Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1.[CH3:27][N:28]=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:29]([NH:28][CH3:27])=[O:30])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1
Reactant: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Reactant: CN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)N[C@@H](C)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, and the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), methyl isocyanate (38.5 mg), triethylamine (68 mg) and THF (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (51.9 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]1[N:14]=[C:13]([C:15](OC)=[O:16])[C:12]([CH2:19][CH2:20]C(OC)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>O1CCCC1.CO>[CH2:1]([N:8]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:9]1[N:14]=[C:13]2[C:15](=[O:16])[CH2:20][CH2:19][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCc2ccc(N(Cc3ccccc3)Cc3ccccc3)nc21
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a suspension of methyl 6-(dibenzylamino)-3-(3-methoxy-3-oxopropyl)pyridine-2-carboxylate (2.02 g, 4.83 mmol) and 60% sodium hydride (386 mg, 9.65 mmol) in tetrahydrofuran (48 mL) was added methanol (1 drop), and the mixture was heated under reflux for 1.5 hr. The reaction solution was concentrated to dryness, 12M hydrochloric acid (24 mL) was added, and the mixture was stirred at 110° C. for 15 min. The reaction solution was diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate solution, and washed with saturated brine. This was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (1.17 g, yield 74%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:12])[C:9](Cl)=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].Cl>CCOCC.C(Cl)Cl>[S:7]1[C:9](=[O:10])[C:8](=[O:12])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]1=2
Reactant: Sc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1Sc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
To a solution of benzenthiol (1 ml, 9.7 mmol) in Et2O (30 ml) at 0° C. oxalyl chloride (0.94 ml, 10.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 hour, then, the solvent was evaporated under reduced pressure. The crude was dissolved in CH2Cl2 (40 ml) and a solution of AlCl3 (4.75 g, 35 mmol) in CH2Cl2 (32 ml) was added dropwise at 0° C. The mixture was stirred for 16 hours at room temperature, then, ice and 1M HCl were added until a clear mixture was obtained. After 1 hour, the phases were separated and the aqueous layer was extracted with CH2Cl2 (3×30 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated, affording 18 (1.2 g, 78%) as orange solid that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.B1(C=C)OB([CH:19]=[CH2:20])OB(C=C)O1.C1C=CN=CC=1>COCCOC.C([O-])([O-])=O.[K+].[K+].CCOCC.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>[CH:9]([O:8][C:5]1[C:4]([CH3:12])=[CH:3][C:2]([CH:19]=[CH2:20])=[CH:7][N:6]=1)([CH3:11])[CH3:10]
Reactant: Cc1cc(Br)cnc1OC(C)C
Reactant: C=CB1OB(C=C)OB(C=C)O1
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: c1ccncc1
Solvent: CCOCC
Solvent: COCCOC
Product: C=Cc1cnc(OC(C)C)c(C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of 5-bromo-2-isopropoxy-3-methyl-pyridine (1.24 g, 5.39 mmol) and 2,4,6-trivinylcyclotriboroxane pyridine complex (1.27 g, 5.26 mmol) in DME (12 mL) and 2 M aq. K2CO3 (5 mL) is degassed and put under argon before Pd(PPh3)4 (112 mg, 0.097 mmol) is added. The mixture is stirred at 80° C. for 15 h before it is cooled to rt, diluted with ether (50 mL), washed with sat. aq. NaHCO3 solution (2×30 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-isopropoxy-3-methyl-5-vinyl-pyridine (703 mg) as pale yellow oil; LC-MS: tR=1.01 min; [M+1]+=178.11.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:66][CH2:65][CH2:64][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[Cl:49])=[O:44])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].C(Cl)(Cl)[Cl:75].CO>Cl.C(OCC)(=O)C>[NH:1]([Cl:75])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:66][CH2:65][CH2:64][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[Cl:49])=[O:44])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NCl)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1

Procedure:
The solution of 100 mg (0.080 mmol) of Boc-Ala-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 13) in 3 ml of hydrogen chloride in ethyl acetate (4 mol/L) was stirred at room temperature for 2 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of Boc-Ala-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 13). The reaction mixture was evaporated under reduced pressure with ethyl acetate, repeatedly, to remove hydrogen chloride. The residue was triturated with ether to provide the title compound as a colorless powder, which was used for the next reaction directly.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCCC2)CC1
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of the product of Example 2 (2.0 g) in DCM (40 mL) was added pyrrolidine (1.0 g) followed by sodium triacetoxyborohydride (2.8 g). The resulting mixture was stirred overnight, and treated with 10% NaOH (20 mL). The resulting mixture was extracted with DCM (300 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated under reduced pressure to give the title compound as a light pink-brown oil (2.4 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[F:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[C:21]([F:24])[C:22]=1[F:23]>>[Br:9][CH2:10][CH2:11][CH2:12][C:13]([N:6]1[CH:7]=[CH:8][C:3](=[O:2])[CH2:4][CH:5]1[C:19]1[CH:18]=[C:17]([F:16])[C:22]([F:23])=[C:21]([F:24])[CH:20]=1)=[O:14]
Reactant: COc1ccncc1
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Reactant: O=C(Cl)CCCBr
Product: O=C1C=CN(C(=O)CCCBr)C(c2cc(F)c(F)c(F)c2)C1

Procedure:
1.02 g of the title compound was obtained from 4-methoxypyridine (1.52 mL), 3,4,5-trifluorophenylmagnesium bromide (0.3 M solution in THF, 50 mL), and 4-bromobutyryl chloride (1.74 mL) according to the method described in Tetrahedron Letters, 1986, vol. 27, p. 4549-4552. The property values of the compound are as follows.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[Cl:41][C:42]1[C:43]([C:52]([F:54])([F:53])[F:55])=[N:44][N:45]([CH2:48][C:49]([N:36]2[CH2:37][CH2:38][N:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=3)[CH2:34][CH2:35]2)=[O:50])[C:46]=1[CH3:47]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Trifluoromethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.38 (m, 1H), 7.11 (m, 3H), 5.00 (s, 2H), 3.79 (m, 2H), 3.73 (m, 2H), 3.27 (m, 2H), 3.23 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+H expected 455.0, found 455.0.
Reaction SMILES: [NH2:1][C:2]1([CH2:20][O:21][CH2:22][CH2:23][C:24]#[N:25])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.C[Al](C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:19][C:5]1[CH:4]=[C:3]2[C:8]([O:9][C:10]3[C:11]([F:18])=[CH:12][C:13]([O:16][CH3:17])=[CH:14][C:15]=3[C:2]32[CH2:20][O:21][CH2:22][CH2:23][C:24]([NH2:25])=[N:1]3)=[CH:7][CH:6]=1
Reactant: COc1cc(F)c2c(c1)C(N)(COCCC#N)c1cc(Br)ccc1O2
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(Br)ccc1O2
Temperature: 90 °C
Reaction time: 0.02 h

Procedure:
A 250-mL round-bottom flask was charged with 3-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)propanenitrile (2.78 g, 6.83 mmol) and toluene (45.5 mL) to give a pale-green solution. Trimethylaluminum (7.17 mL of a 2M solution in toluene, 14.34 mmol) was added, and a reflux condenser was attached. After stirring for 1 min, the flask was heated to 90° C. for 1 h. After this time, the mixture was cooled to RT. Sodium sulfate decahydrate (3.4 g) was added slowly over 5 min, and the mixture was stirred overnight. In the morning, the mixture was diluted with EtOAc (50 mL) and filtered through celite. The filter pad was washed with EtOAc (3×50 mL). The combined filtrates were concentrated to give a pale-yellow solid. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (E)-7′-bromo-4′-fluoro-2′-methoxy-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.53 (d, J=2.4 Hz, 1 H), 7.47 (dd, J=2.5, 8.6 Hz, 1 H), 7.18 (d, J=8.6 Hz, 1 H), 6.95 (dd, J=2.9, 12.3 Hz, 1 H), 6.69 (dd, J=1.5, 2.9 Hz, 1 H), 6.15 (br. s., 2 H), 3.83-3.69 (m, 5 H), 3.64-3.45 (m, 2 H), 3.00-2.74 (m, 2 H). MS m/z=411.0. Calc'd for C18H17BrFN2O3: 407.1.
Reaction SMILES: [S:1]1[C:5]([CH:6]([NH:8][OH:9])[CH3:7])=[CH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.O([NH:21][C:22]([NH:24][C:25](N)=[O:26])=[O:23])C1C=CC=CC=1>O1CCOCC1>[C:22]([NH:24][C:25](=[O:26])[N:8]([OH:9])[CH:6]([C:5]1[S:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[CH:4]=1)[CH3:7])(=[O:23])[NH2:21]
Reactant: CC(NO)c1cc2ccccc2s1
Reactant: NC(=O)NC(=O)NOc1ccccc1
Solvent: C1COCCO1
Product: CC(c1cc2ccccc2s1)N(O)C(=O)NC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of urea (7.27 g, 119 mmol) was added phenyl chloroformate (8.9 g, 57 mmol) followed by pyridine (30 mL). The resulting mixture became highly exothermic and soon solidified. This solid residue was dispersed and washed well with pyridine and ethylacetate to afford the intermediate N-phenoxycarbamoyl urea. A solution of N-(1-benzo[b]thien-2-yl)ethylhydroxylamine (0.50 g, 2.6 mmol) and N-phenoxycarbamoyl urea (0.46 g, 2.6 mmol) in dioxane (12 mL) was heated at 50° C. for 18 h. The mixture was then brought to 75° C. for 24 h. The reaction was cooled to r.t. and concentrated in vacuo. The resulting residue was crystallized in ethanol:hexanes to afford the desired product. (R1 =NHCONH2, A=CHCH3, X=S [2-isomer], Y=H, M=H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([C:35](O)=[O:36])[S:32][C:31]=2[CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:35]([C:33]2[S:32][C:31]3[CH:38]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=3[CH:34]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2Cl)CC1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2cc3ccc(Cl)cc3s2)c2ccccc2Cl)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.8 mmol) and 6-chlorobenzo[b]thiophene-2-carboxylic acid (172 mg, 0.8 mmol) afforded, after purification (SiO2: 50% EtOAc in hexane), 353 mg (77%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Solvent: CCO
Product: CC(C)(C)Nc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A mixture of 2,3-dichloronitrobenzene (92.5 g), tert-butylamine (138 ml) and ethanol (50 ml) is heated in a bomb at 150° for 3 days. Dilution with water, extraction with ethylacetate several times, drying with sodium sulfate, and concentration gives the title compound, IR (neat) 2970, 1532, 1484, 1447, 1366, 1348, 1192 and 755 cm-1 ; NMR (CDCl3) 7.73, 7.61, 7.07, 4.77 and 1.22 δ; MS (m/z) 172, 154, 142, 126, 114, 99 and 90.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:28][CH2:29][C:30]([N:19]1[CH2:18][CH2:17][C:15]2[N:16]=[C:11]([NH:10][CH:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)[N:12]=[CH:13][C:14]=2[CH2:20]1)=[O:31]
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (11.0 g, 41.3 mmol) and triethylamine (7.48 mL, 53 7 mmol) in dichloromethane (200 mL), add 2-chloroacetyl chloride (3.61 mL, 5.13 g, 45.4 mmol) dropwise over five minutes at 23° C. Stir for 30 minutes and pour the reaction mixture into 1:1 50% saturated aqueous sodium bicarbonate: dichloromethane (75 mL). Separate the organic layer from the aqueous layer and further extract the aqueous layer with dichloromethane (2×25 mL). Combine the organic extracts and dry over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in chloroform (10 mL) and purify via silica gel column chromatography (gradient elution: 25% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (9.75 g, 69%). 1H NMR (CDCl3, *=minor amide rotamer) δ 2.77* (t, 2H), 2.84 (dd, 2H), 2.87 (t, 2H), 3.35 (dd, 2H), 3.76 (t, 2H), 3.85* (t, 2H), 4.12 (s, 2H), 4.52* (s, 2H), 4.57 (s, 2H), 4.72-4.82 (m, 1H), 5.48-5.64 (m, 1H), 7.12-7.21 (m, 4H), 8.03-8.10 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([C:32](=[O:36])[C:33](Cl)=[O:34])[CH:23]=[CH:22][C:21]1=2.C12(C3C=C(NC(=O)NC4C=CC(C(OC)=O)=CC=4)C=CC=3OC)CC3CC(CC(C3)C1)C2>C1COCC1.O>[OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:33]([C:32]([C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:37])([CH3:19])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)=[O:36])=[O:34])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)Cl)ccc21
Reactant: COC(=O)c1ccc(N)cc1O
Agent: COC(=O)c1ccc(NC(=O)Nc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.7 g (40 mmol) of methyl 2-hydroxy-4-aminobenzoate, 10 ml (0.12 mol) of pyridine and 50 ml of THF are introduced into a round-bottomed flask. A solution of 10.5 g (40 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylglyoxyloyl chloride, prepared in 1 (c), in 100 ml of THF is added dropwise and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (30:70). After evaporation of the solvents, 7.3 g (45%) of methyl ester, melting point 146°-147° C., are collected.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:20])=[CH:5][C:6]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]>CC(O)=O.C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1C#N
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CN
Yield: 87.9 %

Procedure:
A clear solution of tert-butyl ((5-cyano-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.65 g, 2.344 mmol) in HOAc (5 mL) and Ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min, Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% (5% NH4OH/MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum to give the product tert-butyl ((5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.58 g, 2.061 mmol, 88% yield) as a clear thick oil. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (t, J=6.1 Hz, 1H), 6.63 (s, 1H), 4.06 (d, J=6.3 Hz, 2H), 3.84 (s, 3H), 3.61 (s, 2H), 2.29 (s, 3H), 1.53 (br. s., 2H), 1.41 (s, 9H). MS (ES)+ m/e 282.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH3:33])([CH3:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH3:15][Si:16]([CH3:32])([CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A mixture of 5.0 g. ethyl 4-aminocinnamate, 9.14 g. of 14-(trimethylsilyl)tetradecyl bromide and 3.6 g. of powdered anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[14-(trimethylsilyl)tetradecylamino]cinnamate. The ester is hydrolyzed with.sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the title product as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)[O:6][CH:7]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>O1CCCC1.ClCCl>[ClH:1].[CH:20]1([CH2:19][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:8]([C:5]3[O:6][CH:7]=[C:3]([CH2:2][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[N:4]=3)=[CH:9]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCNCC
Reactant: COc1cccc2c(-c3nc(CCl)co3)cn(CC3CCCCC3)c12
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)Cc1coc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)n1
Product: Cl
Yield: 82.1 %

Procedure:
To a solution of 3-(4-chloromethyl-oxazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (100 mg, 0.28 mmol) in tetrahydrofuran (1 ml) was added diethylamine (0.29 ml, 2.8 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 15 minutes. The reaction mixture was poured into a separating funnel, diluted with dichloromethane (40 ml) and washed with 5% aqueous sodium carbonate solution (2×25 ml), brine (20 ml), dried over magnesium sulfate and the solvent evaporated in vacuo to leave an orange oil. The oil was purified by flash column chromatography using 10% (v/v) methanol in dichloromethane to give the title compound (92 mg, 0.23 mmol) as the free base. The free base was dissolved in dichloromethane and hydrogen chloride (1M solution in diethyl ether; 2 ml, 2 mmol) was added. The mixture was concentrated in vacuo to afford the title compound as a 1:1 hydrochloride salt. 1H NMR (400 MHz, CD3OD): 0.97-1.28 (5H, m), 1.44 (6H, t, J 7.0), 1.5-1.8 (5H, m), 1.8-1.95 (1H, m), 3.3-3.5 (4H, m), 3.97 (3H, s), 4.29 (2H, d, J 7.0), 4.38 (2H, s), 6.8 (1H, d, J 8.0), 7.2 (1H, t, J 8.0), 7.8 (1H, s), 7.82 (1H, s), 8.2 (1H, s); EsIMS: m/z 396.0 [M+H]+, 323.4, 295.4, 268.3.