Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:4][NH:3][CH2:1][CH3:2])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCNC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNCC1CCN(Cc2ccccc2)CC1

Procedure:
N-Ethyl-1-benzyl-4-piperidinyl carboxamide (EXAMPLE 174, 8.03 g, 32.60 mmol) is dissolved in THF and cooled to 0°. Lithium aluminum hydride (1M in THF) is added dropwise. The solution is refluxed 4.5 hr, then quenched at 0° by adding 1.24 ml water, 1.24 ml 15% aqueous sodium hydride, and 3.71 ml water. Filtration through a pad of diatomaceous earth and sodium sulfate and then evaporation of the solvent gives the title compound; NMR (300 MHz, CDCl3) 7.14, 3.32, 2.73, 2.50, 2.35, 1.79, 1.55, 1.34, 1.12 and 0.97δ.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:42][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[CH3:38])=[O:15])[CH:3]=1
Reactant: Cc1ccccc1CN
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccccc2C)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 2-methylbenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 1.31 (t, 3H) 2.28-2.34 (m, 3H) 4.38-4.55 (m, 4H) 7.05-7.10 (m, 1H) 7.11-7.21 (m, 4H) 8.92-8.99 (m, 1H). MS (ESI) positive ion 311 (M+H)+; negative ion 309 (M−H)−.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH3:9][C:10]([NH2:14])([C:12]#[CH:13])[CH3:11]>C(#N)C>[C:1]([NH:3][C:4](=[N:14][C:10]([CH3:11])([C:12]#[CH:13])[CH3:9])[S:5][CH3:6])#[N:2]
Reactant: C#CC(C)(C)N
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: C#CC(C)(C)N=C(NC#N)SC

Procedure:
A solution of dimethyl cyanodithioimidocarbonate (9.0 g, 0.615 mole) and 1,1-dimethylpropargylamine (90% amine, remainder water, 5.68 g, 0.0615 mole) in acetonitrile (125 ml) was stirred at reflux temperature for 13 days. The reaction mixture was evaporated under reduced pressure and the residue chromatographed on silica gel. The appropriate fractions were combined and the product was recrystallized from toluene to give the title product, mp 128°-130.5° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22](O)=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:63])([F:62])[C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>ClCCl.CN(C=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([NH:59][CH2:58][C:57]2[CH:56]=[CH:55][C:54]([C:53]([F:52])([F:62])[F:63])=[CH:61][CH:60]=2)=[O:23])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.15 g, 0.41 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (0.23 g, 0.62 mmol). The mixture was stirred for 15 min followed by addition of 4-trifluoromethylbenzylamine) (0.14 g, 0.82 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a white ppt which was filtered and dried under high vacuum to give the title compound as a white powder (0.08 g, 38%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.1 Hz, 1H), 7.60 (d, J=8 Hz, 1H), 7.45-7.41 (m, 3H), 7.39-7.26 (m, 3H), 7.11-7.07 (m, 2H), 7.01-6.97 (m, 2H), 6.92-6.89 (m, 3H), 6.54 (d, J=8.4 Hz, 2H), 6.21 (s, 1H), 5.93 (s, 1H), 4.54-4.46 (m, 2H), 4.29 (s, 2H), 2.46-2.42 (m, 1H), 1.61-1.49 (m, 2H), 1.22-1.18 (m, 1H). ES-MS m/z 517 (MH+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[CH3:29][O:30][CH2:31][CH2:32][C@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1>>[CH3:29][O:30][CH2:31][CH2:32][C@@H:33]1[NH:34][CH2:35][CH2:36][N:37]([C:6]2[C:5]3[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=3[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=2)[CH2:38]1
Reactant: COCC[C@H]1CNCCN1
Reactant: FC(F)(F)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1

Procedure:
Using the method of Example 305, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione and methyl trifluoromethanesulfonate, and 2-(S)-(2-methoxy-ethyl)-piperazine, followed by purification, eluting with a gradient of a 7% solution of 2M ammonia in methanol, in dichloromethane (0-100%), gives the title compound: mass spectrum (APCI, m/e): 412 (M+1); NMR (1H, 300 MHz, DMSO-d6): δ 8.71 (br. s, 1H), 8.60 (s, 1H), 6.93 (m, 3H), 6.71 (m, 1H), 4.07 (br. m, 2H), 3.46-3.29 (m, 4H), 3.29-3.06 (m, 5H), 2.99 (m, 1H), 2.48 (m, 2H).
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N:7]2.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([O:18][C@@H:12]([C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:23])[N:7]=[C:6]([CH3:24])[CH:5]=[CH:4]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Yield: 79.6 %

Procedure:
Pd(PPh3)4 (68 mg, 0.06 mmol) was added to a mixture of (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (230 mg, 0.59 mmol) and 4-chlorophenylboronic acid (183 mg, 1.17 mmol), K2CO3 (1.0 mL 2 M in water, 2.06 mmol) in 1,2-dimethoxyethane (8 mL). The reaction mixture was flushed with nitrogen, heated at 110° C. for 30 min under microwave, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (200 mg, 80%). LCMS-ESI+ (m/z): 426.2, 428.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C:14](O)=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NC(C)(C)[CH2:26][C:27]([OH:29])=[O:28])=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13]/[CH:14]=[CH:26]/[C:27]([OH:29])=[O:28])[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CCC1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NC1(C/C=C/C(=O)O)CCC1

Procedure:
(2E)-4-(1-(tert-Butoxycarbonylamino)cyclobutyl)but-2-enoic acid was synthesized starting with (1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid analogously to the synthesis of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid starting with of 3-tert-butoxycarbonylamino-3-methylbutanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccnc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(O[C@H]2CCNC2)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of 3-((3S)-N-(tert-butoxycarbonyl)-3-pyrrolidinyloxy)pyridine (0.535 g, 2.024 mmol) in dry CH2Cl2 (5 mL, distilled from LiAlH4) was treated drop-wise with trifluoroacetic acid (3 mL, 4.44 g, 38.94 mmol). After stirring 30 min at 0-5° C., the solution was concentrated by rotary evaporation. The residue was acidified with 1 M HCl solution (15 mL) and extracted with toluene (4×25 mL) to remove impurities (triphenylphosphine oxide). At 0-5° C., the aqueous layer was basified with 1 M NaOH solution to pH 12. The mixture was saturated with NaCl and extracted with CHCl3 (8×20 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and briefly dried under high vacuum to give 240 mg (72.3%) of a light-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:8]2[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:41])([F:40])[F:29])[CH:28]=[CH:27][CH:26]=3)[N:7]=2)=[CH:20][CH:21]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=c1n(Cc2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Product: O=c1n(Cc2cccc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 122, 72 mg (0.15 mmol) of the compound from Example 101A were reacted with 43 mg (0.23 mmol) of 2-(trifluoromethyl)phenylboronic acid. This gave 49 mg (58% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33](/[CH:36]=[CH:37]/[CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:25]([C@H:30]1[CH2:31][CH2:32][C@H:33](/[CH:36]=[CH:37]/[CH2:38][O:39][C:40]2[CH:41]=[CH:42][C:43]([O:5][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:10]([F:11])[C:2]=3[F:1])=[CH:44][CH:45]=2)[CH2:34][CH2:35]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(O)cc2)CC1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OC/C=C/[C@H]3CC[C@H](CCCCC)CC3)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of 2,3-difluoro-4-dodecyloxybenzoic acid, 1.8 g of 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]phenol and 0.1 g of 4-(dimethylamino)pyridine were dissolved in 50 ml of dichloromethane and the solution was treated portionwise within 10 minutes while stirring with 1.4 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight and then filtered. The filtrate was diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with water, dried over magnesium sulphate and concentrated. The crude product obtained was purified by chromatography on silica gel with toluene. The 2,3-difluoro-4-dodecyloxybenzoic acid 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]phenyl ester obtained was recrystallized from ethanol; m.p. (C-SC) 73° C., SC -N 124° C., cl.p. (N-I) 137° C..
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH:39]([C:36]1[CH:35]=[CH:34][C:33]([C@H:17]([NH:16][C:12]2[C:8]3[CH:9]=[CH:10][N:11]=[C:3]([C:2]([NH2:7])=[O:1])[C:4]=3[N:5]=[CH:6][N:14]=2)[CH2:18][NH:19][CH3:32])=[CH:38][CH:37]=1)([CH3:40])[CH3:41]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)c1ccc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)nccc12)c1ccc(C(C)C)cc1

Procedure:
Compound 40 was prepared following general synthesis scheme 8 wherein a mixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and 4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted with N—[(S)-2-Amino-2-(4-isopropyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride. The title compound was isolated as the minor product (white solid). LC/MS [365 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 2H), 8.82-8.58 (m, 2H), 8.40 (s, 1H), 7.82 (s, 1H), 7.42 (d, J=7.8 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.52 (s, 1H), 5.89 (s, 1H), 3.68-3.54 (m, 1H), 3.51-3.43 (m, 1H), 2.98-2.78 (m, 1H), 2.65 (s, 3H), 1.17 (d, J=6.8 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C(C)(C)C.[OH-].[Na+]>O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2oc3ccccc3c2c1
Temperature: 120 °C
Yield: 73.6 %

Procedure:
In a 1 L round-bottom flask, 1-nitro-4-phenoxybenzene (50 g, 232 mmol), potassium carbonate (3.21 g, 23.23 mmol), palladium acetate (2.61 g, 11.62 mmol), and 280 mL of pivalic acid were added. The mixture was heated to 120° C. in air. After 3 days the reaction mixture was cooled in an ice bath. 125 mL of 50% sodium hydroxide solution was added slowly in portions over time. The black emulsion was diluted with a large amount of water and ethyl acetate, filtered through Celite. The organic layer was separated, dried over magnesium sulfate, and filtered. The solvent was evaporated and pre-adsorbed onto Celite. The Celite mixture was purified by silica gel plug eluting with 10% to 50% dichloromethane in hexanes. 36.4 g (63% yield) desired product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.Cl[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1>O1CCOCC1>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][N:22]1[CH2:23][CH2:24][N:19]([C:12]2[N:11]=[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=2)[CH2:20][CH2:21]1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Reactant: COc1cccc(CCl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cccc(CN2CCN(c3nc(Nc4cccc(OC)c4)cc(N(C)C)n3)CC2)c1
Yield: 71.3 %

Procedure:
A solution of N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (36 mg, 0.1 mmol), DIPEA (52 mg, 0.4 mmol), and 1-(chloromethyl)-3-methoxybenzene (20 mg, 0.13 mmol) in 5 mL of dioxane was stirred at 100° C. for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (32 mg, 70%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][O:28][CH3:29])[CH2:23][C:24]([OH:26])=O)[C:14]2=[O:30])=[CH:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:43][N:44]1[CH:48]=[C:47]([S:49]([NH2:52])(=[O:51])=[O:50])[N:46]=[CH:45]1.C1CCN2C(=NCCC2)CC1.Cl>O.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][O:28][CH3:29])[CH2:23][C:24]([NH:52][S:49]([C:47]3[N:46]=[CH:45][N:44]([CH3:43])[CH:48]=3)(=[O:51])=[O:50])=[O:26])[C:14]2=[O:30])=[CH:3]1
Reactant: Cn1cnc(S(N)(=O)=O)c1
Reactant: COCC(CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: COCC(CC(=O)NS(=O)(=O)c1cn(C)cn1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 55 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-butyric acid (30 mg, 0.074 mmol) is dissolved THF (0.70 mL) and CDI (27 mg, 0.17 mmol) is added into it at room temperature. The mixture is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, 1-Methyl-1H-imidazole-4-sulfonic acid amide (24 mg, 0.15 mmol) is added and after 10 min, DBU (0.022 mL, 0.15 mmol) is added. The mixture is stirred for 16 hr at room temperature. 2.0 mL of 1.0 M HCl is added followed by 20 mL of water. The mixture is extracted with EtOAc (3×25 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 17 mg (41%) of 1-Methyl-1H-imidazole-4-sulfonic acid {3-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-butyryl}-amide. LCMS (ESMS): m/z 551.25 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:22])=[CH:15][CH:14]=1
Reactant: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: C1CCNCC1
Product: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 175 %

Procedure:
3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.08 mmol) and piperidine (0.012 ml, 0.12 mmol) were used, and a method similar to that described in Production Example 46 was employed to obtain the title compound (53 mg, 0.14 mmol, yield 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:18])=[CH:15][CH:14]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:59][C:60]1[CH:65]=[CH:64][C:63]([NH2:66])=[C:62]([NH2:67])[CH:61]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:66][C:63]2[CH:64]=[CH:65][C:60]([F:59])=[CH:61][C:62]=2[NH2:67])=[O:27])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Reactant: Nc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cc(F)ccc1NC(=O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
6-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid (396 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (348 mg, 69% yield) as a brown solid. 1H NMR (DMSO-d6)δ1.36 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.60 (m, 2H, CH2), 2.30 (t, J=8.0 Hz, 2H, CH2CO), 3.29 (m, 2H, NCH2), 5.12 (s, 2H, benzene-NH2), 6.27 (t, J=8.0 Hz, 1H, Ar—H), 6.46 (dd, J=4.0 Hz and 8.0 Hz, 1H, Ar—H), 6.88 (m, 1H, Ar—H), 7.10 (m, 2H, Ar—H), 7.71 (s, 1H, vinyl-H), 7.77 (m, 1H, Ar—H), 7.92 (m, 1H, Ar—H), 7.96 (m, 1H, Ar—H), 8.39 (d, J=8.0 Hz, 1H, Ar—H), 8.50 (m, 1H, Ar—H), 9.01 (s, 1H, benzene-NH), 10.68 (s, 1H, CONH). LC-MS (m/z) 505 (M+1).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[C:4](=[O:20])[CH:3]=[CH:2]1.Br[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:20]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:22]3[CH:23]=[C:24]([NH2:25])[CH:26]=[CH:27][CH:28]=3)[CH:6]=2)[O:1][CH:2]=[CH:3]1
Reactant: CC1(C)OB(c2ccc3occc(=O)c3c2)OC1(C)C
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cccc(-c2ccc3occc(=O)c3c2)c1
Temperature: 25 °C
Yield: 43 %

Procedure:
Chromone-6-boronic acid pinacol ester (0.237 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (0-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.059 g in 43% yield.