Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@H:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (235 mg, 0.85 mmol) [prepared according to the procedure of Example 96], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (290 mg, 0.82 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (479 mg, 1.02 mmol) in chloroform (8.5 mL). DIEA (742 μL, 4.25 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (174 mg, 0.30 mmol, 36%): LC-MS (ES) m/z=575 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cc(Br)cnc1Cl
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Yield: 75.3 %

Procedure:
Following the procedure previously described (Example 44, Step 1), 3-amino-5-bromo-2-chloropyridine (770.0 mg, 3.7 mmol) was reacted with 4-fluorobenzenesulfonyl chloride (0.76 g, 3.9 mmol, Oakwood Products, West Columbia, S.C.) to afford N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (1.018 g, 75% yield) after recrystallization from CH2Cl2/EtOAc. LCMS (ESI positive ionization) m/z: 366 (M+1); 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.24 (t, J=9.00 Hz, 2H); 7.53 (d, J=2.25 Hz, 1H); 7.58 (d, J=2.25 Hz, 1H); 7.74 (dd, J=8.95, 5.43 Hz, 2H).
Reaction SMILES: Cl.C([N:9]([C@@H:13]1[C@@:20]2([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:17]([CH2:18][CH2:19]2)[CH2:16][N:15]2[C:25](=[O:41])[C:26]([OH:40])=[C:27]([C:29](=[O:39])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:28]=[C:14]12)C(=O)O)C1C=CC=CC=1.[CH3:42][N:43]([CH3:49])[C:44](=[O:48])[C:45]([OH:47])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][NH:30][C:29]([C:27]2[N:28]=[C:14]3[C@H:13]([NH:9][C:45](=[O:47])[C:44]([N:43]([CH3:49])[CH3:42])=[O:48])[C@@:20]4([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:17]([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:25](=[O:41])[C:26]=2[OH:40])=[O:39])=[CH:37][CH:36]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](N(Cc1ccccc1)C(=O)O)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Reactant: CN(C)C(=O)C(=O)O
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: CN(C)C(=O)C(=O)N[C@H]1c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C[C@H]2CC[C@]1(C)C2(C)C
Yield: 72.8 %

Procedure:
A solution of benzyl((7S,10R,11R)-2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocin-11-yl)carbamate hydrochloride salt (0.0367 g, 0.081 mmol), 2-(dimethylamino)-2-oxoacetic acid (9.53 mg, 0.081 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.031 g, 0.081 mmol) and diisopropyl-ethylamine (0.014 mL, 0.081 mmol) in DMF (3 mL) was stirred at room temperature for 24 h. After this the crude reaction mixture was purified by preparative-HPLC using methanol/water (0.1% trifluoroacetic acid) to afford the title compound (0.0301 g, 0.059 mmol, 72% yield) as a purple solid. 1H NMR (500 MHz, CDCl3) δ: 12.01 (1H, s), 8.76 (1 H, t, J=6.0 Hz), 8.21 (1 H, d, J=9.8 Hz), 7.36-7.41 (2 H, m), 6.99-7.05 (2 H, m), 5.27 (1 H, d, J=9.8 Hz), 5.18 (1 H, dd, J=15.6, 8.9 Hz), 4.50-4.63 (2 H, m), 3.65 (1 H, d, J=15.6 Hz), 3.34 (3 H, s), 2.95 (3 H, s), 2.14 (1 H, t, J=8.2 Hz), 1.83-1.94 (1 H, m), 1.47-1.52 (1 H, m), 1.41 (1 H, dd, J=9.5, 5.2 Hz), 1.36 (3 H, s), 1.06 (1 H, dd, 9.8, 4.6 Hz), 1.03 (3 H, s), 0.97 (3 H, s). LCMS (M+H) calcd for C26H33FN5O5: 514.25; found: 514.29.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[Cl:7][C:8]1[C:9]([F:39])=[C:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:37][CH3:38])=[C:22]([CH2:25][N:26]([CH3:36])[C:27]4([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:23]=3)[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:7][C:8]1[C:9]([F:39])=[C:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:37][CH3:38])=[C:22]([CH2:25][N:26]([CH3:36])[C:27]4([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31][N:30]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:28]4)[CH:23]=3)[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
Methanesulfonyl chloride (7.5 μl, 0.094 mmol) was added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.05 g, 0.085 mmol) and triethylamine (53 μl, 0.38 mmol) in dichloromethane (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, concentrated and purified by preparative LCMS (standard basic system) to give the title product (0.0107 g, 23%) as a white solid; 1H NMR Spectrum: (DMSO-d6) 1.98 (m, 2H), 2.22 (m, 2H), 2.36 (s, 3H), 2.84 (s, 3H), 2.96 (m, 2H), 3.44 (m, 2H), 3.66 (s, 2H), 3.98 (s, 3H), 7.19 (s, 1H), 7.26-7.30 (m, 3H), 7.52-7.53 (m, 2H), 8.33 (s, 1H), 8.42 (s, 1H), 9.70 (s, 1H); Mass Spectrum: (M+H)+ 551.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Li])CCC.[CH3:33][C:34]([CH3:45])([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:35][CH:36]=[O:37]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:36]([OH:37])[CH2:35][C:34]([CH3:33])([CH3:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(CC=O)Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Br)cc3)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CC(C)(C)Cc4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[4′-(4-Bromo-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.100 g, 0.243 mmol) was dissolved in THF (0.25M) and cooled to −78° C. n-Butyllithium (2.5M in hexanes, 0.1068 mL, 0.267 mmol) was slowly added and the reaction stirred for 30 minutes. 3,3-Dimethyl-4-phenyl-butyraldehyde (0.047 g, 0.254 mmol) was added and the reaction was stirred at −78° C. for 30 minutes then warmed to room temperature and continued stirring for 1 hour. The reaction mixture was submitted to standard aqueous workup to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:36]([N:35]([CH2:32][CH2:33][CH3:34])[C:11](=[O:12])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCNCCC
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCC)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.6 μL N-propylbutylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.31 min. (m/Z=304.2, 388.2, 410.2).
Reaction SMILES: C([Li])CCC.[C:6]([NH:10][C:11](=[O:13])[OH:12])([CH3:9])([CH3:8])[CH3:7].Cl[CH2:15][CH2:16][CH2:17][S:18]([NH2:21])(=[O:20])=[O:19]>C1COCC1>[C:6]([NH:10][C:11](=[O:12])[OH:13])([CH3:9])([CH3:8])[CH3:7].[CH:17]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:15][CH2:16]1
Reactant: NS(=O)(=O)CCCCl
Agent: CC(C)(C)NC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NS(=O)(=O)C1CC1
Temperature: -78 °C

Procedure:
A solution of n-butyl lithium (74.7 mL, 119.5 mmol, 1.6M in hexane) was dissolved in dry THF (105 mL) and cooled to −78° C. under a Argon atmosphere. To this solution was added a solution of 3-chloropropylsulfonylamine tert-butylcarbamate (14 g, 54.3 mmol) in dry THF (105 mL) dropwise over 20-30 minutes. The dry ice bath was removed and the reaction mixture was allowed to warm to room temperature over a period of 2 hours. The reaction mixture was quenched with glacial acetic acid (3.4 mL), concentrated in vacuo, and partitioned between dichloromethane (100 mL) and water (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford the cyclopropylsulfonylamine tert-butyl carbamate as a waxy off-white solid (12.08 g, 100%): 1H NMR (CDCl3) δ 1.10 (m, 2H), 1.34 (m, 2H), 1.50 (s, 9H), 2.88 (m, 1H), 7.43 (s, 1H). 13C NMR (CDCl3) δ 6.21, 28.00, 31.13, 84.07, 149.82.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:11][C:12](OC(C)=O)=[O:13].C(C(O)=O)(F)(F)F>>[NH4+:1].[C:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8])(=[O:13])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cncc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cncc(C(=O)[O-])c1
Product: [NH4+]
Temperature: 125 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 4 g (28.96 mmol) of 5-aminonicotinic acid, 35 ml Ac2O, and 2 ml CF3CO2H in a stainless steel bomb was heated 22 hr at 125° C. (oil bath temperature). The reaction mixture was evaporated to dryness at 55° C./20 mm pressure and 55° C./1 mm pressure. The gummy residues were mixed with methanol and again evaporated to dryness. The residues were mixed with 50 ml concentrated NH4OH, allowed to stand about 2 hr at room temperature, and evaporated to dryness at 60° C. under reduced pressure. The residues were mixed with 25 ml ethanol and again evaporated to dryness. The residue afforded a light beige crystalline material upon trituration with warm ethanol. The solid product was collected and dried to afford 4.55 g (80% yield) of 5-acetamidonicotinic acid, ammonium salt.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([I:11])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([I:11])=[CH:9][N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cnc2[nH]cc(I)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.6 %

Procedure:
To a stirred solution of 2-bromo-7-iodo-5H-pyrrolo[3,2-b]pyrazine [Intermediate AT] (1.1 g, 3.5 mmol) in anhydrous THF (20 mL) cooled to 0° C. was added NaH [60% dispersion in mineral oil] (0.17 g, 4.3 mmol). The reaction mixture was stirred for 20 min at 0° C., after which p-toluenesulfonyl chloride (0.73 g, 3.8 mmol) in THF (8 mL) was added. The resulting mixture was stirred at rt for 3 hr, after which it was diluted with EtOAc and washed with H2O and brine. The organic layer was separated, dried over Na2SO4, filtered, and evaporated in vacuo to yield a residue that was triturated with hexanes to yield the title compound (1.6 g, 94%) as a light yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.62 (d, J=7.5 Hz, 2H), 8.03 (s, 1H), 8.00 (s, 1H), 7.47 (d, J=8.1 Hz, 2H), 2.37 (s, 3H). HPLC retention time: 2.84 minutes. MS ESI (m/z): 478.0/480.0 (M+H)+, calc. 477.
Reaction SMILES: C(C(CCCC)CO[C:6](=O)[CH2:7][CH2:8][S:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]1[N:20]=[CH:21][N:22]=[C:15]1[CH:14]=[CH:13]2)C.FC1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=CC=1.CC(C)([O-])C.[K+]>CN(C=O)C>[N:20]1[N:16]2[C:17]3[C:12]([CH:13]=[CH:14][C:15]2=[N:22][CH:21]=1)=[CH:11][C:10]([S:9][C:8]1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[CH:6][CH:7]=1)=[CH:19][CH:18]=3
Reactant: N#CC1(c2cccc(F)n2)CCOCC1
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3ncnn32)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5ncnn54)c3)n2)CCOCC1
Temperature: 90 °C

Procedure:
8e (201 mg, 0.50 mmol) and 4-(6-Fluoro-pyridin-2-yl)-tetrahydro-pyran-4-carbonitrile (8f, 105 mg, 0.51 mmol) were dissolved in DMF at room temperature and degassed for 10 minutes with N2. Potassium tert-butoxide (67 mg, 0.60 mmol) was added, and the mixture was degassed with N2 for another 10 minutes. The reaction was heated to 90° C. for 12 hours, and then concentrated and purified by silica gel chromatography (25-50% EtOAc in hexanes) to give the desired product, 8g.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:6][C@@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Temperature: 50 °C
Yield: 65 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (13.3 g, 39.3 mmol) from Step 1 was dissolved in anhydrous DMF (140 mL). Solid NaN3 (5.18 g, 79.7 mmol) was added and the reaction was warmed to 50° C. for 5 h. The reaction mixture was permitted to cool to rt and the solvent was removed under reduced pressure (150 Torr, 55° C.). This material was taken up into Et2O (150 mL), washed with water (3×10 mL) and brine (3×10 mL), dried (Na2SO4), decanted, and stripped to give 13.9 g crude product. This was separated on a silica column using a gradient from 0-100% EtOAc in hexanes. Solvent was stripped from appropriate fractions to give (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate (7.21 g, 65%) as a clear oil. 1H NMR (CDCl3) δ 0.60-1.80 (m 12H), 1.40 (s, 9H), 2.86 (d, 1H), 3.29 (d, 1H), 4.85 (d, 1H), 4.51 (m, 1H), 8.00 (s, 1H). MS ESI+ve m/z 183 (M(−BOC)+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C>CS(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[O:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
1-BOC-3-hydroxymethylpiperidine (2.15 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) were dissolved in 10 mL DMSO, 15 mL DMSO solution of SO3Py (4.77 g, 30 mmol) was added to the above mixture in dropwise and the result mixture was stirred at rt for 2 hrs. The mixture was poured into 100 mL ice-water, extracted with EtOAc (100 mL×3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The crude product was purified by chromatography on silica gel (PE/EtOAc 5:1) to give 1.46 g product as colorless oil (68.5%). 1H NMR (300 MHz, CDCl3) δ: 9.70 (1 H, s), 3.91-3.93 (1 H, m), 3.62-3.67 (1 H, m), 3.29-3.36 (1 H, m), 3.05-3.13 (1 H, m), 2.40-2.45 (1 H, m), 1.95-1.97 (1 H, m), 1.63-1.72 (1 H, m), 1.49-1.59 (1 H, m), 1.46 (9 H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:22])=[O:21]
Reactant: CCOC(=O)CCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 85.3 %

Procedure:
A solution of monodispersed ethyl 6-hydroxyhexanoate (50.76 ml, 50.41 g, 227 mmol) in dry dichloromethane (75 ml) was chilled in an ice bath and placed under a nitrogen atmosphere. Triethylamine (34.43 ml, 24.99 g, 247 mmol) was added. A solution of methanesulfonyl chloride (19.15 ml, 28.3 g, 247 mmol) in dry dichloromethane (75 ml) was added dropwise from an addition funnel. The mixture was stirred for three and one half hours, slowly being allowed to come to room temperature as the ice bath melted. The mixture was filtered through silica gel, and the filtrate was washed successively with water, saturated NaHCO3, water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo to a pale yellow oil. Final purification of the crude product was achieved by flash chromatography (silica gel, 1/1 hexanes/ethyl acetate) to give the monodispersed compound 2 (46.13 g, 85%) as a clear, colorless oil. FAB MS: m/e 239 (M+H), 193 (M—C2H5O).
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([C:45]([O-:47])=[O:46])=[CH:5][CH:4]=1)=[O:2].[CH2:48]([Mg]Br)[CH3:49].[CH3:52][CH2:53]OCC>>[OH:2][CH:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:5][CH:4]=1)[CH2:52][CH3:53]
Reactant: O=Cc1ccc(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCC
Reactant: CC[Mg]Br
Product: CCOC(=O)c1ccc(C(O)CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Into a solution of 5-formyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate (2.0 g, 3.1 mmol) in dry ether (100 ml) cooled to -78° C. was syringed a solution of ethyl magnesium bromide (1.3 ml of a 3.0M solution in ether; 4.0 mmol) dropwise over 10 minutes. The mixture was allowed to stir for 2 hours while being allowed to warm to room temperature. The mixture was quenched with 10% aqueous ammonium chloride (20 ml) and the organic phase was washed with saturated aqueous sodium bicarbonate (50 ml), saturated aqueous sodium chloride (50 ml) and dried (MgSO4) before being filtered and concentrated to leave 2.0 g (95%) of a white solid which could be chromatographed on silica gel but was generally used without further purification, being one spot by tlc.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].C([O:14][C:15]([C:17]1[C:18](=[O:45])[C:19]2[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[N:21][C:20]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)CCC3)[CH:35]=1)=O)C>CO.O>[CH3:9][O:10][NH:11][C:15]([C:17]1[C:18](=[O:45])[C:19]2[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[N:21][C:20]=2[N:34]([CH:36]2[CH2:44][CH2:43][CH2:42][CH2:38][CH2:37]2)[CH:35]=1)=[O:14]
Reactant: CON
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCn3ccnc3)ncc2c1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CONC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (0.5 mL) was added to a mixture of O-methylhydroxylamine hydrochloride (220 mg) and 2-(3-Imidazol-1-yl-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 28 Step F, 6.0 mg, 0.013 mmol) in 0.5 mL of methanol. The reaction mixture was kept in a sealed tube at 110° C. for 2 days with stirring. After cooling to room temperature, the solution was diluted with water and extracted with dichloromethane. The crude product, after concentration, was loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 2-(3-Imidazol-1-yl-propylamino)-8-cyclohexyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methoxy-amide was obtained as a white solid (4.3 mg, 70%). 1H NMR (400 MHz, CDCl3) δ (ppm): 12.02 (br, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 7.32 (br, 1H), 7.10 (s, 1H), 6.95 (br, 1H), 5.82 (br, 1H), 5.06 (m, 1H), 4.10 (t, J=6.7 Hz, 2H), 3.88 (s, 3H), 3.51 (m, 2H), 2.20-1.20 (m, 12H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C21H27N7O3: 426.22 (M+H). Found: 426.2.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][N:39]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51](O)=[O:52])[CH:47]=[N:48][C:42]=3[NH:41][C:40]2=[O:54])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])[C:51](=[O:52])/[CH:50]=[CH:49]/[C:46]1[CH:47]=[N:48][C:42]2[NH:41][C:40](=[O:54])[N:39]([CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:44][C:43]=2[CH:45]=1
Reactant: CNCc1oc2ccccc2c1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)oc2ccccc12
Yield: 91 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzofuran-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.26 g, 91%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.75 (br s, 1H), 10.11 (s, 1H), 8.39 (d, J=7.5 Hz, 1H), 7.99 (t, J=9.0 Hz, 1H), 7.59-7.47 (m, 3H), 7.29-7.17 (m, 3H), 5.01-4.57 (m, 4H), 3.97-3.95 (m, 2H), 3.81-3.71 (m, 4H), 3.60-3.51 (m, 2H), 3.41-3.31 (m, 2H), 3.21-2.91 (m, 5H), 2.26 (s, 3H); MS (ESI) m/e 490 (M+H)+.