Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[O-2].[Ca+2]>>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:22]([CH:19]3[CH2:21][CH2:20]3)[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[NH:10][C:11]=12
Reactant: NC1CC1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Agent: [Ca+2]
Agent: [O-2]
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Reaction time: 1 h

Procedure:
The process according to claim 3, wherein 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide is heated with cyclopropylamine in the presence of 0.5 to 2 mol of calcium oxide in an inert solvent to a temperature of 130° to 150° C. over a period of 5 to 8 hours, the reaction mixture is then cooled to a temperature below 40° C. and filtered, the filter cake is washed with an inert solvent and the combined filtrates are concentrated, the residue is then diluted with an inert solvent and this solution is added to a solution or suspension of a base in an inert solvent, heated at 120° to 150° C., the reaction mixture is then kept at a temperature of 120° to 150° C. for 30 to 90 minutes, the reaction medium is then distilled off as much as possible and the residue is hydrolysed at a temperature of 20° to 90° C., the hydrolysed residue is cooled down and mixed with an inert solvent and an organic acid and the mixture is stirred at a temperature of 5° to 50° C. for 30 to 90 minutes, the product is then present as a suspension which is isolated and washed with an inert solvent, followed by water and an alcohol to give nevirapine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:27][C:28]([SH:31])([CH3:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:31][C:28]([CH3:30])([CH3:29])[CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)S
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 2-methyl-2-propanethiol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][O:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1O[C@@H]1CCCOC1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c2c1C

Procedure:
Prepared analogously to example 87.1 from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (R)-4-fluoro-2-(tetrahydro-2H-pyran-3-yloxy)aniline (Intermediate XIV).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C1N2CCN(CC2)C1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[S:27]>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][C:26](=[S:27])[N:25]([CH3:29])[CH3:24])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(=S)N(C)C)cc(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
o a solution of 5-hydroxy-isophthalic acid dimethyl ester (D42) (21 g, 100 mmol, 1 equiv) in DMF (300 ml) at room temperature was added DABCO (14.6 g, 130 mmol, 1.3 equiv) followed by dimethylthiocarbamoyl chloride (14.8 g, 120 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 16 h and at 60° C. for 2 h, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H2O and the aqueous phase re-extracted with AcOEt. The combined organic solution was washed sequentially with 5% aqueous citric acid solution, 2N aqueous NaOH solution and brine, then dried over MgSO4 and concentrated in vacuo to give 5-dimethylthiocarbamoyloxy-isophthalic acid dimethyl ester (D55) (23.5 g, 79%) as a pale yellow oil. [M+H]+=298.0, RT=3.06 min
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[C:10]([C:12]#[N:13])[C:9]([CH3:14])=[CH:8][N:7]2[CH:15]=1)([CH3:3])[CH3:2].[I:16]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[I:16][C:15]1[N:7]2[CH:8]=[C:9]([CH3:14])[C:10]([C:12]#[N:13])=[CH:11][C:6]2=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: Cc1cn2cc(C(C)C)nc2cc1C#N
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2c(I)c(C(C)C)nc2cc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.1 %

Procedure:
2-Isopropyl-6-methylimidazo[1,2-a]pyridine-7-carbonitrile (500 mg, 2.51 mmol) obtained in step 2 was dissolved in DMF (3.0 mL), and the solution was stirred at room temperature for 6 hours under light shielding after adding N-iodosuccinimide (621 mg, 2.76 mmol). A sodium carbonate aqueous solution was added to the reaction mixture. The precipitated crystals were collected by filteration, and dried under reduced pressure to give 3-iodo-2-isopropyl-6-methylimidazo[1,2-a]pyridine-7-carbonitrile (752 mg, yield 92%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]3)[C:4]=2[O:3][CH2:2]1.[F:24][C:25]1[CH:26]=[C:27]([NH:31]N)[CH:28]=[CH:29][CH:30]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]4[N:31]([C:27]5[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=5)[N:20]=[CH:19][CH:18]=4)=[N:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OCO3)ccc1=O
Product: O=c1ccn(-c2cccc3c2OCO3)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 1-Benzo[1,3]dioxol-4-yl-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-14) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=377.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:15]=[C:14]([NH2:25])[N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:15]=[C:14]([NH2:25])[N:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(F)cc2)cc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound 4-fluoro phenyl boronic acid, compound 4-chloro-6-(4-fluoro-phenyl)-pyrimidin-2-ylamine, (PPh3)4Pd and sodium carbonate in dimethylformamide was stirred for 1 hour at 25 ° C. and then for 12 hours at 80 ° C. under nitrogen atmosphere followed by purification to yield the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[CH3:15][NH:16][CH3:17].C1COCC1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:16]([CH3:17])[CH3:15])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2ccc(F)cc12
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cnc(Cl)c2ccc(N(C)C)cc12
Temperature: 100 °C
Yield: 70 %

Procedure:
To 1-chloro-6-fluoro-4-methoxyisoquinoline (200 mg, 0.945 mmol) was added dimethylamine 2 M in THF (2 ml, 4.00 mmol) and the solution was heated to 100° C. in a sealed tube for 16 h. The reaction was cooled and the volatiles were removed under vacuum. The crude residue was purified by silica gel chromatography using DCM as eluent. The product factions were collected and the solvent removed under vacuum to give 1-chloro-4-methoxy-N,N-dimethylisoquinolin-6-amine (150 mg, 70% yield). MS m/z 237.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[CH3:9])=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15].Cl>O1CCCC1.C([Li])CCC>[F:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:14]=[O:15])=[CH:3][CH:4]=1)([F:11])[CH3:9]
Reactant: CC(F)(F)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc(C=O)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 1-bromo-4-(1,1-difluoroethyl)benzene (1.00 g) in tetrahydrofuran (10.0 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 1.68 mL) was added at −80° C. and the mixture was stirred at that temperature for 5 minutes. Subsequently, N,N-dimethylformamide (0.522 mL) was added at −80° C. and after stirring the mixture at that temperature for 20 minutes, 2 mol/L hydrochloric acid (2.50 mL) was added. After bringing the reaction mixture to room temperature, two extractions were conducted with ethyl acetate and the combined organic layers were washed with water. After drying over anhydrous magnesium sulfate and the desiccant was removed by filtration; the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-90:10) to give the titled compound as a colorless oil (510 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[NH:18])[NH2:17])=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22].[OH:25][CH:26]=[C:27]([CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)[C:28](OC)=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[NH:17][CH:28]=[C:27]([CH2:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)[C:26](=[O:25])[N:18]=3)=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:21]([F:22])([F:23])[F:24]
Reactant: N=C(N)CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)C(=CO)Cc1cnc(OC)nc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 42.3 %

Procedure:
The suspension of 3-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)propanimidamide hydrochloride (5.9 g, 15.56 mmol), methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (3.49 g, 15.56 mmol) and potassium acetate (4.58 g, 46.7 mmol) in toluene (100 mL) was heated under reflux overnight. Dean-Stark apparatus was used to remove water formed in the reaction. The residue was recrystallized in ethyl acetate and washed with ether to provide the title compound (3.4 g, 42%). LCMS: rt=1.71 min, [M+H+]=517
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(Cn2ccnc2)cn1

Procedure:
Synthesized using 2-methoxyphenylboronic acid (190 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 210 mg, 0.79 mmol, 94%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.85 (s, 3H), 5.17 (s, 2H), 6.95 (brs, 1H), 7.00 (dd, J=8.5, 0.6 Hz, 1H), 7.08 (dt, J=7.6, 1.1 Hz, 1H), 7.12 (s, 1H), 7.38 (ddd, J=8.5, 7.6, 1.9 Hz, 1H), 7.44 (dd, J=8.5, 2.2 Hz, 1H), 7.60 (s, 1H), 7.77 (dd, J=7.6, 1.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 8.60 (d, J=1.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.2, 55.6, 111.4, 119.1, 121.1, 125.2, 128.3, 129.5, 130.2, 130.3, 131.1, 134.6, 137.3, 148.2, 156.4, 157.0; MS (ESI): m/z=266.28 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC.C(=O)C>>[CH3:11][NH:10][CH2:9][CH2:8][N:4]1[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]1
Reactant: CCN1CCC[C@H]1CN
Reactant: O[C@@H]1CCNC1
Agent: CC=O
Product: CNCCN1CC[C@@H](O)C1

Procedure:
By using (R)-3-hydroxypyrrolidine (2.0 g) as a starting material, the title compound (210 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.Cl.O1CCOCC1>C(Cl)Cl>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11]
Reactant: CC(C)COC(C)ONC(=O)c1cnc(N2CC3C(C2)C3N2CCOCC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NO)c1cnc(N2CC3C(C2)C3N2CCOCC2)nc1
Yield: 37.7 %

Procedure:
N-(1-Isobutoxyethoxy) 2-(6-morpholin-4-yl-3-aza-bicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide (10 mg, 0.02 mmol) was dissolved in DCM (2 ml) and treated with 4M HCl in dioxane (0.4 ml, 0.1 mmol). The resultant mixture was stirred at r.t. for 30 min, then evaporated under reduced pressure and azeotroped with MeOH (3×5 ml) to give the title compound as a white solid (2.3 mg, 40%). LCMS purity 90%, m/z 306 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 2.49 (2H, br s), 2.85 (1H, br s), 3.55-3.87 (8H, m), 4.10 (4H, m), 8.72 (2H, s).
Reaction SMILES: C1(C([O:14][C:15](=[O:53])[C@H:16]2[CH2:20][C@@H:19]([N:21]3[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[N:24]([C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:22]3=[O:23])[CH2:18][N:17]2CCNS(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)C2C=CC=CC=2)C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:30]([N:24]1[C:25](=[O:26])[C:27]([CH3:28])=[CH:29][N:21]([C@H:19]2[CH2:18][NH:17][C@@H:16]([C:15]([OH:53])=[O:14])[CH2:20]2)[C:22]1=[O:23])(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1cn([C@@H]2C[C@H](C(=O)OC(c3ccccc3)c3ccccc3)N(CCNS(=O)(=O)c3ccccc3[N+](=O)[O-])C2)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cn([C@H]2CN[C@@H](C(=O)O)C2)c(=O)n(C(=O)c2ccccc2)c1=O

Procedure:
A solution of N-(2-Nitrobenzenesulfonamidoethyl)-cis-4-(benzoylthymin-1-yl)-D-proline diphenylmethyl ester (5) (1.20 g, 0.46 mmol) was dissolved in dichloromethane (5 mL). Boc2O (110 mg, 0.50 mmol) and triethylamine (5 mL) was added with stirring followed by 4-dimethylaminopyridine (10 mg, cat.). The yellow solution was stirred at room temperature for 6.5 h then evaporated to dryness to give N-2-(N′-4-Nitrobenzenesulfonyl-N′-tert-butoxycarbonyl)aminoethyl)-cis-4-(benzoylthymin-1-yl)-D-proline as yellow foam. Treatment of this material (max 0.46 mmol) with anhydrous K2CO3 (85 mg, 0.60 mmol) and thiophenol (66 mg, 0.60 mmol) in DMF (2 mL) at room temperature afforded an orange-yellow solution. The reaction mixture was then diluted with dichloromethane, washed with water and evaporated to dryness. The resulting yellow oil was purified by column chromatography (SiO2; EtOAc:Light Petroleum 1:1→2:1) to give the product as white foam 186.3 mg (62%, 2 steps); δH (200 MHz; CDCl3) 1.46 [9H, s, tBu CH3], 1.90 [3H, s, thymine CH3], 1.95 and 2.60 [2H, 2×m, CH2(3′)], 2.70-3.30 [6H, m, CH2(5′) and 2×aminoethyl CH2], 3.42 [1H, dd, CH(2′)], 5.12 [1H, m, CH(4′)], 5.28 [1H, br m, NH], 6.98 [1H, s, CHPh2], 7.36 [10H, m, Dpm aromatic CH], 7.50 [2H, t, Bz m-CH], 7.63 [1H, t, Bz p-CH], 7.90 [2H, d, Bz o-CH] and 7.98 [1H, s, thymine C(6)H]; m/z (APCI+) 676 (M+Na+, 18.5%), 653 (M+H+, 59), 597 (M−C4H8+, 25), 554 (M−Boc+, 9), 475 (26.5), 167 (Ph2CH+, 100); [α]D22+6.5 (c=1.06, CHCl3)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH2:12].O.O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:12]
Reactant: Nc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc(Br)c1N
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of 109a (5.0 g, 20 mmol) in ethyl acetate (100 mL) was added SnCl2.2H2O (22.6 g, 100 mmol). The reaction was heated at reflux for 2 h. After cooled to room temperature, the reaction mixture was poured into aqueous Na2CO3 (200 mL) and the mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 109b as a dark red liquid (4.3 g, 97%). LCMS: [M+H]+ 223. 1H NMR (500 MHz, CDCl3) δ 6.97 (d, J=2.5 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 3.67 (bs, 4H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:8]([F:24])([F:23])[C:9]([F:22])([F:21])[O:10][C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[S:13]([F:16])(=[O:15])=[O:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(O)(=O)C>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]1([C:8]([C:9]([O:10][C:11]([C:12]([S:13]([F:16])(=[O:14])=[O:15])([F:17])[F:18])([F:19])[F:20])([F:22])[F:21])([F:24])[F:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)I
Reactant: c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
7.82 g (100 mmol) of benzene, 8.52 g (20 mmol) of 5-iodooctafluoro-3-oxapentanesulfonyl fluoride, 4.84 g (20 mmol) of benzoyl peroxide, 0.36 g (2 mmol) of copper (II) acetate, and 100 mL of acetic acid were refluxed for 4 hrs at 115° C. Then the mixture was stirred at room temperature overnight. The mixture was diluted with water (˜100 mL), and the product was extracted with hexane and washed with water until neutral pH was obtained. The solvent was removed to yield dark yellow oil. The product was purified by distillation under reduced pressure (˜27 inch Hg). The first faction was composed of a mixture of the product plus iodobenzene (2.8 g, approximately 1:1 ratio). The second fraction consisted of 2.1 g of pure product (colorless oil) (28% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C:15]4=[CH:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH:5]=1)=[O:3].[Br:24]C1(Br)C(=O)NC(=O)NC1=O.Br>O1CCCC1.C(Cl)Cl>[Br:24][CH2:1][C:2](=[O:3])[C:4]1[C@:8]2([CH3:23])[C@H:7]([C@H:12]3[C@H:11]([CH2:10][CH2:9]2)[C@:16]2([CH3:22])[C:15]([CH2:20][C@@H:19]([OH:21])[CH2:18][CH2:17]2)=[CH:14][CH2:13]3)[CH2:6][CH:5]=1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Agent: Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)CBr)=CC[C@@H]12
Yield: 104.4 %

Procedure:
Dissolve 16-dehydropregnenolone (5.00 g, 15.90 mmol) and 5,5-dibromobarbituric acid (4.55 g, 15.90 mmol) in tetrahydrofuran (60 mL). Add concentrated aqueous hydrogen bromide (100 μL of a 48% solution) to the stirring solution and heat the reaction at reflux for 1 hour. Cool slightly and then concentrate under vacuum to produce a brown oily foam. Dissolve the residue in methylene chloride (350 mL), rinse with 50% saturated sodium bicarbonate (2×200 mL, brine (125 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide 21-bromo-3β-hydroxypregna-5,16-dien-20-one (6.53 g) as an orange-brown solid, slightly contaminated with starting material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][N:20]2[C:25]=1[C:24](=[O:26])[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]([CH:34](OS(C)(=O)=O)[CH2:35][CH3:36])=[N:21]2)=[O:16].C(N(CC)CC)C>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][N:20]2[C:25]=1[C:24](=[O:26])[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]([CH:34]([NH:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH2:35][CH3:36])=[N:21]2)=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCC(OS(C)(=O)=O)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Temperature: 75 °C
Yield: 12.4 %

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (Fluka, 0.054 ml, 0.31 mmol) was added to a solution of 3-benzyl-2-(1-methanesulfonyloxy-propyl)-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxyic acid methyl ester (0.086 g, 0.21 mmol) and triethylamine (0.086 mL, 0.616 mmol) in DMF (1.0 mL) and the reaction mixture was heated to 75° C. for 4 h. The reaction mixture was quenched with saturated NaHCO3 (2 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with 10% LiCl (4×10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 8/1 to 1/1 hexane/EtOAc to afford the title compound (0.013 g, 14%) as a solid: 1H NMR (CDCl3) δ 6.98–7.26 (m, 8H), 5.75 (m, 1H), 4.95 (m, 2H), 3.86 (s, 3H), 3.65 (m, 1H), 3.00 (m, 2H), 2.45 (m, 1H), 2.00 (m, 1H), 1.50–1.75 (m, 4H) 1.36 (s, 9H), 0.88 (m, 3H); MS (ESI+) 498 (M++H); HRMS (ESI+) calculated: 498.2716 (M++H), found: 498.2720 (M++H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:21]([O-])=O)=[C:11]([CH:13]=[C:14]2[NH:18][C:17](=[O:19])[NH:16][C:15]2=O)[CH:12]=1)[CH3:2].CO.II>CN(C)C=O.[Pd]>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:21]=[C:15]3[NH:16][C:17](=[O:19])[NH:18][C:14]3=[CH:13][C:11]=2[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Agent: [Pd]
Agent: II
Solvent: CN(C)C=O
Solvent: CO
Product: CCOCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reaction time: 23 h

Procedure:
A solution of 5-[[5-(2-ethoxyethoxy)-2-nitrophenyl]methylene]-2,4-imidazolidinedione (10.60 g, 33 mmol) in dimethylformamide (120 mL) was hydrogenated over 10% palladium on charcoal (1 g) at 50 p.s.i. in a low pressure hydrogenation apparatus. After 23 hours, the mixture was filtered through kieselguhr and the solvent evaporated to leave a solid which was suspended in refluxing methanol (200 mL) and treated with iodine (8.38 g, 33 mmol) added portionwise. After 15 minutes the mixture was concentrated to about 50 mL and diluted with 10% sodium thiosulfate solution and 10% sodium carbonate solution. The mixture was stirred for 15 minutes and the solid filtered off, washed with water and dried in air before being dissolved in a solution of 10% hydrogen chloride in methanol. Addition of diethyl ether precipitated 7-(2-ethoxyethoxy)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one hydrochloride (4.52 g, 56%), m.p. 290°-293° C. (dec.).