Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[CH3:3][CH:4]([CH3:27])[CH:5]([NH:10][C:11]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:12])[C:6]([O:8][CH3:9])=[O:7]>CCO.C1COCC1.O.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[S:14][C:13]([C:11]([NH:10][CH:5]([CH:4]([CH3:27])[CH3:3])[C:6]([O:8][CH3:9])=[O:7])=[O:12])=[N:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)s1)C(C)C
Temperature: 80 °C
Yield: 92.3 %

Procedure:
Ammonium chloride (1.04 g) and iron (777 mg) were added to a solution of Methyl 3-methyl-2-(5-(4-nitrophenyl)thiazole-2-carboxamido)butanoate (Intermediate 2, step C, 2.15 g) in EtOH (21.5 ml), THF (8.6 ml), and Water (8.6 ml). The reaction mixture was refluxed at 80° C. for 3 hours. It was then cooled, filtered through celite and the solvent was removed under reduced pressure to get dark brown residue. The residue was taken in water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and concentrated to get dark brown residue which was purified by column on silica gel in 2.5:7.5 EtOAc:chloroform to get yellow sticky solid which was crystallized in DCM/pet ether to yield 1.82 g (91%) of the title compound. 1HNMR (DMSO-d6, 300 MHz): δ 8.59 (d, 1H), 8.15 (s, 1H), 7.42 (d, 2H), 6.63 (d, 2H), 5.76 (bs, 2H), 4.31 (m, 1H), 3.67 (s, 3H), 2.27 (m, 1H), 0.91 (d, 6H); MS (ES+): m/z 334 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:10][CH2:11][CH3:12])[CH2:4][C:5]([O:7]CC)=O.[OH:13][CH2:14][C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].CCN(CC)CC>CCO.C1COCC1>[OH:13][CH2:14][CH:15]([CH2:21][N:1]1[CH2:2][CH:3]([CH2:10][CH2:11][CH3:12])[CH2:4][C:5]1=[O:7])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=C(CO)C(=O)OCC
Reactant: CCCC(CN)CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(CC(CO)C(=O)OCC)C1
Reaction time: 6 h
Yield: 37.8 %

Procedure:
In a three neck flask, fitted with a reflux condenser, under argon, a solution of ethyl 3-(aminomethyl)hexanoate (11.8 g, 0.042 mol) in EtOH (50 ml) is added via a pump-syringe (5 ml/h) onto a solution of ethyl 2-(hydroxymethyl)acrylate x278 (5 g, 0.038 mol) and Et3N (8.03 ml) in THF (100 ml) at room temperature. After 6 h, the reaction mixture is filtered on celite, washed with saturated NaHCO3 and the aqueous layer is extracted with CH2Cl2 (2×150 ml), dried with MgSO4, filtered and concentrated in vacuo. The crude reaction mixture is purified by chromatography on silicagel (CH2Cl2/MTBE/MeOH 50/49/1), to afford 3.7 g of ethyl 3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoate c279.
Reaction SMILES: [C:1]([C@@:4]1([OH:29])[C@:8]([C:10](=[O:12])[CH3:11])([OH:9])[C@@H:7]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:6][C@H:5]1[N:18]1[C:28]2[N:27]=[C:25]([NH2:26])[NH:24][C:22](=O)[C:21]=2[N:20]=[CH:19]1)(=[O:3])[CH3:2].CN(C)C1C=CC=CC=1.C(#N)C.P(Cl)(Cl)([Cl:44])=O>[Cl-].C([N+](CC)(CC)CC)C.C(O)(C)C.C(Cl)Cl>[C:1]([C@@:4]1([OH:29])[C@:8]([C:10](=[O:12])[CH3:11])([OH:9])[C@@H:7]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:6][C@H:5]1[N:18]1[CH:19]=[N:20][C:21]2[C:28]1=[N:27][C:25]([NH2:26])=[N:24][C:22]=2[Cl:44])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CC(C)O
Solvent: CN(C)c1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of the compound of Example 1 (480 g, 1.17 M), N,N-dimethylaniline (150 mL), tetraethylammonium chloride (386.4 g) and acetonitrile (0.70 L) is prepared, and then phosphorous oxychloride (400 mL) is added slowly (dropwise) over 3 hours at room temperature under a N2 atmosphere. After the addition, the mixture is heated at 100° C. for 14 minutes, and then cooled to room temperature. Most of the solvent is removed in vacuo to yield a red oil. The oil is treated with methylene chloride (CH2Cl2)(2 L), and then poured into ice water (1.5 L). The organic layer is separated and the aqueous layer extracted with CH2Cl2 (3×500 mL). The separated organic layer and the organic extracts are combined, washed with a saturated sodium bicarbonate solution until a pH of 6 to 7 is reached, and then washed with ice-water (2 ×1 L). The organic layer is dried over sodium sulfate, and the solvent removed in vacuo to yield a thick oil. The oil is treated with isopropanol (200 mL), stirred at 45° C. for 1 hour, allowed to cool to room temperature, and left overnight whereupon a precipitate is formed. The precipitate is isolated by filtering and then the precipitate is washed with cold isopropanol to yield the title compound (235 g, 47%).
Reaction SMILES: I[CH2:2][C:3]([F:6])([F:5])[F:4].[CH2:7]([N:10]1[C:18]2[C:13](=[N:14][C:15]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]5[CH2:31][NH:32][CH2:33][C:28]5=[N:27]4)=[CH:22][CH:21]=3)=[C:16]([Cl:19])[CH:17]=2)[N:12]=[C:11]1[O:34][C@H:35]1[C@H:39]2[O:40][CH2:41][C@@H:42]([OH:43])[C@H:38]2[O:37][CH2:36]1)[CH:8]=[CH2:9].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OCC(F)(F)F)(=O)=O>O1CCOCC1>[CH2:7]([N:10]1[C:18]2[C:13](=[N:14][C:15]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:30]=[C:29]5[CH2:31][N:32]([CH2:2][C:3]([F:6])([F:5])[F:4])[CH2:33][C:28]5=[N:27]4)=[CH:24][CH:25]=3)=[C:16]([Cl:19])[CH:17]=2)[N:12]=[C:11]1[O:34][C@H:35]1[C@H:39]2[O:40][CH2:41][C@@H:42]([OH:43])[C@H:38]2[O:37][CH2:36]1)[CH:8]=[CH2:9]
Reactant: FC(F)(F)CI
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CNC5)cc3)c(Cl)cc21
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CN(CC(F)(F)F)C5)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
2-iodo-1,1,1-trifluoroethane (12.5 μl, 0.127 mmol) was added to a stirred solution of (3R,3aR,6R,6aR)-6-[1-allyl-6-chloro-5-[4-(5,6-dihydro-4H-pyrrolo[3,4-c]pyrazol-2-yl)phenyl]imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (59.9 mg, 0.115 mmol) in dioxane (0.46 ml). The reaction mixture was a pale yellow solution that was heated to 80° C. After 2 days, N,N-diisopropylethylamine (40 μl, 0.229 mmol), 2,2,2-trifluoroethyl trifluoromethane-sulfonate (34 μl, 0.236 mmol), and additional dioxane (0.2 ml) were added to the reaction mixture. After stirring an additional 18 hours, the reaction mixture was cooled to room temperature. The reaction mixture was evaporated under reduced pressure to give a dark amber residue. The residue was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 80% acetonitrile/water+0.05% TFA flush. The product fractions were combined and evaporated under reduced pressure to give the desired product as an amber residue. LC-MS: calculated for C28H26ClF3N6O4 602.17 observed m/e: 603.19 (M+H)+ (Rt 1.20/2 min)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([O:20][CH3:21])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]>C(OCC)(=O)C.N1C=CC=CC=1.O>[NH2:17][C:15]1[C:14]([O:20][CH3:21])=[CH:13][C:3]([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])=[C:2]([Cl:1])[CH:16]=1
Reactant: COc1cc(C(=O)Nc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)Nc2ccccc2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stannous chloride (334 mg, 1.76 mmol) was added to a solution of 2-chloro-5-methoxy-4-nitro-N-phenyl-benzamide (180 mg, 0.59 mmol) in a mixture of ethyl acetate and ethanol (1/1, 8 mL) and the reaction mixture was stirred at room temperature overnight. The resulting mixture was partitioned between ethyl acetate (50 mL) and an aqueous solution of potassium carbonate (5%, 30 mL); the organic layer was separated, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and evaporate under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 70/30) to give 82 mf of 4-amino-2-chloro-5-methoxy-N-phenyl-benzamide as an off-white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][C@@H:29]5[CH2:33][CH2:32][O:31][CH2:30]5)[CH:21]=4)=[CH:18][CH:17]=[N:16]3)=[CH:11][CH:10]=2)C=CC=CC=1.O1CCCC1.Cl.[OH-].[Na+]>O.C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:15]([C:12]3[CH:11]=[CH:10][C:9]([NH2:8])=[CH:14][CH:13]=3)[N:16]=[CH:17][CH:18]=2)=[CH:21][C:22]=1[O:28][C@@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1
Reactant: COc1ccc(-c2ccnn2-c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)cc1O[C@@H]1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccnn2-c2ccc(N)cc2)cc1O[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Into a 1-neck round-bottom flask was added N-(diphenylmethylene)-4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl) aniline (52.0 mg, 0.101 mmol), 1.0 mL of tetrahydrofuran, and 0.1 mL of 2.0 M aqueous HCl. The reaction was stirred at room temperature for 2 hours and 10 mL of 0.5 N HCl in water and 10 mL of a 2:1 mixture of hexanes and ethyl acetate were added. The clear aqueous layer was basified with 1 N NaOH and extracted with 3×10 mL of ethyl acetate. The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure to yield 4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)aniline (28 mg, 79%) as a tan solid. LC/MS (EI) tR 3.11 (Method C), m/z 352.1 (M++1)
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([O:10][C@@H:11]([C:17]1[C:26]([CH:27]=O)=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOC(C)=O>[C:6]([O:10][C@@H:11]([C:17]1[C:26]([CH:27]=[CH2:2])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:7])([CH3:8])[CH3:9]
Reactant: [Li]CCCC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C=O)cc2ccccc2c1-c1ccc(Cl)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (60 mg, 0.168 mmol) in THF (1 mL) at −78° C. was added dropwise n-BuLi (1.6 M in hexanes, 90 μL), followed after 30 min by a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate (12 mg, 0.028 mmol) in THF (1 mL). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. This mixture was added to another mixture, which was made by adding n-BuLi (1.6 M in hexanes, 300 μL) to a suspension of methyltriphenylphosphonium bromide (200 mg, 0.56 mmol) in THF (2 mL) and stirred at −78° C. for 15 min. Then the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with sat. NH4Cl, and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 7.4 mg of the desired product. 1H-MNR 400 MHz (CDCl3) δ: 7.95 (s, 1H), 7.78 (d, J=4.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.43-7.17 (m, 6H), 5.62 (dd, J=8.1, 2 Hz, 1H), 5.25 (dd, J=5.3, 1.8 Hz, 1H), 5.07 (s, 1H), 4.06-4.02 (m, 2H), 1.10 (t, J=7 Hz, 3H), 0.93 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[NH2:20]
Reactant: BrCc1ccccc1Br
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(N)Cc2ccccc2Br)cc1
Temperature: 90 °C
Yield: 48.5 %

Procedure:
To a suspension of 2-bromobenzyl bromide (500 mg, 2.00 mmol) and 4-methoxyphenylhydrazine hydrochloride (348 mg, 2.00 mmol) in N,N-dimethylformamide (8 mL) was added potassium carbonate (1.38 g, 10.0 mmol). The reaction mixture was heated at 90° C. for 4 hours. The reaction was partitioned between water and methylene chloride. The methylene chloride was dried (MgSO4), concentrated and purified by SiO2 chromatography with 10-50% ethyl acetate/hexanes to give 298 mg of the title compound. LC-MS (C14H18BrN2O calculated 306) m/z 307 (M+H).
Reaction SMILES: N1CCCC(C(OCC)=O)C1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][NH:22][CH2:21][CH2:20][N:19]2[C:24]2[CH:42]=[CH:41][C:27]([C:28]([N:30]3[CH2:40][CH2:39][CH2:38][CH:32]([C:33]([O:35]CC)=[O:34])[CH2:31]3)=[O:29])=[CH:26][CH:25]=2)=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][NH:22][CH2:21][CH2:20][N:19]2[C:24]2[CH:25]=[CH:26][C:27]([C:28]([N:30]3[CH2:40][CH2:39][CH2:38][CH:32]([C:33]([OH:35])=[O:34])[CH2:31]3)=[O:29])=[CH:41][CH:42]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccc(N3CCNCC3c3ccncc3)cc2)C1
Agent: CCOC(=O)C1CCCNC1
Product: O=C(O)C1CCCN(C(=O)c2ccc(N3CCNCC3c3ccncc3)cc2)C1
Yield: 35 %

Procedure:
In a similar manner to Example 56 but using ethyl nipecotate, was prepared ethyl 4-[(4-pyridyl)piperazin-1-yl]-benzoylnipecotate in 35% yield as a solid; NMR (d6DMSO) δ 1.15 (3H,t), 1.35-1.75 (3H,m), 1.9-2.05 (1H,m), 2.3-2.5(1H,m), 3.0-3.3 (4H,m), 3.3-3.4 (4H,m), 3.4-3.5 (4H,m), 4.05 (2H,q), 6.85 (2H,d), 6.95 (2H,d), 7.25 (2H,d), 8.15 (2H,d); m/e 423 (M+H)+ ; calculated for C24H30N4 O3.0.5H2O: C, 66.8; H, 7.2; N, 13.0. Found C, 66.4; H, 7.3; N, 13.1%.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.S(Cl)([Cl:20])=O.O>C1C=CC=CC=1.C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:20][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=2[CH2:10]1
Reactant: OC1Cc2cc(I)ccc2Sc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: ClC1Cc2cc(I)ccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.3 g of 10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-ol in 64 ml of benzene, 45 ml of chloroform and 6.3 ml of pyridine is treated dropwise at -5° C with 5.7 ml of thionyl chloride. The mixture is stirred for 90 minutes at room temperature and for 30 minutes at 35°-40° C and is subsequently treated with water. The organic phase is washed successively with aqueous sodium bicarbonate solution and water, dried over magnesium sulphate, filtered and concentrated. There is obtained 10-chloro-10,11-dihydro-2-iodo-dibenzo[b,f]thiepin as a brown oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=O)[N:14]=[N:13]2)=[C:8]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2].C1C=CC2N(O)N=[N:36]C=2C=1.N.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH2:36])=[O:19])[N:14]=[N:13]2)=[C:8]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)O)nn2)c(OCCCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(N)=O)nn2)c(OCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]-2-(3-phenylpropoxy)phenyl}-1H-1,2,3-triazole-4-carboxylic acid (0.14 g) obtained in Example 133e) in DMF (4 ml) were successively added HOBt-NH3 (0.07 g), triethylamine (0.06 ml) and WSC (0.08 g), and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the deposited precipitate was collected by filtration, washed with water, and recrystallized from ethanol-water to give the title compound as a white powder (0.13 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Product: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]

Procedure:
100 g of 2-methyl-3-nitro-benzoic acid and 500 ml of thionyl chloride were refluxed for 15 hours and the mixture was then evaporated to dryness under reduced pressure to obtain 110 g of 2-methyl-3-nitro-benzoyl chloride which was used as in the synthesis.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]([NH:16][C:15]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:2][CH2:3][N:4]([C:35](=[O:36])[CH2:34][CH2:33][NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:5][CH2:6]2)[NH:13][CH:14]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=C(Nc1c[nH]c2nccc(N3CCNCC3)c12)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2ccnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 2 h
Yield: 48.9 %

Procedure:
N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.025 g, 0.058 mmol, see Example 50), 3-(tert-butoxycarbonylamino)propanoic acid (0.0121 g, 0.0637 mmol), HOBT-H2O (0.0124 g, 0.0811 mmol), and EDCI (0.0144 g, 0.0753 mmol) were placed in DCM (3 mL). DIEA (d 0.742; 0.0504 mL, 0.290 mmol) was then added. The reaction was stirred for 2 hours and quenched with saturated Na2CO3. The mixture was then extracted with DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by column chromatography (500:20-500:40) to give tert-butyl 3-(4-(3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.014 g, 48.9% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([C:14]3[O:18][N:17]=[C:16]([CH3:19])[CH:15]=3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[N:3]=1.C[O-].[Na+].CO>C(O)C(C)C>[CH3:19][C:16]1[CH:15]=[C:14]([C:11]2([C:9]3[NH:1][C:2]4=[N:3][C:4]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]6[CH2:29][CH2:30][CH2:31][CH2:32]6)=[O:27])[CH2:21]5)=[CH:5][CH:6]=[C:7]4[N:8]=3)[CH2:12][CH2:13]2)[O:18][N:17]=1
Reactant: Cc1cc(C2(C(=O)Nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3N)CC2)on1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)CO
Solvent: CO
Product: Cc1cc(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)on1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a solution of (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide (94 mg, 0.21 mmol) in isobutanol (2 mL) was added sodium methoxide (25% in methanol, 98 μL, 0.43 mmol) followed by methanol (0.9 mL). The reaction mixture was stirred at 110° C. for 18 h. An additional portion of sodium methoxide (25% in methanol, 98 μL, 0.43 mmol) was added and the reaction mixture was stirred at 110° C. for 3 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford (R)-(1-(2-(1-(3-methylisoxazol-5-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone. MS (ESI+) (M+H) 421.2; HPLC retention time 2.02 min (Method A).
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=[CH2:12].[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>CC(C)=O>[Cl:9][CH2:10][C:11](=[CH2:12])[CH2:13][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1ccccc1O
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(CCl)COc1ccccc1C=O
Yield: 100.2 %

Procedure:
45 g (0.3 mol) of sodium iodide, 16.5 (0.12 mol) of potassium carbonate and 17.36 ml (0.15 mol) of 3-chloro-2-chloromethyl-1-propene are added to 10.4 ml (0.1 mol) of 2-hydroxybenzaldehyde in solution in acetone. The mixture is left at reflux of the solvent for 12 hours and then the solvent is evaporated. The medium is diluted in ether and the organic phases are subsequently washed successively with a saturated sodium sulfite solution and with brine and are then dried over magnesium sulfate. Purification by chromatography on silica gel (ethyl ether/heptane 30/70) provides 21.1 g (70%) of 2-{[2-(chloromethyl)-2-propenyl]oxy}benzaldehyde; 1H NMR (300 MHz, CDCl3): 10.46 (s, 1H), 7.82 (dd, J=8.4 and 2.4 Hz, 1H), 7.5 (dd, J=2.4 Hz and 8.4 Hz, 1H), 7.00 (m, 2H), 5.49 and 5.32 (2s, 2H), 4.78 (s, 2H), 4.01 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:23]=1C=O.C(N)C1C=CC=CC=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8](/[CH:11]=[CH:12]/[C:23]2[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Solvent: NCc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Yield: 28 %

Procedure:
To a solution of 4-methoxy-3-nitrobenzyl sulfonylacetic acid (4.5 g, 15.5 mmol) in 30 mL of glacial acetic acid was added 2,4,6-trimethoxybenzaldehyde (3.05 g, 15.5 mmol) and a catalytic amount of benzylamine (0.6 mL). The resulting mixture was heated at reflux temperature for 6 h. The reaction mixture was then concentrated under reduced pressure to yield a gummy material. The gum was triturated with 2-propanol to yield a solid product. The solid product was recrystallized from a mixture of acetic acid and 2-propanol to provide the 2-((E)-2-(4-methoxy-3-nitrobenzylsulfonyl)vinyl)-1,3,5-trimethoxybenzene product in 28% yield. m.p. 186-187° C.