Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1([CH:10]2[N:15]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9][CH2:8]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([N:15]2[CH:10]([C:7]3([OH:6])[CH2:9][CH2:8]3)[CH2:11][CH2:12][CH2:13][CH:14]2[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)OC1(C2CCCC(c3cccnc3)N2S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C(c2cccnc2)CCCC1C1(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
A solution of the silyl ether of Step 6 (79.2 mg, 1.56 mmol) in THF (20 mL) was treated with TBAF (2.0 mmol, 2.0 mL, 1M in THF). After stirring for 2 h at room temperature, the solvent was removed and the residue was purified by chromatography (eluting with EtOAc) to give 54.4 mg (89%) of the title compound as a white solid. 1H NMR (CDCl3 300 MHz) δ8.75 (1H, s) 8.50 (1H, s), 8.12 (1H, d), 7.80 (2H, d), 7.50 (2H, d), 7.35 (1H, m), 5.18 (1H, m), 3.60 (1H, d), 2.23 (1H, m), 1.97 (1H, m), 1.80 (1H, m), 1.48–1.23 (4H, m), 1.10 (1H, m), 0.64–0.45 (3H, m), MS (ES) m/e 393 (M)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccccc1Cc1ccccc1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccccc1Cc1ccccc1
Yield: 59.8 %

Procedure:
A solution of (2-benzyl-phenoxy)-acetic acid (1.15 g, 4.74 mmol), and benzoic acid N′-isopropyl-hydrazide (704 mg, 3.95 mmol) in DMF (30 ml), was treated with diisopropyl ethyl amine (1.8 ml, 9.88 mmol), and PyBroP (2.76 g, 5.93 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the product as a white solid (950 mg, 60%). MS m/e 403.25 (M+H+)
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.[Li]CCCC.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH2:21][C:20]2=O.O>C1COCC1>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][C:3]1=[C:20]1[C:19]2[C:24](=[CH:25][CH:26]=[C:17]([F:16])[CH:18]=2)[O:23][CH2:22][CH2:21]1
Reactant: O=C1CCOc2ccc(F)cc21
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2c(c1)C(=C1SCCCS1)CCO2
Temperature: 0 °C

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (5.10 g, 26.5 mmol) in 50 mL of anhydrous THF at −60° C. under N2 was added drop-wise n-BuLi (1.6 M solution in hexanes, 16.6 mL, 26.5 mmol). The mixture was left to warm slowly to 0° C. over 3 h and subsequently cooled to −60° C. A solution of 6-fluoro-2,3-dihydrochromen-4-one (4.40 g, 26.5 mmol) in 25 mL of THF was added drop-wise. The mixture was slowly warmed to ambient temperature overnight, then poured into water, and extracted with EtOAc. The combined organic portions were washed with brine, and conc. in vacuo. The crude product was purified by flash column chromatography (0 to 10% of EtOAc in hexanes). The title compound was obtained as a pale oil.
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][CH:17]=[CH:16][C:15]=2[Cl:20])[C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:20][C:15]1[CH:16]=[CH:17][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:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccccc1Cl
Yield: 44.8 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 4.5 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.75 g, 4.5 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.99 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:5]2.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>N1C=CC=CC=1.ClCCl>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:5]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)NCC1Cc2ccc(N)cc2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCC1Cc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2C1
Temperature: 5 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
N-(5-Amino-indan-2-ylmethyl)-propionamide (0.93 g, 4.26 mmol) was dissolved in pyridine-dichloromethane (1:2, 60 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (0.98 g, 4.48 mmol) was added and the solution stirred at 5° C. for 3 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give the product as a brown oil (1.69 g, 99%).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[O:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]2[CH:44]=[CH:45][CH:46]=[CH:47][C:2]1=2.[O:48]1[CH:53]=[CH:52][CH2:51][CH2:50][CH2:49]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[S:1]1[C:5]([C@H:6]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[O:14])[CH2:12][C@H:11]([O:15][CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53][O:48]3)[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]2[CH:44]=[CH:45][CH:46]=[CH:47][C:2]1=2
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H](O)CC(=O)[C@@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@H]1[C@@H](OC2CCCCO2)CC(=O)[C@@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-Methyl 7-((1R,2R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-5-hydroxy-3-oxocyclopentyl)hept-5-enoate (11a, limiting reagent) is dissolved in DCM (0.1 M) under a nitrogen atmosphere. Dihydropyran (1.1 molar equivalent) is added, followed by a catalytic amount of p-toluenesulfonic acid. The reaction is stirred at room temperature under a nitrogen atmosphere and the reaction progress is monitored by TLC. Upon completion, brine is added to the reaction mixture and the layers are separated. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 15a.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:17][CH:16]3[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][NH:21][S:22]([C:25]4[C:26]([CH3:31])=[N:27][O:28][C:29]=4[CH3:30])(=[O:24])=[O:23])[CH2:15]3)[CH2:11]2)=[CH:5][CH:4]=1)#[N:2].[C:34]([O-])([O-])=O.[Cs+].[Cs+].IC>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:17][CH:16]3[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][N:21]([CH3:34])[S:22]([C:25]4[C:26]([CH3:31])=[N:27][O:28][C:29]=4[CH3:30])(=[O:24])=[O:23])[CH2:15]3)[CH2:11]2)=[CH:32][CH:33]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1noc(C)c1S(=O)(=O)NCCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Agent: [Cs+]
Solvent: CI
Product: Cc1noc(C)c1S(=O)(=O)N(C)CCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-3,5-dimethylisoxazole-4-sulfonamide (43 mg, 0.09 mmol, from example 9 above ) and Cs2CO3 (86 mg, 0.26 mmol) were suspended in acetouitrile (2 mL). Iodomethane (17 μl , 0.26 mmol) was added and the reaction mixture was stirred at room temperature overnight under a nitrogen amosphere. More iodomethane (17 μl, 0.26 mmol) was added. The reaction mixture was left to stir for a further 20 h at room temperature overnight under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 39 mg (88%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:21]([CH3:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[C:18]([C:17]1[CH:20]=[C:21]([CH3:22])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([N:28]4[C@H:27]([CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)#[N:19]
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2F)CC1
Yield: 76.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(4-bromo-2-fluorobenzoyl)piperazin-1-yl]-5-methylnicotinonitrile (215 mg) described in Preparation Example 134 and (R)-4-methyloxazolidin-2-one (81 mg) described in Preparation Example 25, the title compound (173 mg) was obtained.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=[O:18]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:17]([C:16]1[C:15]([F:14])=[CH:23][CH:22]=[CH:21][C:20]=1[F:24])=[O:18])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,6-difluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.28-1.38 (m, 2 H) 1.55-1.64 (m, 2 H) 2.20 (s, 3 H) 2.22 (s, 3 H) 3.91-3.96 (m, 2 H) 6.03 (s, 1 H) 7.07-7.15 (m, 2 H) 7.39-7.47 (m, 1 H); MS (ESI) m/z 324 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:36])[C@@H:10]([NH:26][C@H:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[C:32]([O:31][C:29]([C@@H:27]([NH:26][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:17]=1)[C:9]([OH:36])=[O:8])[CH3:28])=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: C[C@H](N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
Step 4′: A suspension of (S)-2-((S)-1-tert-Butoxycarbonyl-ethylamino)-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid benzyl ester (580 mg, 1.10 mmol) and 5% Pd on carbon (0.146 g) in EtOAc (10 mL) was treated with H2 (balloon) and stirred at rt for 1.5 hour. The resulted precipitate was dissolved in methanol and filtered through celite pad. The filtrate was concentrated under reduced pressure and the obtained residue was re-crystallized from EtOAc to give (S)-2-((S)-1-tert-butoxycarbonyl-ethylamino)-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid (438 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.12 (d, 3H, J=7.1 Hz), 1.35 (s, 9H), 2.84 (dd, 2H, J=7.3, 13.6 Hz), 2.95 (dd, 2H, J=6.1, 13.6 Hz), 3.20 (dd, 1H, J=6.8, 13.6 Hz), 3.48 (dd, 1H, J=6.1, 7.3 Hz), 7.33 (d, 2H, J=8.6 Hz), 7.37 (d, 2H, J=8.3 Hz), 7.42-7.49 (m, 2H), 7.60 (d, 2H, J=8.6 Hz); MS: m/z (MH+) 438.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34](#[N:36])[CH3:35]>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>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:35]4[CH:34]=[N:36][C:2]([NH2:7])=[N:3][CH:4]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC#N
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
5-Chloro-2-((4-methylsulfonylpiperazin-1-yl)methyl)-7-morpholinothiazolo[5,4-d]pyrimidine, 5-pyrimidine-2-amine boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 8 minutes. The solvents were removed and the resulting residue was purified by reverse phase silica gel chromatography to give 122.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([C:26]2[C:27]([CH3:29])=[CH:28][C:23]([S:22][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])=[CH:24][C:25]=2[CH3:31])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(SC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 358 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 584.2 [M−H]−.
Reaction SMILES: [C:1]([CH:3]([NH:5]/[C:6](=[C:9](\[NH2:12])/[C:10]#[N:11])/[C:7]#[N:8])[CH3:4])#N.[O:13]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(O)C>[C:10]([C:9]1[NH:12][C:4](=[O:13])[CH:3]([CH3:1])[NH:5][C:6]=1[C:7]#[N:8])#[N:11]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: CC(C#N)N/C(C#N)=C(\N)C#N
Solvent: CCO
Product: CC1NC(C#N)=C(C#N)NC1=O
Yield: 420.2 %

Procedure:
A mixture of 1.0 g of α-cyanoethyldiaminomaleonitrile obtained as described in Example 4 and 0.3 g of phosphorus pentoxide was heated under refluxing for 19 hours in 30 ml of ethanol. Thereafter, the solvent was distilled off, and the resulting residue was treated with ice-water to obtain brown-colored fine crystals. The crystals thus obtained were recrystallized from a mixture of tetrahydrofuran, methanol and water (2:2:1 by volume) to obtain 0.72 g (72% yield) of 5,6-dicyano-2-methyl-1,2,3,4-tetrahydropyrazin-3-one having a melting point of 243°-245° C as a white powder.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:22])=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[CH2:12][CH2:11]1.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:9][C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:22])=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[CH2:12][CH2:11]1)=[O:27]
Reactant: Cc1cc2c(cc1C(=O)O)[C@H](N)CC2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(=O)O)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Triethylamine (4.707 mmol, 1.5 eq.) was added to a solution of (R)-3-amino-6-methyl-2,3-dihydro-1H-indene-5-carboxylic acid hydrochloride (commercially available from NetChem) (1 eq., 3.138 mmol) in methylene chloride (16 ml) at 0° C. 2-Chlorobenzoyl chloride (1.2 eq.) was added dropwise to the reaction mixture at the same temperature and the mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with methylene chloride (50 ml), and washed with NH4Cl solution (20 ml) and sat. NaCl solution (20 ml). The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The crude material was purified by column chromatography (silica, ethyl acetate/cyclohexane 3:2) to yield the desired product (E-12). Yield: 43%
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][NH2:33])=[CH:31][C:26]=2[N:25]=[CH:24]1.CCN(C(C)C)C(C)C>CCO>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][CH2:32][C:30]4[CH:29]=[CH:28][C:27]5[N:23]([CH:18]6[CH2:19][CH2:20][CH2:21][CH2:22][O:17]6)[CH:24]=[N:25][C:26]=5[CH:31]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: NCc1ccc2c(c1)ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2ccc3c(c2)ncn3C2CCCCO2)n1
Temperature: 120 °C
Yield: 81.3 %

Procedure:
A microwave vial was charged with 53 (750 mg, 3.20 mmol), 28 (740 mg, 3.20 mmol), DIPEA (2.0 mL) and EtOH (10.0 mL), sealed and heated at 120° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by SiO2 chromatography eluting with DCM:MeOH (8:1) to afford 1.12 g (81%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (32) as white solid: MS (ESI) m/z=431.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 165 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A mixture of 2,5-dichloropyridine (10.0 g, 67.6 mmol) and piperazine (58.1 g, 675 mmol) was stirred at 165° C. for 2 h. The mixture was allowed to cool, slurried with dichloromethane (200 ml) and the solid collected by filtration. The filtrate was concentrated in vacuo and the procedure repeated. The residue after concentration of the filtrate was purified by flash chromatography twice (eluting with 1% ammonia, 10% methanol in dichloromethane) to give 1-(5-chloro-2-pyridyl)piperazine (12.25 g, 92%) as a tan solid. A portion of this solid (0.484 g, 2.45 mmol) was added to a solution of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.392 g, 2.24 mmol) in toluene (10 ml) and the mixture heated at reflux under nitrogen for 6 h. The mixture was allowed to cool and the crystallised product filtered off. Recrystallisation from toluene gave the title compound (0.229 g, 31%), m.p. 196°-198° C.; (Found: C, 63.16; H, 5.60; N, 21.18. C17H18CIN5. 1PhMe requires C, 63.08; H, 5.62; N, 20.78%); δH (DMSO-d6) 2.46 (4H, t, J 5.0 Hz, 2×piperazinyl CH2), 3.45 (4H, t, J 5.0 Hz, 2×piperazinyl CH2), 3.67 (2H, s, CH2N), 6.82 (1H, d, J 9.1 Hz, 3'-H), 7.04 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.37 (1H, d, J 2.1 Hz, 2-H), 7.56 (1H, dd, J 9.1, 2.7 Hz, 4'-H), 8.05 (1H, dd, J 7.8, 1.4 Hz, 4-H), 8.08 (1H, d, J 2.7 Hz, 6'-H), 8.19 (1H, dd, J 4.6, 1.4 Hz, 6-H), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 328 [(M+H)+, 35Cl ].
Reaction SMILES: C(OC(=O)[NH:10]/[C:11](/[N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])=[CH:28][CH:29]=2)[CH:24]1[C:43]1([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)=[N:12]\C(=O)OCC1C=CC=CC=1)C1C=CC=CC=1.[C:55]([OH:58])(=[O:57])[CH3:56].[H][H]>CO.[Pd]>[C:55]([OH:58])(=[O:57])[CH3:56].[F:53][C:50]1[CH:51]=[CH:52][C:47]([C:43]2([CH:24]3[C:25]4[C:30](=[CH:29][CH:28]=[C:27]([O:33][CH2:34][CH2:35][NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[CH:26]=4)[CH2:31][CH2:32][N:23]3[C:11](=[NH:10])[NH2:12])[CH2:46][CH2:45][CH2:44]2)=[CH:48][CH:49]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(C(=N)N)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dibenzyl[(E)-{1-[1-(4-fluorophenyl)cyclobutyl]-7-{2-[(propylsulfonyl)amino]ethoxy}-3,4-dihydroisoquinolin-2(1H)-yl}methylylidene]biscarbamate (95 mg, 0.126 mmol) was dissolved in methanol (8 mL) under an atmosphere of nitrogen. Acetic acid (0.4 mL) was added followed by 10% palladium on charcoal (40 mg, 0.038 mmol). The nitrogen was replaced by one atmosphere of hydrogen and the reaction mixture was stirred at room temperature for 3 h. The catalyst was removed by filtration and the solution of the product was concentrated in vacuo. The product was dissolved in ethanol (0.5 mL) and water (15 mL) and was lyophilized. Yield: 61 mg (0.125 mmol, 99%).