Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2/[C:13](=[CH:16]/[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)/[C:14]#[N:15])([O-])=O.[Cl-].[NH4+].C(OCC)C.CCCCCCC>C(O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2/[C:13](=[CH:16]/[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)/[C:14]#[N:15]
Reactant: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: CCO
Product: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(N)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (Z)-2-(5-nitro-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile (370 mg, 1.27 mmol, 1.0 eq.) in ethanol (40 mL) were added zinc powder (667 mg, 10.2 mmol, 8.0 eq.) and then, ammonium chloride (679 mg, 12.7 mmol, 10.0 eq.). The reaction mixture was stirred at room temperature for 30 minutes and filtered through a celite pad. The filtrate was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 96/4 to 94/6) to afford, after trituration with diethyl ether, the compound (40) as a orange solid (80 mg, 24%). IR νmax (cm−1): 2216 (νCN), 3340 (νN—H); 1H NMR (DMSO, 500 MHz) δ (ppm): 4.72 (2H, s, aniline H), 6.63 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.4 Hz, H6′), 7.19 (1H, d, J7′-6′=8.9 Hz, H7′), 7.22 (1H, d, J4′-6′=2.4 Hz, H4′), 7.54 (1H, dd, J5″-4″=7.9 Hz, J5″-6″=4.8 Hz, H5″), 7.59 (1H, s, H3), 7.61 (1H, s, H2′), 8.29 (1H, d, J4″-5″=7.9 Hz, H4″), 8.57 (1H, d, J6″-5″=4.8 Hz, H6″), 8.93 (1H, s, H2″), 11.37 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 103.0 (C4′), 109.3 (C2), 109.9 (C3′), 113.2 (C6′), 113.4 (C7′), 118.5 (C1), 124.2 (C5″), 125.1 (C3a′), 127.1 (C2′), 130.9 (C3), 131.1 (C3″), 131.5 (C7a′), 134.7 (C4″), 143.7 (C5′), 149.8 (C6″), 150.2 (C2″); ESI-MS: m/z 261.1 ([M+H]+); HRESI-MS: m/z 261.1153 (calcd for C16H13N4+, 261.1140).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:25])=[CH:20][CH:19]=1.CCN(CC)CC>CCOCC.C1COCC1.O>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([N:26]([C:9](=[O:11])[C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:25])=[CH:22][CH:23]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: CCOC(=O)CN[C@@H](C)c1ccc(OC)cc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(=O)C#Cc1ccccc1)[C@@H](C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of phenylpropiolic acid (10 g, 68.4 mmol) and thionyl chloride (6 mL, 76.6 mmol) in Et2O (50 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure, then diluted with THF (100 mL). This acid chloride solution was added to a 0° C. solution of ethyl 2-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}acetate (15 g, 63.2 mmol) and Et3N (22 mL, 156 mmol) in THF (250 mL) dropwise over 25 min. The reaction mixture was allowed to warm to room temperature, stirred for 1.5 h, then treated with water and extracted with EtOAc. The organic layer was washed with a 1N HCl solution, water, a saturated NaHCO3 solution and a saturated NaCl solution. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give ethyl 2-{N-[(1S)-1-(4-methoxyphenyl)ethyl]-3-phenylprop-2-ynoylamino}acetate (18.9 g, 82%) as a slightly yellow oil: TLC (40% EtOAc/hex) Rf 0.40; 1H NMR (CDCl3) δ 1.14-1.33 (m, 3H), 1.66 (d, J=7.0 Hz, 3H), 3.82 (s, 3H), 4.06-4.21 (m, 4H), 5.59 (q, J=7.4 Hz, 0.6H), 6.03 (q, J=7.4 Hz, 0.4H), 6.86-6.93 (m, 2H), 7.25-7.61 (m, 7H); HPLC ES-MS m/z (rel abundance) 388 (MH+, 100%).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18](=[O:20])[CH3:19])[CH:13]=2)[CH:10]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:3][C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18](=[O:20])[CH3:19])[CH:13]=2)[CH:10]=1
Reactant: CC(=O)c1cc(Cn2cc([N+](=O)[O-])cn2)ccn1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(Cn2cc(N)cn2)ccn1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[4-(4-nitro-pyrazol-1-ylmethyl)-pyridin-2-yl]-ethanone (250 mg, 1.01 mmol), iron powder (172 mg, 3.05 mmol) and NH4Cl (274 mg, 5.08 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 5 h. The reaction mixture was filtered while hot and the filter cake rinsed with EtOH. The filtrate was concentrated under reduced pressure and the residue partitioned between CH2Cl2 (10 mL) and aq. 1M NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. TLC: rf (1:2 hept-EA)=0.05. LC-MS-conditions 02: tR=0.50 min, [M+H]+=217.47.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])[CH3:14]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A mixture of 2-methyl-3-nitrophenol 33.5 g, iodoethane 41 g and potassium carbonate 90 g in acetone 400 mL was stirred with heating under reflux for ten hours. The mixtures were cooled to room temperature and filtered and the resulting filtrates were concentrated. The resulting mixtures were extracted with ethyl acetate and the organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-ethoxy-2-methyl-3-nitrobenzene 39.9 g.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(N2CCOCC2)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 11 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (153 mg, 0.41 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using morpholine instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:methanol=60:40:0 to 0:95:5, 20 mg, 11%) which was obtained as an off-white solid. MS: m/e=437.0 [M+H]+.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([CH3:20])([NH:6][C:7]([N:9]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:8])[CH3:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:32]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[N:42][C:41]([NH2:51])=[N:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[N:42][C:41]([NH:51][C:3]([C:4]([NH:6][C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)=[O:8])([CH3:5])[CH3:20])=[O:21])=[N:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)C(C)(C)NC(=O)N1CC[C@H](c2ccccc2)C1
Reactant: Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(NC(=O)N1CC[C@H](c2ccccc2)C1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
THF (3 mL) was added to a flask containing 2-methyl-2-[((R)-3-phenyl-pyrrolidine-1-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.344 mmol) at 0° C. under N2. In a dropwise fashion 1 M LiHMDS in THF (344 uL, 0.344 mmol) was added to the flask. Upon complete addition the reaction was allowed to warm to room temp. After 2.5 hr 1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-amine (92 mg, 0.344 mmol) in THF (1 mL) was added to the reaction. The reaction was allowed to stir overnight. The next day more 1 M LiHMDS in THF (172 uL, 0.172 mmol) was added. The reaction was stirred an additional 5.5 hr before being quenched with sat. NH4Cl (10 mL). The reaction was diluted with EtOAc (60 mL) and extracted with water (5 mL). The organic phase was dried over Na2SO4 and the solvent evaporated. The residue was purified by silica gel chromatography (60-100 EtOAc/HEP) followed by HPLC (C18, 50-100% MeOH/H2O+5 mM NH4OH) to afford the title compound as a white solid: 1H NMR (400 MHz, DICHLOROMETHANE-d2) 1.58 (d, J=3.92 Hz, 6H) 2.01-2.15 (m, 1H) 2.25-2.36 (m, 1H) 3.36 (t, J=9.22 Hz, 1H) 3.40-3.53 (m, 2H) 3.62-3.70 (m, 1H) 3.87 (t, J=8.21 Hz, 1H) 4.74 (br. s., 1H) 5.44 (s, 2H) 7.19-7.36 (m, 9H) 7.36-7.44 (m, 3H) 7.62-7.70 (m, 2H) 10.76 (br. s., 1H); Rt (method A)=1.61 min (M+H)+=527.2.
Reaction SMILES: S1C=CC=C1S([NH2:9])(=O)=O.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:9])(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: NS(=O)(=O)c1cccs1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
5.2.2 4-nitrobenzenesulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-nitrobenzenesulfonyl chloride, which afforded the title compound 1.953 g (96.6%) as a pale yellow solid, m.p.: 178-180° C. 1H-NMR, 400 MHz, d6-DMSO, δ (ppm): 8.40 (d, J=8.6 Hz, 2H), 8.04 (d, J=8.6 Hz, 2H), 7.72 (br, 2H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[CH:31]=[C:30]([S:32]([CH2:35][CH2:36][CH2:37]O)(=[O:34])=[O:33])[CH:29]=[CH:28][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:16]=1)=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:8][CH2:37][CH2:36][CH2:35][S:32]([C:30]1[CH:29]=[CH:28][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:16]=2)=[O:13])=[C:10]([Cl:9])[CH:31]=1)(=[O:34])=[O:33]
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCO)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCBr)cc1Cl
Reaction time: 1 h

Procedure:
115 mg of NBS was added to a solution of 200 mg of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide and 169 mg of triphenylphosphine in 3 mL of dichloromethane at 0° C. The reaction mixture was stirred at 0˜5° C. for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by prep TLC plate (60% ethyl acetate/hexane) to afford 4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 60 mg of 4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide and 111 mg of cesium carbonate in 0.5 mL of DMF were heated to 100° C. in a sealed microwave reactor for 20 min. The reaction mixture was evaporated, and the product was purified on reverse phase HPLC to yield 4-(allylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 448.0 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[N:35]=[CH:34][CH:33]=[N:32]2)[C:23]=1[C:24](O)=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:24]([C:23]4[C:27]([N:31]5[N:35]=[CH:34][CH:33]=[N:32]5)=[CH:28][CH:29]=[CH:30][C:22]=4[F:21])=[O:25])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CN(c3cnc4cc(F)c(F)cc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C23H18F3N7O, 465.2; m/z found 466.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.32-8.24 (m, 1H), 7.90-7.79 (m, 2H), 7.68 (s, 1H), 7.65 (ddd, J=10.7, 8.5, 4.2, 1H), 7.55-7.38 (m, 2H), 7.22-7.10 (m, 1H), 4.13-3.48 (m, 7H), 3.40-3.05 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH:10]=3
Reactant: O=c1c(Cc2cncnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=c1c(Cc2cncnc2)cn2c3c(cc(OCc4cccnc4)cc13)Sc1ccc(Br)cc1-2
Yield: 66.8 %

Procedure:
According to Example 34, the compound (109 mg) produced in Example 76 was reacted with 3-chloromethylpyridine hydrochloride (62 mg) to obtain the title compound (88 mg; 67%).
Reaction SMILES: [H-].[Na+].CO.[Br:5][CH:6]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]([F:21])[F:20])[N:12]=[C:11]([C:22]([F:25])([F:24])[F:23])[C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7]Br.Cl>C1COCC1>[Br:5][C:6]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]([F:21])[F:20])[N:12]=[C:11]([C:22]([F:23])([F:24])[F:25])[C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH2:7]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1C(Br)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(Br)c1c(C(=O)OC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 5 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a stirred mixture of 0.49 g (0.012 mole) of 60% sodium hydride in oil dispersion and 4 ml of anhydrous THF is added 10 ml of methanol under nitrogen. The reaction mixture is cooled with an ice bath to 5° C. then treated slowly with a solution of 3.0 g (0.0058 mole) of product of Example 128 in 2 ml of anhydrous THF, while the reaction mixture is maintained below 15° C. The mixture is stirred at 0° C. for 2 hours and poured into 180 ml of 1% hydrochloric acid then extracted three times with 50 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and concentrated. The residue is purified by a radially-accelerated preparatory TLC using 10% ethyl acetate/cyclohexane as eluent to give 0.85 g (33%) of the desired product as a light yellow oil, nD25 1.4734.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](I)=[C:12]([C:15]#[N:16])[C:11]([CH3:17])=[N:10]1.[CH3:18]/[C:19](/B(O)O)=[CH:20]/[CH3:21].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:18]/[C:19](/[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]([CH3:17])[C:12]=1[C:15]#[N:16])=[CH:20]/[CH3:21]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(I)c1C#N
Reactant: C/C=C(/C)B(O)O
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: [K+]
Solvent: O
Solvent: COCCOC
Product: C/C=C(/C)c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Yield: 70.7 %

Procedure:
A mixture of 1-(2-fluoro-4-hydroxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (40 mg, 0.12 mmol), (E)-but-2-en-2-ylboronic acid (23.3 mg, 0.23 mmol), K2CO3 (96.7 mg, 0.70 mmol) and Pd(PPh3)4 (13.47 mg, 0.01 mmol) in DME (1 mL) and water (1 mL) was flushed with N2 and irradiated in the microwave at 150° C. for 10 min. Water and DCM were added and the phases were separated. The organic layer was concentrated and the crude product was purified on HPLC to give (Z)-5-(but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (23.0 mg, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 57.5 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), 1.02 g (17.5 mmol) of sodium chloride, and 10 mL of acetone. The resulting mixture was refluxed under stirring at 55-60° C. in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 99.5%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2cccnc2)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5cccnc5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(pyridin-3-yl)piperidine-1-carboxylate (amine intermediate “M”) were reacted to give the title compound. LC/MS (M+H)+: 636. Ret. time: 1.53 min. (Condition G); analytical HPLC Ret. time: 6.11 min (Condition H).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[ClH:14]>O>[ClH:14].[CH3:12][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4][C:3]([OH:13])=[O:2]
Reactant: CCCCCN(C)CCC(=O)OC
Agent: Cl
Solvent: O
Product: CCCCCN(C)CCC(=O)O
Temperature: 24 °C
Yield: 82.7 %

Procedure:
68.8 g (367.4 mmol) N-methyl-N-pentyl-β-alanine methyl ester was hydrolyzed by refluxing with 138 ml water. Then the water is partly distilled off and 83 ml (472.7 mmol) hydrochloric acid (19%) was added. Water was distilled off again and 230 ml methyl ethyl ketone was added to remove residual water by azeotropic distillation. The reaction mixture was then cooled to 24° C. The crystallized product was separated and washed with methyl ethyl ketone and subsequently dried in vacuo. 63.7 g (82.7%) N-methyl-N-pentyl-β-alanine hydrochloride were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH3:8].C(Cl)Cl.C(N)CN>C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1nccn1C
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1nccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methyl-1H-imidazol-2-yl)-ethyl]-amide (300 mg, 0.531 mol) was dissolved in a 4:6 solution of TFA:DCM (142 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure. The crude material was then dissolved in dichloromethane and treated with ethylenediamine (319 mg, 5.31 mmol). After stirring at room temperature overnight, the precipitate was collected by filtration to afford 100 mg (43%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methyl-1H-imidazol-2-yl)-ethyl]-amide as a yellow solid. MS: (M+H)+=435; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.12 (s, 1H) 8.50-8.63 (m, 2H) 8.49-8.50 (m, 1H) 7.96 (d, J=1.51 Hz, 1H) 7.29 (dd, J=8.69, 1.51 Hz, 1H) 7.09 (s, 1H) 6.85 (s, 1H) 5.40-5.68 (m, 1H) 4.15 (s, 3H) 3.63-3.77 (m, 3H) 1.61 (d, J=6.80 Hz, 3H).
Reaction SMILES: C(S[CH2:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][N+:16]([O-:18])=[O:17])[CH2:11][CH2:10]1)=[O:7])(=O)C.O([C@H:23]1CC[C@H](N)CC1)[N+]([O-])=O.C(SCC(Cl)=O)(=O)C>>[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][N+:16]([O-:18])=[O:17])[CH2:11][CH2:10]1)(=[O:7])[CH2:5][CH3:23]
Reactant: CC(=O)SCC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Reactant: N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Agent: CC(=O)SCC(=O)Cl
Product: CCC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1

Procedure:
2-acetylmercapto-N-(trans-4-nitroxycyclohexyl)acetic acid amide from trans-4-nitroxycyclohexylamine and 2-acetylmercaptoacetic acid chloride melting point: 127°-129° C. (ether), yield: 67% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:32][CH2:31][C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(ncn2CCC(=O)OC(C)(C)C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (0.50 g, 1.25 mmol) is dissolved in DMF (8 mL) under N2 and K2CO3 (0.26 g, 1.88 mmol) is added followed by t-butyl acrylate (1.84 mL, 12.54 mmol). The reaction mixture heated to 90° C. with stirring. After 4 hours, the reaction mixture is cooled to rt and diluted with ethyl acetate. The organic layer is washed with water (3×) and brine, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromotography eluted with 19:1 methylene chloride:ethyl acetate gives 0.41 g (62%) desired product.