Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:5][C:6](O)=[O:7])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:42]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[CH2:1]([O:3][CH:4]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:5][C:6]([NH:51][S:48]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:50])=[O:49])=[O:7])[CH3:2]
Reactant: CCOC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(CC(=O)NS(=O)(=O)c1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid (45 mg, 0.11 mmol) is dissolved in dry THF (1.0 mL) and 1,1′-carbonyl diimidazole (40 mg, 0.25 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, benzenesulfonamide (34 mg, 0.22 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.033 mL, 0.22 mmol) is added. The mixture is stirred for 4 hr at room temperature and 1.0 M HCl solution (3 mL) is added followed by water (30 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 6% MeOH in CH2Cl2 with 1.0% concentrated aqueous NH4OH solution (28%) affords 22 mg (36%) of N-{3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionyl}-benzenesulfonamide. LCMS (ESMS): m/z 550.15 (M+H+).
Reaction SMILES: I[CH3:2].[CH2:3]([N:10]1[CH:16]2[CH2:17][CH2:18][CH:11]1[CH2:12][NH:13][CH2:14][CH2:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CCOCC>[CH2:3]([N:10]1[CH:16]2[CH2:17][CH2:18][CH:11]1[CH2:12][N:13]([CH3:2])[CH2:14][CH2:15]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: c1ccc(CN2C3CCNCC2CC3)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCC2CCC(C1)N2Cc1ccccc1

Procedure:
Neat Iodomethane (0.173 ml, 2.77 mmol) was added dropwise to a stirred solution of 9-benzyl-3,9-diazabicyclo[4.2.1]nonane (0.4 g, 1.849 mmol) and TEA (2.58 ml, 18.49 mmol) in THF (5 ml). The resultant suspension was stirred at rt for 3 hrs and diluted with ether and then filtered. The filtrate was evaporated to dryness to afford 9-benzyl-3-methyl-3,9-diazabicyclo[4.2.1]nonane as a light yellow oil. LC/MS: m/e 231 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH3:12])[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([CH3:12])[CH2:5][N:6]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C(C)CNC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Yield: 101.3 %

Procedure:
Under an argon atmosphere, a solution of 26.86 g (0.145 mole) of (rac)-3-cyclopentylamino-2-methyl-propanoic acid methyl ester in 25 mL of ethyl acetate was added over 5 minutes to a cooled (5 degrees) and stirring mixture of 28.13 g (0.145 mole) of 2,4-dichloro-5-nitro-pyrimidine, 48.72 g (0.58 mole) of sodium bicarbonate and 300 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The mixture was concentrated under reduced pressure to give 50.37 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-propanoic acid methyl ester (IV-1) as a thick oil, which contained a small portion of a regioisomer. This material was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:32]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([C:19]2[CH:18]=[N:17][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[N:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)OC1(C)C
Reactant: Brc1ccc(I)nc1
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: C1COCCO1
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)nc1
Temperature: 90 °C
Yield: 97 %

Procedure:
A mixture of 1-phenyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1H-benzo[d]imidazole (Compound 16) (12 mmol), 2-iodo-5-bromo pyridine (6.816 g, 24 mmol), Pd(PPh3)4 (0.69 g, 0.6 mmol) and K2CO3 (3.3 g, 24 mmol) in dioxane/water (100 mL/20 mL) was degassed and heated at 90° C. for 20 hours. The whole was allowed to cool to RT, white precipitate formed. After filtration, a solid (Compound 17) was collected (5.0 g, in 97% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(NC2CCCCC2)CCCCC1.CN1CCOCC1.ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][OH:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCOC(=O)Cl
Agent: [Al+3]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 83A from 300 mg (0.60 mmol) of (2S)-2,4-bis[(tert-butoxycarbonyl)amino]butanoic acid-N-cyclohexylcyclohexanamine (1:1) in 10 ml of tetrahydrofuran with 61 mg (0.60 mmol) of 4-methylmorpholine, 65 mg (0.60 mmol) of ethyl chloroformate and 1.2 ml (1.20 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The product is reacted without further purification.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([N:17]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])[CH3:16])C.O[Li].O>C1COCC1.CO.O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([N:17]([CH:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])[CH3:16])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])(=[O:27])=[O:28])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCOc1ccccc1C(C)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccccc1OCCCC(=O)O)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 40.7 %

Procedure:
A solution of ethyl-4-[2-(1-{[(4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl)phenoxy]butanoate (1.16 g, 2.2 mmol) in THF (5.2 mL), methanol (1.7 mL) and H2O (1.7 mL) was treated with LiOH.H2O (91 mg, 2.2 mmol) at 25° C. for 3 h. The reaction was then quenched with 1 N HCl solution. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with H2O and sat. NaCl aqueous solution, then dried over MgSO4. Concentration and chromatography afforded the desired product (457 mg, 41%) as white crystal: m.p. 141.0-142.0° C.; Rf 0.14 (10:10, hexane-ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 11.08 (br s, 1H), 7.62 (d, 2H, J=8.4 Hz), 7.35 (d, 2H, J=8.7 Hz), 7.16 (t, 1H, J=7.5 Hz), 6.38-6.93 (m, 6H), 6.03 (br s, 1H), 4.06 (m, 2H), 2.70 (t, 2H, J=7.0 Hz), 2.17 (m, 2H), 1.57 (d, 3H, J=6.9 Hz); LCMS 3.05 min, m/z 527.2 (C24H22ClF2NO5S requires 509.95).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=O)[O:14][C:10]=2[CH:9]=1>ClC1C=CC=CC=1Cl>[Cl:2][C:13]1[O:14][C:10]2[CH:9]=[C:8]([Cl:7])[CH:17]=[CH:16][C:11]=2[N:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Solvent: Clc1ccccc1Cl
Product: Clc1ccc2nc(Cl)oc2c1
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
400 ml of o-diohIorobenzene and 1,040 g (5 moles) of phosphorus pentachloride are heated to 150° to 160° C. Then 169.5 g (1 mole) of 6-chlorobenzoxazolin-2-one, suspended in 600 ml of o-dichlorobenzene, are metered in within 2 hours with heating such that the interior temperature does not drop below 150° C. The addition being complete, stirring is continued for a further 10 minutes. working up analogously to Example 8 results in a yield of 145 g of 2,6-dichlorobenzoxazole, corresponding to 77% of theory. GC purity: 99.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:18]([O-])=O.CO>C(OCC)(=O)C.[Pd].[C]>[NH2:18][C:3]1[CH:4]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:17])[CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(=O)c1ccc(Oc2ccc(N)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(Oc2ccc(N)c(N)c2)cc1
Reaction time: 24 h

Procedure:
1-{4-[(4-amino-3-nitrophenyl)oxy]phenyl}ethanone (437 mg) was dissolved in 1:1 ethyl acetate: methanol and hydrogenated over 500 mg of 10% Pd/carbon (wet, Degussa type) under an atmosphere of H2 gas. After 24 hours, the reaction was filtered through Celite and concentrated to give crude 1-{4-[(3,4-diaminophenyl)oxy]phenyl}ethanol which was used without further purification. (M+1) 245.2, 1.05 min (LC/MS method A)
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[C:50]([C:52]1[N:56]([CH2:57][CH2:58][CH2:59][OH:60])[N:55]=[CH:54][C:53]=1[C:61]1[N:66]=[C:65]([C:67](=[O:70])[NH:68][CH3:69])[C:64]([NH:71][C:72]2[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][N:75]=[C:74]([NH:82][C:83]3[CH:97]=[CH:96][C:86]([CH2:87][P:88](=[O:95])([O:92]CC)[O:89][CH2:90][CH3:91])=[CH:85][C:84]=3[O:98][CH3:99])[N:73]=2)=[CH:63][CH:62]=1)#[N:51]>>[C:50]([C:52]1[N:56]([CH2:57][CH2:58][CH2:59][OH:60])[N:55]=[CH:54][C:53]=1[C:61]1[N:66]=[C:65]([C:67](=[O:70])[NH:68][CH3:69])[C:64]([NH:71][C:72]2[C:77]([C:78]([F:79])([F:81])[F:80])=[CH:76][N:75]=[C:74]([NH:82][C:83]3[CH:97]=[CH:96][C:86]([CH2:87][P:88](=[O:92])([OH:95])[O:89][CH2:90][CH3:91])=[CH:85][C:84]=3[O:98][CH3:99])[N:73]=2)=[CH:63][CH:62]=1)#[N:51]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4C#N)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4C#N)nc3C(=O)NC)n2)c(OC)c1
Yield: 79.6 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[5-cyano-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 53B, 191 mg, 0.266 mmol) to afford 146 mg of the title compound (80%). 1H NMR (400 MHz, CD3OD) δ 9.15 (br. s., 1H), 8.47 (br. s., 1H), 8.33 (s, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.61 (br. s., 1H), 7.12 (s, 1H), 6.95 (d, J=8.1 Hz, 1H), 4.49 (t, J=7.1 Hz, 2H), 3.83-3.93 (m, 5H), 3.60 (t, J=6.2 Hz, 2H), 2.99-3.07 (m, 2H), 2.97 (s, 3H), 2.16 (quin, J=6.5 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H). MS (ESI): m/z=690.62 [M+H]+. UPLC: tR=1.26 min (UPLC-TOF: polar—2 min).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:10]3[S:9][C:8]([NH2:11])=[N:7][C:6]=3[CH:5]=[C:4]([CH3:12])[C:3]=2[O:13][CH3:14])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1c(C)cc2nc(N)sc2c1Br
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: COCCOC
Product: COc1c(C)cc2nc(N)sc2c1-c1ccc(Cl)cc1

Procedure:
The mixture of 7-bromo-6-methoxy-5-methylbenzo[d]thiazol-2-amine (8A) (1.72 g, 6.32 mmol), 4-chlorophenyl boronic acid (1.2 g, 7.67 mmol), K2CO3 (2.63 g, 18.9 mmol), Pd(PPh3)4 (364 mg, 0.315 mmol) in DME (8 ml) and H2O (4 ml) was reacted in microwave at 110° C. for 1 h. Then 4-chlorophenyl boronic acid (100 mg, 0.64 mmol), Pd(PPh3)4 (100 mg, 0.086 mmol) were added and reacted in microwave at 110° C. for 0.5 h and 120° C. for 20 min. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI+: calc'd for C15H13ClN2OS: 305.0 (M+H+). Found: 305.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[C:35]([O:37][CH3:38])=[O:36])[CH:6]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C(=O)OC)[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-((S)-indan-1-ylaminomethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:32]5[CH:31]=[N:30][C:29]([N:24]6[CH2:25][CH2:26][CH2:27][CH2:28]6)=[CH:34][CH:33]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC1(C)OB(c2ccc(N3CCCC3)nc2)OC1(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(N4CCCC4)nc3)cc1-2
Yield: 62 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were reacted to give 399 (0.078 g, 62%). 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=2.4, 1H), 8.41 (d, J=2.2, 1H), 8.08 (d, J=24.7, 1H), 7.78 (dd, J=8.7, 2.6, 1H), 7.52 (dd, J=8.4, 2.5, 1H), 7.13 (d, J=8.4, 1H), 6.57 (d, J=8.7, 1H), 5.79 (dt, J=13.1, 6.5, 1H), 4.35 (dd, J=39.9, 34.8, 2H), 3.65-3.37 (m, 6H), 2.11-1.80 (m, 4H), 1.58 (d, J=6.6, 6H). MS (ESI(+)): m/z 459.2 (M+H)
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)N(C)CCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: C1CSCCN1
Solvent: CN1CCCN(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCSCC2)c2cccnc2c1O
Temperature: 25 °C

Procedure:
A solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.25 g, 0.67 mmol), thiomorpholine (0.19 mL, 2.0 mmol) and diisopropylethylamine (0.06 mL, 0.67 mmol) in DMPU (3.0 mL) were heated at 135 C for 23 hr. The reaction was cooled to room temperature, neutralized by the addition of TFA and purified by reverse phase HPLC. (Vydak C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 30 mL/min over 15 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1
Reactant: OCCO
Reactant: O=CCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: BrCCCCCCCCC1OCCO1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
9-Bromononanal (28.0 g, assumed 120 mmol), ethylene glycol (33.6 mL, 600 mmol) and para-toluenesulphonic acid (2.7 g, 13 mmol) in toluene (210 mL) were heated at reflux for 20 hours. The reaction was cooled to RT and quenched with saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was extracted with diethyl ether (2×500 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (300 mL), water (300 mL), brine (100 mL), dried (magnesium sulfate), filtered and evaporated under reduced pressure to afford the title compound (25.2 g, 79%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH:21]=[CH:22][C:23](N(OC)C)=[O:24]>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH:21]=[CH:22][C:23](=[O:24])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1]
Reactant: CON(C)C(=O)C=Cc1ccc(F)cc1F
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccc(F)cc1F)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (79.0 mL, 66.0 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (44.0 mL, 66.0 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(2,4-difluoro-phenyl)-N-methoxy-N-methyl-acrylamide (5.0 g, 22.0 mmol, in diethyl ether 30.0 mL) prepared in Step 2 was slowly added thereto at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 6.2 g of the titled compound as a yellow liquid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([OH:19])=O)=[CH:14][C:13]=3[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][NH:34][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:20][C:13]=3[CH:14]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (156 mg, 0.50 mmol) and 4-(2-aminoethoxyl)benzoic acid methyl ester hydrochloride (129 mg, 0.56 mmol) in DMF (4.5 ml) in a 20 ml vial was added diisopropylethylamine (0.88 ml, 5.1 mmol). A solution of 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (740 μL, 0.82 M, 0.61 mmol) in DMF was added to give a bright yellow solution. The vial was purged with nitrogen and stirred at room temperature for 18 h. The solution was removed and the residue was dissolved in EtOAc (25 ml) and washed with H2O, 1.0M aqueous K2CO3, and brine. The organic layer was dried over anhydrous MgSO4 and solvent was removed on a rotary evaporator. Purification of the residue by column chromatography on a silica gel column using 93:5:2 CH2Cl2:MeOH:TEA eluent provided 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester as a beige solid (174 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:47].Cl>>[ClH:47].[ClH:47].[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[C:13]5=[C:14]([F:22])[CH:15]=[N:16][C:17]6[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=65)[CH2:10]4)[CH2:4][CH2:3]3)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=c1ccc2ncc(F)c3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Yield: 71 %

Procedure:
The title compound was prepared from (4R)-4-[(4-amino-1-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one Enantiomer 1 and 2,3-dihydro-1,4-benzodioxin-6-carboxaldehyde (Aldrich) according to the general method of Example 2(h) (except that the dihydrochloride was prepared) in 71% yield.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][O:9][C:10](=[O:29])[C@H:11]([CH:26]([CH3:28])[CH3:27])[NH:12][C:13](=[O:25])[C:14]([CH3:24])([CH3:23])[NH:15]C(OC(C)(C)C)=O>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:8][O:9][C:10](=[O:29])[C@H:11]([CH:26]([CH3:27])[CH3:28])[NH:12][C:13](=[O:25])[C:14]([CH3:24])([CH3:23])[NH2:15]
Reactant: COC(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Reaction time: 2 h
Yield: 82 %

Procedure:
A 50% (v/v) solution of TFA in CH2Cl2 (350 mL) was added to N-tert-butoxycarbonyl α,α-dimethylglycyl L-valine methyl ester (5) (33.50 g, 0.1059 mol) at room temperature and the reaction mixture stirred for 2 hours. The solvent and bulk of excess TFA were removed under reduced pressure. The residue was washed with Et2O (3×200 mL) and dried under reduced pressure affording a clear oil. Dichloromethane (3×200 mL) was added and evaporated under reduced pressure affording a sticky white solid (28.51 g, 82%); δH (300 MHz; d6-DMSO) 8.42 (1H, d, J 8, NH), 8.26 (3H, br s, NH3+), 4.17 (1H, dd, J 8 and 8, CαH(Val)), 3.64 (3H, s, OCH3), 2.16-2.05 (1H, m, CH(CH3)2), 1.52 (3H, s, CH3(Aib)), 1.50 (3H, s, CH3(Aib)), 0.91 (3H, d, J 6, CH3(Val)), 0.88 (3H, d, J 6, CH3(Val)); δC (75 MHz; d6-DMSO) 172.0, 171.6, 158.1 (q, JcF 32), 116.9 (q, JCF 297), 58.3, 56.5, 51.7, 29.5, 23.2, 23.1, 19.0, 18.6; m/z (ESI) 217.1556 (M+; C10H21N2O3 requires 217.1552)