Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:8][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH:16]([O:15][CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][O:9]3)[CH2:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: C1CCC(OC2CCNC2)OC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Brc1cccc(N2CCC(OC3CCCCO3)C2)c1
Reaction time: 8 h

Procedure:
Into a 250 mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-dibromobenzene (7.0 g, 29.91 mmol) in toluene (100 mL). To this was added 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine (5.6 g, 32.75 mmol). Addition of Pd(OAc)2 (66.9 mg, 0.30 mmol) was next. This was followed by the addition of Cs2CO3 (24.27 g, 74.49 mmol). To the mixture was added BINAP (556 mg, 0.89 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). A filtration was performed. The filter cake was washed 3 times with 100 mL of brine. The mixture was dried over MgSO4. The residue was purified by eluting through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 1.36 g (13%) of 1-(3-bromophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine as a yellow liquid.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1)[CH:10]=[CH:9]2)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]#[C:16][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([OH:5])[CH:15]=[CH:14]3)=[CH:23][CH:22]=1
Reactant: CC(C)[Si](Oc1ccc2cc(C#Cc3ccc(CCCO)cc3)ccc2c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCc1ccc(C#Cc2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8.0 g (17.4 mmol) of 3-[4-(6-triisopropylsilanyloxynaphthalen-2-ylethynyl)-phenyl]propan-1-ol are dissolved in 100 ml of THF, and 22 ml (22 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF are added with ice-cooling. After 30 min, the cooling is removed, and the batch is left to stir for 1 h at room temp. The batch is added to water, acidified using dil. hydrochloric acid and extracted three times with ethyl acetate. The combined org. phases are dried over sodium sulfate, the solvent is removed in vacuo, and the residue is chromatographed on silica gel with toluene/ethyl acetate/ethanol (60:39:1). Crystallisation of the crude product from toluene gives 6-[4-(3-hydroxypropyl)phenylethynyl]naphthalen-2-ol as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold solution of 4-fluorobenzaldehyde (1 g) in conc. H2SO4 was added conc. HNO3 drop-wise at 0° C. The reaction mass was stirred at 0° C. for 1 h. The reaction mass was quenched in water and filtered to afford 1.2 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.82 (t, J=9.3 Hz, 1H), 8.32 (m, 1H), 8.68 (d, J=7.2 Hz, 1H), 10.06 (s, 1H); MS [M+H]+: 184.08.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9](S([O-])(=O)=O)[NH:10]S([O-])(=O)=O)=[CH:5][CH:4]=1.ClC1C=CC(N)=CC=1.S([O-])([O-])=O.[OH-].[Na+]>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])NN(c1ccc(Cl)cc1)S(=O)(=O)[O-]
Agent: Cl
Agent: Nc1ccc(Cl)cc1
Agent: O=S([O-])[O-]
Solvent: CCCCO
Product: NNc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In a 2 l four-necked flask fitted with dropping funnel, stirrer and condenser, 95 g of HCl 30% strength and 57 g of n-butanol (saturated with water, approximately 80% strength) are initially charged. The solution is heated to 50° C. and, over a period of 2 hours, admixed with a total of 720 g of an aqueous solution of 4-chlorophenylhydrazinedisulfonate- prepared by diazotization of 34.4 g (0.27 mol) of 4-chloroaniline (100 g of water, 78 g of HCl 30% strength, 55 g of NaNO2) and subsequent reduction with sulfite (186 g of NaHSO3 +57 g of NaOH). The reaction emulsion is kept at 50° C. for another 60 minutes, the pH is adjusted to 6.9 using 119 g of aqueous sodium hydroxide solution 33% strength, and the aqueous phase that is formed is separated off. The aqueous phase is extracted three times with 5 ml of n-butanol each time, and the combined organic phases are cooled to 15° C. The 4-chlorophenylhydrazine that is formed is filtered off with suction at 15° C. as a crystalline solid, using a 500 ml suction filter, washed with 50 ml of n-butanol and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](Cl)=[O:23]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:22](=[O:23])[C:21]2[CH:25]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=2[O:26][CH3:27])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1OCC
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(Cl)ccc2OC)cc1OCC
Reaction time: 3 h

Procedure:
10.4 g of 2-ethoxy-4-amino-benzoic acid ethyl ester were suspended in a mixture of 6.8 ml of triethylamine and 200 ml of toluene and 10.3 g of 5-chloro-2-methoxy-benzoyl chloride dissolved in a small amount of toluene were added dropwise. The whole was stirred for 3 hours under reflux and, after cooling, it was washed with water, dilute hydrochloric acid and a sodium bicarbonate solution and dried over sodium sulfate. Upon concentration of the solution under reduced pressure, the 2-ethoxy-4-(5-chloro-2-methoxy-benzamido)-benzoic acid ethyl ester was obtained in the form of a solid product having a crude melting point of 108°-111° C.
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[C:30](B(O)O)=[CH:31][S:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCO>[CH3:27][S:24]([N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:13]2[N:12]=[C:11]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([C:30]5[C:29]([CH3:28])=[CH:33][S:32][CH:31]=5)[C:10]=4[N:9]=[N:8]3)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20]1)(=[O:26])=[O:25]
Reactant: Cc1cscc1B(O)O
Reactant: CS(=O)(=O)N1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cscc1-c1cccc2c1nnn2-c1ccnc(NC2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
A mixture of [4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine (364 mg), 4-methyl-3-thiopheneboronic acid (109 mg) and Na2CO3 (2 M aq, 1.1 mL, degassed), toluene (13 mL, degassed) and EtOH (1 mL), was bubbled with argon and stirred at RT for 10 min in a screw cap pressure flask. To this was added Pd(PPh3)4 (25 mg), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was then cooled to RT, diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a solid. The solid was chromatographed on silica, eluting with 0-30% Magic Base/DCM, then chromatographed again on silica using 0-100% EtOAc/hexanes. The product was titurated with Et2O, filtered, and evaporated in vacuo overnight to provide (1-methanesulfonyl-piperidin-4-yl)-{4-[4-(4-methyl-thiophen-3-yl)-benzotriazol-1-yl]-pyrimidin-2-yl}-amine (Compound 5, 219 mg). Mp=244.0-245.0° C.; M+H=470.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[CH2:23]([O:22][CH2:21][CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1)[CH2:24][CH3:25]
Reactant: CCCOCCCl
Reactant: Oc1ccc2ccoc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1ccc2ccoc2c1
Temperature: 95 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To a solution of 6-hydroxybenzofuran (1.38 g) in DMF (40 ml) were added potassium carbonate (3.70 g) and sodium iodide (4.01 g) and then was added 2-chloroethylpropylether (2.52 g), and the mixture was stirred, under nitrogen atmosphere, at 95° C. for 3 days and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate (twice). The organic layer was washed with 1N sodium hydroxide solution (4 times), water (three times) and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give yellow oil of 6-propoxyethoxybenzofuran (1.50 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3O[CH:8]3[C:7]=2[CH:15]=1)#[N:2].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25]([O:27][CH2:28]C)=[O:26].[H-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:17]3[C:25]([O:27][CH3:28])=[O:26])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccccc2n1C1=CC(C)(C)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (2.0 g, 9.95 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194), and indole-2-carboxylic acid, ethyl ester (2.25 g, 11.9 mmol) in dimethylforamide (10.0 mL) at 0° C. under argon was added sodium hydride (476 mg of 60% oil dispersion, 11.92 mmol) in portions. After the addition was finished, the reaction mixture was allowed to warm up to room temperature and then heated at 90° C. for 16 hours. It was cooled to 0° C. in ice bath and diluted with ethyl acetate. To the resulting solution was added 1N hydrochloric acid until pH~5. The organic layer was separated and the aqueous layer was reextracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue in dichloromethanemethanol (90:10) at 0° C. was treated with freshly prepared diazomethane. The reaction mixture was warmed up to room temperature and stirred for 1 hour. Few drops of acetic acid were added to decompose excess diazomethane (until reaction mixture turned colorless) and the solvent was evaporated to yield a brown oil It was purified by flash chromatography (dichloromethane) to yield the less polar 1-(6-cyano-2,2-dimethyl-2H-benzopyran-4-yl)-1H-indole-2-carboxylic acid, methyl ester (1.6 g). Further elution furnished the more polar title compound (380 mg) as a colorless solid, m.p. 197°-200° C. (isopropyl ether): IR (KBr) 2227, 1710, 1489, 1207 cm-1 : 1H NMR (DMSO-d6) δ 7.7 (m, 2 H), 7.47, 7.41 (s, 1 H), 7.15 (m, 3 H), 7.0, 6.85 (d, J=10 Hz, 1 H), 6.6 (m, 1 H), 5.75 (d, J=5.8 Hz, 1 H), 4.5, 4.2 (m, 2 H), 3.9, 3.5 (s, 3 H), 1.48, 1.45 (s, 3 H), 1.37, 1.27 (s, 3 H) (doubling of signals due to rotamers present in solution); 13C NMR (DMSO-d6) 162.1, 156.2, 136.3, 133.3, 131.9, 129.8, 126.9, 124.7, 123.4, 123.2, 120.6, 118.5, 112.5, 111.0, 103.3, 81.25, 68.84, 54.8, 51.9, 26.5, 18.25 ppm. The peaks due to the minor rotamer appear at 132.5, 125.2, 123.0, 122.3, 121.0, 117.8, 113.2, 71.4, 56.2, 51.6, 26.8, 22.8, 18.7 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 29.7 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (301 mg, 1.02 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (600 mg, 2.05 mmol) to obtain the desired product (168 mg, 30%) as an purple semi-solid.: ESI MS m/z 554 [C27H32BrN5O3+H]+.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[C:5]1([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:5]1([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:1][CH2:2][CH3:3])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCI
Reactant: O=C(NCCCNCCc1ccc(Cl)cc1)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CCCNC(=O)Nc1ccccc1)CCc1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 72.2 %

Procedure:
Propyl iodide (51 mg, 0.30 mmol) was added to a mixture of N-phenylcarbamoyl-N′-[2-(4-chlorophenyl)ethyl]-1,3-diaminopropane (33 mg, 0.10 mmol) and potassium carbonate (28 mg, 0.20 mmol) in CH3CN (2 ml). The mixture was stirred at 75° C. for 5 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was purified by preparative normal phase HPLC using linear gradients of (A) chloroform and (B) methanol (0-5% B, in 0-10 min; 5-10% B, in 10-30 min; 10-15% B, in 30-40 min) at a flow rate of 10 ml/min. Fractions containing the major peak were pooled and concentrated to afford N-phenylcarbamoyl-N′-[2-(4-chlorophenyl)ethyl]-N′-propyl-1,3 diaminopropane (27 mg, 59%): MS(ES+) m/e 374 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=8.3 Hz, 2H), 7.25 (m, 4H), 7.07 (m, 3H), 5.98 (br, 1H), 5.00 (br, 1H), 3.31 (m, 2H), 2.78 (m, 6H), 2.59 (m, 2H), 1.76 (m, 2H), 1.52 (m, 2H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(OC(NC(NCCO[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:35]=3[CH2:36][CH2:37][CH2:38][N:39]4[C:44](=[O:57])[CH2:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=3[CH3:56])[CH:31]=[N:30]2)[CH:23]=1)=NC(=O)OC(C)(C)C)=O)(C)(C)C.C(OC(NC(NC(OC(C)(C)C)=O)=N)=O)(C)(C)C.[Br:76][CH2:77][CH2:78][CH2:79][OH:80]>>[Br:76][CH2:77][CH2:78][CH2:79][O:80][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:35]=2[CH2:36][CH2:37][CH2:38][N:39]3[C:44](=[O:57])[CH2:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=2[CH3:56])[CH:31]=[N:30]1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c5)c4)cccc32)c1C
Reactant: OCCCBr
Agent: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCCBr)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to tert-butyl (tert-butoxycarbonylamino)(2-(3-((4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)methyl)phenoxy)ethylamino)-methylenecarbamate except that 1,3-bis(tert-butoxycarbonyl)-guanidine was replaced with 3-bromopropan-1-ol. LCMS, [M+H]+=616.3.
Reaction SMILES: O=S(Cl)Cl.[OH:5][C:6]1[C:11]2[CH2:12][C@@H:13]3[C:18]([CH3:20])([CH3:19])[C@:17]([CH3:21])([C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH2:15][N:14]3[C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1)=[O:23].[CH2:33](O)[CH3:34]>>[CH2:33]([O:31][C:30]([CH:27]1[CH2:28][CH2:29][CH:24]([C:22]([N:14]2[CH2:15][CH2:16][C@:17]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:13]2[CH2:12][C:11]2[C:6]([OH:5])=[CH:7][CH:8]=[CH:9][C:10]=23)=[O:23])[CH2:25][CH2:26]1)=[O:32])[CH3:34]
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)C1CCC(C(=O)O)CC1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(C(=O)N2CC[C@@]3(C)c4cccc(O)c4C[C@@H]2C3(C)C)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
SOCl2 (5 mL) is added dropwise to a suspension of 4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclohexanecarboxylic acid (100 mg) in ethanol (5 mL) cooled to −20° C. Then, the cooling bath is removed and the resulting mixture is stirred at ambient temperature overnight. The solution is concentrated under reduced pressure and the residue is triturated with acetone and dried.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[C:22]([CH2:27][NH2:28])=[N:23][CH:24]=[CH:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:22]2[C:21]([CH3:20])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cccnc1CN
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cccnc1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(3-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18](=[N:20]O)[NH2:19]>N1C=CC=CC=1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]1[N:20]=[C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:9][N:19]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: NC(=NO)c1cc(F)ccc1F
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nc(-c2cc(F)ccc2F)no1
Yield: 770.5 %

Procedure:
Ethyl 3-chloro-3-oxopropanoate (1.7 mL; 13.2 mmol) was added to 2,5-difluoro-N′-hydroxybenzenecarboximidamide (JRD-Fluorochemical, 1.13 g; 0.6 mmol) in pyridine (30 mL). The mixture was heated to reflux for 4 hours and the solvent removed in vacuo. The residue was taken up into DCM (20 mL) and washed with water (10 mL). The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified on a Biotage 25+M column, eluting with petrol containing increasing amounts of EtOAc to give ethyl 2-(3-(2,5-difluorophenyl)-1,2,4-oxadiazol-5-yl)acetate (1.24 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:12]=1[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:8][C:3]1[C:2]([NH:1][CH2:13][C:12]2[CH:15]=[C:16]([O:19][C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][C:11]=2[O:10][CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 75 mL 3-necked round bottom flask fitted with mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were charged 29 mL acetic acid and 1.45 grams (11.3 mmoles) 3-amino-2-chloropyridine. The mixture was agitated for 5 minutes at 25° C. for dissolution. To the resulting solution was added 3.10 grams (14.1 mmoles/1.25 equivalents) of 2-methoxy-5-trifluoromethoxy benzaldehyde. Sodium triacetoxyborohydride, (4.79 grams, 22.6 mmoles, 2.0 equivalents) was added in portions while maintaining the temperature below 25° C. The reaction mixture was stirred 22 hours at 25° C. before adding another 0.5 grams of sodium triacetoxyborohydride. After stirring an additional 1 hour and 15 minutes, the reaction mixture was vacuum concentrated to 12.5 mL and partitioned between 26 mL each of methylene chloride and water. The pH was adjusted to 9.5 with 25% sodium hydroxide solution while maintaining a temperature of 25°-30° C. with cooling. The layers were separated, and the aqueous layer was washed with 14.5 mL methylene chloride. The methylene chloride layers were combined and dried with magnesium sulfate. The magnesium sulfate was removed by filtration, and the methylene chloride filtrate was evaporated and displaced with ethyl acetate, which resulted in a yellow oil (3.49 gms/92.8% weight yield). The structure of the product was established by high resolution NMR and GC/MS. 1H NMR (CDCl3) 7.70 (dd, 1H), 7.09 (bs, 1H), 7.02 (m, 2H), 6.85 (m, 2H), 4.95 (t, 1H), 4.36 (d, 2H), 3.88 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].O>CO.O>[N+:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)([O-:17])=[O:16]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 108.4 %

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester 15 (194 mg, 0.83 mmol) and KOH (342 mg, 5.25 mmol) were stirred in MeOH/water (8 mL/4 mL) at room temperature for 21.5 h. More water was added to dilute the solution. The mixture was concentrated to remove the organic solvent. The remaining solution was washed with DCM (100 mL). The aqueous solution was adjusted with 1 N HCl to pH 2.9, extracted with EtOAc (2×15 mL). The combined EtOAc extraction was washed with brine, dried over sodium sulfate, concentrated to afford the product as solid (185.5 mg, 97% yield). 1H-NMR (DMSO-d6): 8.718 (d, J=2.0-2.5 Hz, 1H, Ar—H), 8.116 (dd, J=2.0-2.5 Hz and 9.0-9.5 Hz, 1H, Ar—H), 7.583 (d, J=9.0-9.5 Hz, 1H, Ar—H), 7.378 (d, J=1.5 Hz, 1H, Ar—H). LC-MS: 207.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([N:16]([CH3:15])[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:5]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)ccc1F
Reaction time: 8 h

Procedure:
2-Fluoro-5-trifluoromethylbenzoyl chloride (80 mg, 0.35 mmol, CAS RN 207981-46-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (35 mg, 0.18 mmol, example 1, intermediate a) and DIPEA (92 μL, 0.53 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (36 mg, 53%). MS (ESI): m/z=389.0 [M+H]+.