Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 70 %

Procedure:
To a mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethylamine and 20 ml of methylene chloride were added 115 μl (0.935 m mol) of pivaloyl chloride (trimethylacetyl chloride) with stirring at the room temperature, followed by further stirring for 3.5 hours. After the completion of the reaction, the mixture solution was washed thrice with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain the pure intended compound. (yield: 191 mg, yield: 70%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:22][C:9]2[C:10]([OH:21])=[C:11]([C:17](OC)=[O:18])[N:12]([CH3:16])[S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1.[F:23][C:24]1[CH:41]=[CH:40][C:27]([O:28][C:29]2[O:33][C:32]([C:34]3[N:35]=[C:36]([NH2:39])[S:37][CH:38]=3)=[CH:31][CH:30]=2)=[CH:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:41]=[CH:40][C:27]([O:28][C:29]2[O:33][C:32]([C:34]3[N:35]=[C:36]([NH:39][C:17]([C:11]4[N:12]([CH3:16])[S:13](=[O:15])(=[O:14])[C:8]5[CH:7]=[C:6]([C:2]6[O:1][CH:5]=[CH:4][CH:3]=6)[S:22][C:9]=5[C:10]=4[OH:21])=[O:18])[S:37][CH:38]=3)=[CH:31][CH:30]=2)=[CH:26][CH:25]=1
Reactant: Nc1nc(-c2ccc(Oc3ccc(F)cc3)o2)cs1
Reactant: COC(=O)C1=C(O)c2sc(-c3ccco3)cc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nc(-c3ccc(Oc4ccc(F)cc4)o3)cs2)=C(O)c2sc(-c3ccco3)cc2S1(=O)=O
Reaction time: 4.5 h

Procedure:
0.339 g (0.99 mmol) of methyl 6-(2-furanyl)-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylate 1,1-dioxide and 0.398 g (1.44 mmol) of 4-[5-(4-fluorophenoxy)-2-furanyl]-2-thiazolamine are heated to boiling in 3 ml of absolute xylene. After 4.5 h, the suspension is cooled, and the precipitated product is filtered off, digested several times with diethyl ether and recrystallized from dimethyl sulphoxide/acetone 10:1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=S)=[CH:5][CH:4]=1.[CH3:14][NH:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[CH:18][C:17]=1[NH2:31].CCN(C(C)C)C(C)C.[Cl-].ClC1N(C)CC[NH+]1C>CC#N.O>[CH3:14][N:15]1[C:16]2[CH:30]=[CH:29][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[CH:18][C:17]=2[N:31]=[C:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: CNc1ccc(Oc2ccnc(C#N)c2)cc1N
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Cn1c(Nc2ccc(C(F)(F)F)cc2)nc2cc(Oc3ccnc(C#N)c3)ccc21
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
4-(Trifluoromethyl)phenyl isothiocyanate (9.65 g, 0.0475 moles) was added to a solution of 4-(4-methylamino-3-amino-phenoxy)-pyridine-2-carbonitrile (12.0 g, 0.05 moles) in MeCN (60 mL). HPLC analysis indicated complete conversion of the amine after 40 min. The mixture was filtered and the removed solids washed with MeCN (2×12 mL). DIPEA (17.5 mL, 0.1 moles) was added to the filtrate. 2-Chloro-1,3-dimethylimidazolinium chloride (DMC) was added in 4×2.11-g portions (8.44 g, 0.05 moles) every 10 min. After the final addition, the mixture was allowed to stir an additional 10 min when HPLC analysis indicated complete conversion. The mixture was then heated to 50° C. (internal temperature). After 45 min at 50° C., HPLC analysis indicated complete conversion to the product. The mixture was allowed to cool to ambient temperature and then H2O (45 mL) was added. The reaction mixture was initially homogeneous before compound began to precipitate from the mixture. After stirring for 2 h, the solid was collected by filtration and washed with 2:1 MeCN/H2O (2×20 mL). The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 16.10 g (78%) of the title compound 1H NMR (400 MHz, DMSO-d6) δ 9.5 (m, 1 H), 8.5 (m, 1 H), 8.0 (m, 2 H), 7.7 (m, 2H), 7.6 (m, 1H), 7.4 (m, 1 H), 7.3 (m, 1 H), 7.1 (m, 1 H), 6.9 (m, 1 H), 3.7 (m, 3 H); APCI MS [M+H]+=410; HPLC >99% (LCAP).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:34]=[CH:33][O:32][CH:31]=1)(=[O:29])=[O:28].[CH3:35][Zn]C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:35])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:34]=[CH:33][O:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccoc1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (115 mg, 0.214 mmol) and dimethyl zinc in toluene (0.214 mL, 0.427 mmol), the title compound was obtained as a solid (60 mg, 51% yield). MS (ESI): 519 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[CH2:25]([N:27]1[C:32](=[O:33])[N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:30](=[O:41])[C:29]([C:42](O)=[O:43])=[N:28]1)[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:42]([C:29]2[C:30](=[O:41])[N:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:32](=[O:33])[N:27]([CH2:25][CH3:26])[N:28]=2)=[O:43])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2OC)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenylamine and 2-ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid using the procedure for example 1. mp=264-6° C.; LCMS m/z=588 (M+1);); 1H NMR (DMSO): 11.00 (s, 1H), 8.47-8.52 (m, 2H), 7.51 (s, 1H), 7.38-7.46 (m, 5H), 7.10 (m, 1H), 6.88 (m, 1H), 6.53 (d, 1H, J=5 Hz), 4.10 (q, 2H, J=7 Hz), 3.94 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 1.35 (t, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:23][CH3:24])[CH2:20][CH2:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH2:4]1.[CH3:25]N1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.[Cl-].[NH4+]>O.C1COCC1>[CH3:24][O:23][C:3]1([O:2][CH3:1])[CH2:20][CH2:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[C@H:11]([CH3:25])[CH2:10]4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH2:4]1
Reactant: COC1(OC)CCC2=C(C[C@@H](C)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: CN1CCCN(C)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COC1(OC)CCC2=C(C[C@@H](C)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](C)C[C@@H]32)C1
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 63.5 %

Procedure:
A solution of (7α)-3,3-dimethoxy-7-methylestr-5(10)-en-17-one (1.5 g, 4.5 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 1.2 mL, 9.9 mmol) in 30 mL dist. THF was added in approx. 8 minutes to a stirred solution of lithium bis(trimethylsilyl)amide (LiHMDS, 4.96 mL, 1M in THF) in 15 mL distillated THF at −40° C. under a nitrogen atmosphere. The reaction mixture was stirred for 45 minutes at −40° C. A solution of iodomethane (730 μL, 11.7 mmol) in 1 mL dist. THF was added and stirred for 1 hour and the temperature was allowed to warm up to 0° C. Water and sat. ammonium chloride solution were added and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated to dryness. Column Chromatography using heptane/ethyl acetate 95/5 (v/v %) as eluent gave (7α,16α)-3,3-dimethoxy-7,16-dimethylestr-5(10)-en-17-one (990 mg, yield 65%).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1>C(O)(C(F)(F)F)=O>[F:40][C:2]([F:1])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)ccc2cc1F
Yield: 75 %

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (109 mg, 0.194 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (67 mg, 74.8% yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 461 (M+H). Specific rotation: [α]20D=+1.07° (c=0.96, MeOH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Mg+2:11].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+].OCl>O>[NH2:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Mg+2:11].[NH2:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: NCCC(=O)O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: OCl
Solvent: O
Product: NCCC(=O)[O-]
Reaction time: 0.08 h

Procedure:
Magnesium β-alaninate was prepared by reacting 3.6 g. of β-alanine with 1.8 g. of basic magnesium carbonate in 40 g. of water, while agitating at 75° C. for one half hour. To the cooled slurry was added 2.5 g. of sodium tartrate. After five minutes of stirring, 80 g. of zirconyl hydroxychloride solution (14.4% Zr) was added to the above slurry with agitation. The solution cleared on stirring and had a final pH of 3.3. The product was oven-dried at 55° C. under a vacuum of 40 cm. of Hg and found to contain 33.1% Zr, 1.3% Mg, 1.4% Na, and 10.3% β-alanine.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([C:25]4([NH:29]C(=O)OC(C)(C)C)[CH2:28][O:27][CH2:26]4)[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[NH2:29][C:25]1([C:23]2[O:22][N:21]=[C:20]([C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:11])[CH:14]=3)[N:24]=2)[CH2:26][O:27][CH2:28]1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: Cc1ccc(-c2noc(C3(NC(=O)OC(C)(C)C)COC3)n2)cc1NC(=O)c1cnc2ccccn12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2noc(C3(N)COC3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(3-(3-(3-(Imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)oxetan-3-yl)carbamate (46) (29.5 mg, 0.06 mmol) was dissolved in TFA (0.5 mL) and stirred at room temperature for 10 minutes. Then TFA was removed under vacuum to yield crude N-(5-(5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (47) as a TFA salt which was used without further purification. MS m/z 391.1 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][O-:15].[Na+]>>[CH3:14][O:15][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[O-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1C#N
Reaction time: 8 h
Yield: 53.7 %

Procedure:
2-Bromo-5-trifluoromethylbenzonitrile (2.5 g.; prepared as described by M. Gordon, I. J. Pachter and J. W. Wilson, Arzneimittel-Forsch., 1963, 13, 802) and a solution of sodium methoxide (prepared from 0.5 g. sodium and 20 ml. anhydrous methanol) were stirred and refluxed together for 4 hours, and allowed to stand at room temperature overnight. The methanol was evaporated and the residue was acidified with 2N hydrochloric acid, with cooling. The mixture was extracted with diethyl ether, and the extract was dried over anhydrous sodium sulphate, filtered and the filtrate was evaporated, and the residue was recrystallised from pentane to give 2-methoxy-5-trifluoromethylbenzonitrile (1.0g.), m.p. 31°-33° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br-].[CH3:21][C:22]([CH3:25])=[CH:23][CH3:24]>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:24][CH:23]=[C:22]([CH3:25])[CH3:21])[CH:3]=1
Reactant: Cc1cccc(S)c1
Reactant: CC=C(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCSc1cccc(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 g (40 mmol) of 3-methylthiophenol, 5.6 g (40 mmol) of potassium carbonate and 50 ml of DMF are introduced into a three-necked flask. 7.2 g (48 mmol) of 3-methyl-2-butene bromide are added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 7.8 g (100%) of the expected product are collected in the form of a yellow oil.
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>O.C1COCC1.CO>[C:1]1(=[N:15][OH:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=C1CC2CCCc3cccc1c32
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: ON=C1CC2CCCc3cccc1c32
Temperature: 75 °C
Yield: 101.7 %

Procedure:
To a mixture of 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-one (12.2 g, 70.9 mmol), hydroxylamine hydrochloride (7.85 g) and water (90 ml) were slowly added sodium acetate (14.5 g), methanol (120 ml), THF (30 ml) and water (60 ml) with stirring while heating at 75° C., and the mixture was stirred for 2 hr and 40 min. After cooling to room temperature, methanol was evaporated under reduced pressure, and the obtained precipitate was collected by filtration, and washed with water to give 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-one oxime (13.5 g).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:20][CH:19]3[CH:15]([CH2:16][N:17]([C:21](=[O:34])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:18]3)[C:14]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])([OH:35])[CH2:13]2)(=O)=O)=CC=1.[C-:44]#[N:45].[K+]>>[C:44]([CH2:11][CH:12]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:21](=[O:34])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:18]2)[C:14]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])([OH:35])[CH2:13]1)#[N:45]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC3CN(C(=O)Cc4ccccc4N4CCCC4)CC3C(O)(c3ccccc3F)C2)cc1
Reactant: [C-]#N
Agent: [K+]
Product: N#CCC1CC2CN(C(=O)Cc3ccccc3N3CCCC3)CC2C(O)(c2ccccc2F)C1
Yield: 45.1 %

Procedure:
The procedure is as described for Example 13, starting from 0.07 g of (3aRS,4RS,6SR,7aSR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol and 0.015 g of potassium cyanide, and gives 0.024 g of (3aRS,4RS,6SR,7aSR)-6-cyanomethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4](OC)(=[O:13])[C:5]1[CH:10]=[CH:9][C:8](OC)=[CH:7][CH:6]=1.O.Cl>CS(C)=O>[C:4]([CH2:2][C:1]#[N:3])(=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: N#CCC(=O)c1ccccc1
Temperature: 60 °C
Yield: 68.7 %

Procedure:
To a solution of acetonitrile (76 g) in DMSO (100 mL) was added methyl p-anisate (100 g) and the mixture was stirred with heating at 60° C. for one hour. The reaction mixture was allowed to cool, and cold water (500 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give benzoylacetonitrile (60 g) as colorless crystals. A solution of 2-chlorobenzaldehyde (1.7 g), 3-aminopyrazole (1.0 g) and benzoylacetonitrile (1.8 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.63 g) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2](C)[CH:3]([C:10]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=1[CH:12]=O)[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[NH2:23][C:24]1[CH:29]=[N:28][C:27]([Br:30])=[CH:26][N:25]=1.[BH4-].[Na+].C(OCC)(=O)C>C1COCC1.CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[Br:30][C:27]1[N:28]=[CH:29][C:24]([NH:23][CH2:12][C:11]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:10]=2[CH:3]([N:4]2[CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:2][CH3:1])=[N:25][CH:26]=1
Reactant: CC(C)C(c1ccc(C(F)(F)F)cc1C=O)N1CCOCC1
Reactant: Nc1cnc(Br)cn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(c1ccc(C(F)(F)F)cc1CNc1cnc(Br)cn1)N1CCOCC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 2-(2-Methyl-1-morpholin-4-yl-propyl)-5-trifluoromethyl-benzaldehyde (126 mg, 0.418 mmol) in THF (0.5 mL) was added 2-amino-5-bromopyrazine (81 mg, 0.465 mmol) followed by titanium isopropoxide (0.2 uL; 0.675 mmol). The resulting mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with MeOH (0.5 mL). To this was added sodium borohydride (20 mg, 0.528 mmol). The resulting mixture is stirred at room temperature for 16 hours. Ethyl acetate and water were added and stirred for 15 minutes. Reaction is poured over a pad of celite and silica gel. The mother liquor is washed with water (2×) and brine. The organic layer is dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel) (eluting with 10-50% ethyl acetate/hexanes) to afford the title compound (97 mg, 0.205 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[F:14][CH:15]([F:27])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH3:24])=[C:19]([CH3:26])[CH:18]=1.C1CCCCC1.C(OCC)(=O)C>O1CCCC1>[Br:8][C:4]1[CH:3]=[C:2]([C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH:15]([F:14])[F:27])=[CH:18][C:19]=2[CH3:26])=[CH2:24])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)c1ccc(OC(F)F)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C=C(c1cccc(Br)c1)c1ccc(OC(F)F)cc1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-dibromobenzene (7.6 g, 32.2 mmol, 1 eq) in 64 mL of dry tetrahydrofuran at −78° C. under N2 atmosphere, n-butyllithium (1.6 N in hexane, 20 mL, 1.1 eq) was added dropwise. The mixture was stirred at −78° C. for 1 h, then was added via cannula to a solution of 1-(4-difluoromethoxy-2-methyl-phenyl)-ethanone (6.5 g, 32.2 mmol, 1 eq) in dry tetrahydrofuran at −78° C. The mixture was allowed to warm to room temperature. The reaction mixture was examined after 1 h by TLC (cyclohexane/ethyl acetate 9:1) which showed complete conversion to the desired product. Sat. aqueous ammonium chloride (30 mL) was added, the tetrahydrofuran layer was separated aqueous phase was extracted with dichloromethane (30 mL). The organic fractions were collected, dried over sodium sulfate and evaporated. The crude was dissolved in acetic acid (65 mL) and cone. sulfuric acid (13 mL) was added and mixture was stirred at room temperature for 2 h. A solution of 15% NaOH was added to the mixture until pH 6-5, then extracted with dichloromethane (50 mL). The organic phases were collected, dried and evaporated. The crude was purified by flash chromatography eluting with cyclohexane. 6.10 g of clean product was obtained as colorless oil (yield: 55%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:38]4[CH:37]=[CH:36][CH:35]=[C:34]([NH:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH:39]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: O=C1N(c2ccccc2)C(c2cccc(Br)c2)CN1S(=O)(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-phenyl-imidazolidin-2-one (example 5, step 2) was reacted with (3-methylsulfonylaminophenyl)boronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give N-[3′-(1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl)-biphenyl-3-yl]-methanesulfonamide as an off-white solid. MS: 548.2 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH:9]=[N:8][NH:7][C:6]1=[O:10].[OH-].[Na+].[Br:17]Br>O>[Br:17][C:9]1[N:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[F:1])[C:6](=[O:10])[NH:7][N:8]=1
Reactant: O=c1[nH]ncn1Cc1ccccc1F
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]nc(Br)n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
The product from Step b (3.35 g, 17.3 mmol) is placed in 37 ml water together with sodium hydroxide (970 mg, 24.2 mmol). Bromine (893 μl, 17.3 mmol) is added dropwise with stirring at RT. During the addition, a light brown solid precipitates. Stirring is continued overnight at RT. The precipitated solid is filtered off at the pump, washed with a little water and then dried under high vacuum. 4.25 g of the target product of adequate purity (ca. 83% by LC/MS) are obtained.