 (99% yield). 1HNMR (CD3OD) δ 8.5 (s, 1H), 8.12 (s, 2H), 7.9 (m, 2H), 7.7 (d, 2H), 7.5 (d, 2H); MS 536 (M+H+).
Reaction SMILES: [OH2:1].[H-].C[O:4]CCO[Al+]OCCOC.[Na+].[H-].[Cl:16][C:17]1[C:18](=[O:38])[NH:19][C:20](/[C:23](/[C:30]2[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=2)=[CH:24]/[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:22]=1>C1COCC1.CO>[Cl:16][C:17]1[C:18](=[O:38])[NH:19][C:20](/[C:23](/[C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:37])(=[O:4])=[O:1])=[CH:32][CH:31]=2)=[CH:24]/[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:22]=1
Reactant: COCCO[Al+]OCCOC
Reactant: CSc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Water (3 mL) and Oxone(R) (853 mg) were sequentially added to a solution of 3-chloro-6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}pyridin-2(1H)-one obtained in Example 1-1 (160 mg) in THF-methanol (1:1, 6 mL), and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:hexane=10:0→9:1). The resulting crude product was recrystallized from a chloroform:ethyl acetate:hexane (1:1:1, 6 mL) solution to give the title compound as a colorless powder (130 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]4[CH:29]=[CH:28][N:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)[CH2:19][CH2:18]3)[C:11]=1[O:12][CH2:13][C:14](O)=[O:15])[N:8]=[CH:7][CH:6]=[CH:5]2.Cl.[CH3:37][O:38][C:39]([CH:41]1[CH2:44][NH:43][CH2:42]1)=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][O:38][C:39]([CH:41]1[CH2:44][N:43]([C:14](=[O:15])[CH2:13][O:12][C:11]2[C:10]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]4[CH:29]=[CH:28][N:27]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:26]=4)[CH2:19][CH2:18]3)=[C:9]3[C:4]([CH:5]=[CH:6][CH:7]=[N:8]3)=[CH:3][C:2]=2[CH3:1])[CH2:42]1)=[O:40]
Reactant: COC(=O)C1CNC1
Reactant: Cc1cc2cccnc2c(N2CCCN(Cc3ccn(-c4ccccc4)n3)CC2)c1OCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(C(=O)COc2c(C)cc3cccnc3c2N2CCCN(Cc3ccn(-c4ccccc4)n3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A mixture of {6-Methyl-8-[4-(1-phenyl-1H-pyrazol-3-ylmethyl)-[1,4]diazepan-1-yl]-quinolin-7-yloxy}-acetic acid (100 mg, 0.21 mmol), 3-Azetidinecarboxylic methyl ester HCl salt (35.4 mg, 0.23 mmol), HATU (97 mg, 0.25 mmol) and DIEA (0.222 ml) in DMF (1 ml) was stirred at rt for 2 hrs. After an aqueous workup, the mixture was purified by flash chromatography to give a light yellow solid (70 mg, 59%). MS (ES) m/z 569.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:14]2[CH:21]=[CH:20][S:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:14]3[CH:21]=[CH:20][S:19][C:15]=3[N:16]=[CH:17][N:18]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Clc1ncnc2sccc12
Product: Cc1ccc2[nH]c(C)c(-c3ncnc4sccc34)c2c1
Product: Cl

Procedure:
The sub-title compound was prepared by the method of Example 15 step a) using 2,5-dimethylindole and 4-chloro-thieno[2,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH2:24])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH:24][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(N)CCOc1ccc(OC(C)(C)C(=O)OCC)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
A sample of 2-amino-4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid ethyl ester (612 mg, 1.73 mmol) and benzaldehyde (220 mg, 2.08 mmol) was dissolved in 10 mL of methylene chloride followed by addition of sodium triacetoxyborohydride (550 mg, 2.60 mmol). After 4 hours of stirring at room temperature the reaction mixture was partitioned between additional methylene chloride (50 mL) and 0.1 N HCl (50 mL). The pH of the mixture was then adjusted to ˜13 with 1.0 N NaOH and the layers separated. The aqueous later was extracted with additional methylene chloride (25 mL). The combined organic phases were dried over sodium chloride, then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate/hexanes) to yield 492 mg of product (64%) as an oil. HPLC RT1=2.78 min; 1H NMR (400 MHz, CDCl3) δ 7.28-7.18 (m, 5H), 6.79-6.76 (m, 2H), 6.70-6.68 (m, 2H), 4.22-4.12 (m, 4H), 4.08-4.02 (m, 1H), 3.99-3.91 (m, 1H), 3.83-3.80 (d, J=12.7 Hz, 1H), 3.65-3.62 (d, J=12.7 Hz, 1H), 3.49-3.47 (m, 1H), 2.17-2.09 (m, 1H), 2.00-1.92 (m, 1H), 1.49 (s, 6H), 1.26-1.20 (m, 6H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:15](=O)[C:16]([CH3:19])([CH3:18])[CH3:17].C(O)(=O)C.C([BH3-])#N>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C@H:3]([NH:2][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.022 g, 4.57 mmol) and pivalaldehyde (0.502 mL, 4.57 mmol) were combined in dichloromethane (25 mL). Acetic acid (1.0 mL) was added. The reaction was stirred at room temperature for 5 minutes, then PS-cyanoborohydride (3.90 g, 9.14 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the solvent was removed in vacuo. The crude material was diluted with dichloromethane and basified using saturated aqueous sodium bicarbonate to give (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.04 (t, J=7.4, 1H), 2.40 (d, J=11.1, 1H), 2.09 (d, J=11.1, 1H), 1.86-1.70 (m, 1H), 1.46 (s, 10H), 1.40 (t, J=7.2, 3H), 0.95-0.89 (m, 6H), 0.89 (s, 9H), (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(neopentylamino)pentanoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.89-8.37 (m, 1H), 8.34-8.03 (m, 1H), 3.82 (t, J=6.5, 1H), 2.88 (d, J=12.3, 1H), 2.62 (d, J=12.2, 1H), 1.83-1.67 (m, 2H), 1.67-1.56 (m, 1H), 1.00 (s, 9H), 0.97-0.88 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33](Cl)=[O:34])[C:27]=2[N:26]=[CH:25]1.CCN(CC)CC.O>C(Cl)Cl>[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([N:13]3[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]4[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:8][C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:11][CH2:12]3)=[O:34])[C:27]=2[NH:26][CH:25]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=C(Cl)c1cccc2[nH]cnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2cccc3nc[nH]c23)CC1
Yield: 54655828 %

Procedure:
To a solution of COMPOUND 249 (0.100 g, 0.322 nmol) in CH2Cl2 (5 mL) was added 1H-benzoimidazole-4-carbonyl chloride (0.118 g, 0.653 mmol) (White, A. W. et al. J. Med. Chem. 2000, 43, 4084-4097) and Et3N (0.37 g, 0.37 mmol). After the mixture was stirred overnight water (10 mL) was added, and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on silica gel columns (column 1, 6:1 EtOAc/MeOH; column 2, 100:5:1 CH2Cl2/MeOH/NH4OH), affording a white solid (0.080 g, 56%). Conversion to the HBr salt using General Procedure D gave a white solid. 1H NMR (D2O) δ 1.55-1.84 (m, 2H), 1.95-1.99 (m, 1H), 2.18-2.22 (m, 1H), 2.45 (s, 6H), 2.88-3.20 (m, 3H), 3.72-3.77 (m, 1H), 4.32 (s, 4H), 4.63-4.70 (m, 1H), 7.61-7.67 (m, 2H), 7.74-7.80 (m, 2H), 7.89-7.93 (m, 1H), 8.28 (d, 2H, J=8.1 Hz), 8.50 (d, 2H, J=5.7 Hz), 9.20 (s, 1H); 13C NMR (D2O) δ 17.41, 27.50, 28.20, 42.48, 47.56, 51.01, 60.02, 117.02, 121.50, 125.51, 126.16, 127.09, 127.71, 131.38, 137.93, 138.77, 140.71, 148.67, 151.08, 167.43. ES-MS m/z 455 (M+Na). Anal. Calcd. for C27H30N6O.3.5HBr.0.25H2O.0.3C4H10O: C, 42.07; H, 5.20; N, 10.44; Br, 34.74. Found: C, 41.86; H, 5.18; N, 10.39; Br, 34.98.