Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=1[C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[C:21]([C:13]1[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1OCCO[Si](C)(C)C(C)(C)C
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(N)cc1OCCO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of tert-butyl-[2-(2-tert-butyl-5-nitro-phenoxy)-ethoxy]-dimethylsilane (353 mg, 1.0 mmol) and calcium chloride (131 mg, 1.16 mmol) in ethanol (5 mL) and water (1 mL) add iron powder (660 mg, 11 mmol). Heat the solution at reflux for 2 hours, cool and filter through Celite. Concentrate under reduced pressure, re-dissolve in ethyl acetate and wash with brine (200 mL). Concentrate under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:27]=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:27]=[N:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN(c3ccc(Cl)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine (621 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].ClC1C=C(C2C=CC=C(Cl)C=2)C=CC=1.Cl[C:32]1[CH:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:46]=3)[CH:39]=2)[CH:35]=[CH:36][CH:37]=1>CCOCC.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:36]1[CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:46]=3)[CH:39]=2)[CH:33]=[CH:32][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Agent: Clc1cccc(-c2cccc(Cl)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cccc(Oc3cccc(-c4cccc(Oc5cccc(Oc6ccccc6)c5)c4)c3)c2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A 500 ml. four-necked flask equipped with stirrer, thermometer, and Dean-Stark strap surmounted by a Friedrichs condenser, was charged with 93.5 g. (0.505 mole) of m-phenoxyphenol, and 30.8 g. (0.50 mole) of potassium hydroxide was added in increments with stirring at 100°C. After the initial exothermic reaction had subsided, 80 ml. of toluene was added and water azeotroped from the reaction mixture until the theoretical amount had been collected, including that from the potassium hydroxide. The toluene was distilled from the reaction mixture until the pot temperature reached 230°C. After cooling to 150°C., 100 ml. of diglyme was added together with 7 g. of cuprous chloride and 2 g. of copper powder. The reaction mixture was then heated with stirring to 170°C. and 129.3 g. (0.57 mole) of 3,3'-dichlorobiphenyl was added over a 1 hr. period. Diglyme was distilled from the reaction mixture until the pot temperature reached 235°C. when reaction was continuted for 18 hours. On cooling, the reaction mixture was diluted with an equal volume of ether, and filtered to remove copper and potassium salts. The ethereal solution was washed three times with 150 ml. portions of 20% potassium hydroxide followed by water washing until nuetral. The water and potassium hydroxide layers were extracted with additional ether, the ether solutions combined and dried over anhydrous magnesium sulfate. After filtration, the ether was removed under vacuum and a dark red-brown oil was distilled to yield 71.4 g. of the intermediate compound 3-chloro-3'-(m-phenoxyphenoxy)biphenyl, bp 220°-222°C/0.04 mm. and 17.2 g. of the desired product, bp 312°C./0.05 mm. Final purification of the desired product was effected by dissolving in ethyl ether, treating with 1.0 g. of activated charcoal, followed by filtration through filter aid and removal of ethyl ether under vacuum.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C@@H:9]1[C@H:13]([CH2:14]I)[CH2:12][CH2:11][N:10]1[C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C@@H:9]1[C@H:13]([CH2:14][N:1]=[N+:2]=[N-:3])[CH2:12][CH2:11][N:10]1[C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1[C@H](CI)CCN1[C@@H](C)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H](CN=[N+]=[N-])CCN1[C@@H](C)c1ccccc1
Reaction time: 18 h

Procedure:
Sodium azide (5.34 mmol) was added to a solution of (2S,3R)-3-iodomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (Stage 36.5) (3.56 mmol) in DMF (30 mL) at rt. After 18 h, the reaction mixture was poured onto water and extracted with MTBE (2×). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep° silica gel column to to afford the title compound as a brown oil. HPLC: tR=3.26 min (method G); ESI-MS: [M+H]+ 289.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 186, Step A, 360 mg, 0.752 mmol) in DCM (3.76 mL) was added Dess-Martin periodinane (383 mg, 0.903 mmol) and the reaction was stirred at rt for 20 minutes. After this time the reaction was treated with Na2S2O3 (30 mL, saturated aqueous solution) and DCM (40 mL) and stirred at rt for 10 minutes. The organic layer was separated and washed with Na2S2O3 (20 mL, saturated aqueous solution) and NaHCO3 (20 mL, saturated aqueous solution), dried over MgSO4, filtered and concentrated to give the title compound. MS (ESI) m/z=476.0 (M+1).
Reaction SMILES: C(C1C=CC(C=CC(O)=O)=CC=1)=O.Cl.[NH2:15][CH2:16][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.[CH3:27][O:28][C:29](=[O:40])[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.ClC(Cl)C.C([O-])([O-])=O.[K+].[K+]>[CH3:27][O:28][C:29](=[O:40])/[CH:30]=[CH:31]/[C:32]1[CH:33]=[CH:34][C:35]([CH2:38][NH:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)C=Cc1ccc(C=O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(Cl)Cl
Product: COC(=O)/C=C/c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Yield: 86.7 %

Procedure:
4-formylcinnamic acid methylester is produced by adding 4-formylcinnamic acid (25 g, 0.143 mol) in MeOH and HCl (6.7 g, 0.18 mol). The resulting suspension is heated to reflux for 3 hours, cooled and evaporated to dryness. The resulting yellow solid is dissolved in EtOAc, the solution washed with saturated NaHCO3, dried (MgSO4) and evaporated to give a pale yellow solid which is used without further purification (25.0 g, 92%). To a solution of tryptamine (16.3 g, 100 mmol) and 4-formylcinnamic acid methylester (19 g, 100 mmol) in dichloroethane, NaBH(OAc)3 (21 g, 100 mmol) is added. After 4 hours the mixture is diluted with 10% K2CO3 solution, the organic phase separated and the aqueous solution extracted with CH2Cl2. The combined organic extracts are dried (Na2SO4), evaporated and the residue purified by flash chromatography to produce 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (29 g). A solution of KOH (12.9 g 87%, 0.2 mol) in MeOH (100 mL) is added to a solution of HONH2·HCl (13.9 g, 0.2 mol) in MeOH (200 mL) and a precipitate results. After 15 minutes the mixture is filtered, the filter cake washed with MeOH and the filtrate evaporated under vacuum to approximately 75 mL. The mixture is filtered and the volume adjusted to 100 mL with MeOH. The resulting solution 2M HONH2 is stored under N2 at −20° C. for up to 2 weeks. Then 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (2.20 g, 6.50 mmol) is added to 2 M HONH2 in MeOH (30 mL, 60 mmol) followed by a solution of KOH (420 mg, 6.5 mmol) in MeOH (5 mL). After 2 hours dry ice is added to the reaction and the mixture is evaporated to dryness. The residue is dissolved in hot MeOH (20 mL), cooled and stored at −20 ° C. overnight. The resulting suspension is filtered, the solids washed with ice cold MeOH and dried under vacuum, producing N-Hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 336 [MH+]).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:38]([CH3:39])[CH2:37][CH2:36][N:35]([CH3:40])[C:34]2=[O:41])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH:33]5[N:38]([CH3:39])[CH2:37][CH2:36][N:35]([CH3:40])[C:34]5=[O:41])=[CH:31][CH:32]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(C5C(=O)N(C)CCN5C)cc4)nn23)cn1

Procedure:
3-{4-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1061. Product isolated as an orange foam (79 mg, 61%). LCMS (m/e) 444 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.73-8.67 (m, 2H), 4.67 (dd, 1H, J=2.2 and 8.7 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.33 (d, 2H, J=8.4 Hz), 6.95-6.81 (m, 4H), 4.03 (s, 3H), 3.79-3.67 (m, 2H), 3.26-3.18 (m, 1H), 3.07-2.98 (m, 1H), 2.99 (s, 3H), 2.73-2.64 (m, 1H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[C:11]([CH3:10])=[N:15][C:14]([CH3:16])=[N:13]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: Cc1cc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-n2nc(C)nc2C)cc(Cl)n1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloro-6-methylpyridine (24-1, 2.15 g, 13.3 mmol), 3,5-dimethyl-1H-1,2,4-triazole (1.29 g, 13.3 mmol), and cesium carbonate (5.20 g, 16.0 mmol) in DMF (15 mL) was heated at 100° C. for 20 hours and cooled to room temperature. The mixture was diluted with ethyl acetate (250 mL) and washed with brine (4×250 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-90% ethyl acetate in hexanes) to afford 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridine (24-2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 1H), 7.29 (m, 1H), 2.64 (s, 3H), 2.62 (s, 3H), 2.41 (s, 3H). LRMS m/z (M+H) 223 found, 223 required. The regioisomer (24-3) was also obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.71 (m, 1H), 7.10 (m, 1H), 2.83 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H). LRMS m/z (M+H) 223 found, 223 required.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N+:18]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>[Fe]>[CH3:15][O:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][C:11]=1[O:16][CH3:17])[N:18]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: COc1cc(C=C(C#N)C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Fe]
Product: COc1cc2cc(C(N)=O)c(N)nc2cc1OC
Temperature: 90 °C

Procedure:
Iron powder (65.2 g., 1.22 moles) is added over a period of 1/2 hour to a slurry of α-cyano-β-(2-nitro-4,5-dimethoxyphenyl)acrylamide (75.0 g., 0.271 mole) in a 50% solution of acetic acid-N,N-dimethylgformamide (750 ml.) at 75° C. When addition of the iron powder is complete, the mixture is heated to 90° C. for 4 hours and then filtered while hot. The filter cake is washed with hot acetic acid (150 ml.). The dark red filtrate is gradually added to IN hydrochloric acid (1500 ml.) and the pink precipitate recovered by filtration and recrystallized from an excess (10%) of aqueous sodium hydroxide. The solid is filtered, washed with cold isopropanol and dried to give the title product as yellow crystals. Yield = 57.1 g. (83.5%); mpp. 274°-275° C.
Reaction SMILES: [NH2:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[C:28]([NH:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1)(=[O:30])[CH3:29]
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (120 mg, 0.333 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (24.0 μL, 0.338 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (89.1 mg, 66%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])[CH3:14]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CCN
Product: CCNC(=O)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and ethylamine; MS: 189.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([NH:25][C@H:26]([C:31](O)=[O:32])[C@H:27]([CH2:29][CH3:30])[CH3:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[C:18]([NH:25][CH:26]([CH:27]([CH3:28])[CH2:29][CH3:30])[C:31]([NH:17][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:32])([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NC(CC(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg of 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (II) and 210 mg of Boc-isoleucine (R in Formula is Boc) was dissolved in anhydrous THF (5 mL). 220 mg DCC was dissolved in 25 mL anhydrous THF. The solution of DCC in THF was added dropwisely into the reaction solution, and then stirred overnight at room temperature to give white precipitate. The solid was filtered off and washed for at least three times with anhydrous ethyl ether. The filtrate and washed ethyl ether were collected, evaporated and purified by column chromatography to give title compound 2-(Boc-amino)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-3-methylvaleramide (Formula I, wherein R is Boc).
Reaction SMILES: NC1C=CC=C(F)N=1.[F:9][C:10]1[N:15]=[C:14]([N:16]2[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][N:18]=[N:17]2)[CH:13]=[CH:12][CH:11]=1.[N:34]([C:37]1[N:42]=[C:41]([N:43]2[C:47]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[N:46][N:45]=[N:44]2)[CH:40]=[CH:39][CH:38]=1)=[N+]=[N-].[BH4-].[Na+]>CO.O>[F:9][C:10]1[N:15]=[C:14]([N:16]2[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][N:18]=[N:17]2)[CH:13]=[CH:12][CH:11]=1.[NH2:34][C:37]1[N:42]=[C:41]([N:43]2[C:47]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[N:46][N:45]=[N:44]2)[CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(N=[N+]=[N-])n2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(F)n2)CC1
Agent: Nc1cccc(F)n1
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(N)n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Part C′: When the procedures described above were employed utilizing 2-amino-6-fluoropyridine as the commercial starting material the isolated crude product of part C was 3.90 g of a mixture of tert-butyl 4-(1-(6-fluoropyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate and tert-butyl 4-(1-(6-azidopyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate. This crude product was dissolved in a mixture of 120 mL of methanol and 20 mL of water. To this solution at 25° C. was added in portions 1.60 g of sodium borohydride, and the mixture was stirred at 25° C. for 4 h. The reaction mixture then was concentrated under vacuum, and the residue was diluted with water and ethyl acetate. The phases were separated, and the organic phase was washed with water (×2) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-100% diethyl ether/methylene chloride) afforded tert-butyl 4-(1-(6-fluoropyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (3.26 g) [Mass Spec.: m/e: 350.32 (M+H)+ [calc'd: 350.17]; 1H NMR (300 MHz, CDCl3) δ 8.05 (m, 1H), 7.78 (m, 1H), 7.05 (m, 1H), 3.60 (m, 4H), 3.40 (m, 4H), 1.46 (s, 9H)] and tert-butyl 4-(1-(6-aminopyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (0.28 g) [Mass Spec.: m/e: 347.37 (M+H)+ [calc'd: 347.19]; 1H NMR (300 MHz, DMSO-D6) δ 7.64 (t, 1H, J=8 Hz), 6.79 (d, 1H, J=8 Hz), 6.60 (d, 1H, J=8 Hz), 6.55 (br s, 2H), 3.40 (m, 4H), 3.24 (m, 4H), 1.41 (s, 9H)].
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11](Cl)[S:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:14]>>[CH2:1]([C:8]1[N:12]=[C:11]([NH2:14])[S:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cc2ccccc2)ns1
Reactant: N
Product: Nc1nc(Cc2ccccc2)ns1
Temperature: 50 °C

Procedure:
A mixture of 3-benzyl-5-chloro-[1,2,4]thiadiazole (105 mg, 0.5 mmol) in ammonia (2 N in MeOH, 2 ml) was heated in a pressure tube at 50° C. for 5 h. The solvents were evaporated, the residue diluted with dichloromethane, the white solid (ammonium chloride) was filtered off, the filtrate was concentrated and then purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a light yellow liquid (40 mg, 41%). MS ISP (m/e): 192.1 (100) [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=O.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])[C:15]([CH3:17])=O.[Sn](Cl)Cl>C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][C:3]=1[F:13])[N:10]=[C:15]([C:14]([O:19][CH2:20][CH3:21])=[O:18])[CH:17]=[CH:7]2
Reactant: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)=O
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)c1ccc2cc(Br)c(F)cc2n1
Temperature: 70 °C
Yield: 20.4 %

Procedure:
5-Bromo-4-fluoro-2-nitro-benzaldehyde (1.50 g, 6.05 mmol) and ethyl pyruvate (737.4 mg, 6.35 mmol) in ethanol (15 mL) was added via canula to zinc(II)chloride (4.12 g, 30.24 mmol), tin(II)chloride (5.73 g, 30.24 mmol), and activated 4 Å molecular sieve pellets (1.50 g) in ethanol (15 mL) under argon. The mixture was heated at 70° C. in an oil bath for four hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 368.5 mg (20%) of ethyl 6-bromo-7-fluoro-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.63 (d, J=8 Hz, 1H), 8.58 (d, J=9 Hz, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 4.42 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 297 (M+H)+.