Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][O:8][C@@H:9]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[CH2:10][CH2:11][N:12]([CH3:34])[C:13](=[O:33])[NH:14][C@@H:15]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:16][N:17](C)[C:18](=O)OC(C)(C)C)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:41][C:37]1[CH:36]=[C:35]([C@H:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:10][CH2:11][N:12]([CH3:34])[C:13](=[O:33])[NH:14][C@@H:15]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:16][NH:17][CH3:18])[CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)NCCO[C@H](CCN(C)C(=O)N[C@@H](CC1CCCCC1)CN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC[C@H](CC1CCCCC1)NC(=O)N(C)CC[C@@H](OCCNC(=O)OC)c1cccc(Cl)c1
Yield: 26.7 %

Procedure:
tert-butyl (S)-2-(3-((R)-3-(2-(methoxycarbonylamino)ethoxy)-3-(3-chlorophenyl)propyl)-3-methylureido)-3-cyclohexylpropyl(methyl)carbamate (40 mg) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (5 mL). The reaction mixture was concentrated in vacuo. The residue was purified by Preparative HPLC to afford isomer 1 methyl (4S,10R)-10-(3-chlorophenyl)-4-(cyclohexylmethyl)-7-methyl-6-oxo-11-oxa-2,5,7-triazatridecan-13-ylcarbamate (8.88 mg, 27%) LC-MS (3 min) tR=2.195 m/z=497. 1H NMR (CD3OD) d 0.99 (m, 2H), 1.54 (m, 1H), 1.70 (m, 4H), 1.87 (m, 3H), 2.73 (s, 3H), 2.94 (s, 3H), 3.09 (m, 1H), 3.63 (s, 3H), 4.26 (m, 2H), 7.29 (m, 4H). isomer 1 methyl (4S,10R)-10-(3-chlorophenyl)-4-(cyclohexylmethyl)-7-methyl-6-oxo-11-oxa-2,5,7-triazatridecan-13-ylcarbamate and isomer 2 methyl (4S,10S)-10-(3-chlorophenyl)-4-(cyclohexylmethyl)-7-methyl-6-oxo-11-oxa-2,5,7-triazatridecan-13-ylcarbamate. LC-MS (3 min) tR=2.149 m/z=497. 1H NMR (CD3OD) d 0.96 (m, 2H), 1.25 (m, 5H), 1.54 (m, 1H), 1.69 (m, 4H), 1.89 (m, 3H), 2.71 (s, 3H), 2.93 (s, 3H), 3.06 (m, 1H0, 3.64 (s, 3H), 4.14 (m, 1H), 4.30 (m, 1H), 7.31 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[Cl:27])[O:28][CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 40 mg, 0.11 mmol) in dimethylsulfoxide (0.5 mL) was added 3,4-dichlorophenol (18 mg, 0.11 mmol) followed by addition of potassium carbonate (31 mg, 0.22 mmol). The reaction was left to stir at room temperature for 18 hours. The reaction mixture was poured into water (50 mL) and acidified with 2M HCl (2 mL), then extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (20 mL), then dried over magnesium sulfate and evaporated in vacuo to give a colourless glass (44 mg). The solid was then triturated with 1:1 ether:heptane (4 mL), sonicated and the supernatant decanted. The resulting solid was dried in vacuo to give an off-white solid as the title compound (47 mg, 98%).
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[C-]#N.[K+].[CH3:10][C@:11]12[CH2:28][CH:27]=[C:26]3[C@@H:16]([CH2:17][CH2:18][C:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=[O:29])[CH:20]=4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:30].CO>O>[C:3]([C@@:12]1([OH:30])[CH2:13][CH2:14][C@H:15]2[C@H:16]3[C:26](=[CH:27][CH2:28][C@:11]12[CH3:10])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)#[N:4]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Reaction time: 3.5 h

Procedure:
Acetone cyanohydrin (5 ml) and sufficient potassium cyanide to adjust the pH to 9.9 is added to a slurry of androst-4,9(11)-dien-3,17-dione (0,5 g), methanol (40 ml) and water (2.5 g) at 40°. The reaction becomes homogeneous followed by precipitation of the product. After 3.5 hours, water (7.5 ml) is added dropwise and the reaction is allowed slowly to stir at 20°-25° overnight. The slurry is cooled on an ice bath, filtered, the solids washed with methanol/water (1/1) and dried under reduced pressure to give the title compound (4.54 g); [α]D (c=1, CHCl3)=+118°; MS=311, 296 and 284 m/e; NMR (CDCl3)=0.97, 1.37, 2.9, 5.5 and 5.70 δ.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][SH:6].Cl[CH2:8][CH:9]=[C:10]([CH3:52])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:52][C:10]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:9][CH2:8][S:6][CH2:5][CH2:4][NH2:3]
Reactant: NCCS
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCN
Yield: 61.3 %

Procedure:
Under an atmosphere of argon, sodium hydride (1.43 g, 35.8 mmol, 60% dispersion in mineral oil) was added to a solution of 2-aminoethanethiol (2.76 g, 35.8 mmol) in 90 ml of tetrahydrofuran. The mixture was heated at reflux temperature for 15 minutes and cooled in an ice bath. To the reaction mixture, 18-crown-6 (20 mg, 0.08 mmol) was added and then a solution of 1-chloro-3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,22,26,30,34-hexatriacontanonaene [23.2 g, 35.7 mmol, prepared as described in Item a) given above] in 90 ml of tetrahydrofuran was added in dropwise for 10 minutes. The reaction mixture was heated at reflux temperature for 4 hours and then cooled. After addition of water (1 ml), the solvent was evaporated in vacuo to dryness. The remaining residue was partitioned between water and n-hexane. The aqueous layer was extracted with n-hexane to combine the n-hexane layers. The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The remaining residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (50:1-20:1) to afford 15.1 g (61.3%) of the desired compound, as a pale brown oil.
Reaction SMILES: [C:1]([C:6]1[C:7]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.[C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH3:28]>>[OH:5][C:1]([C:6]1[C:7]([NH:12][C:13](=[O:18])[C:14]([CH3:16])([CH3:15])[CH3:17])=[N:8][CH:9]=[CH:10][CH:11]=1)([CH:2]([CH3:4])[CH3:3])[CH2:28][C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)C(=O)c1cccnc1NC(=O)C(C)(C)C
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)C(O)(CC(=O)OC(C)(C)C)c1cccnc1NC(=O)C(C)(C)C

Procedure:
A solution of N-(3-isobutyrylpyridin-2-yl)pivalamide (3.10 g, 12.5 mmol), LDA (1.5 M, 17.50 mL, 2.1 eq) and t-butyl acetate (3.5 mL, 2.1 eq) were reacted as outlined in Scheme 1 to give tert-butyl 3-hydroxy-4-methyl-3-(2-pivalamidopyridin-3-yl)pentanoate which was used in the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][CH:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C1C(=CC=CC=1)C(OCC)=O>CCCCCC>[OH:22][C:20]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9][C:10]=12
Reactant: CCOC(=O)C(=CNc1ccnn1-c1ccccc1)C(=O)OCC
Agent: CCOC(=O)c1ccccc1C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1O

Procedure:
A mixture of 18.1 g. (0.055 mole) of diethyl {[(1-phenyl-5-pyrazolyl)amino]methylene}malonate and 150 ml of diethyl phthalate was heated at 240-250° for 1 hour. The mixture was chilled and diluted with hexane. Chilling and filtering gave crystals which were washed with hexane and with hexane-ethanol (1:1) to give 11 g. (70%) of off white crystals m.p. 149-150° C. From a similar small scale run 1.75 g. was recrystallized from 110 ml. of ethanol to give 1.58 g. of off white crystals, m.p. 149-150° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:32]([C:40]1[C:41]([C:53]([F:56])([F:55])[F:54])=[C:42]2[C:46]3=[C:47]([CH2:49][NH:50][CH2:51][CH2:52][N:45]3[CH:44]=[CH:43]2)[CH:48]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.[C:58]([NH:65][CH2:66][C:67](O)=[O:68])([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>C1COCC1>[O:68]=[C:67]([CH:51]1[NH:50][CH2:49][C:47]2=[C:46]3[C:42](=[C:41]([C:53]([F:56])([F:55])[F:54])[C:40]([CH2:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:48]2)[CH:43]=[CH:44][N:45]3[CH2:52]1)[CH2:66][NH:65][C:58](=[O:59])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 8 h

Procedure:
HATU (172 mg, 0.45 mmol) and triethylamine (1.97 mmol) was added to a mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 150 mg, 0.39 mmol) and N-Boc-glycine hydrochloride (72 mg, 0.41 mmol) in THF (7 mL). After stirring overnight, the resulting mixture was partitioned between ethyl acetate and water. The organic phase was washed sequentially with NaHCO3 (sat'd., aq) and brine, then dried and concentrated. The resulting residue was purified by reverse-phase chromatography to yield tert-butyl (2-oxo-2-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethyl)carbamate (200 mg, MS m/z 502 (MH+).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]
Reactant: NC1CCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Cyclobutylamine (0.192 g, 2.7 mmol) was added to a solution of Example 133 (0.600 g, 1.3 mmol) in DMF (1 mL). The reaction mixture was stirred at 120° C. for 4 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 3-4% methanol/chloroform) to obtain the title compound. Yield: 0.450 g, (66.6%); 1H NMR (CDCl3-d6): δ 1.80 (m, 6H, 3CH2), 1.94 (t, 3H, CH3), 2.2 (t, 1H, CH), 2.9 (s, 3H, CH3), 3.3 (s, 2H, CH2), 3.9 (s, 3H, CH3), 4.7 (s, 2H, CH2), 7.5 (s, 1H, Ar), 7.8 (s, 1H, Ar), 8.4 (s, 1H, Ar), 9.5 (s, 1H, Ar); MS: m/e (ES+) 423 (M+1).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OB(O)c1cccnc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3cccnc3)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-[4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (example 45) was reacted with pyridin-3-yl-boronic acid to give the title compound as light brown oil. MS: 530.3 (MH+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1([O:17][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([O:35][C:36]1[N:41]=[CH:40][C:39]([C:42]2([C:45](N3CC[C@@]4(C5C=CC=CC=5C(=O)O4)C3)=[O:46])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[N:41]=[CH:40][C:39]([C:42]2([C:45]([OH:46])=[O:17])[CH2:43][CH2:44]2)=[CH:38][CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(OCc5ccccc5)nc4)CC3)C2)c2ccccc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(O)C1(c2ccc(OCc3ccccc3)nc2)CC1

Procedure:
Following the BOP coupling the desired product, (1R)-1′-({1-[6-(benzyloxy)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one, was purified by prep-HPLC. LC/MS: 441.2 (M+H+).
Reaction SMILES: [C:1]1([C@H:7]([CH2:12][CH3:13])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=O>C(Cl)Cl>[CH2:12]([C@H:7]([C:8]1[C:9](=[O:11])[O:10][C:8]2[CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:15]=2[C:14]=1[OH:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC[C@H](CC(=O)O)c1ccccc1
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)c1c(O)c2c(oc1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3[R]-Phenylvaleric acid of formula VV-3 (400 mg) is added to methylene chloride (5 mL) followed by oxalyl chloride (0.21 mL). That mixture is heated at reflux for 3 hours. The methylene chloride is removed and 1,3,5-trimethylbenzene (10 mL) is added. The solution of the acid chloride is then heated to reflux temperatures and the title product of Preparation 87 [VV-2](210 mg) and triethylamine (210 mg) (both in 1.5 mL of 1,3,5-trimethylbenzene) are added dropwise. After complete addition the reaction is heated for an addition 3 hours. The reaction is cooled to room temperature and the solid removed by filtration. The filtrate is evaporated and the resulting residue is diluted with methanol (35 mL) and 0.5N NaOH (4 mL) and that mixture stirred at room temperature overnight. The methanol is removed and water (35 mL) added. The aqueous is extracted with ether/hexane (2×35 mL) and the aqueous is acidified with 1.6N HCl at 0° C. to pH 3. That aqueous is extracted with ethyl acetate, dried and solvent removed in vacuo to yield 318.5 mg of the title product VV-5. Chromatography over silica gel (EtOAc/methylene chloride 1:8) affords 249.2 mg of the title product.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:8]=[N:9][N:10]([CH3:22])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.[N:23]1([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([Cl:35])[N:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[N:23]1([C:27]2[C:32]([CH:33]([C:7]3[CH:8]=[N:9][N:10]([CH3:22])[C:11]=3[C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=3)[OH:34])=[C:31]([Cl:35])[N:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cn1
Reactant: O=Cc1c(Cl)ncnc1N1CCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(C(O)c2c(Cl)ncnc2N2CCC2)c1-c1ccc(C(F)(F)F)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 74 μL, 0.185 mmol) was slowly added drop-wise to a −78° C. solution of 2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine (C14) (50 mg, 0.14 mmol) in tetrahydrofuran (2 mL). The reaction mixture was allowed to stir at −78° C. for 1 hour, and then a solution of 4-(azetidin-1-yl)-6-chloropyrimidine-5-carbaldehyde (C12) (28.1 mg, 0.142 mmol) in tetrahydrofuran (1 mL) was added. Stirring was continued for 1.5 hours at −78° C., then water was added, and the reaction mixture was removed from the cooling bath. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluent: 94:5:1 dichloromethane/methanol/triethylamine) provided the product. Yield: 40 mg, 0.094 mmol, 67%. LCMS m/z 425.2, 427.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.17-2.26 (m, 2H), 3.72 (s, 3H), 3.89-3.97 (m, 2H), 4.23-4.31 (m, 2H), 6.32 (s, 1H), 7.58 (s, 1H), 7.79 (br d, J=8 Hz, 1H), 7.85 (s, 1H), 7.92 (br dd, J=8, 2 Hz, 1H), 8.58 (br d, J=2 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:33])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](O)([C:36]([F:39])([F:38])[F:37])=[O:35]>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH:33][C:34](=[O:35])[C:36]([F:39])([F:38])[F:37])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)C(F)(F)F
Product: O=C(Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(Cc2ccccc2)CC1)C(F)(F)F

Procedure:
1-Benzenesulfonyl-N*4*-(1-benzyl-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (500 mg, 1.08 mmol) in TFA (5 mL) was heated to reflux for 5 hours. After cooling the mixture was concentrated under vacuum affording N-[1-benzenesulfonyl-4-(1-benzyl-piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-yl]-2,2,2-trifluoro-acetamide as an orange residue which was used for the next step without further purification. LCMS (Method B, ESI): RT=2.68 min, m+H=558.35.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][C:26](Cl)=[N:27][OH:28].C(N(CC)CC)C>O1CCCC1>[F:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][C:26]1[CH:2]=[C:1]([C:3]2[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=2)[O:28][N:27]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1F
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2F)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of the 3-ethynyl-pyridin-2-ylamine (38.4 mg, 0.325 mmol) described in Manufacturing Example 1-2-3 and (2-fluoro-4-(pyridin-2-yloxymethyl)-phenyl)acetohydroximoyl chloride (150 mg, 0.509 mmol) described in Manufacturing Example 204-1-8 was added triethylamine (97.2 μL, 0.697 mmol), which was stirred for 2 hours at 60° C. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (46 mg, 24%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2].CO.[OH-].[Na+].Cl>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: COC(=O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=C(O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of methyl 3-(2-nitrobenzenesulfonylamino)-propionate (6.15 g) in ethanol (20 mL)-methanol (5 mL) was added 5 mol/L aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid (55 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with n-hexane and ethyl acetate. The precipitated crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-(2-nitrobenzenesulfonylamino)propionic acid (5.83 g). To a solution of the obtained 3-(2-nitrobenzenesulfonylamino)propionic acid (0.5 g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (0.35 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1-methylpiperazine (0.46 g), and the mixture was stirred at 50° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol=40/1) to give the title compound (0.61 g).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:21]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH2:23]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:23]([C:18]1[CH:19]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:15]=[N:16][CH:17]=1)[CH:22]=[CH2:21]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Yield: 29.7 %

Procedure:
3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromopyridine (0.95 g, 2.77 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine) palladium (100 mg) and allyltributyltin (1.72 mL, 5.54 mmol). The mixture was stirred and refluxed for two days. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (250 mg, 30%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.22-2.42 (m, 2H), 3.37 (d, 2H, J=7.0 Hz), 3.87-3.92 (m, 2H), 4.16 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 5.07-5.17 (m, 2H), 5.9 (m, 1H), 7.07 (m, 1H), 8.08 (m, 1H), 8.19 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 305 (M+H)+.