Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]([NH:22][C:23]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44]([C:46]1([OH:52])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)#[CH:45].C#C>C1COCC1.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>[OH:52][C:46]1([C:44]#[C:45][C:2]2[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH:9]3[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]([NH:22][C:23]([N:25]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)=CCN(c1ccc(I)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Reactant: C#CC1(O)CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)=CCN(c1ccc(C#CC2(O)CCCCC2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
(S)-Azepane-1-carboxylic acid (1-{4-[(4-iodo-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide (0.50 g, 0.49 mmol) was dissolved in THF (4 mL), treated with triethylamine (0.34 mL, 2.45 mmol), 1-ethynyl-1-cyclohexanol (94 RL, 0.74 mmol), Pd(Ph3P)2Cl2 (34 mg, 0.049 mmol), and cuprous iodide (4.8 mg, 0.028 mmol). The reaction was stirred overnight at room temperature, then heated to 40° C. overnight. Another 1.5 equivalents of the acetylene, 0.1 equivalents of Pd(Ph3P)2Cl2, and 0.05 equivalents of cuprous iodide were added and the reaction was heated to 40° C. overnight. The reaction was then concentrated in vacuo and chromatographed on silica gel eluting with 4:3 hexane/EtOAc to give 116 mg (39%) of the desired product.
Reaction SMILES: CN(C)C.CN(C=O)C.Cl/[CH:11]=[C:12]1/[C:13](=[N:22]/[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)/[S:14][CH:15]2[CH:20]([CH2:21]/1)[CH2:19][CH2:18][CH:17]=[CH:16]2.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23](/[N:22]=[C:13]2\[S:14][CH:15]3[CH:20]([CH2:21]\[C:12]\2=[CH:11]/[S:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:19][CH2:18][CH:17]=[CH:16]3)=[CH:24][CH:25]=1
Reactant: Sc1ccccc1
Reactant: Cl/C=C1\CC2CCC=CC2S\C1=N/c1ccc(Cl)cc1
Agent: CN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(/N=C2\SC3C=CCCC3C\C2=C/Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
65 mg of trimethylamine and 1 ml of DMF solution including {3-[1-chloro-(E)-methylidene]-3,4,4a,5,6,8a-hexahydro-thiochromene-(2Z)-ylidene}-(4-chloro-phenyl)-amine were added to 2 ml of DMF solution including 47 mg of thiophenol at 0° C. The resulting solution was stirred at room temperature for an additional 30 minutes, and added with water, and then extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.17 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[H-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][CH2:24][Br:23])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Reactant: BrCCCOCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ccc(OCCCOCCCBr)c(C(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.5 %

Procedure:
Under an argon atmosphere, 1 g of [(8-acetyl-7-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester was added to a suspension of 0.16 g of 60% sodium hydride in 15 ml of anhydrous dimethylformamide. The mixture was stirred at room temperature for 40 minutes and then 4.75 g of bis(3-bromopropyl)ether was added. The mixture was stirred at room temperature for 20 hours. The mixture was concentrated in vacuo to an oil which was dissolved in ethyl acetate, washed with water and concentrated to give an oil which was purified by column chromatography using 7.5% ethyl acetate-toluene to yield 1 g (60%) of [[8-acetyl-7-[3-(3-bromopropoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([OH:13])=O)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:28]([O:32][C:33]([CH:35]1[CH2:43][CH:42]2[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[N:36]1[C:44](=[O:61])[CH:45]([NH:50][C:51](=[O:60])[CH:52]([NH2:59])[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C>[C:28]([O:32][C:33]([CH:35]1[CH2:43][CH:42]2[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[N:36]1[C:44](=[O:61])[CH:45]([NH:50][C:51](=[O:60])[CH:52]([NH:59][C:11]([C:5]1[NH:6][C:7]([CH3:10])=[C:8]([CH3:9])[C:4]=1[C:1](=[O:3])[CH3:2])=[O:13])[CH:53]1[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1)[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:34])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)C(N)C1CCCCC1)C(C)(C)C
Reactant: CC(=O)c1c(C(=O)O)[nH]c(C)c1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)c1c(C(=O)NC(C(=O)NC(C(=O)N2C(C(=O)OC(C)(C)C)CC3CCCCC32)C(C)(C)C)C2CCCCC2)[nH]c(C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
3-acetyl-4,5-dimethyl-2-pyrrole carboxylic acid 10b (2.5 g, 13.7 mmol) in DMF (56 mL) was treated with EDC (2.75 g, 14.4 mmol) and HOBt (2.20 g, 14.4 mmol) and stirred at RT for 15 minutes. Amine 16b (6.23 g, 13.0 mmol) in DMF (10 mL) was added, the reaction mixture stirred at RT and monitored by HPLC. The mixture was concentrated in vacuo, then dissolved in EtOAc. 1.0N glycine sodium salt aqueous solution was added until all excess amino ester 16b was consumed (several hours). The mixture was washed with 1N HCl (3×), brine, bicarb (3×), and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification through a short plug of silica gel (25%EA/Hex) afforded 7.08 g, (85%) of 1-(2-{2-[(3-acetyl-4,5-dimethyl-1H-pyrrole-2-carbonyl)-amino]-2-cyclohexyl-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic acid tert-butyl ester 17b.
Reaction SMILES: [NH2:1][C:2](=[O:40])[C@@H:3]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:23]=[CH:22][C:14]3[N:15]([CH2:19][CH2:20][OH:21])[C:16](=[O:18])[S:17][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1.O>CN(C=O)C>[NH2:1][C:2](=[O:40])[C@@H:3]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[O:26])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:23]=[CH:22][C:14]3[N:15]([CH2:19][CH2:20][O:21][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:16](=[O:18])[S:17][C:13]=3[CH:12]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO)cc1)C(N)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO[Si](C)(C)C(C)(C)C)cc1)C(N)=O
Reaction time: 4 h
Yield: 78.4 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-1-amino-3-(4-(3-(2-hydroxyethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)piperidine-1-carboxylate (138 mg), tert-butyldimethylsilyl chloride (40.2 mg) and imidazole (41.3 mg) in DMF (1 mL) was stirred for 16 h. Further tert-butyldimethylsilyl chloride (40.2 mg) and imidazole (41.3 mg) were added and stirred for 4 h. Water was added and the mixture was extracted thrice with ethyl acetate. The organic layers were washed twice with water, combined, dried over magnesium sulfate, evaporated and purified by flash silica chromatography eluting with 1:2 acetone/isohexane to give the subtitle compound (130 mg) as a colourless gum.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]=[CH:5]2.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>O1CCOCC1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]=[CH:5]2
Reactant: CN(C)CCN
Reactant: Clc1ccc2nc(NCCOc3ccccc3)ccc2c1
Solvent: C1COCCO1
Product: CN(C)CCNc1ccc2nc(NCCOc3ccccc3)ccc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
(6-Chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine (100 mg, 0.33 mmol) was dissolved in 1.5 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. N,N-Dimethylethylendiamine (149 mg, 1.69 mmol), sodium tert.-butylate (80 mg, 0.83 mmol), 1,1′-bis(diphenylphosphin)ferrocen (21 mg, 0.037 mmol) and 1,1′-bis(diphenyl-phosphin)ferrocen-palladium(II)chloride (10 mg, 0.012 mmol) were added. The reaction mixture was stirred in a sealed tube at 120° C. overnight. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient). The title compound was obtained as a brown oil (35 mg, 30%), MS: m/e=351.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4].[Br:22]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:22])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: COc1ccc2c(c1)CC(C)N(C(=O)C(F)(F)F)CC2C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Reaction time: 8 h

Procedure:
A solution N-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.452 g, 1.50 mmol) in acetonitrile (20 mL) was treated with N-bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (100 mL), washed with sodium bisulfite (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.32 (s, 1 H), 6.62 (m, 1 H), 4.37 (m, 1 H), 3.87 (s, 3 H), 3.81 (m, 1 H), 3.28-3.10 (m, 3 H), 2.73 (m, 1 H), 1.31 (m, 3 H), 1.25 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>>[CH2:27]([O:26][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[CH2:7]2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH3:28]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: CN(C)C(=O)Cl
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)N(C)C)c3C2=O)ccc1OC
Yield: 49.1 %

Procedure:
A mixture of (1S)-7-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (0.5 g, 1.2 mmol) and dimethylcarbamyl chloride (0.6 mL, 6.5 mmol) was heated to reflux for 2 hours. The solvent was removed in vacuo. The residue was extracted with methylene chloride (50 mL) and sodium hydrogen carbonate (sat, 50 mL). The organic layer was washed with brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified with prep HPLC to give (1S)-3-(2-[1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3,dihydro-1H-isoindol-4-yl}-1,1-dimethyl-urea as a white solid (280 mg, 48% yield): mp 170-172° C.; 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.91 (s, 3H, CH3), 3.11 (s, 6H, 2 CH3), 3.70 (dd, J=5, 15Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.16-4.25 (m, 2H, CHH, NCHH), 4.41 (d, J=17Hz, 1H, NCHH), 5.69 (dd, J=5, 10 Hz, 1H, NCH), 6.83-6.95 (m, 4H, Ar), 7.43 (t, J=8 Hz, 1H, Ar), 8.33 (d, J=8Hz, 1H, Ar), 9.85 (s, 1H, NH); 13C NMR(CDCl3) δ 14.71, 3.32, 41.50, 48.06, 51.89, 55.99, 56.16, 64.65, 131.62, 112.30, 115.09, 116.63, 116.77, 119.34, 129.51, 133.68, 139.67, 141.19, 148.93, 149.80, 155.31, 170.64. Analy. Calculated for C23H29N3O6S+1 H2O: C 55.97; H 6.33; N 8.51; H2O 3.65. Found: C 55.57; H 6.02; N 8.44; H2O, 2.97.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:41]5[S:40](=[O:43])(=[O:42])[N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:38][C:37]=5[CH:36]=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)=[O:25])=[CH:22][C:21]([C:51]([F:54])([F:53])[F:52])=[N:20]2)=[CH:15][C:14]=1[C:55]#[N:56]>CN(C=O)C>[C:2](=[N:4][O:5][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]4[C:41]5[S:40](=[O:43])(=[O:42])[N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:48])[CH3:49])=[O:45])[CH2:38][C:37]=5[CH:36]=[CH:35][CH:34]=4)=[CH:31][CH:32]=3)=[O:25])=[CH:22][C:21]([C:51]([F:52])([F:53])[F:54])=[N:20]2)=[CH:15][C:14]=1[C:55]#[N:56])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1Cc2cccc(-c3ccc(NC(=O)c4cc(C(F)(F)F)nn4-c4ccc(F)c(C#N)c4)cc3)c2S1(=O)=O
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=NOc1ccc(-n2nc(C(F)(F)F)cc2C(=O)Nc2ccc(-c3cccc4c3S(=O)(=O)N(C(=O)OC(C)(C)C)C4)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a solution of acetone oxime (74 mg, 1.0 mmol) in DMF (6 mL) was added sodium t-butoxide (1 M in THF, 1.0 mL). The mixture was stirred at room temperature for half hour followed by addition of a solution of 1,1-dimethylethyl 7-[4-[[[1-[4-fluoro-3-cyanophenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]amino]phenyl]-1,2-benzisothiazole-2(3H)-carboxylate 1,1-dioxide (0.22 g, 0.34 mmol) prepared according to Example 15 in DMF (4 mL). The reaction was stirred at room temperature for 5 hours. The reaction mixture was then partitioned between ethyl acetate and HCl (5%), washed with HCl (5%), four times with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography (30% ethyl acetate/hexane) gave 100 mg of 1,1-dimethylethyl 7-[4-[[[1-[4-isopropylideneaminooxy-3-cyanophenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]amino]phenyl]-1,2-benzisothiazole-2(3H)-carboxylate 1,1-dioxide. The intermediate (100 mg, 0.14 mmol) was dissolved in ethanol (4 mL) and to the solution was added HCl (20%, 4 mL). The reaction mixture was stirred at 80° C. for three hours. The reaction mixture was cooled to room temperature. The white precipitate was filtered to give the product that was purified by HPLC utilizing gradient elution with a mixture of water: acetonitrile with 0.05% of trifluoroacetic acid on a reverse phase C18(60 angstrom) column to give the title compound (37 mg, 19%). LRMS (ES+) 577.1 (M+Na)+.
Reaction SMILES: BrC1C=C2C(C=CC([C@H](N[C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:27])[C@@H:24]([NH2:26])[CH3:25])[NH:18]3)=[O:16])C)=N2)=CC=1.FC(F)(F)C(O)=[O:31]>ClCCl>[NH2:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([OH:16])=[O:31])[NH:18]1)=[O:27]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@H](N)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Solvent: ClCCl
Product: C[C@H](N)C(=O)N1CCC[C@@H](C(=O)O)N1
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (330 mg, 0.618 mmol) in dichloromethane (10 mL) at 0° C. was added trifluoroacetic acid (3.3 mL) and the reaction mixture stirred for 1 hour and then evaporated. The residue was dissolved in dichloromethane and washed with saturated bicarbonate solution (2×), the aqueous extracts washed with dichloromethane and the combined organic extracts passed through a hydrophobic frit and evaporated to give a yellow foam (232 mg) that was carried through to the next step directly.
Reaction SMILES: CON(C)[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].[CH2:26]([Mg]Cl)[CH:27]([CH3:29])[CH3:28]>C1COCC1.C(OCC)C>[CH3:26][CH:27]([CH3:29])[CH2:28][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23]
Reactant: CC(C)C[Mg]Cl
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (4.80 g, 14.1 mmol) in THF (100 mL) in a dry ice/isopropanol bath was added a solution of isobutylmagnesium chloride (28 mL of a 2 M solution in diethyl ether, 56 mmol) over a period of several minutes. When addition was complete, the reaction flask was removed from the cold bath and the mixture stirred for 4 hours at room temperature. A 10% solution of hydrochloric acid in water (3 mL) was added slowly, followed by a saturated solution of sodium bicarbonate in water (15 mL) and dichloromethane (100 mL). The layers were separated, the aqueous phase extracted with dichloromethane (1×75 mL), and the combined organics dried over potassium carbonate, filtered, and concentrated under reduced pressure. After chromatography on silica gel (elution with 5% methanol in dichloromethane) 6-methyl-1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-4-one (2.40 g) was obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8](I)[N:7]=3.N#N.C[Si](C)(C)N[Si](C)(C)C.C[N:29](C)[CH:30]=[O:31]>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>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:30]([NH2:29])=[O:31])[N:7]=3
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: N#N
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Yield: 76 %

Procedure:
Alternatively, a solution of 8-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (10.00 g, 0.02558 mol) in N,N-Dimethylformamide (250 mL) was thoroughly degassed with N2. Bis(triphenylphosphine)palladium(II) chloride (0.807 g, 0.00115 mol) was added followed by Hexamethyldisilazane (21.58 mL, 0.1023 mol). The solution was flushed with CO for 2 minutes and then sealed with a CO balloon attached. The reaction was heated to 70° C. for 2.5 hours. Methylene chloride and saturated NH4Cl were added and the mixture was extracted 4 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. A small amount of isopropanol was added and the mixture was triturated overnight. The mixture was filtered to yield 5.97 g (76% yield) of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a fine brown powder. MS (ESI+) 308.0/310.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[C:11]1([O:17][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)c1cccc(Cl)c1

Procedure:
Phenyl-3-chlorobenzoate is prepared by reacting 3-chlorobenzoyl chloride with phenol in toluene with some pyridine (1 mol equivalent per acid chloride) to trap the HCl that evolves. After aqueous extraction of the pyridinium salt and any excess starting materials, the product is crystallized from the toluene solution.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[N:24]=1)C(O)=O>C1(C)C=CC=CC=1>[C:11]([O:10][C:6](=[O:5])[C:18]1[CH:22]=[C:23]([CH3:25])[N:24]=[C:16]([Cl:15])[CH:17]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
N,N-dimethylformamide-di-tert.-butyl-acetal (19 mL, 80 mmol) is added during 40 min to a hot (65° C., flask temperature) suspension of 2-chloro-6-methyl-isonicotinic acid (3.40 g, 19.8 mmol) in dry toluene (100 mL). The clear orange solution is stirred at 80° C. for 48 h, cooled to rt and diluted with toluene (100 mL). The solution is washed with water (2×40 mL), sat. aq. NaHCO3 (3×30 mL) and sat. aq. NaCl (25 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, DCM-MeOH) to give 2-chloro-6-methyl-isonicotinic acid tert-butyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)CC1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 53 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.63 g, 1.37 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.38 g, 53%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(OC(=O)NC1C2C1CN(CCO)C2)(C)(C)C.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:30][S:31]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39][CH2:38]1)(=[O:33])=[O:32].S([O-])(=O)(=O)C>C(Cl)(Cl)Cl>[CH3:30][S:31]([O:34][CH2:35][CH2:36][N:37]1[CH2:38][CH:39]2[CH:41]([CH:40]2[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42]1)(=[O:32])=[O:33]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)NC1C2CN(CCO)CC21
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1C2CN(CCOS(C)(=O)=O)CC21
Temperature: 25 °C

Procedure:
To a mixture of tert-butyl[3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate (Intermediate 96) (376 mg, 1.55 mmol) and triethyl amine (0.283 mL, 3 mmol) in anhydrous chloroform (15 mL) was added at 0° C. methanesulfonyl chloride (228 mg, 3 mmol) via syringe. The reaction was allowed to warm to room temperature over 1 hr and worked up as described for Intermediate 6. The crude mesylate was used for the next step without delay.