Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:18][CH2:19][C:20]#[CH:21])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:18][CH2:19][C:20]#[C:21][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(Br)cccc2o1
Product: Brc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 45 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (63 mg, 0.40 mmol) and 4-bromo-2-(but-3-ynyl)-benzo[d]oxazole (100 mg, 0.40 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 60 mg (0.18 mmol, 46%) of 4-bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid with a purity of 8.5%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: Nc1c(I)cccc1C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(I)cccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 2-amino-3-iodobenzoic acid (5.00 g), benzyl alcohol (2.17 mL) and triphenylphosphine (7.97 g) in tetrahydrofuran (76 mL) was added a 40% toluene solution (13.2 g) of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 0.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-15:85) to give the title compound (5.56 g, yield 83%) as an orange oil. MS m/z 354 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C#N)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](Cl)=[O:32])[CH:26]=1.[CH3:34][OH:35]>O1CCCC1.CN(C)C=O.ClCCl>[C:26]([CH:27]1[CH2:31][O:32][CH:30]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:34](=[O:35])[CH2:3][CH:4]([CH3:8])[CH3:5])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CO
Reactant: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC(=O)Nc1cccc(-c2nn(C3CCC(C#N)CO3)c3ccccc23)c1
Yield: 47 %

Procedure:
The title compound was prepared according to the procedure described in Example 330 A, using 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (1.0 g, 3.0 mmol), and pyridine-3-carbonyl chloride (1.07 g, 6.0 mmol) in 30 mL of tetrahydrofuran and 1 mL of dimethyl formamide. The product was isolated as an off-white solid after column chromatography (2.5–5% methanol in dichloromethane) (0.600 g, 47% yield):); ES-MS (m/z) 424 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C@H:7]([CH:13]=C)[CH2:8][CH2:9][C:10]#[C:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Cl)Cl>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[C:1]([Si:5]([O:6][C@H:7]1[CH2:8][CH2:9][C:10]([C:11]([CH3:12])=[CH2:17])=[CH:13]1)([CH3:15])[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCl
Reactant: C=C[C@H](CCC#CC)O[Si](C)(C)C(C)(C)C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Product: C=C(C)C1=C[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
A solution of compound (5a) (263.8 mg, 1.106 mmol) and degassed DCM (37) was cooled to −78° C. The flask was flushed with ethylene gas over a period of 10 minutes before ethylene gas was bubbled through the solution itself for 3 additional minutes. Grubbs I catalyst (136.4 mg, 0.1657 mmol) was added and once again ethylene gas was bubbled through the resulting mixture for one minute. The icebath was removed and the mixture stirred for 24 hours. The flask was flushed with argon and the solvent was evaporated. Chromatography of the residue (pentane/ether 200/1) furnished 226.6 mg of compound of (6a) as clear colourless oil with 86% yield.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[NH:20][NH2:21]>C(Cl)Cl>[NH:21]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[NH:20][C:19]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)NN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (100 mL) and benzyl chloroformate (103 mL) were added to ethyl carbazate (50.0 g) in methylene chloride (400 mL) at 0° C., followed by stirring at room temperature for 18 hours. The reaction mixture was partitioned by use of saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was washed with brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give benzyl ethyl hydrazine-1,2-dicarboxylate as an oily product (31.7 g, 27.7%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[O:4]1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[O-:29][C:30]#[N:31].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(Cl)Cl>[CH2:10]([NH:31][C:30]([O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[O:4]1)=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: N#C[O-]
Reactant: OC[C@@H]1CC[C@H](CO)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCNC(=O)OC[C@H]1CC[C@@H](CO)O1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A suspension of 2.64 g (20 mmol) of cis-2,5-bis(hydroxymethyl)tetrahydrofuran, 7.99 g (24 mmol) of octadecyl bromide, 2.43 g (30 mmol) of potassium cyanate and 0.966 g (3 mmol) of tetrabutyl ammonium bromide in 100 ml of dry acetonitrile was refluxed, with stirring, at 100° C. for 20 hours. The resultant mixture was then diluted with hot methylene chloride, filtered and the filtrate concentrated in vacuo. The crude product was then purified by flash silica gel chromatography employing successive mixtures of petroleum ether and ethyl acetate in ratios of 4:1, 2.33:1 and 1:1 as the eluent to yield the title compound as a solid, m.p. 79°-80° C.
Reaction SMILES: C(N)C#C.ClC=CC(Cl)Cl.[CH2:11]([NH:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[C:12]#[CH:13].[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>>[CH2:11]([N:14]([CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[C:22](=[O:23])[CH:21]([Cl:25])[Cl:20])[C:12]#[CH:13]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C#CCNCC=C(Cl)Cl
Agent: C#CCN
Agent: ClC=CC(Cl)Cl
Product: C#CCN(CC=C(Cl)Cl)C(=O)C(Cl)Cl

Procedure:
From propargylamine and 1,3,3-trichloropropene, proceeding as in Example 1, there was prepared N-propargyl-N-(3,3-dichloroallyl)amine: b.p.15 mm =88°-91° C., from which, by reaction with dichloroacetyl chloride, there was obtained N-propargyl-N-(3,3-dichloroallyl)dichloroacetamide, (Applicants' Mark 8341), a yellowish oil.
Reaction SMILES: [CH:1]1(O)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:12][C:13]([F:26])([F:25])[S:14]([O:17]S(C(F)(F)F)(=O)=O)(=[O:16])=[O:15].[C:27]1([S:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CCCCC>[F:12][C:13]([F:26])([F:25])[S:14]([O-:17])(=[O:16])=[O:15].[CH:1]1([S+:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCC1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)([O-])C(F)(F)F
Product: c1ccc([S+](c2ccccc2)C2CCC2)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of cyclobutanol (1.00 g, 13.9 mmol) in 25 ml of DCM was chilled to −20° C. and dry pyridine (1.35 ml, 16.6 mmol) added, followed by trifluoromethanesulfonic anhydride (2.33 ml, 13.9 mmol) (in 5 ml of DCM). The solution was allowed to warm to room temperature over 1 hr. Pentane (40 mL) was added and the resulting mixture shaken and filtered. The filtrate was concentrated under reduced pressure with a room temperature bath until all volatile solvents were removed. The residual oil was chilled to −20° C. and diphenylsulfane (10.2 ml, 61.0 mmol) added. The mixture was stirred at 25° C. for 20 hr, warmed to 45 ° C. for 30 minutes and cooled to room temperature. Pentane was added, the solution shaken and the resulting solid collected by vacuum filtration to give cyclobutyldiphenylsulfonium trifluoromethanesulfonate (1.82 g, 4.86 mmol, 35.0%). MS: m/z (ES+): 241 [C16H17S]+. 1H NMR (D6-DMSO): δ 8.10 (dt, 4H, J1=7.8, J2=3.1), 7.84–7.72 (m, 6H), 5.90–5.78 (m, 1H), 5.15 (ddd, 2H, J1=14.9, J2=10.3, J3=1.4), 4.48 (t, 2H, J=14.2), 2.45 (dd, 2H, J1=13.8, J2=7.1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C@@H:5]([CH2:15][O:16]C2CCCCO2)[CH2:4][S:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CCO>[OH:16][CH2:15][C@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCCCCN1C(=O)SC[C@@H]1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CCCCCCCN1C(=O)SC[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of 4-1 (0.97 g, 3.0 mmol) in 10 mL EtOH was added p-toluene sulfonic acid (50 mg) and the resulting solution was stirred overnight at room temperature. Triethylamine (0.1 mL) was added and the solution was concentrated in vacuo. The compound was purified by flash chromatography using 50–80% EtOAc/hexanes to yield 0.65 g of 4-2 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.92–3.73 (m, 3H), 3.68–3.60 (m, 1H), 3.42 (dd, 1H), 3.28 (dd, 1H), 3.10 (m, 1H), 2.37(t, 2H), 1.71–1.46 (m, 6H), 1.39–1.33 (m, 2H); MS (+ESI): m/z 243.1 (M+1)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[K+].S(=O)(=O)(O)[OH:15].[OH-].[Ca+2].[OH-]>O>[N+:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[OH:15])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1O
Temperature: 55 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
159.1 g (1 mol) of 2,4-difluoronitrobenzene and 550 g of water are initially introduced and are heated to 55° C. With vigorous stirring, 241.2 g (2.15 mol) of 50% strength potassium hydroxide solution are added dropwise over 4 hours and the temperature is maintained at 55° C. (exothermic reaction). Stirring is then continued for another 2 hours at this temperature. The pH is then adjusted to 4.3 (25° C.) using 88 g of sulfuric acid, and 74.1 g of calcium hydroxide are added. The pH is readjusted to 5.0 and the introduction of steam is started. During distillation the pH is decreased from 5 to 1.5 by dropwise addition of sulfuric acid. The product is isolated by cooling and filtering the distillate. After drying, 117.9 g (0.750 mol, 75% of theory) of bright yellow 2-nitro-5-fluorophenol is obtained, which is more than 99.9% pure according to GC and HPLC (solidification point 32.1° C.).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:14](OCC)=O)[C:10]([CH3:30])([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10]([CH3:30])([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2C)cc1OC
Reaction time: 2 h
Yield: 97 %

Procedure:
14.5 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-carbethoxy-piperazine (cf. Example 5) are dissolved in 170 ml of dry tetrahydrofuran and added dropwise, with stirring over a period of two hours, to a boiling suspension of 3.42 g of lithium aluminum hydride in 150 ml of dry tetrahydrofuran. The batch is kept at the boiling point for a further 2 hours. After careful addition of water, the mixture is filtered and the filtrate evaporated. The remaining oil is further worked up as in Example 4. 12.4 g (82 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-methyl-piperazine are obtained in the form of the dihydrochloride. m.p. = 192° C. (ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:18]=1)([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[N:9][C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccncc3)nc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2oc(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
To a solution of 5-nitro-2-(pyridine-4-yl) benzo[d]oxazole 3 (600 mg, 2.48 mmol) in ethyl acetate/MeOH (10 mL) was added catalytic amount of 10% Pd—C under hydrogen atmosphere and stirred it for 6 h at room temperature and filtered by flash column chromatography (100% ethyl acetate) to afford 5-amino-2-(pyridine-4-yl) benzo[d]oxazole 4 (450 mg, 86%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 6.78 (dd, J1=12 Hz, J2=2.4 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 7.40 (d, J=4.8 Hz, 1H), 8.05 (dd, J1=8 Hz, J2=1.6 Hz, 2H), 8.79 (dd, J1=4 Hz, J2=1.6 Hz, 2H), 3.78 (s, 2H).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(=O)(O)[O-].[Na+].[CH:26]1([CH2:29]Cl)[CH2:28][CH2:27]1>CN(C)C=O>[CH:26]1([CH2:29][N:15]2[CH2:16][CH2:17][C@@:6]34[C:5]5[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=[CH:1][C:14]=5[CH2:13][C@@H:12]2[C@@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[CH2:28][CH2:27]1
Reactant: ClCC1CC1
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CC1CC1)CC3
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a mixture of 0.8 g of (-)-1-(morphinan-3-yl)-ethanone, 0.6 g of sodium bicarbonate and 10 ml dimethylformamide, was added 0.3 g of cyclopropylmethyl chloride. After the mixture had been heated at reflux for 18 hours, it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 60 ml ether. The ether solution was washed with water, dried over magnesium sulfate and removal of the solvent gave 0.8 g (83%) of crude (-)-1-[N-(cyclopropylmethyl)morphinan-3-yl]ethanone. For analysis, a sample of this compound was distilled, bp 185°-195° (0.1 mm), [α]25D-83.21° (c 1.02, MeOH).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:2]1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37])([O-:32])=[O:31].CN(C)CCCN>ClCCl.CN(C)C1C=CN=CC=1>[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:2]1)=[O:37])([O-:32])=[O:31]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: O=C(CCCc1c[nH]c2ccccc12)OCc1ccccc1
Agent: CN(C)CCCN
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1cn(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc12)OCc1ccccc1
Yield: 93.7 %

Procedure:
To a solution of benzyl 4-(3-indolyl)butyrate (33.70 g) in dichloromethane (400 ml) were added triethylamine (30 ml), 4-dimethylaminopyridine (1.22 g) and 3-nitrobenzoyl chloride (30.0 g). After refluxed for 16 hours, 3-nitrobenzoyl chloride (10.5 g) and triethylamine (5 ml) were added to the mixture. The mixture was allowed to reflux for 19 hours and 3-dimethylaminopropylamine (15 ml) was added at 0° C. The mixture was washed with diluted hydrochloric acid (200 ml ×2) and water (200 ml×4) and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid of benzyl 4-[1-(3-nitrobenzoyl)indol-3-yl]butyrate (47.61 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([I:17])[CH:9]=1>CS(C)=O.CCOCC.C(OCC)(=O)C>[I:17][C:10]1[CH:9]=[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(I)cc(N2CCOCC2)c1
Temperature: 120 °C

Procedure:
Morpholine (2.53 mL, 28.1 mmol) was added to a solution of 1-fluoro-3-iodo-5-nitrobenzene (3 g, 11.2 mmol) in DMSO (22.5 mL) under nitrogen. The reaction was heated at 120° C. for 2 hours, then cooled to room temperature and diluted with a mixture of ether and ethyl acetate. The organic layer was washed with water (2×) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexanes) to afford 4-(3-iodo-5-nitrophenyl)morpholine as deep yellow solid.
Reaction SMILES: [OH-:1].[K+].[CH3:3]O.Cl[C:6]1[C:11]2[CH:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=3[Cl:25])[C:10]=2[CH:9]=[CH:8][N:7]=1.O>CS(C)=O>[Cl:25][C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=1[N:14]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([O:1][CH3:3])[C:11]=2[CH:12]=[CH:13]1
Reactant: FC(F)(F)c1ccc(-n2ccc3c(Cl)nccc32)c(Cl)c1
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1nccc2c1ccn2-c1ccc(C(F)(F)F)cc1Cl
Reaction time: 18 h

Procedure:
Potassium hydroxide (0.7 g, 12 mmol) and methanol (2 ml) were stirred together in dimethyl sulfoxide (20 ml) at room temperature for 30 minutes. 4-chloro-1-(2-chloro-4-trifluoromethylphenyl)-pyrrolo[3,2-c]pyridine (2.0 g, 6 mmol) was added and stirring continued for 18 hours. The mixture was poured into water and the precipitate collected by filtration. Further purification by flash column chromatography on silica gel gave 1-(2'-chloro-4'-trifluoromethylphenyl)-4-methoxy-pyrrolo[3,2-c]pyridine (0.35 g) as a pale yellow solid, m.p. 112°-115° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]#N)=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:30][Si:31]([C:34]#C)([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>CC#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][Si:31]([C:34]#[C:28][C:26]1[CH:25]=[CH:24][C:23]2[N:19]([CH2:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:20]=[N:21][C:22]=2[CH:27]=1)([CH3:33])[CH3:32]
Reactant: N#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (109 mg, 0.24 mmol) from Step 6 of Example 108, (trimethylsilyl)acetylene (68 μL, 0.48 mmol), and DIEA (62 μL, 0.36 mmol) in CH3CN (2 mL), was purged with a stream of argon for 5 min. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and argon was bubbled into the mixture for an additional 5 min. The reaction vessel was sealed and the mixture was heated at 80° C. for 5 h. The mixture was cooled to rt and was partitioned between EtOAc (100 mL) and 1 M aq NaHCO3 (50 mL). The organic layer was washed with brine (50 mL), dried over Mg2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford (1R,2R)-2-((6-((5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (61 mg, 54%) as an amber oil. LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH:36]([C:38](=[O:48])[CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[NH2:37]>O1CCCC1>[C:43]([O:42][C:41](=[O:47])[NH:40][CH2:39][C:38]([NH:36][NH:37][C:18]([CH:13]1[CH2:12][CH2:11][CH:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:48])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCC(=O)NN
Reactant: O=C(O)C1CCC2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NNC(=O)C1CCC2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (153 mg, 0.554 mmol) in tetrahydrofuran (3 mL) were added triethylamine (0.232 mL) and isobutyl chloroformate (89.1 μl) under ice-cooling, followed by agitating at 0° C. for 45 minutes. To the reaction solution was added a solution of tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (129 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6) in tetrahydrofuran (3 mL) at 0° C., followed by stirring at room temperature for 2.5 hours and concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-0/10) to afford 179 mg of the title compound (yield 72%).