Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([N+:26]([O-:28])=[O:27])[CH:18]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C>Cl>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:5]([NH2:4])[C:6]([OH:8])=[O:7])=[CH:18][C:19]=1[N+:26]([O-:28])=[O:27])(=[O:25])[CH3:24]
Reactant: CCOC(=O)C(Cc1ccc(C(C)=O)c([N+](=O)[O-])c1)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: CC(=O)c1ccc(CC(N)C(=O)O)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Diethyl 2-acetamido-2-(4-acetyl-3-nitrobenzyl)malonate (2.0 g) was dissolved in 10 mL 37% HCl, heated at 100° C. overnight, and cooled down. The resulting solid was collect by filtration, affording 3-(4-acetyl-3-nitrophenyl)-2-aminopropanoic acid. 1H NMR (400 MHz, D2O): δ 8.01(s, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 4.07 (m, 1H), 3.20-3.34 (m, 2H), 2.52 (s, 3H); 13C NMR: δ 201.39, 170.78, 174.89, 140.02, 137.84, 136.28, 129.59, 126.46, 54.46, 36.56, 30.01; ESI-MS (m/z) 253.22 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:6]=[CH:5]2.C([Li])CCC.[B:37](OC)([O:40]C)[O:38]C>C1COCC1>[Si:15]([O:14][CH2:13][CH2:12][CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([B:37]([OH:40])[OH:38])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)([C:28]([CH3:31])([CH3:29])[CH3:30])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OCCCn1ncc2cc(Br)ccc21)(c1ccccc1)c1ccccc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCn1ncc2cc(B(O)O)ccc21)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
5-Bromo-1-[3-(tert-butyl-diphenylsilanyloxy)-propyl]-1H-indazole (3 s) (200 mg, 0.41 mmol) was dissolved in 4.0 mL THF and cooled to −78° C. A solution of n-butyl lithium in hexanes (2.5M, 0.17 mL) was added slowly. The yellow solution was stirred for 30 minutes. Trimethyl borate (130 mg, 1.2 mmol) was added and the reaction was warmed to room temperature and stirred for 30 min. The reaction was quenched with 10 mL of a 0.3% aqueous HCl solution and the resulting mixture was stirred for 30 min. The reaction was diluted with Et2O and the layers were separated. The organic phase was washed with brine. The aqueous phases were extracted once with Et2O. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was partially purified on silica gel with 3% MeOH/CH2Cl2 to afford (4s) (97 mg, 52%). MS (ESI+) m/z 459 (M+H)+. HPLC (5 to 95%) 3.74 min. This mixture was carried on to the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=3)[C:16]=2[CH2:36][O:37][Si](C(C)(C)C)(C)C)=[C:8]([C:10](O)=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)[O:64]N1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[C:13](=[O:64])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=4)[C:16]=3[CH2:36][OH:37])[CH2:10][C:8]=2[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1cc(-c2cccc(NCc3sc(C(C)(C)C)nc3C(=O)O)c2CO[Si](C)(C)C(C)(C)C)cc(Nc2ccncn2)c1=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(-c2cccc(N3Cc4nc(C(C)(C)C)sc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.2 %

Procedure:
To a solution of 2-tert-butyl-5-((2-((tert-butyldimethylsilyloxy)methyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenylamino)-methyl)thiazole-4-carboxylic acid (125e) (500 mg, 0.78 mmol) in methylene chloride (40 mL) was added N,N-Diisopropylethylamine (503 mg, 3.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (900 mg, 2.37 mmol). The mixture was stirred at 25° C. for 2 h. After flash column purification with PE:EA (1:3 to 1:6) as eluent, 125 was obtained as white solid (32 mg, 10%). LCMS: (M+H)+ 503. 1H NMR (500 MHz, MeOD) ppm 8.84 (d, J=2 Hz, 1H), 8.66 (s, 1 H), 8.29 (d, J=5.5 Hz, 1H), 7.49-7.56 (m, 4 H), 7.09 (d, J=5.5 Hz, 2 H), 5.04 (s, 2 H), 4.57 (s, 2 H), 3.73 (s, 3 H), 1.54 (s, 9 H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][C@H:33]([CH:36]([CH3:38])[CH3:37])[C:34]#[N:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:34]([C@H:33]([NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH:36]([CH3:38])[CH3:37])#[N:35]
Reactant: CC(C)[C@@H](N)C#N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 39.8 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 40 mg, 0.093 mmol), (R)-2-amino-3-methylbutanenitrile (Int-VII, 9.10 mg, 0.093 mmol), HATU (45.8 mg, 0.121 mmol), and 4-methylmorpholine (37.5 mg, 0.371 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 2—CH3CN/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 35 min, 20 mL/min, 220 nM, product retention=30.3 min) to provide single enantiomer N—((R)-1-cyano-2-methylpropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.037 mmol, 40.1% yield): LCMS=512.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.90 (1 H, d, J=8.58 Hz), 8.13-8.26 (2 H, m), 7.50-7.81 (7 H, m), 5.21 (1 H, s), 4.54-4.69 (1 H, m), 2.05-2.25 (1 H, m), 1.09 (3 H, d, J=6.82 Hz), 0.98 (3 H, d, J=6.60 Hz); HPLC peak RT=10.5 min (Method A).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(CCC(=O)OC(C)(C)C)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)CCc1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a solution of tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoate (27 mg, 0.055 mmol) in DCM (1.7 mL) at 0° C. was added BBr3 (1.0 M in DCM, 0.220 mL, 0.220 mmol) dropwise (reaction turned brown in color and a solid immediately precipitated from the solution). The resulting mixture was stirred at 0° C. for 1 h after which the reaction was quenched with ice water (3.0 mL) and allowed to warm to room temperature with vigorous stirring. The resulting mixture was concentrated in vacuo and dissolved in MeOH (2 mL) then purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford 3-(4-((6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)propanoic acid (7 mg, 0.02 mmol, 31% yield). LC/MS (m/z, MH+): 407.0943.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CO.[BH4-].[Na+]>>[NH2:11][C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-chloro-2-nitrobenzoic acid (2.01 g, 10.0 mmol) in anhydrous methanol (100 mL) nickel(II)chloride hexahydrate (4.75 g, 20.0 mmol) was added, and the reaction mixture was cooled to room temperature. To this green solution was added NaBH4 (2.27 g, 60.0 mmol) in small portions over a period of 20 min. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The solvents were removed under vacuum and water (100 mL) was added, before neutralization to pH approximately equal to 4 with aqueous 2 N HCl. After extraction with methylene chloride (2×100 mL), the organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give 2-amino-3-chlorobenzoic acid as an off-white solid. Yield 0.90 g (52%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([O:18][CH3:19])=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([O:18][CH3:19])=[CH:11][C:12]([O:16][CH3:17])=[C:13]([NH:14][S:27]([C:24]3[CH:25]=[CH:26][C:21]([I:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH:15]=2)[CH2:3]1
Reactant: COc1cc(OC)c(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: COc1cc(OC)c(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(I)cc1

Procedure:
The title compound was prepared from 5-(cis-3,5-dimethyl-1-piperazinyl)-2,4-bis(methyloxy)aniline (D25) and 4-iodobenzenesulfonyl chloride using a similar procedure to that described for Example 81. MS (ES+) m/e 532 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:7]2)([O-])=O>CO.[Pd]>[N:13]1([CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[CH2:9]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(N1CCCC1)C2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CC(N1CCCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 55B (7.25 g, 31.2 mmol) in 156 mL of methanol was added palladium on carbon (10% wt) (7.25 g, 6.81 mmol). The reaction mixture was evacuated and backfilled with nitrogen three times then evacuated and backfilled with hydrogen. The mixture was then allowed to stirred under H2 (1 atm, balloon) at ambient temperature overnight. The mixture was filtered through a celite pad then concentrated and the crude product was recrystallized in ethyl acetate/hexane mixture to obtain the title compound. MS (ESI) m/z 203.1 (M+H)+.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.[C:26](O)(=[O:28])[CH3:27]>CCO.[OH-].[OH-].[Pd+2]>[C:26]([O:18][C:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]1)([CH3:16])[CH3:17])(=[O:28])[CH3:27]
Reactant: CC(C)(O)C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)OC(C)(C)C1CCC(N)CC1

Procedure:
2-(4-Dibenzylamino-cyclohexyl)-propan-2-ol (15 g) in EtOH (300 mL, abs) was treated with Pd(OH)2 (12.5 g). Acetic acid (6.3 mL) was added, and H2 was added slowly over 4.5 h. The reaction mixture was allowed to stand, then was filtered through a glass frit, washed with EtOH, filtered through a second glass frit, and the solvent removed in vacuo. The product was dissolved in hexane, and the hexane removed in vacuo (×3). The product was then triturated with ether, and the resultant solid filtered. The filtrate was evaporated, the residue dissolved in EtOH and solvent removed in vacuo. The product was then triturated in ether and the product filtered. The solvent was removed from both solid portions to yield 2-(4-aminocyclohexyl)-propan-2-ol acetate (6.52 g).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[N:23]1([CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N>ClCCl.C1CCCCC1.CO>[N:23]1([CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][NH:4][C:5]([N:7]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[NH:11][C:10](=[O:18])[C:9]4=[CH:19][S:20][C:21]([CH3:22])=[C:8]34)=[O:6])[CH2:35][CH2:34]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1scc2c1N(C(=O)NCCBr)c1ccccc1NC2=O
Reactant: C1CCCN(CCCC2CCNCC2)CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: C1CCCCC1
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCN3CCCCCC3)CC1)c1ccccc1NC2=O
Yield: 29 %

Procedure:
Prepared analogously to Example 109 from 4-[[[2-bromo-ethyl]amino]carbonyl]-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[3-(hexahydro-1H-azepin-l-yl)propyl]piperidine in a yield of 29% of theory. Colourless crystals m.p. 144°-145° C. RF =0.5 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/2 v/v).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([C:26]([F:29])([F:28])[F:27])[CH:16]=2)=[CH:4][C:5]2[O:9][C:8]([C:10]#[N:11])=[CH:7][C:6]=2[CH:12]=1.[NH4+].[Cl-].[N-:32]=[N+:33]=[N-:34].[Na+].Cl>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:3]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[C:17]([C:26]([F:29])([F:27])[F:28])[CH:16]=2)=[CH:4][C:5]2[O:9][C:8]([C:10]3[NH:34][N:33]=[N:32][N:11]=3)=[CH:7][C:6]=2[CH:12]=1
Reactant: N#Cc1cc2cc(F)c(CNc3ccc(OC(F)(F)F)c(C(F)(F)F)c3)cc2o1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2cc(-c3nnn[nH]3)oc2cc1CNc1ccc(OC(F)(F)F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
To the solution of 5-fluoro-6-(((4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)amino)methyl)-benzofuran-2-carbonitrile (637 mg, 1.523 mmol) in 15 mL DMF was added NH4Cl (326 mg, 6.09 mmol) and NaN3 (198 mg, 3.05 mmol). After the reaction mixture was stirred at room temperature overnight, the mixture was adjusted to pH=1 by addition of 1N HCl aqueous solution. The mixture was then diluted with AcOEt and washed with water, brine, dried over Na2SO4, and concentrated. The crude product was purified on basic HPLC (ammonium hydroxide modifier) 15-45% MeCN/Water to give N-((5-fluoro-2-(1H-tetrazol-5-yl)benzofuran-6-yl)methyl)-4-(trifluoromethoxy)-3-(trifluoromethyl)aniline (194 mg). LCMS retention time=1.41 minutes (LC method 1); MS (m+1)=462.1. 1H NMR (400 MHz, DMSO-d6) δ 4.50 (d, J=5.2 Hz, 2H), 6.93 (dd, J=9.2, 3.0 Hz, 1H), 7.00 (br. s., 1H), 7.05 (d, J=2.8 Hz, 1H), 7.33 (d, J=9.0 Hz, 1H), 7.61-7.69 (m, 2H), 7.75 (d, J=5.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19](O)=[O:20])[CH:17]=2)[N:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:38][CH:39]([CH3:42])[C:40]#[N:41].CCCP(=O)=O>CN(C=O)C>[C:40]([CH:39]([NH:38][C:19](=[O:20])[CH2:18][N:16]1[CH:17]=[C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:5][CH2:4][C:3]3[C:2]([F:1])=[CH:25][C:24]([F:26])=[CH:23][C:22]=3[F:27])[CH:11]=[CH:10][N:9]=2)[CH:14]=[N:15]1)[CH3:42])#[N:41]
Reactant: O=C(O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Reactant: CC(N)C#N
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C#N)NC(=O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid I-2 (0.1 g, 0.26 mmol, prepared by Procedure B), DIPEA (0.15 mL, 0.8 mmol), 2-aminopropanenitrile hydrochloride (34 mg, 0.3 mmol), propylphosphonic anhydride solution (50% in DMF) (0.17 g, 0.5 mmol) in DMF was stirred overnight at room temperature then extracted into water and washed with DCM. The aqueous layer was neutralised with aqueous sodium bicarbonate and extracted with three times with DCM. The combined organic layer was concentrated in vacuo and purified by prep. HPLC to afford N-(1-cyanoethyl)-2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide I-5 (80 mg, 0.18 mmol). LC-MS (Method B), RT=5.15 min. (ES+) 431.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=1>>[C:33]([NH:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)(=[O:10])=[O:11])=[CH:27][CH:28]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2ccc(NC(C)=O)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and N-(4-(chloromethyl)phenyl)acetamide. MS (M−H, 467.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.0 (s, 3H), 3.69 s, 3H), 4.23 (s, 4H), 6.78 (d, 2H, J=7.6 Hz), 6.98 (m, 4H), 7.41 (d, 2H, J=8 Hz), 7.94 (d, 2H, J=8 Hz), 8.09 (d, 2H, J=8 Hz), 9.90 (s, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.CC1(C)C(C)(C)OC([C:37]2[CH:45]=[C:44]3[C:40]([CH2:41][NH:42][C:43]3=[O:46])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:37]5[CH:45]=[C:44]6[C:40](=[CH:39][CH:38]=5)[CH2:41][NH:42][C:43]6=[O:46])[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC1(C)OC(c2ccc3c(c2)C(=O)NC3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1NCc2ccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)cc4ccccc34)cc21
Temperature: 120 °C

Procedure:
N-(1-Bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (45 mg, 0.10 mmol) was dissolved in 1 mL of 1,2-dimethoxyethane in a reaction tube. 6-(4,4,5,5-Tetramethyl-1,3-dioxolan-2-yl)isoindolin-1-one (38 mg, 0.15 mmol), 0.1 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0050 mmol) were added and the reaction mixture was heated at 120° C. for ten minutes under microwave irradiation. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate/hexanes. ESI-MS m/z calc. 499.5. found 500.3 (M+1)+. Retention time 1.93 minutes.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH2:7]1.O1CCCC1.C(Br)CCC>CCCCCC>[CH2:1]([CH:7]1[S:8][CH2:9][CH2:10][CH2:11][S:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: C1CSCSC1
Solvent: CCCCBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1SCCCS1
Reaction time: 2 h

Procedure:
30 ml. of a 1.6M solution of n-butyllithium in n-hexane were added dropwise to a solution of 4.8 g. of 1,3-dithiane in 150 ml. of tetrahydrofuran under an atmosphere of nitrogen at -20° to -25° C. After 2 hours stirring, 6 g. of n-butyl bromide in 60 ml. of tetrahydrofuran were added dropwise to the reaction mixture, which was stirred for 1 hour at -20° to -25° C. and for a further 30 minutes at room temperture and then concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 6.8 g. of the title compound having the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:17]O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17]
Reactant: O=c1c(C=NO)c(Cl)ccn1-c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1c(Cl)ccn(-c2ccccc2Cl)c1=O
Temperature: 90 °C
Yield: 98.3 %

Procedure:
To a solution of 4-chloro-1-(2-chlorophenyl)-3-((hydroxyimino)methyl)pyridin-2(1H)-one obtained in Step C (968 mg) in acetonitrile (6.80 mL) was added phosphorus oxychloride (0.319 mL) at room temperature. The reaction mixture was heated at 90° C. for 1 hr, cooled to room temperature, and poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The aqueous layer was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (891 mg). 1H NMR (400 MHz, CDCl3) δ 6.47 (1H, d, J=7.6 Hz), 7.35 (1H, dd, J=7.6, 1.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.42-7.50 (2H, m), 7.60 (1H, dd, J=7.6, 1.6 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:4].[CH3:9][C:10]1([CH3:19])[C:14]([CH3:16])([CH3:15])[O:13][B:12](C=C)[O:11]1>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:1][C:2]([CH3:8])([CH2:5]/[CH:6]=[CH:7]/[B:12]1[O:13][C:14]([CH3:16])([CH3:15])[C:10]([CH3:19])([CH3:9])[O:11]1)[CH2:3][OH:4]
Reactant: C=CCC(C)(C)CO
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC(C)(CO)C/C=C/B1OC(C)(C)C(C)(C)O1
Temperature: 40 °C

Procedure:
To a solution of 2,2-dimethylpent-4-en-1-ol (4.9 g, 42.9 mmol) in DCM (500 mL) is added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (22 mL, 128 mmol) and Grubbs catalyst (3.53 g, 4.29 mmol), and the mixture is heated at 40° C. for 18 h. The mixture is concentrated and washed with sat. NaHCO3 and purified to give the title compound as a greenish crystalline.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:24])[CH:20]([CH3:23])[CH2:21][CH3:22])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:34]>CO.[OH-].[OH-].[Pd+2]>[ClH:34].[CH3:27][O:26][CH2:25][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:24])[CH:20]([CH3:23])[CH2:21][CH3:22])=[N:18][C:12]=2[O:11]1
Reactant: CCC(C)N(C)c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)N(C)c1cnc2c(n1)O[C@@H](COC)CNC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of (6R)-8-benzyl-6-(methoxymethyl)-N-methyl-N-(1-methylpropyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (297 mg) in methanol (10 mL) was added 20% Pd(OH)2/C (40 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 4 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (220 and the mixture was stirred for 1 hr. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (141 mg, 55%).