Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)#[N:16].[H-].[Na+].C(O)(=O)C>CN(C=O)C>[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C:10]1=[O:14])#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a stirred solution of 4-Boc-2-piperazinone (2.0 g, 10 mmol), 3-cyanobenzyl bromide (1.8 g, 10 mmol) in DMF (35 mL) at 0° C. was added sodium hydride (480 mg of a 60% suspension in mineral oil, 12 mmol) in several portions over a period of 15 min. The mixture was stirred a 0° C. for 1 h and then at ambient temperature for 1 h. Acetic acid (1 mL) was added and the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The EtOAc layer was separated, dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was triturated in ether and the white solid was collected by filtration to give 1-(3-cyanobenzyl)4-Boc-2-piperazinone (2.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:11]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18][CH:12]3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1.[C:30]1([O:36][CH2:37][CH2:38]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:11]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18][CH:12]3[N:13]([CH2:38][CH2:37][O:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Nc3cccc(-c4ccc(Cl)cc4Cl)c3C2CC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2c3c(-c4ccc(Cl)cc4Cl)cccc3N(CCOc3ccccc3)C2CC1
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 10-(2,4-dichlorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate (54 mg) in DMF (1.2 ml) was added KH (10 mg) and 2-bromoethyl phenyl ether (30 mg). The reaction mixture was stirred 24 h, poured into satd NaHCO3, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. Purification via flash chromatography provided the title compound: 1H NMR (CDCl3) δ 1.63, 2.30-2.50, 2.92, 3.14, 3.42, 3.75, 4.26, 4.53, 6.84, 6.96, 7.20-7.51.
Reaction SMILES: [CH:1]1([B:6]([O:11][CH:12]([CH3:14])[CH3:13])OC(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([Li])#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl.[B].C=C(C)C>C(OCC)C>[CH:1]1([B:6]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[O:11][CH:12]([CH3:13])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)OB(OC(C)C)C1CCCC1
Reactant: [Li]C#CCCCCCC
Agent: C=C(C)C
Agent: Cl
Agent: [B]
Solvent: CCOCC
Product: CCCCCCC#CB(OC(C)C)C1CCCC1

Procedure:
Cyclopentyldiisopropoxyborane (2.33 g, 37 mmol) in ethyl ether (37 mL) was added to an ethereal solution of 1octynyllithium (41 mmoL in 41 mL ethyl ether), then quenched with HCl in ethyl ether (12.0 mL, 41 mmol). Workup as described in Example 14 yielded 6.95 g (76%), bp 100°-102° C. (0.1 mm Hg); n20D 1.4557; proton NMR (CDCl3) δ4.63 (septet, J=18 Hz, 1H), 2.23 (triplet, 1H), 1.17 (d, J=18 HZ, 6H), 0.83 (triplet, 3H); boron NMR (EE) δ+41.2 ppm(s); mass spectrum (chemical ionization, isobutene) m/e 249 (M+H), 40%); IR (thin film) 2186, 1344 cm-1. Calcd. for C16H29BO: C, 77.42; H, 11.78. Found: C, 77.02; H, 11.92.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:12][OH:13])[C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:3]1.[Si:14](OS(C(F)(F)F)(=O)=O)([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16].N1C(C)=CC(C)=CC=1C.[Si](O[C@H](CCC)[C@@H](C)C=O)(C(C)(C)C)(C)C>>[CH2:15]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[O:3][C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:2]([CH3:1])[CH:12]=[O:13])[CH3:16]
Reactant: C[C@]1(CO)O[C@@H]1Cc1ccccc1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC[Si](CC)(CC)O[C@H](Cc1ccccc1)[C@H](C)C=O
Yield: 80 %

Procedure:
Epoxy alcohol 10, 1.2 eq of TESOTf, and 1.5 eq of collidine were reacted as in the preparation of 16 give 80% of aldehyde 11. 1H NMR (CDCl3, 500.35 MHz) δ:9.64 (1H, d J=0.77 Hz), 7.30-7.05 (5H,m) 4.37 (1H, J=3.06, 10.40 Hz), 2.76 (1H, d J=6.64 Hz), 2.75 (2H, d J=7.42 Hz), 2.27 (1H, qdd, J=7.00, 3.38, 0.77 Hz), 1.10 (3H, d, J=7.04 Hz), 0.95-0.75 (6H, m), 0.6-0.4 (9H, m). 1H NMR integration of δ 9.64 to the contaminant δ 9.71 indicated a 93.6:6.4 ratio.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.Cl.[CH3:14][NH:15][O:16][CH3:17].CC1C=CC=C(C)N=1>ClCCl>[CH3:14][N:15]([O:16][CH3:17])[C:3](=[O:4])[CH:2]([F:6])[F:1]
Reactant: CNOC
Reactant: O=C(O)C(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CON(C)C(=O)C(F)F
Temperature: 35 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of difluoroacetic acid (4.1 g, 42.7 mmol) in dry dichloromethane (80 ml), under N2, was treated with oxalyl chloride (5.69 g, 44.8 mmol). After stirring at 35° C. for 3 h, the reaction was cooled to 0° C. and treated with N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.2 mmol), then cooled to -20° C., and treated dropwise with 2,6-dimethylpyridine (19.86 ml, 171 mmol). The reaction was allowed to warm up to room temperature over 2 h then quenched by the addition of ice and water. Orthophosphoric acid (2M) was added until the aqueous layer reached pH4. The aqueous and organic phases were separated and the organic layer was washed with 2M orthophosphoric acid (2×50 ml). The organic layer was dried (Na2SO4) then concentrated in vacuo and the residue was distilled to afford the title compound (D5) as a clear oil (3.72 g, 63%) b.p. 60° C. at 1.5 mm Hg (Kugelrohr).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=O.Cl.[CH2:19]([O:23][NH2:24])[CH:20]([CH3:22])[CH3:21]>CO>[CH3:1][O:2][C:3](=[O:17])/[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=[N:24]/[O:23][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: CC(C)CON
Agent: Cl
Solvent: CO
Product: COC(=O)/C(=N/OCC(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
(3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 90 mg, 3.26 mmol) was stirred in methanol (7 mL) and warmed in a 70° C. oil bath. O-Isobutylhydroxylamine hydrochloride (511 mg, 4.07 mmol) was added. After 3 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid methyl ester as a white solid (395 mg, 35%): H1-NMR (400 MHz, CDCl3) δ=0.91 (6H, d, J=6.8 Hz), 2.04 (1H, m), 3.30 (3H, s), 3.91 (3H, s), 4.10 (2H, d, J=6.8 Hz), 7.50 (1H, dd, J=8.2 Hz, J=1.6 Hz), 7.61 (1H, d, J=1.6 Hz), 8.18 (1H, d, J=8.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([CH3:20])([CH3:19])[NH:14][Si](C)(C)C>>[CH3:12][Si:13]([CH3:20])([CH3:19])[NH:14][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)NS(=O)(=O)c1ccc(F)cc1
Temperature: 115 °C

Procedure:
A glass reactor equipped with a stirrer, reflux condenser and gas inlet was charged with solid 4-fluorobenzenesulfonyl chloride 0.250 mol, 49.65 g). Hexamethyldisilazane (0.263 mol, 56.6 ml) was added to the reactor and the mixture was gradually heated with stirring to a temperature of 115° C., at which time it became clear. The mixture was then heated at the boiling point for 21 hours. Analysis of the mixture by 1H NMR indicated that the reaction was about 50% complete. Volatile materials were then removed by heating at a temperature of 65° C. under reduced pressure to yield a brown liquid which was distilled to remove unreacted sulfonyl chloride. The residue was redistilled under a pressure of 0.03 mm. Hg. The fraction collected from 40° to 97° C. was analyzed by 1H NMR and was found to contain the N-mono- and N,N-bis(trimethylsilyl)sulfonamides in a 1:1 molar ratio. Using the same analytical technique a second fraction collected within the range from 97° and 122° C. was found to contain the N-mono- and N,N-bis(trimethylsilyl)sulfonamides in a 8.5:1 molar ratio. The second fraction was used as the starting material (3c) for the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:2]([NH:1][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=2)=[C:3]([CH:21]=1)[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccc(C(F)(F)F)cc2)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
In methanol (20 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) obtained in Example 1 (2) and 4-trifluoromethylbenzaldehyde (0.28 g). To the solution were added acetic acid (0.1 g) and cyano sodium borohydride (0.17 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was concentrated, to which were added ethyl acetate (30 ml) and water (20 ml), followed by extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 5-chloro-2-(4-trifluoromethylbenzylamino)-α-(3-tert-b-utoxycarbonylaminomethylphenyl)benzyl alcohol (0.6 g) as a colorless oily product.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14](ON1C(=O)CCC1=O)([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15].Cl>O.O1CCOCC1>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
All Fmoc amino acids were synthesized from the corresponding free amino acids by the following general procedure. To a solution of D-allo-Thr (25) (1.62 g, 13.6 mmol) and NaHCO3 (3.4 g, 41 mmol) in H2O (60 mL) was added a solution of Fmoc-OSu (4.58 g, 13.6 mmol) in dioxane (60 mL) and the turbid reaction mixture stirred at RT overnight. The mixture was then diluted with H2O, acidified to pH≤4 by addition of 37% HCl and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with saturated NaCl (2×100 mL), dried (MgSO4) and taken to dryness by rotary evaporation to give a colorless oil which was crystallized from ethyl acetate/hexane, yielding Fmoc-D-allo-Thr (26) as white crystals (3.7 g, 80%), mp 152°-153° C. Anal. (C19H19NO5) C, H, N.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH3:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:34]=1[C:35](O)=[O:36].[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47]>C(Cl)Cl>[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47].[CH3:30][N:29]([CH:26]1[CH2:27][CH2:28][N:23]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25]1)[C:35](=[O:36])[C:34]1[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:33]=1[O:32][CH3:31]
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)N(C)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-dicyclohexylcarbodiimide (10.3 g; 0.05 moles) and 1-benzyl-4-methylaminopiperidine (10.2 g; 0.05 moles) were added successively to a solution of 2-methoxy-5-chlorobenzoic acid (9.3 g; 0.05 mole) in methylene chloride (250 ml). After stirring overnight at room temperature, the insoluble N,N'-dicyclohexylurea was filtered off, the solution was washed with water, dried (Na2SO4) and the solvent removed in vacuo to give an oil. It was salified with fumaric acid as described in Example 1 to give 10.3 g of N-methyl-N-(1-benzylpiperid-4-yl)-2-methoxy-5-chlorobenzamide fumarate, m.p. 192°-194° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>C(#N)C>[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[CH:37]=1)[C:32]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:33])([O-:28])=[O:27]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)cc23)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3,5-dinitrobenzoyl chloride (0.158 g, 0.684 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from acetonitrile to yield 0.17 g (63%) of the title compound: mp 254°-256° C. Analysis calculated for C22H21N5O5 : C, 60.68; H, 4.86; N, 16.08. Found: C, 60.59; H, 4.73; N, 15.88.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C:17](=[C:28]([F:30])[F:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[F:29][C:28]([F:30])=[C:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:51])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1C(=C(F)F)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C(=C(F)F)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 99 %

Procedure:
The title compound II-bf was prepared in 99% yield from 3,3:17,17-bis(ethylendioxy)-6-difluoromethyleneandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.85-0.95 (m, 20H), 1.12 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](Br)=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:23]=[O:24].OP(O)(O)=O>C1COCC1.C1(C)C(C)=CC=CC=1>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:23][OH:24])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1nn(Cc2ccccc2)c2ccccc12
Reactant: C=O
Agent: CC(C)[Mg]Cl
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: OCc1nn(Cc2ccccc2)c2ccccc12
Temperature: -10 °C
Yield: 34 %

Procedure:
A solution of 2M i-PrMgCl in THF (69 mL, 138 mmol, 4.0 eq.) was added to a suitably thoroughly dried flask maintained under a nitrogen atmosphere. The solution was cooled to approximately −10° C. A solution of 1-benzyl-3-bromo-1H-indazole (10 g, 34.8 mmol, 1.0 eq.) in anhydrous THF (40 mL) was added over approximately one hour keeping the temperature constant. The reaction mixture was kept stirred for at least 6 hours, and a yellow suspension was obtained. Gaseous formaldehyde (generated by heating a suspension of 16.7 g of paraformaldehyde in 60 mL of xylene at approximately 115° C.) was passed over this for approximately two hours at a temperature of below 0° C. When the reaction was complete, dilute H3PO4 was added and the excess of re-polymerised paraformaldehyde was removed by filtration. Me-THF (60 mL) was added to the mixture and the phases were separated. The organic phase was washed with a dilute solution of NaHCO3. After concentration of the organic phase an oily residue containing the product was obtained. Subsequent purification of the crude product by silica gel chromatography yielded 2.8 g of white solid (yield: 34%).
Reaction SMILES: [Na].F[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[NH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1>C(O)C1C=CC=CC=1>[CH2:7]([O:13][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[NH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[C:6]1[CH:11]=[CH:12][CH:3]=[CH:4][CH:5]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: [Na]
Solvent: OCc1ccccc1
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 118.4 %

Procedure:
Sodium metal (4.4 g, 191 mmol) was added to benzyl alcohol (100 ml) at ambient temperature and the mixture stirred for 30 minutes then heated at 80° C. for 1 hour. The mixture was then cooled to 40° C. and 7-fluoro-3,4-dihydroquinazolin-4-one (7.8 g, 47 mmol), was added. The reaction mixture was stirred at 130° C. for 4 hours and allowed to cool to ambient temperature and stirred for 18 hours. The solution was quenched with water (800 ml) and acidified to pH3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and ether and dried for 4 hours at 60° C. under high vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (7.02 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[N:9][CH:8]=1)=[O:5].[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:25]2[CH:24]=[N:23][N:22]([CH2:21][CH2:20][O:19][CH3:18])[CH:26]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[N:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccnnc1
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCn1cc(-c2cnc(N)c(C(=O)Nc3ccnnc3)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridazin-4-yl-nicotinamide (see step 1 in the synthesis of “A16”) with 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A24”;
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH:11]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:15][C:16]([O:2][N:1]=[C:3]2[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]2)=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: CC1=NC(=NO)SC1(C)C
Reactant: O=C=NC1CCC1
Product: CC1=NC(=NOC(=O)NC2CCC2)SC1(C)C

Procedure:
2-oxo-4,5,5-trimethyl-3-thiazoline-oxime was reacted with cyclobutyl isocyanate as described in Example 4 to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(cyclobutylcarbamoyl)-oxime, m.p. 94°-96° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.II.CN([CH:16]=[O:17])C.Cl>C1COCC1.O>[CH:16]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)=[O:17]
Reactant: CN(C)C=O
Reactant: Brc1ccc2occc2c1
Agent: Cl
Agent: II
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2occc2c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 539.3 %

Procedure:
A mixture of 5-bromo-1-benzofuran (0.5 g), Mg (0.92 g, 0.038 mol), I2 (1 crystal) in dry THF (2.5 mL) under N2 atmosphere was refluxed for 30 min. To this was added a solution of 5-bromo-1-benzofuran (4.5 g) in 25 mL of dry THF) as soon as the 12 color disappear and refluxed for another 2 h. The reaction mixture was then cooled to −40° C. and added dry DMF (3.6 g) drop-wise and slowly warmed to RT for a period of 12 h. The reaction mixture was then cooled to 0° C. and acidified with 3N HCl to pH=2 and stirred for 30 min. The reaction mixture was then diluted with water (500 mL), extracted with ethylacetate (2×200 mL), washed with brine and dried. The solvent was removed under vacuum and purified by column chromatography over silica gel (pet. ether/CH2Cl2) to give 5-formyl-1-benzofuran (2 g, 54%) as a liquid. LC-MS: M/Z ESI: 1.47 min, 147.34 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:10][C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[C:6]([CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)cc1
Temperature: -80 °C
Yield: 75.9 %

Procedure:
To a suspension of N-(2,6-diisopropyl-4-nitro-phenyl)-4-methyl-benzenesulfonamide (3.72 g) in ethanol (50 mL) was added stannous(II) chloride dihydrate (11.2 g) and the mixture was heated to −80° C. for 1.5 hour. It was then poured onto ice (300 mL), made strongly basic with solid sodium hydroxide (20 g) and diluted with ethyl acetate (100 mL). The suspension was filtered and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 2.60 g (76%) of the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3): 0.95 (d, 12H), 2.40 (s, 3H), 3.02 (m, 2H), 3.68 (b, 2H), 5.74 (s, 1H), 6.39 (s, 2H), 7.23 (d, 2H), 7.60 (d, 2H).