Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[N:9]([CH3:25])[S:10](=[O:24])(=[O:23])[C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]([CH3:20])[C:12]=2[C:21]=1[OH:22])=[O:7])CCC.NC1[S:28][CH:29]=[CH:30][N:31]=1>>[CH3:25][N:9]1[C:8]([C:6]([NH:5][C:1]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:7])=[C:21]([OH:22])[C:12]2[N:13]([CH3:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[S:10]1(=[O:24])=[O:23]
Reactant: CCCCNC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Nc1nccs1
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Yield: 37 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(2-thiazolyl)-1,2-thiazino-[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 36 from N-(n-butyl)-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide and 2-amino-thiazole with a yield of 37% of theory; M.p.: 260°-261° C. (decomp.)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[O:10][CH2:9][C@@H:8]([CH3:11])[N:7](CC2C=CC=CC=2)[CH2:6]1)[CH3:3]>CCO.[Pd]>[CH3:3][N:2]([CH2:4][C@H:5]1[O:10][CH2:9][C@@H:8]([CH3:11])[NH:7][CH2:6]1)[CH3:1]
Reactant: C[C@@H]1CO[C@@H](CN(C)C)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CO[C@H](CN(C)C)CN1
Temperature: 130 °C

Procedure:
(2S,5R)-2-[Dimethylamino(methyl)]-5-methyl-4-benzylmorpholine (28 g, 113 mmol, 1 equivalent), was dissolved in EtOH (1 M), and the solution was transferred to a stainless steel high pressure vessel equipped with a pressure gauge. 10% Pd/C was added (2.8 g, 10 wt. %), and the vessel charged with H2. The reaction mixture was stirred at 130° C. and 200 psi of H2 overnight. The reaction mixture was cooled to room temperature, filtered and evaporated. The desired amine was obtained in quantitative yield as a yellow oil. GC/MS: 128 (10%, M+-2xCH3), 58 (100%, NHCH2CHO), Rt 8.16 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2.C(=O)(O)[O-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([O:22][C:21]([C:6]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)=[O:23])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To a mixture of 5-bromo-1-(4-nitro-benzyl)-1-H-indole-2-carboxylic acid (1.66 g, 4.43 mmol) and sodium bicarbonate (0.93 g, 11.1 mmol) in dry dimethylformamide at room temperature under nitrogen was added benzyl bromide (2.275 g, 1.58 ml, 13.3 mmol). The reaction mixture was warmed to about 60° C. for about 16 hours and then the mixture was cooled, diluted with ethyl acetate, washed with dilute sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was flash chromatographed on silica (60 g) with 20% ethyl acetate/hexanes. The purified product was taken up in hot toluene/heptane and allowed to crystallize slowly. The light brown solid was washed with heptane and dried in air, then under vacuum to give the title compound (1.73 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:39][O:40][C:41](=[O:52])[CH:42]([NH2:51])[C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:39][O:40][C:41](=[O:52])[CH:42]([NH:51][C:10](=[O:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: COC(=O)C(N)C(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (5.49 g; 17.42 mmol) was dissolved in dry tetrahydrofuran (200 ml) and N-methylmorpholine (1.92 ml; 17.42 mmol) was added. The reaction mixture was cooled to -20° C. and stirred 15 min. Isobutyl chloroformate (2.27 ml; 17.42 mmol) was dissolved in dry tetrahydrofuran (3 ml) and added dropwise to the reaction mixture at -20° C. N-methylmorpholine (1.92 ml; 17.42 mmol) and 2-amino-3-oxo-3-phenylpropionic acid methylester (4.0 g; 17.42 mmol) were added and and the mixture was stirred 30 min at -20° C. The reaction mixture was heated to room temperature and the solvent was removed in vacuo. The residue was dissolved in methylene chloride (200 ml), washed with water (200 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (5×45 cm) using heptane/ethyl acetate/methylene chloride (2:1:1) as eluent to afford 6.19 g of a diastereomeric mixture of 2-((2R)-2-tert-butoxycarbonylamino-3-(2-naphthyl)propionylamino)-3-oxo-3-phenylpropionic acid methylester.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:23][N:20]1[CH:21]=[CH:22][C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]4[C:30]([OH:32])=[O:31])[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:34][CH:33]=4)[C:11]=3[CH:12]=2)=[N:19]1
Reactant: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Reactant: C1CCNCC1
Product: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCCCC5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions to Example 152 using piperidine. MS (ESI): mass calcd. for C31H37N5O3, 527.67; m/z found, 528.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.51 (dd, J=8.2, 5.5, 2H), 7.01 (d, J=8.7, 2H), 6.97 (d, J=2.3, 1H), 6.94-6.87 (m, 3H), 6.27 (d, J=2.3, 1H), 5.45-5.34 (m, 2H), 4.99 (s, 2H), 3.83 (s, 3H), 3.63-3.53 (m, 1H), 3.15-3.06 (m, 4H), 2.85-2.76 (m, 1H), 2.43-2.25 (m, 1H), 1.99-1.75 (m, 4H), 1.74-1.63 (m, 5H), 1.63-1.52 (m, 2H), 1.53-1.34 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]([O:25]CC)=O)[N:12]([CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[NH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([NH:28][C:23]([C:11]2[N:12]([CH3:22])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2Cl)n1C
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of ethyl 4,5-di-(2,4-dichlorophenyl)-1-methylimidazole-2-carboxylate (20 mg, 0.045 mmol) from Step D in neat 1-aminopiperidine (1 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (1 mm, silica) (25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[O:6][C:7]=1[NH:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])=[CH:11][CH:10]=1)#[N:2].C(=O)(O)[O-:41].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[NH:20]1[CH2:19][CH2:18][CH:17]([CH2:16][NH:15][C:13]([C:12]2[CH:30]=[CH:31][C:9]([NH:8][C:7]3[O:6][C:5]([C:32]4[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=4[F:39])=[N:4][C:3]=3[C:1]([NH2:2])=[O:41])=[CH:10][CH:11]=2)=[O:14])[CH2:22][CH2:21]1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(Nc3oc(-c4c(F)cccc4F)nc3C#N)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)NCC2CCNCC2)cc1
Yield: 14 %

Procedure:
A solution of tert-butyl 4-((4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzamido)methyl)piperidine-1-carboxylate (0.028 g, 0.052 mmol) in concentrated sulfuric acid (1 mL) was stirred at room temperature for 1.5 hours. The solution was neutralised by pouring into saturated sodium bicarbonate solution. The aqueous phase was then basified to pH14 with 5M NaOH and extracted with EtOAc. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford 5-(4-((piperidin-4-ylmethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.003 g, 0.007 mmol, 14%) as a yellow solid. 1H NMR (CD3OD) δ 1.51 (2H, m), 2.00 (3H, m), 2.99 (2H, t), 3.35 (2H, m), 3.45 (2H, m), 7.22 (2H, t), 7.53 (2H, d), 7.60 (1H, m), 7.87 (2H, d), 8.55 (1H, br s). LCMS (2) Rt: 1.85 min; m/z (ES+) 456.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[N:15]=[CH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Br:24])[CH:18]=3)(=O)=O)=CC=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:24][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([CH2:13][CH2:12][N:27]3[CH2:28][CH2:29][CH2:30][C@H:26]3[CH3:25])[N:15]=[CH:16]2)=[CH:21][CH:20]=1
Reactant: C[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3ccc(Br)cc3cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2ccc(Br)cc2cn1
Temperature: 52.5 °C

Procedure:
The product from Example 52F was dissolved in a solution of (2R)-2-methylpyrrolidine (0.26 g, 3.0 mmol) in acetonitrile (20 mL). The solution was treated with potassium carbonate (0.5 g, 3.6 mmol) and heated at 50-55° C. for 20 hours in a sealed flask. The mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was diluted with MTBE (20 mL) and water (20 mL) and the pH was adjusted to 3-3.5 with concentrated HCl. The aqueous layer was separated, extracted with MTBE (10 mL), adjusted to a pH of 8-8.5 with potassium carbonate, and extracted with isopropyl acetate (20 mL). The organic layer was separated and concentrated in vacuo. The residue was dissolved in heptane (20 mL), filtered, and the filtrate concentrated under vacuum to provide the title compound. 1H NMR (CDCl3) δ 1.10 (d, J=6.1 Hz, 3H); 1.35-1.49 (m, 1H); 1.62-1.85 (m, 2H); 1.85-1.98 (m, 1H); 2.23 (q, J=8.8. Hz, 1H); 2.28-2.42 (m, 1H); 2.46-2.57 (m, 1H), 3.04-3.19 (m, 2H); 3.19-3.30 (m, 2H); 7.47 (s, 1H); 7.60 (d, J=8.8 Hz, 1H), 7.647.70 (m, 1H), 8.05 (m, 1H); 9.09 (s, 1H); HRMS Calcd. for [C16H19BrN2+H+]: 319.0810. Found: 319.0795.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([C:29]([OH:31])=[O:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[CH2:17][OH:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:32](Cl)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([C:29]([OH:31])=[O:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[CH2:17][O:18][C:32](=[O:34])[CH3:33])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)c1ccc2cc(-c3ccc(CO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
2.42 g (5.87 mmol) of the alcohol obtained in Example 12 in 12 ml of pyridine are treated with 0.63 ml of acetyl chloride for 30 min. The reaction medium is poured into ice cold water, and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated to give, after recrystallization from the ethyl acetate/hexane mixture, 1.67 g (63%) of a product which melts at 251° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:37]1([C:43]#[CH:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1.[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:44]#[C:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(I)cc2)n1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(C#Cc3ccccc3)cc2)n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-tert-butoxycarbonylamino-5-(4-iodophenyl)imidazole-1-carboxylic acid tert-butyl ester (0.100 g, 0.206 mmol) was dissolved in anhydrous THF (8 mL) and to this solution was added DIPEA (0.359 mL, 2.06 mmol), CuI (0.004 g, 0.021 mmol), and PdCl2(PPh3)2 (0.014 g, 0.021 mmol). The solution was then degassed at ambient temperature for 10 minutes. During this time a solution of the phenyl acetylene (0.105 g, 1.03 mmol) in anhydrous THF (3 mL) was also degassed. The solution of alkyne was added drop-wise to the solution of aryl iodide and the reaction was stirred at room temperature for 12 h. The reaction was filtered through a Celite® pad and the filter cake rinsed with EtOAc (10 mL). The filtrate was washed with sat. NH4Cl (2×10 mL), brine (2×10 mL), and dried (Na2SO4). Filtration and evaporation afforded the crude product which was purified via flash column chromatography (10-50% EtOAc/Hexanes) to obtain 0.085 g (90%) of the target 2-tert-butoxycarbonylamino-5-(4-phenylethynylphenyl) imidazole-1-carboxylic acid tert-butyl ester as a yellow solid: mp=131-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.00 (s, 1H), 7.86 (d, 2H, J=7.6 Hz), 7.42-7.57 (m, 7H), 1.58 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 152.9, 146.8, 139.9, 136.3, 133.0, 131.7, 131.4, 128.8, 124.9, 122.4, 126.8, 120.9, 113.7, 89.9, 89.5, 85.4, 80.1, 27.9, 27.3; HRMS (ESI) calcd for C27H19N3O4Na (MNa+) 482.2050. found 482.2051.
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:16]([CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1)[C:17]1[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=1)(=[O:34])[CH3:33]
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc(/C=C/C(=O)OCC)cc2)cc1
Reactant: CC(=O)Cl
Product: CCCCCCCCC#Cc1ccc(CN(C(C)=O)c2ccc(/C=C/C(=O)OCC)cc2)cc1

Procedure:
The title compound was prepared following the procedure E using ethyl (2E)-3-{4-[(4-dec-1-ynylbenzyl)amino]phenyl}acrylate and acetyl chloride as a yellow oil (97%). M+ (ESI): 460.2. HPLC, Rt: 6.0 min (purity: 98.8%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][OH:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:34](N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][O:12][CH3:34])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccnc(NC(=O)Nc2ccc(-c3c(CO)cn4ncnc(N)c34)cc2)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C)ccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of DCM (5 mL) was added N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(4-methylpyridin-2-yl)urea (Example 262) (40 mg, 0.10 mmol) followed by 2M thionyl chloride in DCM (0.51 mL, 1.03 mmol). The solution was stirred at rt for 1 h and was then evaporated in vacuo. THF (5 mL) and MeOH (5 mL) were added to the crude reaction followed by triethylamine (43 μL, 0.31 mmol). The solution was heated to 50° C. for 3 d and then evaporated in vacuo and purified by MPLC (Isco) 0-5% MeOH/DCM. The resulting purified fractions were combined and evaporated producing 25 mg of the title compound (0.061 mmol, yield 60%). 1H-NMR (DMSO-d6) δ 10.86 (s, 1H), 9.46 (s, 1H), 8.14 to 8.13 (d, J=6.3 Hz, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.65 to 7.63 (d, J=8.7 Hz, 2H), 7.36 to 7.34 (d, J=8.6 Hz, 2H), 7.27 (s, 1H), 6.87 to 6.86 (d, J=5.0 Hz, 1H), 4.27 (s, 2H), 3.20 (s, 3H), 2.30 (s, 3H); MS [M+H]+=404.0; LCMS RT=1.99 min.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([C@H:12]([N:18]4[CH:22]=[C:21]([CH2:23][C@@H:24]([NH:28][S:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[C:25](O)=[O:26])[N:20]=[N:19]4)[CH2:13][CH2:14][O:15]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=[N:43]C2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-].CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]1([NH:6][CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([C@H:12]([N:18]4[CH:22]=[C:21]([CH2:23][C@@H:24]([NH:28][S:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)(=[O:30])=[O:31])[C:25]([NH2:43])=[O:26])[N:20]=[N:19]4)[CH2:13][CH2:14][O:15]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2cccnc21
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCOc4cc(CNC5CCCC5)ccc43)nn2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCOc4cc(CNC5CCCC5)ccc43)nn2)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoic acid (61 mg, 0.11 mol), HOAt (18 mg, 0.12 mmol), i-Pr2NEt (60. mL, 0.45 mmol), NH4Cl (25 mg, 0.45 mmol), and EDCI (24 mg, 0.12 mmol) in 5 mL DMF was stirred for 24 h at RT. The reaction mixture was concentrated, taken up in H2O, and the white solid was filtered and air-dried to afford the title compound. MS (m/z, m+1): 539.4.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH:38][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])=[N:13][C:12]=3[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CCCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: CCCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H23ClN4O3 (m/e) 426, obsd 427 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][C@:9]3([CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[C:8]2=[O:17])[CH2:3][CH2:2]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:13]2[CH2:14][CH2:15][CH2:16][C@@:9]3([C:8](=[O:17])[N:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:11][CH2:10]3)[CH2:12]2)=[N:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C1N(C2CCOCC2)CC[C@]12CCCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)nc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of (5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one [90 mg, 0.0004 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 92, steps 1-3], 2-chloro-5-nitropyridine (69 mg, 0.00044 mol), and potassium carbonate (160 mg, 0.0012 mol) in N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at 120° C. for 1.5 hours. After cooling the reaction mixture to ambient temperature, the solid was filtered off and the filtrate was concentrated in-vacuo to afford the desired product. LC-MS: 361.2 (M+H)+. The resulting residue was dissolved in methanol and to this solution was added 10% Pd on carbon and the reaction vessel was placed under a H2 (g) atmosphere and stirred at rt for 1.5 h. The catalyst was filtered off from the mixture and the filtrate was concentrated to afford the desired product in quantitative yield and was used in the next step without further purification. LC-MS: 331.2 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])O1.Cl[C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].CC#N>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.O>[OH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)COC(=O)N1CCN(c2ccnc(Cl)c2)CC1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
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: O
Solvent: CC#N
Product: CC(C)COC(=O)N1CCN(c2ccnc(-c3ccccc3O)c2)CC1
Temperature: 120 °C

Procedure:
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (25/μL, 120 μmol), 3a (30 mg, 100 μmol), Pd(Ph3P)4 (12 mg, 10 μmol), K2CO3 (28 mg, 200 μmol), CH3CN (900 μL), and H2O (100 μL) were sealed in a microwave vessel and heated by microwave irradiation at 120° C. for 15 minutes. The reaction was filtered and purified by reverse phase HPLC to give compound 1. (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA). LCMS: m/z 356.1 (M+H)+ at 2.24 minutes (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA).