Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]1[CH2:7]CC[CH2:4]1.Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1.C([Mg]Cl)(C)C.O1CCCC1.C([Li])CCC.CCCCCC.C(Br)C=C.[Cl-].[NH4+]>C(OCC)C>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH:3]=[CH2:4]
Reactant: COC1CCCC1
Reactant: Brc1ccc(Br)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCc1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
Cyclopentyl methyl ether (CPME) (90 ml) was added to 1,4-dibromobenzene (1) (15 g, 15.9 mmol) under a nitrogen atmosphere, the mixture was cooled to around −10° C. with brine ice, a solution of 2 M isopropylmagnesium chloride in tetrahydrofuran (THF) (iPrMgCl solution) (0.35 equivalent amount, 11.2 ml) and a solution of 1.67 M n-butyllithium in hexane (nBuLi solution) (0.7 equivalent amount, 26.8 ml) were respectively added dropwise. The mixture was stirred at around −10° C. for 2 hours, allyl bromide (1.1 equivalent amount, 6.8 ml) was then added, and the mixture was stirred at room temperature for 14 hours. Diethyl ether was added to the reaction mixture, and the mixture was neutralized with a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with diethyl ether, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under a reduced pressure to give a crude product of 1-allyl-4-bromobenzene (2) (yield amount: 13.0 g, tentative yield: 103%), as shown in the following chemical reaction formula.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc2c(Br)cccn2n1
Product: COc1ccc(CNc2cccn3nc(Cl)nc23)cc1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-methoxy-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol), and 4-methoxy-benzenemethanamine, (1.26 mL, 9.72 mmol) in a manner analogous to Example 2d. Product isolated as an off-white solid, (1.51 g. 61%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.06 (d, J=6.90 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.19 (m, 1H), 6.94 (t, J=14.4, 7.6 Hz, 1H), 6.87 (d, J=7.4 Hz, 2H), 6.42 (d, J=8.0 Hz, 1H), 4.40 (d, J=6.1 Hz, 2H), 3.71 (s, 3H). MS=289 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(Cl)[Cl:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cl)Cc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorophenylacetyl chloride is prepared according to the method described in Example 8, using 3,4-dichlorophenylacetic acid (2.62 g, 12.8 mmol) to give a yellow oil which is dissolved in chloroform (15 mL). This solution is refluxed for 9 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (2.25 g, 12.2 mmol) in chloroform (10 mL) under nitrogen. The solvent is removed in vacuo, and the residue is partitioned between 1M hydrochloric acid (75 mL) and ether (75 mL). The ether layer is separated and the aqueous is washed with more ether (2×30 mL), and then basified to pH14 by the addition of 50% sodium hydroxide solution. This is then extracted with ether (4×30 mL), and the combined ether extracts are washed with water until GC shows no unreacted aminoalcohol in the ether. The ether containing the product is then dried over sodium sulfate, and the solvent is removed to leave the crude free ester. The residue is dissolved in ether (20 mL) and treated with HCl in ether to precipitate the salt. It is washed with ether and recrystallised from hot methanol to yield the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([OH:17])=O)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][C@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38]([NH:40][CH2:41][CH2:42][CH3:43])=[O:39])[N:29]2[C:28]1=[O:44]>>[CH2:18]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:26][C@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38](=[O:39])[NH:40][CH2:41][CH2:42][CH3:43])[N:29]2[C:28]1=[O:44])=[O:11])[C:15]([NH:26][C@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38](=[O:39])[NH:40][CH2:41][CH2:42][CH3:43])[N:29]2[C:28]1=[O:44])=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)O)Cc1ccccc1
Reactant: CCCNC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Agent: Cl
Product: CCCNC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)NCCC)N4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(2R,5R)-2,5-Dibenzyl-N1,N6-bis((4S,7S,10aS)-5-oxo-7-(propylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure F using Intermediate 3 (7.9 mg, 0.024 mmol) and Intermediate 38 (18 mg, 0.056 mmol) to give a light yellow solid (15 mg, 70% yield). Anal. Calcd. for C46H64N6O6S2 m/z 860.7. found: 861.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.24-7.13 (m, 10H), 5.31 (m, 2H), 4.94 (m, 4H), 3.33-3.13 (m, 6H), 2.76 (m, 6H), 2.35 (m, 4H), 2.08 (m, 4H), 1.70-1.47 (m, 18H), 0.90 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24](S(C(F)(F)F)(=O)=O)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[CH:35][CH:36]=1
Reactant: O=c1cc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a 500-mL three-neck round bottom flask with stir bar, heating mantel, reflux condenser with N2 outlet, septa with N2 inlet (needle) and temperature probe was added 6-(bis(4-chlorophenyl)methyl)-4-(1-(trifluoromethylsulfonyl)piperidin-4-ylamino)quinolin-2(1H)-one (6.06 g; 9.93 mmol) and THF (120 mL). To this solution was added LAH (pellets, 1.48 g; 38.99 mmol) at room temperature and the resulting mixture was heated to reflux while stirring for 8 hr and cooled room temperature overnight. A 2nd charge of LAH (0.45 g; 11.86 mmol) was added and the resulting mixture was maintained at 60° C. for 6 hr. A 3rd charge of LAH (0.45 g; 11.86 mmol) was added and the resulting mixture was maintained at 60° C. for additional 3 h. The reaction was stopped and cooled to 0° C. with ice bath. Water (2.6 mL) (Note: highly exothermic) was added, then 15% NaOH (2.6 mL), then water (7.5 mL). The resulting mixture was stirred for 15 min and then Na2SO4 and THF was added. The reaction solution was filtered through CELITE. The filtrate was concentrated and the resulting solid residue was triturated with DCM (10 mL)/diethyl ether (25 mL) in an ice bath for 20 min to yield 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one as a pink solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13](Br)[CH:14]=[CH2:15].[OH-].[Na+].C(OC(=O)C)C>CCCCCC>[CH2:15]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCSc1nc2cc(C)c(C)cc2[nH]1
Yield: 93 %

Procedure:
2-Allylthio-5,6-dimethylbenzimidazole (III) was prepared as described above for I from 2,67 g (0,015 mol) 2-mercapto-5,6-dimethyl-benzimidazole, 2,1 g (0,017 mol) allylbromide in the presence 0,7 g (0,017 mol) sodium hydroxide, yield 2,5 g (76%), m.p. 119-120° C. (from mixture ethylacetate with hexane). 1H NMR (CDCl3), δ: 2,33 (6H, s, 2CH3); 3,89 (2H, d, CH2S); 5,10 (HB, d, CHC═CHAHB); 5,25 (HA,d, CHC═CHACHB); 7,30 (2H, broad s, ArH); 10,11 (1H, broad s, NH).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C(N(CC)CC)C.C([O:43][CH:44]=[CH:45][CH3:46])C>O>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:44](=[O:43])[CH2:45][CH3:46]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC=COCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 1500 mg, 2.5 mmol), bis[1,2-bis(diphenylphosphino)ethanelpalladium(0) (230 mg, 0.25 mmol), triethylamine (7.5 ml, 54 mmol) and ethylpropenyl ether (900 μl, 7.5 mmol) in DMP (45 ml) was heated at 100° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate and the solvent was removed under reduced pressure. The crude product was then dissolved in DMP (25 ml) and 2M HCl (25 ml) and then stirred for 1.5 h. The reaction mixture was then poured into aqueous NaHCO3 and extracted with ethyl acetate. The extracts were separated, evaporated under reduced pressure, and the residue was chromatographed on silica using ethyl acetate/heptane (2/1, 4/1, 10/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (1.3 g, >99%).
Reaction SMILES: [Si]([C:8]1[S:9][C:10]([C:13]2([OH:31])[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH:21]([NH:23]C(=O)OC(C)(C)C)[CH2:20]3)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)(C(C)(C)C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:23][CH:21]1[CH2:22][CH:19]([N:16]2[CH2:15][CH2:14][C:13]([C:10]3[S:9][CH:8]=[N:12][CH:11]=3)([OH:31])[CH2:18][CH2:17]2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CC(N2CCC(O)(c3cnc([Si](C)(C)C(C)(C)C)s3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CC(N2CCC(O)(c3cncs3)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl 3-(4-(2-(tert-butyldimethylsilyl) thiazol-5-yl)-4-hydroxypiperidin-1-yl)cyclobutylcarbamate (as prepared in the previous step) (950 mg, 2.03 mmol, 1.00 equiv) in dichloromethane (10 mL) and CF3COOH (2 mL). The reaction mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)[CH3:2].OO.C(=O)([O-])[OH:21].[Na+]>C(O)(=O)C.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([O:3][CH2:4][CH2:5][S:6]([C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)=[O:21])[CH3:2]
Reactant: CCOCCSc1nc(-c2cccnc2)cs1
Reactant: O=C([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOCCS(=O)c1nc(-c2cccnc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Dissolved in 1.7 ml of acetic acid were 0.33 g (1.24 mmol) of the compound obtained in Example 1, and 0.15 ml (1.32 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic amount of sodium tungstate were successively added to the solution, which was stirred at room temperature for 4 hours. The reaction solution was poured in 34 ml of water, neutralized with sodium hydrogencarbonate and extracted with 34 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 0.27 g of white crystalline powders (77% yield).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:5]([CH2:12][CH:13]([OH:20])[CH2:14][CH2:15][O:16][CH2:17][O:18][CH3:19])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1>O1CCOCC1>[CH3:19][O:18][CH2:17][O:16][CH2:15][CH2:14][CH:13]1[O:20][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:12]1
Reactant: COCOCCC(O)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCOCCC1Cn2cc([N+](=O)[O-])nc2O1
Yield: 46.3 %

Procedure:
Sodium hydride (1.33 g, 33.23 mmol) was added to a solution of 2-chloro-1-(2-hydroxy-4-methoxymethoxybutyl)-4-nitroimidazole prepared in Example 23 (8.45 g, 30.21 mmol) in 1,4-dioxane (100 ml) with cooling on ice-bath followed by stirring under reflux for 40 hours. The reaction mixture was concentrated under reduced pressure, and cooled on ice-bath. Water was added to the residue, and the resulting mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-diisopropyl ether to afford 2-(2-methoxymethoxyethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (3.4 g, yield 47%) as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][S:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][S:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(SC#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C#CSc3ccc(C(=O)O)cc3)ccc21

Procedure:
In a manner similar to that of Example 2, by reaction of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate in THF, and after crystallization from heptane, the expected derivative is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:3]=1[CH:4]=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][C:26]#[N:27]>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]1[C:26]([NH2:27])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[CH:8][CH:9]=2
Reactant: COc1ccccc1CCC#N
Reactant: Nc1ccc(N2CCOCC2)cc1C=O
Product: COc1ccccc1Cc1cc2cc(N3CCOCC3)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-morpholin-4-ylbenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[C:23]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)[CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[C:23]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ccc3[nH]c4c(c3c2)CCN(C(=O)c2ccccc2)CC4)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3[nH]c4c(c3c2)CCN(Cc2ccccc2)CC4)cc1
Yield: 104.6 %

Procedure:
A solution of lithium aluminum hydride (0.26 g, 6.86 mmol) in tetrahydrofuran (5.0 mL) and a solution of 3-benzoyl-9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.257 g, 0.65 mmol) in tetrahydrofuran (5.0 mL) were reacted in a manner similar to Example 1 to give 0.26 g (100%) of the title compound as a white crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.79, 7.58-7.54, 7.46-7.31, 6.97, 3.89, 3.85, 3.10-2.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O.[BH4-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:11][CH2:10][CH2:9]2
Reactant: COc1cccc(CCNC(=O)Cc2ccc(OCc3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of N-[2-(3-methoxyphenyl)ethyl]-2-[4-(phenylmethoxy)phenyl]acetamide (5.739 g, 15.3 mmol) and phosphorous oxychloride (15 mL) in acetonitrile (40 mL) under nitrogen was heated at 80° C. for 5 hours. Solvents were evaporated. Ethyl acetate was added and evaporated three times. The residue was dissolved in methanol (50 mL) and sodium borohydride (2.00 g, 52.9 mmol) was carefully added to the solution in small portions. After 2 hours, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 0-10% methanol/CH2Cl2) to provide the title compound (1.54 g, 28% yield): 1H NMR (CDCl3) 7.36 (m, 6H), 7.12 (d, 2H), 6.91 (d, 2H), 6.73 (dd, 1H), 6.62 (m, 1H), 5.04 (s, 2H), 4.97 (t, 1H), 4.17 (br, 1H), 3.78 (s, 3H), 3.73 (m, 1H), 3.16 (m, 2H), 2.83 (m, 3H); ES-MS (m/z) 360 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([N+:18]([O-])=O)[CH:6]=1)[CH3:2].Cl[Sn]Cl>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([NH2:18])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CCOC(=O)c1ccc(Sc2ccccc2)c(N)c1

Procedure:
The product from Example 53b was reacted with the SnCl2 following the procedure from Example 1f giving the title compound as a solid.
Reaction SMILES: C([O-])([O-])=[O:2].[Na+].[Na+].OO.O.[CH3:10][O:11][CH:12]([O:22][CH3:23])[CH2:13][C:14]1[S:18][C:17]([CH3:19])=[N:16][C:15]=1[C:20]#[N:21]>CC(C)=O>[CH3:23][O:22][CH:12]([O:11][CH3:10])[CH2:13][C:14]1[S:18][C:17]([CH3:19])=[N:16][C:15]=1[C:20]([NH2:21])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: COC(Cc1sc(C)nc1C#N)OC
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(Cc1sc(C)nc1C(N)=O)OC
Reaction time: 2 h

Procedure:
2M Na2CO3-solution (64 ml, 127 mmol), H2O2 (30%, 43.3 ml, 424 mmol) and 45 ml water were placed and a solution of 5-(2,2-dimethoxy-ethyl)-2-methyl-thiazole-4-carbonitrile (4.5 g, 21 mmol) in 45 ml acetone was added dropwise at room temperature. The white suspension was stirred for 2 hrs. Acetone was evaporated and the aqueous residue was extracted three times with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (4.8 g, 98%) was used without any further purification for the next step.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([O-:16])=[O:15].[F-].[K+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[S:6][C:5]([C:7]3([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: OC1(c2ncc(I)s2)CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2cnc(C3(O)CCOCC3)s2)cc1
Temperature: 90 °C

Procedure:
A solution of Example 1B (1.0 g, 3.2 mmol), 4-nitrophenylboronic acid (0.75 g, 4.5 mmol), KF (0.56 g, 9.6 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.22 g, 0.32 mmol) in a solvent mixture of dimethoxyethane (5 mL) and methanol (5 mL) was heated to 90° C. for 16 h. The reaction was cooled to room temperature and partitioned between ethyl acetate (10 mL) and H2O (10 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×10 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane; to give the title compound. MS (ESI) m/z 307 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]>C1COCC1>[CH3:1][NH:2][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: CN
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Methylamine (4.5 ml of 2.0 M solution in THF) was added to a stirred solution of 2-chloro-1,3-dinitrobenzene (0.90 g, 4.4 mmol) in 40 ml of THF and the mixture was stirred for 30 min. The reaction was quenched by the addition of water and ether. The aqueous layer was separated and extracted twice with ether. The combined organic extracts were washed with saturated NaHCO3, brine and dried over magnesium sulfate. Filtration, removal of solvent and purification of residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to gave 0.80 g (91%) of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([OH:14])[CH3:13])=[CH:8][CH:7]=1.CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>>[OH:14][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]2[O:10][C:9]([CH2:11][N:12]([OH:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:8]=1)[CH3:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(O)Cc1ccc(CSCCN)o1
Product: CN(O)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCSCc2ccc(CN(C)O)o2)o1
Yield: 45.5 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N-hydroxy-N-methyl-2-furanmethanamine base (1.48 g) and 1,1-bis-(methylthio)-2-nitroethene (0.57 g) was heated at 98°-100° for 3 hr. The oily residue was chromatographed (silica/acetone) and the appropriate eluate evaporated to give the title compound (0.78 g) as an amber oil.