Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH2:17]Cl)[C:6]=1[CH2:19]Cl)(C)(C)C.[C:21]([O:26]C)(=O)[CH:22]([CH3:24])[CH3:23].O>BrCCBr.C1COCC1>[C:6]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][CH:5]=[C:6]3[C:7]=2[CH2:17][C:21]([CH:22]([CH3:24])[CH3:23])([OH:26])[CH2:19]3)=[CH:12][CH:13]=1)([CH3:19])([CH3:7])[CH3:5]
Reactant: CC(C)(C)c1ccc(-c2ccccc2)c(CCl)c1CCl
Reactant: COC(=O)C(C)C
Solvent: O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)C1(O)Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
633 mg (26 mmol, 4 eq.) of Mg powder (50 mesh/Aldrich) were dried under reduced pressure with the aid of a hair dryer. 10 ml of THF and 10 drops of 1,2-dibromoethane were added. The mixture was heated to reflux until gas evolution took place and the activation was complete. The solvent was removed under reduced pressure and 10 ml of fresh THF were added. A solution of 2.0 g (6.5 mmol) of tert-butyl-2,3-bis(chloromethyl)biphenyl in 120 ml of THF was added and the suspension was stirred vigorously at room temperature for 3 hours. Stirring was continued overnight and the slightly greenish turbid solution obtained was filtered to remove excess magnesium. The filtrate was cooled to −78° C. and a solution of 665 mg (6.51 mol) of methyl isobutyrate in 60 ml of THF was added dropwise over a period of 1 hour. The reaction solution was warmed to 0° C. over a period of 2 hours. 80 ml of water were subsequently added and the solution was concentrated under reduced pressure. To dissolve the magnesium salts, 3 ml of concentrated hydrochloric acid were added and the aqueous phase was extracted with methylene chloride (3×50 ml). The combined organic phases were dried over magnesium sulfate, and the solvent was subsequently removed under reduced pressure. The product was purified by column chromatography, with the nonpolar by-products being separated off using a heptane/dichloromethane mixture and the product being eluted with pure dichloromethane, giving a yellow product. Yield: 0.66 g (2.14 mmol/33% 96% by GC). 1H NMR (400 MHz, CDCl3): δ=7.41–7.21 (m, 7H, aromat.), 3.18–2.91 (m, 4H, CH2), 1.92 (m, 1H, CH), 1.36 (s, 9H, tert-butyl), 1.02 (t, 6H, CH3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[C:5]([O:16][CH3:17])=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[N:8]=[C:7]2OC.[NH2:20][NH2:21]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[C:5]([O:16][CH3:17])=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[N:8]=[C:7]2[NH:20][NH2:21]
Reactant: NN
Reactant: COc1nc(OC)c2c(OC)c(OC)cc(Cl)c2n1
Solvent: CO
Product: COc1nc(NN)c2c(OC)c(OC)cc(Cl)c2n1
Yield: 66.7 %

Procedure:
A mixture of 8-chloro-2,4,5,6-tetramethoxyquinazoline (1.0 g, 0.0035 moles), anhydrous hydrazine (5 ml, 0.16 moles) and methanol (50 ml) was stirred at reflux for 0.5 hours. The solvent was removed in vacuo and the residue was recrystallized from methanol. The resulting crystals were washed with methanol (20 ml) and dried under vacuum at 50° C. to afford the product (0.665 g), mp 166°-168° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>O1CCCC1>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
Cyclohexylamine (9.111 g) was dissolved in tetrahydrofuran (100 ml), followed by the addition of 4-bromobenzoyl chloride (5.04 g)/tetrahydrofuran solution (30 ml) under ice-cooling, and the mixture was stirred for 20 min. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was recrystallized from ethyl acetate/hexane, to give the title compound as a pale pink solid (5.236 g, yield; 83%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:45])[CH2:14][CH2:15][CH:16]1[CH2:23][N:22]2[C:24]3[CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=[CH:28][C:29]=3[C:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:21]2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17]1)(C)(C)C>O.C(Cl)Cl>[CH:31]1([C:30]2[C:29]3[CH:28]=[CH:27][C:26]([C:37]([O:39][CH3:40])=[O:38])=[CH:25][C:24]=3[N:22]3[C:21]=2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17][CH:16]([CH2:15][CH2:14][C:13]([OH:45])=[O:12])[CH2:23]3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)O)COc1ccccc1-3
Temperature: 60 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
TFA (>150 eq) and a few drops of water were added to a stirred solution of methyl 7-(3-tert-butoxy-3-oxopropyl)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.03 M) in DCM at RT. The reaction was heated at 60° C. (oil bath temp) for 1 h. Further TFA was introduced (circa 60 eq) and heating continued for 2 h. Volatiles were removed in vacuo. The residue was taken up in EtOAc and washed with 1N HCl (aq), brine before being dried (Na2SO4) filtered and concentrated in vacuo. Residual tert-BuOH was removed by sonication in Et2O/PE to afford the product (45%). (ES+) m/z 462 (M+H)+; 484 (M+Na)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17](=O)[CH2:18][CH2:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)CO.CCOC(C)=O>[CH2:1]([N:8]1[C:9](=[O:10])[C:11]2[S:12][CH:13]=[CH:14][C:15]=2[N:16]=[C:17]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1ccsc1C(=O)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCCc1nc2ccsc2c(=O)n1Cc1ccccc1
Temperature: 135 °C

Procedure:
N-Benzyl-3-(butyrylamino)thiophene-2-carboxamide (1-4, 2.00 g, 6.60 mmol) was dissolved in ethylene glycol (15.0 mL) and treated with NaOH pellets (26 mg, 0.66 mmol). The reaction was heated to 135° C. for 3 h and allowed to cool. The reaction was diluted with EtOAc (100 mL) and washed with NH4Cl, H2O (2×20 mL), NaCl (30 mL) and dried with MgSO4. Organics were concentrated to provide 3-benzyl-2-propylthieno[3,2-d]pyrimidin-4(3H)-one (1-5). 1H NMR (300 MHz, CDCl3) δ7.77 (d, J=5.2 Hz, 1H), 7.30 (m, 4H), 7.17 (d, J=6.4 Hz, 2H), 5.43 (s, 2H), 2.73 (m, 2H), 1.85 (m, 2H), 0.98 (t, J=7.3 Hz, 3H); MS 285.0 found 284.3 required.
Reaction SMILES: BrC(Br)C.C[Si](Cl)(C)C.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([N:47]2[C:51]([CH3:52])=[CH:50][CH:49]=[C:48]2[CH3:53])[N:42]=1>O1CCCC1.[Zn].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N:47]3[C:51]([CH3:52])=[CH:50][CH:49]=[C:48]3[CH3:53])[N:42]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(C)n1-c1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: [Pd]
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 60 °C
Reaction time: 0.05 h
Yield: 30.8 %

Procedure:
284 mg (4.34 mmol) of electrolytic zinc is put into suspension under an argon atmosphere, to which 0.033 ml of 1-2 dibromoethane and 1 ml of tetrahydrofuran are added. After stirring for 3 minutes at 60° C. the reaction medium is left to return to ambient temperature. 0.047 ml of trimethylsilyl chloride is added and stirring is carried out for 30 minutes at ambient temperature. 1 g (3.2 mmol) of 2 solubilized beforehand in 2 ml of tetrahydrofuran is added. This reaction mixture is stirred for 45 minutes at ambient temperature and it is added to a solution containing 30 mg (0.032 mmol) of tris(dibenzylideneacetone) dipalladium marketed by Aldrich and 30 mg (0.13 mmol) of tris(2-furyl)phosphine marketed by LANCASTER. Then 1 g (4 mmol) of 3 solubilized beforehand in 10 ml of tetrahydrofuran is added. The reaction mixture is left under magnetic stirring at 60° C. for 2 hours, then left to return to ambient temperature, filtered on clarcel and extracted between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. After extracting the aqueous phase twice with ethyl acetate, the organic phases are combined and dried over magnesium sulphate. The ethyl acetate is evaporated off under reduced pressure (2 kPa) and the crude residue is purified by chromatography on silicagel eluting with a heptane/ethyl acetate mixture 4:1. 350 mg (yield=30%) of expected product is recovered in the form of a yellow oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([C:17]#[C:18][C:19]#[C:20][C:21]#[C:22][C@@H:23]2[O:25][C@H:24]2[CH:26]=[CH:27][CH:28]=[O:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.O1CCCC1>[C:11]1([C:17]#[C:18][C:19]#[C:20][C:21]#[C:22][C@@H:23]2[O:25][C@H:24]2[CH:26]=[CH:27][CH2:28][OH:29])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Diisobutylaluminum hydride (0.35 ml of a 1.76M solution in toluene, 0.61 mmole) was added dropwise to a stirred -78° C. solution of (trans)-3-[3-(6-phenyl-1,3,5-hexatriynyl)oxiranyl]-2-propenal (50 mg, 0.20 mmole; see example 5) in 6 ml of dry tetrahydrofuran. The mixture was stirred for 2 hours at -78° C. and was then quenched at that temperature by the dropwise addition of ca. 0.5 ml of a solution of methanol-acetic acid 4:1. The mixture was warmed to room temperature, water was added and the mixture was extracted with ether. The combined ether extracts were washed with water and saturated aqueous sodium chloride and were dried over anhydrous magnesium sulfate. Removal of solvent gave an oil which was purified by preparative thin layer chromatography (ethyl acetate-hexane 1:1) to afford 34 mg pure title compound, melting point 65°-66° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].C([O-])([O-])=O.[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1.O.CCOC(C)=O>[CH2:26]([O:25][C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[F:15])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the product from Step D (10 g, 45.8 mmol) in THF (90 mL) and water (20 mL) was added K2CO3 (8.23 g, 59.6 mmol). Once the solid was dissolved benzyl chloroformate (7.19 mL, 50.4 mmol) was added. The reaction was stirred vigorously at ambient temperature for 5.0 hours. Once the reaction was complete by TLC the reaction was diluted with EtOAc (100 mL) and water (20 mL). The layers were separated and the organic layer was washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by column chromatography (EtOAc/hexane) to afford 12.9 g (80%) of a sticky, white foam.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([OH:10])[N:4]=1
Reactant: O=[N+]([O-])O
Reactant: CSc1nc(O)cc(O)n1
Solvent: CC(=O)O
Product: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 3 h
Yield: 49 %

Procedure:
2-Methylsulfanyl-pyrimidine-4,6-diol (10 g, 63 mmol) was added portion wise to a stirring solution of glacial acetic acid (25 mL) and concentrated nitric acid (10 mL) at 50° C. After 3 h, the reaction mixture was poured onto crushed ice and the product was isolated by filtration as a yellow solid (6 g, 49%). MS (ESI, negative mode): mass calcd. for C5H5N3O4S, 203.0; m/z found, 202.4 [M−H].
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]([CH3:29])[CH3:28])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)C>ClCCl>[CH:27]([O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])([CH3:29])[CH3:28]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC(C)C)c1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC(C)C)c1

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g), morpholine (2.76 g) and ethanol (50 ml)--dichloromethane (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and dichloromethane (50 ml) was added to the residue. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1:1, v/v) gave ethyl 4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate as an oil. This oil was dissolved in ethanol (20 ml), and a solution of hydrogen chloride in ethanol (23%, 1.05 g) was added. The mixture was stirred at room temperature for 10 minutes, and the solvent was evaporated under reduced pressure. The crystals were separated by filtration and recrystallized from ethanol-ether to give ethyl 4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate hydrochloride (1.62 g, 45%). Colorless crystals, mp. 185°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[N+:10]([C:13]1[CH:14]=[CH:15][C:16](O)=[N:17][CH:18]=1)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)nc1
Temperature: 120 °C
Yield: 48 %

Procedure:
A mixture of 3-flouro-benzyl alcohol (1.07 g, 8.48 mmol), 5-nitro-pyridin-2-ol (1.34 g, 8.48 mmol) and K2CO3 (1.41 g, 10.2 mmol) in DMA (10 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with MeOH(10 ml), filtered and purified by preparative HPLC to give 13A (1.01 g, 48%).
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=[CH2:2])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C=O)ccc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 130.5 %

Procedure:
T a suspension of methyltriphenylphosphonium bromide (8.1 g, 22.7 mmol) in THF (140 mL) at 0° C. was added nBuLi (1.6 M in hexanes, 14.2 mL, 22.7 mmol) dropwise over 10 min. After 20 min of stirring, a solution of the 5-formyl-indole-1-carboxylic acid tert-butyl ester (4.63 g, 14.8 mmol) in THF (20 mL) was introduced slowly over 20 min. The reaction was warmed slowly to room temperature, stirred 30 min. The reaction mixture was poured into saturated ammonium chloride and the separated aqueous phase was extracted with ethylacetate (3×100 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (methylene chloride to 1% acetone-methylene chloride) to give 5-vinyl-indole-1-carboxylic acid tert-butyl ester (4.7 g, 100%) or similarly 6-vinyl-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[Li]C(CC)C.Br[C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43].[NH4+].[OH-]>CC(OC)(C)C.[Cl-].[Cl-].[Zn+2].CC([O-])=O.CC([O-])=O.[Pd+2].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F>[F:42][C:40]1[CH:41]=[CH:36][C:37]([F:43])=[CH:38][C:39]=1[C@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: Fc1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: CC(=O)[O-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
A solution of tert-butyl pyrrolidine-1-carboxylate (20 g, 116.8 mmol) and (−)-sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to −78° C. and sec-BuLi (100 mL, 140 mmol, 1.4 M in cyclohexane) was introduced drop-wise via cannula, keeping the internal temperature under −70° C. The resulting solution was stirred for 3 hours at −78° C., followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, 1M in Et2O) drop-wise with rapid stirring, keeping the internal temperature below −65° C. The resulting light suspension was stirred at −78° C. for 30 minutes and then warmed to ambient temperature. The resulting mixture was sequentially charged with 2-bromo-1,4-difluorobenzene (14.5 mL, 128 mmol), Pd(OAc)2 (1.31 g, 5.8 mmol) and t-Bu3P—HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, concentrated NH4OH (10.5 mL) was added and the reaction was stirred for 1 hour. The resulting slurry was filtered through Celite and the filter cake washed with Et2O (1 L). The filtrate was washed with a 1M aqueous HCl solution (0.5 L) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtOAc/hexanes to give product (R)-tert-butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate as yellow oil (23.9 g, 72% yield).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:2][NH2:3])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCl)c1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(CNN)c1
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
While a solution of hydrazine monohydrate (1.32 g, 26.4 m mol) in ethanol (20 ml) was heated under reflux, a solution of 3-tert-butoxycarbonylaminobenzyl chloride (1.06 g, 4.4 m mol) in ethanol (10 ml) was added dropwise thereto over a period of 5 minutes. After this mixture was further refluxed for 0.5 hour, the solvent was distilled off under reduced pressure. The resulting oily residue was extracted with ether (2×20 ml). After the extract was concentrated under reduced pressure, the resulting residue was subjected to chromatography on silica gel (50 g) using chloroform-methanol (10:1), so that the desired compound (0.91 g, 87%) was obtained as an oily material.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]3=[N:22][CH:23]=[C:24]([CH3:25])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[Cl-:30].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.Cl.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]3=[N:22][CH:23]=[C:24]([CH3:25])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: Cc1cnc2n1N=C(c1ccc(N)cc1)c1cc3c(cc1C2)OCO3
Agent: [Cu+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: Cc1cnc2n1N=C(c1ccc(Cl)cc1)c1cc3c(cc1C2)OCO3
Reaction time: 0.75 h
Yield: 51.4 %

Procedure:
160 mg of 5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is dissolved in 2 ml of water and 2 ml of concentrated hydrochloric acid, and it is diazotized at 0° C. with a solution of 36 mg of sodium nitrite in 0.5 ml of water. Stirring is continued for 45 minutes at 0° C. To this solution at room temperature is added in drops a solution which is prepared as follows: 256 mg of copper sulfate pentahydrate is mixed in 1 ml of water with 87 mg of sodium chloride and mixed drop by drop with a solution of 68 mg of sodium sulfite in 0.6 ml of water. The white precipitate is separated from the supernatant by decanting, washed twice with water and dissolved in concentrated hydrochloric acid. After this solution is added, it is heated for 10 minutes in a steam bath and stirred for 1 more hour at room temperature. It is diluted with water, made alkaline with ammonia solution and extracted with ethyl acetate. The ethyl acetate phase is washed with saturated sodium chloride solution, dried, filtered and concentrated by evaporation. After chromatography on silica gel with methylene chloride:ethanol=10:1, 87 mg of 5-(4-chlorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH+:9]([O-])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:3][CH:2]=1.C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:22]([C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][N:1]=1)#[N:23]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)[NH+]([O-])CCc1ccncc1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCCc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.1 %

Procedure:
tert-Butyl 2-(4-pyridyl)ethylcarbamate N-oxide (7.4 g, 31 mmol) was dissolved in nitroethane (100 ml), and trimethylsilyl cyanide (9.2 g, 92 mmol) and N,N-dimethylcarbamoyl chloride (6.7 g, 62 mmol) were added thereto. The mixture was stirred at room temperature for 10 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (6.6 g, 86%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:20][C@@H:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:32]([O:34][CH3:35])=[O:33])[C@@H:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@@H](C)Cc2ccccc2)c1
Reactant: COC(=O)Cl
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 4, using the following starting materials: (3-{4-bromo-2-[((S)-1-methyl-2-phenyl-ethylamino)-methyl]-phenoxy}-phenyl)-acetic acid methyl ester and methyl chloroformate.