Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:32])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(OC([NH:40][C@H:41]([C:45]([NH:47][C@H:48]([C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[CH2:49][CH2:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:46])[CH:42]([CH3:44])[CH3:43])=O)(C)(C)C>>[C:1]([NH:40][C@H:41]([C:45]([NH:47][C@H:48]([C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[CH2:49][CH2:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:46])[CH:42]([CH3:43])[CH3:44])(=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Yield: 50 %

Procedure:
Starting from triacontanoic acid (452 mg) and dibenzyl N-(N-tert-butoxycarbonyl-L-valyl)-L-glutamate (526 mg), dibenzyl N-(N-triacontanoyl-L-valyl)-L-glutamate (430 mg) was obtained as powder according to a similar manner to that of Example 28.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.CON(C)[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31]>C(OCC)C.CCCCCC>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:23]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[O:32])[CH3:2]
Reactant: CCOC(OCC)c1ccccc1Br
Reactant: CON(C)C(=O)c1ccc(Cl)cc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(OCC)c1ccccc1C(=O)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 142.3 %

Procedure:
A stirred solution of 10.6 g of 2-bromobenzaldehyde diethyl acetal in 100 ml of diethyl ether was cooled to −40° C. To this cold solution was added rapidly 46 ml of a 1.2 M solution of butyllithium in hexane. The solution was warmed to 0° C. over 30 min. The solution was cooled down to −40° C. and a solution of 11.9 g of N-Methoxy-N-methyl-4-chloro-2-fluorobenzamide in 100 ml of diethyl ether added by cannular. The solution was warmed to 0° C. and stirred for 0.75 h then quenched by the addition of 100 ml of water and 200 ml of ether added. The organic layer was separated and the aqueous layer was extracted with 200 ml of ether. The combined organic layers were dried over sodium sulfate and evaporated to yield 19.6 g of crude [2-(diethoxymethyl)-phenyl](4-chloro-2-fluorophenyl)-methanone as a gum, GC-M.S. (E.I.) (M/Z): 336 [M]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Clc1ccc(N2CCNCC2)nn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Temperature: 62 °C

Procedure:
3-Chloro-6-piperazin-1-ylpyridazine (9.93 g, 50 mmol) was suspended in THF (80 mL), and water (18.9 mL), [(1-ethoxycyclopropyl)oxy]trimethylsilan (17.423 g, 100 mmol), acetic acid (8.5 mL, 150 mmol) and sodium cyanoborohydride (4.08 g, 65 mmol) were added. The mixture was heated at 62° C. for 16 h, solvents removed in vacuo and the remainder stirred with DCM (100 mL) and water (75 mL). The pH was adjusted to 10, the organic phase was separated, washed with water and dried over magnesium sulphate. Evaporation in vacuo yielded 3-chloro-6-(4-cyclopropylpiperazin-1-yl)pyridazine as a solid which was recrystallized from acetonitrile to yield the product, 8.18 g, 69%.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:33]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]([O:36]C(C)(C)C)=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@@H:33]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]([OH:36])=[O:35])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC[C@@H](O)C(=O)OC(C)(C)C
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Product: CCCCCC[C@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and tert-butyl (R)-2-hydroxyoctanoate, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 72-74° C.; MS m/e 673 (M−H)+;
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[CH:33]=2)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C.CN(C)C=O>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[CH:24][C:23]([NH:22][C:7]([C:5]5[N:4]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:44][CH:43]=4)=[CH:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (197 mg, 973 μmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (80 μL, 973 μmol) and N,N-dimethylformamide under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A solution of N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 649 μmol) in N,N-dimethylacetamide (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from ethanol/water to give the title compound (138 mg, 29%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[CH:17][C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:37][CH2:38]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:37]([O:23][C:22]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[N:13]([CH2:12][C:9]1[CH:8]=[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:11][N:10]=1)[C:14]([C:25](=[O:36])[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]1)=[CH:15]2)=[O:24])[CH3:38]
Reactant: CCO
Reactant: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.6 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid in 10 ml DMF sequentially 0.4 ml EtOH, 110 mg DMAP and 256 mg DCC were added and the reaction mixture was stirred for 16 h at room temperature. The precipitate was then filtered off and the filtrate was concentrated and purified by chromatography on silica gel eluting with DCM/MeOH/AcOH/H2O 95:3:0.5:0.5. The fractions containing the product were collected and the solvent evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]([OH:25])=[N:14][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:16][C:17]=2[CH3:18])=[O:11])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[H-].[Na+].Br[CH2:34][CH2:35][O:36][CH3:37]>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]([O:25][CH2:34][CH2:35][O:36][CH3:37])=[N:14][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:16][C:17]=2[CH3:18])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCOCC2)nc(O)c1C(=O)NCc1cccc(F)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of 200 mg (0.58 mmol) N-[(3-Fluorophenyl)-methyl]-2-hydroxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 19) in DMF (8 ml) 15 mg (0.64 mmol, 60% w/w in mineral oil) NaH were added, followed by stirring at RT for 30 min. Then 88 mg (0.64 mmol) 2-bromoethyl-methylether were added and the RM was heated to 50° C. for 16 h. Subsequently water (10 ml) and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:7) provided 90 mg (0.22 mmol, 39%) N-[(3-Fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 21). [M+H]+404.2.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.C(OCC)(=O)C.[F-].[Na+]>C1(C)C=CC=CC=1.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>[CH3:17][O:16][C:4]1[CH:3]=[C:2]([CH:18]=[CH2:19])[N:7]=[N:6][C:5]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC)c(Oc2ccccc2C)nn1
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
In toluene (2 mL) was dissolved 123 mg (0.490 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 246 mg (0.776 mmol) of tributyl(vinyl) tin, and then, 119 mg (0.103 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours. The reaction mixture was allowed to stand for cooling, ethyl acetate (5 mL), water (3 mL) and sodium fluoride were added to the mixture, and the resulting mixture was stirred for 30 minutes and allowed to stand at room temperature overnight. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, then the organic layer was separated and washed with brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=1:2) to obtain 105 mg (0.434 mmol, Yield: 88.6%) of 4-methoxy-3-(2-methylphenoxy)-6-vinylpyridazine.
Reaction SMILES: [Br:1][C:2]1[C:23]([Br:24])=[CH:22][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)=[N:8][C:4]=2[C:3]=1[N+:25]([O-:27])=[O:26].[OH-].[Na+].I[CH:31]([CH3:33])[CH3:32].[ClH:34]>C(#N)C.CO.O1CCOCC1>[ClH:34].[Br:1][C:2]1[C:23]([Br:24])=[CH:22][C:5]2[N:6]([CH:31]([CH3:33])[CH3:32])[C:7]([N:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:8][C:4]=2[C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c([N+](=O)[O-])c(Br)c(Br)cc3[nH]2)CC1
Reactant: CC(C)I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CC#N
Product: CC(C)n1c(N2CCNCC2)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-(5,6-dibromo-4-nitro-1H-1,3-benzodiazol-2-yl)piperazine-1-carboxylate (Method 4A) (0.4 mmol, 200 mg) was dissolved in acetonitrile (5 ml). Next, NaOH (0.5 mmol, 19 mg) was added. The mixture was stirred at RT for 0.5 h. Then 2-Iodopropane (32 mmol, 538 mg) was added dropwise. The resulting mixture was stirred at 85° C. in a sealed tube until the reaction was complete (18 hours) by LC/MS. The mixture was allowed to cool to RT and concentrated in-vacuo. The product was taken up into ethyl acetate and washed with water. The organic extract was dried over MgSO4, filtered and concentrated. The product was purified on silica gel using EA/hex (1:4). The obtained product (0.3 mmol, 180 mg) was dissolved in MeOH (3 ml), then hydrogen chloride, (4M in 1,4-dioxane, 1 ml) was added dropwise. The resulting mixture was stirred at RT overnight. Solid was filtered and washed with Et2O to afford 5,6-dibromo-4-nitro-2-(piperazin-1-yl)-1-(propan-2-yl)-1H-1,3-benzodiazole hydrochloride (130 mg). 1H NMR (600 MHz, DMSO) δ 9.37 (s, 2H), 8.28 (s, 1H), 4.62 (hept, J=6.9 Hz, 1H), 3.47-3.44 (m, 4H), 3.28-3.26 (m, 4H), 1.54 (d, J=6.9 Hz, 6H); m/z 472; rt 2.4.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH:11]2[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]2)[C:5]([F:18])=[C:4]([F:19])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]#[N:31]>CC#N>[F:8][C:7]1[C:2]([O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:30]#[N:31])=[N:3][C:4]([F:19])=[C:5]([F:18])[C:6]=1[O:9][CH2:10][CH:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1
Reactant: CC1(C)OCC(COc2c(F)c(F)nc(F)c2F)O1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OCC(COc2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)O1
Reaction time: 24 h
Yield: 56.1 %

Procedure:
To 2,3,5,6-tetrafluoro-4[(2,2-dimethyldioxolan-4-yl)methoxy]pyridine (3.2 g, 11 mmol) in CH3CN (20 mL) was added Cs2CO3 (3.8 g, 12 mmol) and 3-hydroxy-4-(benzyloxy)benzonitrile (2.5 g, 11 mmol). After stirring for 24 hours the reaction was partitioned with water and ethyl acetate. The layers were separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was triturated with hexane/ethyl acetate (1/1) and the resulting solid was collected by filtration to give 3-[[3,5,6-trifluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (3.0 g)
Reaction SMILES: C(O)=O.[CH2:4]=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]3)[NH:13]2)[CH:7]=1.[OH-].[Na+]>O>[CH3:4][N:13]1[CH:12]([C:8]2[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=2)[CH:17]2[CH2:18][CH2:19][CH:14]1[CH2:15][CH2:16]2
Reactant: c1cncc(C2NC3CCC2CC3)c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN1C2CCC(CC2)C1c1cccnc1
Temperature: 0 °C
Yield: 88 %

Procedure:
Formic acid (5 mL, 95-97%) and formaldehyde (0.5 mL, 37%) were added to 3(3-pyridyl)-2-azabicylo[2.2.2]octane (XIII) (170 mg) and refluxed for 24 hours under N2. The reaction mixture was cooled to 0° C. (ice bath), basified by addition of a solution of 40 % w/v NaOH in water (pH=9) and extracted with chloroform (4×10 mL). The combined extracts were dried over anhydrous K2CO3, filtered and concentrated. The resulting oil was purified by distillation under reduced pressure (116°-118° C./0.4 mm Hg) to give 160 mg (88%) of (±)-2-methyl-3-(3-pyridyl)-2-azabicylo[2.2.2]octane (XV).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH3:24])=[C:18](Br)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH2:27]([S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28].COCCOC.[F-].[Cs+]>CN(C=O)C.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>[CH2:27]([S:29]([C:32]1[CH:37]=[C:36]([C:18]2[C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=[C:16]([C:15]([NH:14][C:5]3([C:3]([OH:2])=[O:4])[CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)=[O:26])[CH:17]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:30])=[O:31])[CH3:28]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)C1(NC(=O)c2cc(F)c(OC)c(Br)c2)Cc2ccccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)cc(F)c2OC)c1
Temperature: 130 °C

Procedure:
300 mg (0.71 mmol) of the compound of step 4 and 175 mg (1.07 mmol) of 3-ethanesulfonylphenylboronic acid were dissolved in 4 ml of DMF and 4 ml of 1,2-dimethoxyethane under an argon atmosphere. 216 mg (1.42 mmol) of cesium fluoride and 41.08 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was heated to 130° C. in a microwave reactor for 15 min. After cooling, the solvent was evaporated and the residue purified by preparative RP HPLC (water/ACN gradient) to yield the methyl ester of the title compound. 135.1 mg (0.26 mmol) methyl ester were dissolved in 5 ml of a mixture of THF and water (9:1), 12.65 mg (0.53 mmol) of lithium hydroxide were added and the mixture was stirred for 3 days. The solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient). 123 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:29]([CH3:30])[C:28](=[O:31])[N:27](C(OC(C)(C)C)=O)[C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.[C:39]([N:43]=C(N(C)C)N(C)C)(C)(C)[CH3:40].BrCC#N.[NH4+].[Cl-].C(O)(C(F)(F)F)=O>C1COCC1>[NH2:1][C:2]1[C:3]2[C:29]([CH2:40][C:39]#[N:43])([CH3:30])[C:28](=[O:31])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: CC1C(=O)N(C(=O)OC(C)(C)C)c2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Agent: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC#N)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of the intermediate from Step B above (102 mg, 0.182 mmol) stirred in THF (3566 μl) was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (34.2 μl, 0.182 mmol) followed by 2-bromoacetonitrile (19.02 μl, 0.273 mmol). After stirring for 5 minutes at room temperature, saturated aqueous NH4Cl was added. The reaction mixture reaction was then partitioned between EtOAc and water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The crude material was taken up in DCM (1 mL) and TFA (280 μl, 3.64 mmol) was added. After 3 hours the reaction was quenched with aq. NaHCO3 and partitioned between water and EtOAc. The organic layer was dried, concentrated in vacuo and purified by silica gel column chromatography using a hexanes/EtOAc gradient to afford the product as a white solid. Chiral separation using SFC provided both enantiomers of the title compound. 1H NMR (500 MHz, CHCl3-d): δ 8.45 (d, J=8.72 Hz, 1H); 7.43 (s, 1H); 7.18 (dd, J=8.75, 1.62 Hz, 1H); 5.48 (s, 2H); 4.71 (t, J=7.69 Hz, 2H); 2.99 (d, J=16.98 Hz, 1H); 2.81-2.68 (m, 2H); 2.67 (d, J=16.98 Hz, 1H); 1.68 (s, 3H). m/z=500.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)[N:15]=[C:14]([C:25]([N:27]3[CH2:31][C:30](=[O:32])[NH:29][CH2:28]3)=[O:26])[CH:13]=2)[CH:8]=[C:9]([F:11])[CH:10]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)=O.ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>C(O)=O>[Cl:24][C:19]1[CH:18]=[C:17]([N:16]2[C:12]([C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:10]=[C:9]([F:11])[CH:8]=3)=[CH:13][C:14]([C:25]([N:27]3[CH2:31][C:30](=[O:32])[NH:29][CH2:28]3)=[O:26])=[N:15]2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OCCCl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: C1CCNC1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OCCN4CCCC4)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 119A and pyrrolidine without the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 29. 2.5 mg (5% of theory) of the title compound are obtained.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[S:7])C=1.[C:13]([O:17][C:18](=[O:33])[N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH2:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18](=[O:33])[N:19]([CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]=[C:6]=[S:7])=[CH:30][CH:31]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCN(CCCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a cooled (−20° C.) solution of 1,1-thiocarbonyldiimidazole (811 mg, 4.415 mmol) (Aldrich) in N,N-dimethylformamide (11 mL) was added dropwise a solution of [3-(4-aminophenoxy)propyl]-ethyl-carbamic acid tert-butyl ester (1.175 g, 3.99 mmol) (from Step B above) in N,N-dimethyl-formamide (11 mL) over 25 minute. After the addition was complete, the mixture was stirred at −20° C. for 20 minutes and then at room temperature for 1 hour. Ice-water was added and the mixture was extracted with ether. The ether layer was dried (Na2SO4), filtered, and evaporated. The residue was purified on silica gel with 85:15 hexane/ethyl acetate to give ethyl-[3-(4-isothiocyanatophenoxy)propyl]carbamic acid tert-butyl ester (1.24 g, 92% yield). HRMS, Observed: 336.1496; Calcd for M+:336.1508.