Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:12]1[Br:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)cn(CCOCc3ccccc3)c2n1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOCc3ccccc3)c2n1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a solution of ethyl 1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (888 mg, 2.18 mmol) in carbon tetrachloride (20 ml) was added N-bromosuccinimide (505 mg, 2.84 mmol), and the mixture was heated under reflux for 12 hr. The mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=6:1) to give ethyl 1-(2-benzyloxyethyl)-2-bromo-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (592 mg, yield 56%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:16][C:12]3([CH2:15][O:14][CH2:13]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[BrH:18].C([O-])(O)=O.[Na+]>CCOCC>[Br:18][CH2:13][C:12]1([CH2:15][OH:14])[CH2:16][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CC3(COC3)C2)cc1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CC(CO)(CBr)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
6-(p-Toluenesulfonyl)-2-oxa-6-azaspiro[3.3]heptane (7.99 g, 31.5 mmol) was suspended in Et2O (300 mL) and cooled to 0° C. A solution of HBr (48% in AcOH; 10 mL) in Et2O (20 mL) was added dropwise over 20 min. The resulting mixture was warmed to rt and stirred for 1 h. Reaction was monitored by LC-MS. NaHCO3 (aq. satd., 200 mL) was added and the resulting phases were separated. The aq layer was extracted with Et2O (100 mL) and then combined Et2O layer was dried (MgSO4), filtered, concentrated to dryness to give the title compound as a white solid (10.2 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 3.69 (d, J=4.8 Hz, 2H), 3.62 (d, J=8.5 Hz, 2H), 3.55 (d, J=8.5 Hz, 2H), 3.46 (s, 2H), 2.48 (s, 3H), 1.55 (t, J=5.0 Hz, 1H); MS ESI 333.9, 335.9 [M+H]+, calcd for [C12H16BrNO3S+H]+334.0, 336.0.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](SC)=[C:18]([C:21]#[N:22])[C:19]#[N:20])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:26][NH2:27]>CO>[NH2:20][C:19]1[NH:27][N:26]=[C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:11][CH:12]=2)[C:18]=1[C:21]#[N:22]
Reactant: CSC(Nc1ccc(CNC(=O)OC(C)(C)C)cc1)=C(C#N)C#N
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2n[nH]c(N)c2C#N)cc1

Procedure:
A mixture of 117.8 g (342 mmol) of 3-[4-(N-Boc-aminomethyl)-phenylamino)2-cyano-3-methylmercaptoacrylonitrile, 20.54 ml (41.45 mmol) of hydrazine hydrate and 750 ml of methanol is heated under reflux for 3 hours and then concentrated by evaporation in vacuo at 50° C., yielding 5-amino-3-[4-(N-Boc-aminomethyl)-phenylamino]-4-cyano pyrazole in the form of an amorphous residue; TLC-Rf=0.28 (methylene chloride/methanol [9:1]).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[C@@H:10]([CH3:24])[CH2:9]3.O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)C[C@@H]1C)CC3>>[CH3:22][C@@H:15]1[C@@:16]2([CH2:17][OH:18])[C:11]([C@@H:10]([CH3:24])[CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])=[CH:12][C@@H:13]([OH:23])[CH2:14]1
Reactant: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@]2(CO)C1=CC(=O)C[C@@H]2C
Agent: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Product: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@]2(CO)C1=C[C@@H](O)C[C@@H]2C

Procedure:
Substituting 17β,19-dihydroxy-1α,17α-dimethyl-4-androsten-3-one and 17β,19-dihydroxy-1α,6α-dimethyl-4-androsten-3-one for 17β,19-dihydroxy-1α-methyl-4-androsten-3-one above results in the formation of 1α,17α-dimethyl-4-androstene-3β,17β,19-triol and 1α,6α-dimethyl-4-androstene-3β,17β,19-triol, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[Br:12]Br.S(=O)(=O)(O)O>[N+]([O-])([O-])=O.[Ag+]>[Br:12][C:3]1[C:2]([F:1])=[CH:7][C:6]([CH3:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: BrBr
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (1.00 g), silver nitrate (2.21 g), bromine (0.37 ml) and conc. sulfuric acid (6 ml) was stirred for 1 hour under cooling with ice. The reaction mixture was added dropwise to ice water and then subjected to extraction with chloroform. The organic layer was washed with saturated sodium hydrogencarbonate solution, dried with anhydrous magnesium sulfate and then concentrated at reduced pressure to give the titled compound in admixture with its regioisomer at a ratio of 5:3 (yield, 83%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C>ClCCl>[CH2:15]([NH:14][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=2)=[CH:28][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(N)cc2)cc1)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Add trifluoroacetic acid (0.24 mL) dropwise to a solution of {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (100 mg, 0.24 mmol) in dichloromethane (5 mL) at room temperature and stir overnight. Concentrate on a rotary evaporator, dilute with saturated aqueous sodium bicarbonate then extract with dichloromethane (3×50 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenylamine, (38 mg): 1H NMR (CDCl3, 300.00 MHz): 7.42-6.67 (m, 14H), 3.86 (s, 2H), 3.61 (s, 2H), 2.88 (m, 4H); m/z=319.2 (M+1); HPLC=97% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[O:14][N:13]=1>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:6])[C:3]([NH:11][C:12]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[O:14][N:13]=1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)no1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
N,N-Dimethylcarbamoyl chloride (7.91 g) and aluminum chloride (9.80 g) are added to toluene (100 ml), and the mixture is stirred at room temperature for 30 minutes. To this mixture is added 3-amino-5-t-butylisoxazole (9.81 g), and the resulting mixture is refluxed for 6 hours with stirring. After cooling, the reaction mixture is mixed with water, stirred at room temperature and shaken with toluene. The organic layer is evaporated to remove the toluene, whereby 1,1-dimethyl-3-(5-t-butyl-3-isoxazolyl)urea (14.63 g) is obtained. Yield is 98.9%. Melting point of the colorless crystalline product is 119 to 120.5° C. (after recrystallization from benzene).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:24])[CH2:12][S:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.[BH4-].[Na+].O.Cl>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:24])[CH2:12][S:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: O=C(CSc1ccnc2ccccc12)c1ccc2ccccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(CSc1ccnc2ccccc12)c1ccc2ccccc2c1
Temperature: -15 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
4-[2-(2-Naphtyl)-2-oxoethylthio]quinoline (Compound 2; 450 mg, 1.37 mmol) was dissolved in ethanol (50 ml), added at -15° C. with sodium borohydride (70 mg, 3.04 mmol), and stirred at -15° C. for two hours. The reaction mixture was added with water and neutralized by 2N hydrochloric acid. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed by silica gel column chromatography (hexane:ethyl acetate=1:4) to obtain 165.7 mg of the titled compound (36.5%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.FC(F)(F)C(O)=O.[N:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)=[N:22][CH:21]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCN(CC)CC>[N:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:27][CH2:28][CH:29]([NH:32][C:10]([C:2]3[NH:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:12])[CH2:30][CH2:31]2)=[N:22][CH:21]=1
Reactant: NC1CCN(c2ccncn2)CC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(c2ccncn2)CC1)c1nc2ccccc2[nH]1
Reaction time: 3 h

Procedure:
To a solution of 80 mg 1H-Benzoimidazole-2-carboxylic acid in 1 mL DMF and 0.2 mL NEt3, 200 mg 1-Pyrimidin-4-yl-piperidin-4-ylamine trifluoroacetate and 125 mg BOP-Cl were added and the mixture was stirred for 3 h. Finally, 3 mL saturated NaHCO3 solution were added and the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate. After removal of the solvent under reduced pressure the crude product was subjected to the next reaction step without further purification. Yield: 160 mg.
Reaction SMILES: [CH2:1]([CH:4]([CH2:33][CH2:34][CH3:35])[CH:5]=[C:6]([C:9]1[N:10]=[N:11][N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:13]=1)[C:7]#[N:8])[CH2:2][CH3:3].CO.Cl>O=[Pt]=O.C1COCC1>[CH2:33]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH:6]([C:9]1[NH:13][N:12]=[N:11][N:10]=1)[CH2:7][NH2:8])[CH2:34][CH3:35]
Reactant: CCCC(C=C(C#N)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)CCC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(CCC)CC(CN)c1nnn[nH]1
Reaction time: 30 h
Yield: 51.2 %

Procedure:
To a solution of 4-propyl-2-(2-trityl-2H-tetrazol-5-yl)-hept-2-enenitrile (1.60 g, 3.47 mmol) in 50 mL 1:1 MeOH:THF was added PtO2 (0.1 g), concentrated HCl (1.09 g), and the mixture was hydrogenated in a Parr shaker at 48 psi for 30 h. The mixture was filtered and concentrated. Flash chromatography of the residue on silica gel (0.25:1.25:3.5 conc. NH4OH (aq):MeOH:CH2Cl2), followed by a second column using the same conditions, provided 0.40 g (51%) of 4-propyl-2-(1H-tetrazol-5-yl)-heptylamine as a colorless solid. 1H NMR (D2O) δ 3.29 (m, 1H, —CHCH2NH2), 3.09 (m, 2H, —CH2NH2), 1.56 (m, 1H, —CHCHHCH—), 1.37 (m, 1H, —CHCHHCH—), 0.80-1.07 (m, 9H, —CH2CHCH2—, —CH2CH2—), 0.58 (t, J=6.6 Hz, 3H, CH3—), 0.47 (t, J=6.6 Hz, 3H, CH3—). Anal. Calcd for C11H23N5: C, 58.63; H, 10.29; N, 31.08. Found: C, 57.87; H, 10.04; N, 30.73.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1.[CH2:16]([O:18][CH2:19][CH2:20]Br)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:16]([O:18][CH2:19][CH2:20][NH:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1)[CH3:17]
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Reactant: CCOCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCNC1CCc2cc3c(cc2C1)OCC3
Reaction time: 20 h

Procedure:
A mixture containing 7.8 g of the compound of Example 2, 6.7 g of 2-bromoethyl ethyl ether and 6.2 g of sodium carbonate in ethanol is brought to reflux with stirring for 20 hours.
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH2:6][SiH:7]([Cl:9])[Cl:8])[Cl:5]>>[Cl:3][Si:4]1([Cl:5])[CH:2]=[CH:1][Si:7]([Cl:9])([Cl:8])[CH2:6]1
Reactant: C#C
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Product: Cl[Si]1(Cl)C=C[Si](Cl)(Cl)C1
Reaction time: 10 h
Yield: 22.4 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)methane in the presence of H2PtCl6 /PPh3. Into the same apparatus as described in Example 1 were placed 235 μl of 0.1 M H2PtCl6 /IPA, the flask was purged with dry nitrogen and the IPA removed under vacuum. Into the flask were added 10 g of bis(dichlorosilyl)methane, 235 μl of 0.1 M PPh3 /benzene solution, and 20 ml of dried benzene. Acetylene gas was blown into the flask content at a rate of 90 ml/min for 10 hours. The products were vacuum distilled at 67 Pa to yield a mixture comprising 8.35 g of 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-ene (TCD-GC area 22.4%); 1,1,3,3-tetrachloro-1,3-disilacyclopentane (TCD-GC area 27.4%), and 1,1,3,3,6,6,8,8-octachloro-1,3,6,8-tetrasilaoctane (TCD-GC area 22.9%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:22]([NH:24][O:25][CH3:26])=[O:23])=[N:5][C:6]([S:16][CH3:17])=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].I([O-])(=O)(=O)=[O:32].[Na+]>C(O)C.O>[C:1]([C:3]1[C:4]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:22]([NH:24][O:25][CH3:26])=[O:23])=[N:5][C:6]([S:16]([CH3:17])=[O:32])=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH3:10])#[N:2]
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(N(C)CC(C)(C)C)c2C#N)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CONC(=O)c1ccc(C)c(Nc2nc(S(C)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Temperature: 70 °C
Yield: 86.8 %

Procedure:
To a solution of 3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methylsulfanyl-pyrimidin-4-ylamino}-N-methoxy-4-methyl-benzamide (0.10 g) in ethanol (5 mL) was added the solution of sodium periodate (0.2 g) in water (1 mL). The resulting solution was heated to 70° C. for overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, and concentrated, and the residue was purified by silica gel column chromatography to afford the sulfoxide product (90 mg). MS (m/z): 445 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1ccc(-c2cn3ccccc3n2)c(Cl)c1
Reaction time: 14 h
Yield: 38.3 %

Procedure:
A mixture of 8.4 g (89.2 mmol) 2-aminopyridine and 20.1 g (89.9 mmol) of 2,2′,4′-trichloroacetophenone in 300 ml of ethanol was heated at reflux with stirring for 14 h. At this point, another 5.0 g (22.4 mmol) of 2,2′, 4′-trichloroacetophenone was added and the reaction mixture heated an additional 6 h. Ethyl acetate (400 ml) and excess saturated aqueous sodium bicarbonate were slowly added. After thorough mixing, the ethyl acetate layer was separated and washed with two fold excess water, saturated brine, and dried over magnesium sulfate. Evaporating the solvent in vacuo to almost dryness gave a wet solid residue to which n-butyl chloride was added. This solid was filtered and washed thoroughly with n-butyl chloride before drying. A yield of 9.0 g of the title compound was obtained (m.p. 173-175° C.) as a technical material which was not purified further but used directly in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([I:12])[CH:6]=[CH:5][C:4]=1[NH:13][C:14](=[O:26])[C@:15]([O:21][Si](C)(C)C)([CH3:20])[C:16]([F:19])([F:18])[F:17]>CO>[Cl:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([I:12])[CH:6]=[CH:5][C:4]=1[NH:13][C:14](=[O:26])[C@:15]([OH:21])([CH3:20])[C:16]([F:18])([F:19])[F:17]
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Nc1ccc(I)c([N+](=O)[O-])c1Cl)C(F)(F)F
Agent: Cl
Solvent: CO
Product: C[C@@](O)(C(=O)Nc1ccc(I)c([N+](=O)[O-])c1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
2M Hydrochloric acid (2.5 ml) was added to a solution of (R)-N-(2-chloro-3-nitro-4-iodophenyl)-2-trimethylsilyloxy-2-methyl-3,3,3-trifluoropropanamide (Method 69) (1150 mg) in MeOH (25 ml) and the reaction mixture was stirred for 4 hours at ambient temperature. The volatile material was removed by evaporation and the residue was partitioned between EtOAc (150 ml) and water (75 ml). The organic phase was separated, washed with brine (75 ml) and dried. The volatile material was removed by evaporation to give the title compound (943 mg). NMR: 1.58 (s, 3H), 7.70 (d, 1H), 8.00 (d, 1H); m/z 437.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(CN)O.O>COCC(O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: O
Solvent: COCC(C)O
Solvent: NCCO
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 108 °C
Yield: 91.9 %

Procedure:
Thebaine (500.0 g containing 24.4 wt % water, 378.0 g dry basis, 1.21 mol, 1.0 equiv) is placed in a mixture of 1-methoxy-2-propanol (1304.2 g) and ethanolamine (130.6 g, 2.13 mol, 1.76 equiv) and is heated to 108±2° C. to give almost a complete solution. In another vessel, p-toluenesulfonylhydrazide (PTSH) (480.0 g, 2.57 mol, 2.12 equiv) is dissolved in a mixture of ethanolamine (960.1 g, 15.72 mol, 13.0 equiv) and 1-methoxy-2-propanol (80.1 g) and held at 20-25° C. The PTSH solution is then added slowly to the thebaine mixture at such a rate that the batch temperature remains in the range 108±2° C. and the gas evolution vents safely. After the complete addition, the reaction mixture is allowed to agitate at 108±2° C. and is monitored for reaction completion 0.3 area % thebaine remaining) by in-process HPLC analysis. On completion, the batch is cooled to 15±5° C. Water (1200 g) is then charged to the batch while maintaining the batch temperature at ≦30° C. The resulting slurry is stirred and further cooled to 5±3° C. and held for a minimum of 0.5 to 1 hours. The product is collected by filtration, washed with water (2400 g) and then dried at 55±5° C. to a constant weight to give 8,14-dihydrothebaine (yield, 348.4 g, 91.6% yield; purity, 99.2 area % by HPLC). The process described here in Example 1 is shown schematically in FIG. 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:7][N:6]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cnc(-n2cncn2)cn1

Procedure:
2,5-Dichloropyrazine (298 mg, 2.0 mmol) and 1,2,4-triazole (145 mg, 2.1 mmol) were added in DMF (10 mL), then cesium carbonate was added and the reaction was at room temperature over night. Water (20mL) was added, extracted with ethyl acetate (30 mL), second wash with brine (20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 22% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:20]3[CH:19]=[C:18]([N+:21]([O-])=O)[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1.Cl.[OH-].[K+]>C(O)C.O.[Fe].[OH-].[Fe+2].[OH-]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:24][C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[C:20]3[CH:19]=[C:18]([NH2:21])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2
Agent: [Fe+2]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2
Yield: 82.5 %

Procedure:
1.68 g (4.27 mmole) of 9,9-bis(4-pyridinylmethyl)-2-nitrofluorene was suspended in 5 ml of ethanol/water (1:1) and 1.43 g of powdered iron was added. The mixture was heated to boiling and 0.3 ml conc. hydrochloric acid was added dropwise. After completion of addition, the mixture was refluxed 2 hrs. The cooled mixture was basified with KOH, iron hydroxide filtered off and the filtrate evaporated. The residue was dissolved in ether-CH2Cl2 (3:1), washed with water, saturated sodium chloride, dried (MgSO4) and evaporated to yield 1.28 g of the title product. NMR (CDCl3, 200 MHz) δ: 3.33(s,4H), 6.53(dd,4H), 6.60(d,J=2.0 Hz,1H), 6.79(d,J=2.0 Hz,1H), 7.18(d,4H), 7.37(dd,1H), 8.11(dd,4H), m.p. (trihydrochloride) >300°. HRMS calculated for C25H21N3 : 363.1735 Found: 363.1728.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:19](=[O:20])[C:18]3[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=3)[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCN(C2CCCCC2)C1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
To 8.0 g. (0.05 mole) of 3-amino-1-cyclohexylpyrrolidine in chloroform was added with stirring 12 g. (0.052 mole) of 3,5-dinitrobenzoylchloride. After stirring one hour, the solution was extracted with dilute sodium hydroxide, dried over sodium sulfate and concentrated. The residue was recrystallized from isooctane-ethyl acetate. The product weighed 5.1 g. (29%) and melted at 159°-161° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH2:11]([S:18]C1C=CC(C#N)=CC=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH3:8])[C:11]([C:12]1[CH:13]=[CH:14][C:15]([CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:16][CH:17]=1)=[S:18]
Reactant: Cc1ccc(Br)cc1F
Reactant: N#Cc1ccc(SCc2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C(=S)c2ccc(Cc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A solution of 95 g (500 mmol) of 4-bromo-2-fluorotoluene in 200 ml of anhydrous ethyl ether is added dropwise to a suspension of 12.2 g (500 mmol) of magnesium turnings covered with anhydrous ethyl ether. When the addition has ended, the mixture is stirred for 30 minutes at room temperature and a solution of 50 g of 4-(benzylthio)benzonitrile in 200 ml of anhydrous tetrahydrofuran is then added dropwise. The ethyl ether is distilled and the mixture is refluxed for 6 hours. After cooling, the mixture is run dropwise into 600 ml of 6N hydrochloric acid solution and the resulting solution is refluxed for 6 hours. After the addition of isopropyl ether, the crystals formed are filtered off and washed with ethanol and then with ethyl ether to give 55.4 g of 3-fluoro-4-methyl-4'-benzylthiobenzophenone in the form of crystals melting at 122° C.