Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].[CH3:13][C:14]([CH3:16])=[O:15].Cl>CCOCC>[OH:15][C:14]([CH3:16])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: CC(C)=O
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a mixture of magnesium turnings 13.16 g (0.541 mol) in 200 ml of anhydrous Et2O was added 100.0 g (0.492 mol) of 1-bromo-3-phenyl propane as a solution in 100 ml of Et2O. After of 5-10 ml of the solution had been added, the addition was stopped until the formation of the Grignard reagent was in progress. The remaining bromide was then added over 1 hour. The Grignard reagent was stirred for 20 minutes at 35° C. and then 31.64 g (0.541 mol) of acetone was added over a 45 minute period. The reaction was stirred overnight at room temperature before being cooled to 0° C. and acidified by the careful addition of 20% HCl. The aqueous layer was extracted with Et2O (3×200 ml) and the combined organic layers washed with water, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvent under reduced pressure and distillation of the residue afforded 63.0 g (72%) of the product as a pale-yellow oil, bp 99-102° C./0.5 mm Hg. 1H NMR (CDCl3): δ 7.28-7.18 (5H, m), 2.63 (2H, t, J=7.5 Hz), 1.68 (2H, m), 1.52 (2H, m), 1.20 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][CH2:7][CH2:8][C:9]([CH2:12][Cl:13])=[C:10]([CH3:11])[C:4]=2[CH:3]=1.[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[ClH:13].[C:17]([S:18][CH2:12][C:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][C:4]=2[C:10]=1[CH3:11])(=[NH:16])[NH2:19]
Reactant: NC(N)=S
Reactant: CC1=C(CCl)CCOc2ccc(Br)cc21
Solvent: CCO
Product: CC1=C(CSC(=N)N)CCOc2ccc(Br)cc21
Product: Cl
Yield: 102 %

Procedure:
To a solution of 7-bromo-4-(chloromethyl)-5-methyl-2,3-dihydrobenzo[b]oxepine from step H7 (2.05 g, 7.13 mmol) in ethanol (75 mL) was added thiourea (0.651 g, 8.55 mmol). The mixture was refluxed for 3 h. A white solid precipitated. The solvent was removed. The solid residue was washed with hexanes and dried in vacuo to give a (7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepin-4-yl)methyl carbamimidothioate hydrochloride (2.64 g, 7.26 mmol, 102% yield). The crude mixture was used in the next step without further purification. 1H NMR (500 MHz, methanol-d4) δ 7.48 (d, J=2.4 Hz, 1H), 7.43-7.36 (m, 1H), 6.97 (d, J=8.5 Hz, 1H), 4.53 (t, J=6.3 Hz, 2H), 4.25 (s, 2H), 2.34 (t, J=6.1 Hz, 2H), 2.18 (s, 3H).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.[NH:15]([C:17]1[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([CH3:32])[C:26]([CH3:34])([CH3:33])[CH2:25]2)=[O:22])=[CH:19][CH:18]=1)[NH2:16].C(O)(=O)C>C(O)C>[O:6]=[C:4]1[N:15]([C:17]2[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH:24]3[CH2:25][C:26]([CH3:33])([CH3:34])[N:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH2:29]3)=[O:22])=[CH:19][CH:18]=2)[NH:16][C:2]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:3]1
Reactant: CCOC(=O)CC(=O)c1cnccn1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-n3[nH]c(-c4cnccn4)cc3=O)cc2)CC1(C)C

Procedure:
3-Oxo-3-pyrazin-2-yl-propionic acid, ethyl ester (78 mg) and 4-hydrazino-N-(1,2, 2,6,6-pentamethyl-piperidin-4-yl)-benzamide (141 mg) were dissolved in ethanol (3.5 ml) and acetic acid (0.5 ml) and the solution stirred at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product. LC/MS: main peak is product (m/z: 434)
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([CH2:8][N:9]=[N+:10]=[N-:11])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl>C(Cl)Cl.O>[CH2:25]([O:24][C:22]([NH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]=[N+:10]=[N-:11])=[CH:12][CH:13]=1)=[NH:2])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [N-]=[N+]=NCc1ccc(C(=N)N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
The crystals from (ii) above were dissolved in 500 ml methylene chloride and the resulting solution was dried (K2CO3), filtered and 27 ml (194 mmol) triethyl amine was added. 25 ml Benzyl chloroformate was slowly added to the stirred solution while the reaction mixture was cooled in an ice bath. After 30 minutes an additional 2 ml benzyl chloroformate was added and stirring was continued for another 30 minutes. Subsequently, water was added and the aqueous phase was adjusted to pH 7 with 2M HCl. The organic phase was dried (MgSO4) and the solvent was removed in vacuo. 4(benzyloxycarbonylamidino) benzyl azide was finally isolated as colorless crystals from ether/methylene chloride/hexane.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([NH:5][C@@H:6]1[CH2:31][CH2:30][N:9]2[C:10]3[CH:23]=[CH:22][C:21](C4N=NN(C)N=4)=[CH:20][C:11]=3[C@H:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@H:8]2[CH2:7]1)=[O:4].[N+:34]([O-])([OH:36])=[O:35]>C(Cl)Cl>[F:1][C:2]([F:32])([F:33])[C:3]([NH:5][C@@H:6]1[CH2:31][CH2:30][N:9]2[C:10]3[CH:23]=[CH:22][C:21]([N+:34]([O-:36])=[O:35])=[CH:20][C:11]=3[C@H:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@H:8]2[CH2:7]1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: C[C@@H]1c2ccccc2[C@H]2C[C@H](NC(=O)C(F)(F)F)CCN2c2ccc(-c3nnn(C)n3)cc21
Solvent: ClCCl
Product: C[C@@H]1c2ccccc2[C@H]2C[C@H](NC(=O)C(F)(F)F)CCN2c2ccc([N+](=O)[O-])cc21

Procedure:
A solution of 10 (8═H, R2═COCF3; 76 mg, 0.2 mmol) in DCM (1.5 mL) was cooled to 0° C. and fuming nitric acid (21 μl, 0.5 mmol) was added in portions. The ice/water bath was removed and the reaction mixture turned red. After 10 min the reaction was quenched with aqueous NaHCO3, extracted with DCM, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (Heptane:Ethyl acetate=7:3) followed by preparative HPLC. Freeze-drying from acetonitrile/H2O afforded rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-nitrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide) (10, R8═NO2, R2═COCF3; 6 mg, 7%. Data: (m/z)=420 (M+H)+.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[CH2:14]([C:16]1[CH:17]=[CH:18][C:19]([F:23])=[C:20]([OH:22])[CH:21]=1)[CH3:15].C(OCC)C>CN(C=O)C.O>[C:6]([Si:10]([O:22][C:20]1[CH:21]=[C:16]([CH2:14][CH3:15])[CH:17]=[CH:18][C:19]=1[F:23])([CH3:13])[CH3:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1ccc(F)c(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
After adding 9.16 g of imidazole and 19.4 g of t-butyldimethylchlorosilane to a solution of 16.4 g of 5-ethyl-2-fluorophenol in 40 ml of DMF, the reaction mixture was stirred at room temperature for 18 hours. After then adding 500 ml of diethyl ether and 500 ml of water to the reaction mixture, the organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order and then dried over anhydrous magnesium sulfate, the desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to distillation to give the title compound (25.38 g) as a colorless liquid (boiling point: 133-135° C., 20 mmHg).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][N:29]5[CH2:34][CH2:33][NH:32][CH2:31][C:30]5=[O:35])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[C:36](Cl)(=[O:38])[CH3:37].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[C:36]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:15]3[C:16](=[O:19])[C:17]4[S:18][C:10]([C:7]5[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=5)=[CH:11][C:12]=4[N:13]=[CH:14]3)=[CH:27][CH:26]=2)[C:30](=[O:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: O=C1CNCCN1Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(Cc2ccc(CCn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A mixture of the compound (30 mg) obtained in Example 38, acetyl chloride (4.7 mg), triethylamine (19 mg) and tetrahydrofuran (2 ml) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (20 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[S:17][C:10]=2[NH:11][C:12](=O)[CH:13]([CH3:15])[N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[S:17][C:10]=2[NH:11][C:12](=[S:41])[CH:13]([CH3:15])[N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=O)C(C)N=C3c2ccccc2Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=S)C(C)N=C3c2ccccc2Cl)cc1
Yield: 99.9 %

Procedure:
A suspension of 2 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 188°-191° C. and 1.04 g of Lawesson reagent in 37 ml of toluene is stirred at 40°-45° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 1.2 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]([O:21][CH3:22])=[C:7]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:20])[CH3:19])[CH:8]=1)=[O:2].CN(C=O)C.O>[Pd](Cl)Cl.CCOC(C)=O>[C:18]([N:17]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[C:9]1[C:7]1[C:6]([O:21][CH3:22])=[CH:5][C:4]([O:23][CH3:24])=[C:3]([CH:8]=1)[CH:1]=[O:2])(=[O:20])[CH3:19]
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1NC(C)=O
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(C)=O)cc1C=O
Temperature: 80 °C
Yield: 40.6 %

Procedure:
N-[2-(5-Formyl-2,4-dimethoxy-phenyl ethynyl)phenyl]acetamide (Ex-57E, 535 mg, 1.6 mmol) was added to 150 mL of DMF (nitrogen purged) at room temperature and the resulting solution was heated to 80° C. Palladium(II) chloride (22 mg) was added in one portion. After 6 h the reaction mixture was poured into water (50 mL) and EtOAc (50 mL), and the layers were cut. The organic layer was filtered through Celite, washed with brine, and concentrated to an orange solid. The crude was purified by silica gel chromatography (25% ethyl acetate/hexane) to yield 210 mg (39%) of 5-(1-acetyl-1H-indol-2-yl)-2,4-dimethoxybenzaldehyde as a white solid. 1H-NMR (300 MHz, DMSO-d6) 10.22 (s, 1H), 8.13 (d, 1H, J=8.1 Hz), 7.71 (s, 1H), 7.55 (d, 1H, J=6.3 Hz), 7.25 (m, 2H, J=6.9 Hz), 6.84 (s, 1H), 6.64 (s, 1H), 4.01 (s, 3H), 3.87 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22].N>C>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Nc1ncc2cc(-c3c(F)cccc3F)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Agent: C
Agent: N
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(F)cccc1F

Procedure:
The title compound was prepared from 0.25 g of 6-(2,6-difluoro-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 63 and 0.112 mL of tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (1:1) to EtOAc to afford the pure product; mp >300° C., CIMS (1% ammonia in methane): m/z (relative intensity) 373 (MH+ +1, 60), 374 (MH+ +2, 10), 274 (100)
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:50]2[N:51]=[C:52]([NH:55]C(OC(C)(C)C)=O)[S:53][CH:54]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[CH:40]=[C:39]([CH2:41][NH:42]C(OC(C)(C)C)=O)[N:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH2:41][C:39]1[N:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:50]3[N:51]=[C:52]([NH2:55])[S:53][CH:54]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:33])=[O:32])[CH:40]=1
Reactant: CC(C)(C)OC(=O)NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 13.6 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (1.74 g, 1.94 mmol), DCM (19.4 mL) and TFA (8.95 mL, 116 mmol). After 3 h at rt, it was cooled to 0° C. and more TFA (200 μL, 2.6 mmol) was added whereupon it was allowed to warm to rt. After another 1 h at rt, it was cooled to 0° C. and more TFA (200 μL, 2.6 mmol) was added, again allowing to warm to rt. After an additional 1 h at rt it was diluted with DCM and concentrated in vacuo. Half of the crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (140 mg, ca 23%) as a white powder. LCMS: Rt=0.27 min, m/z=530.1 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 8.07 (s, 1H), 7.08-6.99 (m, 1H) 5.42-5.31 (m, 1H), 4.88-4.74 (m, 2H assumed; partially obscured by solvent residual peak), 4.74-4.68 (m, 1H), 4.20 (s, 2H), 1.36-1.23 (m, 2H), 1.23-1.07 (m, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([F:25])([F:24])[C:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])([CH3:17])[CH3:16])(=O)=O)=CC=1.C(N(C(C)C)CC)(C)C.[I-:35].[Na+]>CC(C)=O>[CH2:22]([O:21][CH:19]([O:18][C:15]([CH3:17])([CH3:16])[C:14]([F:25])([F:24])[CH2:13][CH2:12][I:35])[CH3:20])[CH3:23]
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CCOC(C)OC(C)(C)C(F)(F)CCI
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 3.50 g (0.0087 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol 1-(4-methylbenzenesulfonate), 40 mL of acetone, 0.5 mL of diisopropylethylamine and 13.10 g (0.087 mol) of sodium iodide was stirred at 25° C. for 64 hr. The mixture was evaporated to dryness. The residue was partitioned between 5% aqueous sodium sulfite solution and methylene chloride. The organic phase was washed with saturated aqueous sodium bicarbonate solution. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was chromatographed on 0.06-0.20 mm silica gel to yield 4-(1-ethoxyethoxy)-3,3-difluoro-1-iodo-4-methylpentane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C:10]2=[N:9][N:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C:10]2=[N:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2ccccn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2nnc3n2CCNC3)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 3-(2-pyridinyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I100)(115 mg, 0.382 mmol) in dichloromethane (DCM) (1 mL), TFA (0.588 mL, 7.63 mmol) was added and mixture was stirred at RT for 3 h. Volatiles removed under reduced pressure and residue purified by SCX cartridge eluting first with MeOH and then with 2.0N NH3 in MeOH. Ammonia fractions were concentrated under reduced pressure yielding desired product as a pale yellow solid.60 mg.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].CS(Cl)(=O)=O.[CH2:30]([N:32](CC)CC)[CH3:31]>O.C(#N)C>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:31][C:30]#[N:32])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
In a 50 ml-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 200 mg (0.69 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2 mL of acetonitrile and 41.5 mg (1.04 mmol) of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0° C. To the chilled mixture were added 0.08 mL (1.03 mmol) of methanesulfonyl chloride and 0.15 mL (1.08 mmol) of triethylamine, and the mixture was stirred for 3 hours at the same temperature. Subsequently, to the mixture was added 5 mL of chilled water, and the mixture was extracted with three portions of ethyl acetate (15 mL) which were previously chilled in an ice bath. The mixture was dried over anhydrous magnesium sulfate. The organic portion was then filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 180 mg (yield: 83%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2[C:16]2C=[C:18]([NH:22][S:23](C3C(F)=CC=CC=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.N1(S(Cl)(=O)=O)CCCCC1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([NH:55][S:23]([N:22]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:16]3)(=[O:25])=[O:24])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)N1CCCCC1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCCCC1
Yield: 29 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (200 mg, 0.510 mmol) and 1-piperidinesulfonyl chloride (0.201 mL, 1.531 mmol) the title compound of Step A was obtained as a yellow foam (193 mg, 41% and 29% yield, repeated twice). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (s, 1H), 8.15-8.44 (m, 1H), 7.45-7.67 (m, 1H), 7.22-7.42 (m, 2H), 6.61 (d, J=5.4 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.7 Hz, 4H), 3.03 (t, J=5.0 Hz, 4H), 1.24-1.66 (m, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)=[O:4].C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CC#N>[O:4]=[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)[C@@H:2]([NH:1][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cccc(-c2ccncc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccncc2)c1
Yield: 15.1 %

Procedure:
To a flask with (S)-2-amino-3-(4-fluorophenyl)-N-(3-(pyridin-4-yl)phenyl)propanamide (200 mg, 0.6 mmol) was added CH3CN as solvent, N-ethyl-N-isopropylpropan-2-amine (0.15 mL, 0.89 mmol) and tert-butyl 2-bromoacetate (0.097 mL, 0.66 mmol) and was heated at 55 degree for 5 hours. Reverse phase purification on HPLC followed by silica gel purification afforded 39 mg (15%) 34.4. 1H NMR (400 MHz, MeOH) δ ppm 8.50-8.68 (m, 2H) 7.88-7.99 (m, 1H) 7.61-7.75 (m, 2H) 7.55-7.60 (m, 1H) 7.42-7.52 (m, 2H) 7.23-7.31 (m, 2H) 6.97-7.04 (m, 2H) 3.53 (t, J=6.85 Hz, 1H) 3.29 (s, 2H) 3.05-3.12 (m, 1H) 2.95-3.03 (m, 1H) 1.43 (s, 9H)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:35]2[NH:39][C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][NH:41]3)=[N:37][CH:36]=2)=[CH:31][N:30]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][C:52](O)=[O:53])[CH:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:35]2[NH:39][CH:38]=[N:37][CH:36]=2)=[CH:31][N:30]=1.[N:41]1([CH:51]([C:47]2[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=2)[CH:52]=[O:53])[CH2:40][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(O)Cc1cccnc1
Reactant: Clc1ncc(-c2cnc([C@@H]3CCCN3)[nH]2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1ncc(-c2cnc[nH]2)cn1
Product: O=CC(c1cccnc1)N1CCCC1
Yield: 24.7 %

Procedure:
HATU (0.60 g, 1.57 mmol) was added in one portion to a stirred solution of intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidine trihydrochloride (0.46 g, 1.43 mmol, theoretical amount), 2-(pyridin-3-yl)acetic acid (0.25 g, 1.43 mmol) and DIEA (1.0 mL, 5.72 mmol) in anhydrous DMF (10 mL) at ambient temperature. The mixture was stirred at room temperature for 2 h before the DMF was removed in vacuo. The residue was taken up in CH2Cl2 and subjected to Biotage™ flash chromatography on silica gel (40M column, preequilibration with 0% B for 600 mL followed by step gradient elution with 0% B to 0% B for 150 mL followed by 0% B to 15% B for 1500 mL followed by 15% B to 25% B for 999 mL where B=MeOH and A=CH2Cl2). There was isolated the title compound (0.131 g, 25%, 2 steps) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:6])[CH2:3][C:4]#[N:5].N1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O.CC[OH:16]>O>[O:16]=[C:10]1[CH2:11][CH2:12][N:1]([C@H:2]([CH3:6])[CH2:3][C:4]#[N:5])[CH2:8][CH2:9]1
Reactant: O=C1CCCCN1
Reactant: C[C@H](N)CC#N
Reactant: CCO
Solvent: O
Product: C[C@H](CC#N)N1CCC(=O)CC1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of the above amine (6.85 g, 81.5 mmol) in EtOH (150 mL) heated to 100° C. was added a solution of the above piperidone salt (32.9 g, 122 mmol) in H2O (150 mL) dropwise. The resulting solution was stirred at reflux for 1 hour and then slowly cooled to room temperature. The mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO3 (120 mL) and extracted with CH2Cl2 (4×150 mL). The combined organic extracts were washed with H2O (150 mL) and the organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to give (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile as an orange liquid (11.74 g, 87%). 1H NMR (CDCl3) δ 1.22 (d, 3H, J=6.0 Hz), 2.38-2.59 (m, 6H), 2.82-2.83 (m, 4H), 3.20-3.27 (m, 1H).