Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=2)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].C(O)CO>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)c1cccnc1)n2Cc1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)cc(Cc1cccnc1)n2Cc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
1-(4-fluorobenzyl)-5-methanesulfonyl-2-nicotinoylindole (0.14 g), hydrazine monohydrate (0.17 g), potassium hydroxide (0.05 g) and ethylene glycol (3 ml) were added under nitrogen atmosphere and the mixture was stirred at 110° C. for 8 hours. To the reaction solution was added water, and the mixture was extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 13 mg of the desired product.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N+:16]([O-])=[C:17](N)[N:18]=[N+:19]([O-])[C:14]=2[CH:13]=1)[CH:9]=[CH2:10]>CN(C=O)C>[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[CH:17][N:18]=[N:19][C:14]=2[CH:13]=1)[CH:9]=[CH2:10]
Reactant: C=CCOc1ccc2c(c1)[n+]([O-])nc(N)[n+]2[O-]
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2ncnnc2c1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) in DMF (15 ml) at 60°-65° C. was added 7-allyloxy-3-amino-1,2,4-benzotriazine-1,4-dioxide 23 (205 mg, 0.875 mmol) in small portions over 5 min. After 30 min additional t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) was added, and shortly thereafter the deep red solution effervesced and lightened appreciably in color over a period of a few minutes. After an additional 30 min the resultant orange solution was reduced under vacuum to a brown solid which was sequentially flash chromatographed (10% EtOAc/CH2CL2) and crystallized (CH2 Cl2 /petroleum ether) to give 72 mg (38% yield) of the product 24 as light orange crystals, m.p 147°-148° C. NMR:δ (400 MHz, d6 :acetone) 4.89 (2H, ddd, H-1', J1'2' =5.5, J1'·3'cis =J1'·3'trans =1.5 Hz), 5.36(1 H, ddd, H-3', J3'·2'cis =10.5 J3'·3' =1.5 Hz), 5.52 (1 H, ddd, H-3', J3'·2'trans =17.5, J3'·3' =3, J3'1' =1.5 Hz), 6.14 (1 H, ddd, H-2', J2',3'cis =10.5, J2'·1' -5.5 Hz), 7.70 (1 H, d, H-8, J8.6 =2.5 Hz), 7.74 (1 H, dd, H-6, J6.5 =9.5, J6.8 -2.5 Hz), 8.33 (1 H, d, H-5, J5.6 =9.5 Hz), 8.93 (1 H,s, H-3). UV:λmax 425, 410, 365, 355, 320, 245, 200. MS m/z (relative intensity) 220(4), 219(34 M+), 103(4), 77(4), 75(4), 63(13), 62(4), 42(3), 41(100), 39(16). Anal. Calc'd. for C10H9N3O3 : C, 54.79; H, 4.14; N, 19.17. Found: C, 54.73; H, 4.16; N, 9.15.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH:10]([CH3:16])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][CH:10]1[NH:11][C:12](=[O:15])[CH2:13][CH2:14][NH:8][CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CCC(=O)N1
Agent: [Pd]
Solvent: CCO
Product: CC1CNCCC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.4 %

Procedure:
A mixture of 1-benzyl-3-methyl-[1,4]diazepan-5-one (1.88 g, 8.62 mmol) and palladium (10% on activated charcoal, 188 mg) in ethanol (50 ml) was stirred at room temperature under a hydrogen atmosphere (3 bar). After 18 h, the catalyst was removed by filtration and the filtrate evaporated to afford the title compound (1.12 g, 99%). White solid, MS: m/e=128 (M+).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.S(=O)(=O)(O)O.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:16]>>[CH3:14][C:15]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7])([CH3:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(O)cc1
Reactant: C=C(C)c1ccccc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(O)c(C(C)(C)c2ccccc2)c1
Reaction time: 20 h

Procedure:
Two hundreds and sixteen grams of paracresol is placed in a 500 ml. four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. 4 g. of sulfuric acid is added therein and 236 g. of α-methyl styrene is dropped gradually at 60°C. with stirring. The dropping speed is adjusted to complete dropping in about 20 hours. Thus, 2-(α, α-dimethylbenzyl)-4-methylphenol is obtained. The resulting material is dissolved in 500 ml. of xylene and water is azeotropically removed with dropping an aqueous solution containing 80 g. of caustic sodium. The solution is transferred to an autoclave having a capacity of 1000 ml., and treated by the same way as in Example 9, to yield about 300 g. of 3-(α, α-dimethylbenzyl)-5-methylsalicylic acid. By same treatments as in each Example, 900 ml. of a composition containing 100 g. of 3-(α, α-dimethylbenzyl)-5-methylsalicylic acid zinc, 20 g. of styrene-butadiene copolymer, 15 g. of acrylamide-methylol acrylamide copolymer, 0.3 g. of a sulfonic acid salt type surface active agent and water is prepared. About 5~15 g. of the composition is applied to 1m2 of the surface of a sheet and dried to form the support of a dyestuff acceptor.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: O=C(C=Cc1ccc(Cl)cc1Cl)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 2,4-dichlorobenzaldehyde and acetophenone, 3-(2,4-dichlorophenyl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>Cl>[C:1]1([C:9]2[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=2)([C:9]2[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC1
Reactant: Oc1ccccc1
Agent: Cl
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC2)cc1

Procedure:
Cyclobutanone (1.2 g, 17 mmol) and phenol (4.8 g, 51 mmol) were stirred in concentrated HCl (7 mL) at 40° C. for 72 h. The resulting slurry was filtered and the filter cake was dissolved in EtOAc and washed with saturated NaHCO3 (aq) and brine. The organic layer was concentrated to give a solid which was recrystallized from EtOAc/CH2Cl2 to provide the title compound. LCMS (ESI, neg. ion): m/z=239 [M−H]−; 479 [2M−H]−. 1H NMR (500 MHz, CD3OD): δ 7.10 (d, J=8.6 Hz, 4H), 6.70 (d, J=8.6 Hz, 4H), 2.65 (t, J=7.5 Hz, 4H), 1.93 (quint, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:38][CH2:39][CH2:40][OH:41]>CC(=O)CC>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:38][CH2:39][CH2:40][OH:41])=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCCCO
Yield: 132.5 %

Procedure:
A mixture of 5-(N,N-dibenzylglycyl)salicylamide (10.0 g), sodium iodide (4.0 g), potassium carbonate (3.7 g) and 3-chloropropan-1-ol (2.56 g) in butanone (100 ml) was heated under reflux for 24 hours, and filtered to give a cream solid (15.3 g). This was extracted with boiling ethanol and the clear solution was cooled to give a yellow solid (4.0 g) which was crystallised from methanol as colourless crystals (3.4 g). It had m.p. 171°-175°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[I:12][C:11]1[NH:10][CH:9]=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Ic1[nH]cnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-phenyl-1H-imidazole (4.75 g, 33 mmoles) in CH2Cl2 (250 mL) is added N-iodosuccinimide (6.75 g, 30 mmoles). After 2 hours at room temperature, CH2Cl2 is removed under reduced pressure. The residual solid is triturated in hot ACN (150 mL), cooled down to room temperature and filtered. The white-off solid is triturated in hot ACN (60 mL), cooled down to room temperature and stirred overnight at room temperature. After a filtration, 5-iodo-4-phenyl-1H-imidazole is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH3:18])=[C:16]([NH:19][C:20]2[CH:21]=[C:22]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38]C(=O)C)[N:33]=3)[CH:23]=[CH:24][C:25]=2[N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl.C(#N)C.[OH-].[Na+]>>[NH2:38][C:34]1[N:33]=[C:32]([C:22]2[CH:23]=[CH:24][C:25]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:20]([NH:19][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]=3[CH3:18])[CH:21]=2)[CH:37]=[CH:36][N:35]=1
Reactant: CC(=O)Nc1nccc(-c2ccc(N3CCOCC3)c(Nc3c(C)c(-c4ccccc4F)nc4ccccc34)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(-c2ccnc(N)n2)ccc1N1CCOCC1
Reaction time: 18 h

Procedure:
A solution of N-(4-(3-(2-(2-fluorophenyl)-3-methylquinolin-4-ylamino)-4-morpholinophenyl)pyrimidin-2-yl)acetamide (20 mg, 36 μmol) and concentrated aq. hydrochloric acid (1.50 mL, 18.0 mmol) in acetonitrile (4.00 mL, 76.6 mmol) was heated to 90° C. After 18 h the pH was made alkaline by addition of sodium hydroxide. The reaction mixture was partitioned between 30 mL ea EtOAc and water. The organic layer was stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow solid. The product was purified by chromatography on silica gel eluting with 5-10% MeOH in DCM to afford a colorless solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.07-8.27 (2H, m), 7.84 (1H, d, J=8.2 Hz), 7.51-7.67 (3H, m), 7.37-7.49 (2H, m), 7.27 (1H, t, J=7.4 Hz), 7.01-7.23 (5H, m), 6.78 (1H, br. s.), 5.10 (2H, br. s.), 3.87 (4H, t, J=4.5 Hz), 3.11 (4H, br. s.), 2.06-2.21 (3H, m). Mass Spectrum (ESI) m/e=507.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(Cl)[n+]1[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Temperature: 90 °C
Reaction time: 3 h

Procedure:
2-chloro-6-methylpyridine 1-oxide (60 g, 0.42 mol) was dissolved in 98% sulfuric acid (60 mL) at 0° C., then a solution of HNO3 (50 mL) and H2SO4 (50 mL) was added dropwise at the same temperature. After the addition was complete, the reaction was stirred at 90° C. for 3 h. The reaction was poured into ice-water, neutralized with NaHCO3, and then extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over magnesium sulfate, filtered and concentrated to afford 2-chloro-6-methyl-4-nitropyridine 1-oxide which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=2.7 Hz, 1H), 8.07 (d, J=0.6 Hz, 1H), 2.62 (s, 3H). LRMS calc'd for (C6H6ClNO) [M+H]+, 189; found 189.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH2:21][CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:27]2[NH:28][C:29](=[O:31])[S:30][C:26]=2[CH:25]=1>>[CH2:21]([N:17]([CH:18]([CH3:20])[CH3:19])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([NH:23][C:24]4[C:33]([O:34][CH3:35])=[CH:32][C:27]5[NH:28][C:29](=[O:31])[S:30][C:26]=5[CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:16])[CH3:22]
Reactant: CCN(C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1)C(C)C
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: CCN(C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1)C(C)C

Procedure:
40 mg (118 μmol) (RS)-4-chloro-N-ethyl-N-isopropyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 86a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 10.9 mg (18%) of the title compound.
Reaction SMILES: C(#N)[CH:2]([CH2:4][C:5]#[N:6])O.C(O)(=O)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19]>C(O)C.C(OCC)(=O)C>[S:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:2]1[CH2:4][C:5]#[N:6]
Reactant: Nc1ccccc1S
Reactant: N#CCC(O)C#N
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#CCc1nc2ccccc2s1
Reaction time: 16 h

Procedure:
To a solution of malonitrile (6.61 g) and acetic acid (60 ml) in ethanol (100 ml) was added o-amino thio-phenol (7 ml) and the reaction was conducted at room temperature for 16 hours. This reaction mixture was diluted with ethyl acetate (200 ml) and washed with 5% aqueous sodium chloride solution. The organic layer was further washed with 3N NaOH (200 ml) and saturated NaCl solution (200 ml) and dried and the solvent was distilled off under reduced pressure. The residue was crystallized from IPE to give 2-benzothiazoleacetonitrile (13.8 g). This crystalline product (10.45 g) was dissolved in DMF (100 ml), and after addition of 60% sodium hydride (1.44 g) under ice-cooling, the solution was heated to 60° C. and stirred for 30 minutes. After cooling to room temperature, ethyl 6-bromohexanoate (5.31 ml) was added and the reaction was conducted at 60° C. for 30 minutes. After cooling to 10° C. or less, the reaction mixture was diluted with pure water (300 ml) and extracted with ethyl acetate (200 ml) twice. The pooled organic layer was washed with saturated aqueous sodium chloride solution and dried. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to provide ethyl 7-(benzothiazol-2-yl)-7-cyanoheptanoate (3.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([N:14]1[CH2:17][CH:16]([NH:18][C@H:19]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[O:25])[CH2:20]3)[CH2:15]1)=[O:13])[CH2:6][CH2:5]2.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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]>[C:31]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([C:12]([N:14]2[CH2:15][CH:16]([NH:18][C@H:19]4[CH2:23][CH2:22][N:21]([C:24]([C:26]5[S:27][CH:28]=[CH:29][N:30]=5)=[O:25])[CH2:20]4)[CH2:17]2)=[O:13])[CH2:6][CH2:5]3)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1nccs1)N1CC[C@H](NC2CN(C(=O)N3CCc4cc(Br)ccc4C3)C2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(c1nccs1)N1CC[C@H](NC2CN(C(=O)N3CCc4cc(-c5ccccc5)ccc4C3)C2)C1
Yield: 86 %

Procedure:
A mixture of compound 10 (82 mg, 0.167 mmol), phenyl boronic acid 2a (35 mg, 0.284 mmol), Pd(dppf)Cl2.CH2Cl2 (14 mg, 0.0167 mmol) and Na2CO3 (35 mg, 0.334 mmol) in dioxane (0.8 mL) and water (0.2 mL) in a capped vial was heated at 80° C. for 6 h. The reaction mixture was diluted with EtOAc and water. The organic layer was concentrated and purified by chromatography (silica gel, 5% MeOH/EtOAc) to give compound 11 (70 mg). MS m/z (M+H+) 488.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3]([OH:5])=[O:4])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(D)-proline (0.78 g, 6.77 mmol) is suspended in methylene chloride (25.0 mL). To this solution is added triethylamine (1.13 mL, 8.12 mmol) and 4-methoxybenzenesulfonyl chloride (1.4 g, 6.77 mmol), and the reaction is stirred at room temperature for two days. The reaction is then diluted with methylene chloride and washed successively with 1N hydrochloric acid, water, and brine. The organic phase is dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% methanol/ethyl acetate) to give 1-[4-methoxybenzenesulfonyl]-pyrrolidine-2(R)-carboxylic acid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][CH:5]1[C:9]([Si:10](Cl)([CH3:12])[CH3:11])=[C:8]([CH3:14])[C:7]([CH3:15])=[C:6]1[CH3:16].C1COCC1>>[CH3:1][N:2]([Si:10]([CH:9]1[C:5]([CH3:4])=[C:6]([CH3:16])[C:7]([CH3:15])=[C:8]1[CH3:14])([CH3:11])[CH3:12])[CH3:3]
Reactant: CNC
Reactant: CC1=C(C)C(C)C([Si](C)(C)Cl)=C1C
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)N(C)C)C(C)=C1C
Temperature: 15 °C
Reaction time: 16 h

Procedure:
A 250 mL roundbottom flask equipped with a condenser, stirrer, thermometer and dropping funnel with nitrogen inlet was charged with 100 mL of dimethylamine solution (2.0 M in THF, 0.20 mol) and cooled to 15° C. A solution of tetramethylcyclopenta-dienyldimethylsilylchloride in THF (10.1 g in 30 mL THF, 47 mmol) was added and the solution stirred for 16 hours allowing the temperature of the reaction mixture to rise to room temperature. A precipitate was filtered off and the solvent evaporated. The remaining residue was distilled at sub-atmospheric pressure (2.6 mbar) at 80-81° C. to obtain [(N,N-dimethylamino)dimethylsilyl]tetramethyl-cyclopentadiene (4.2 g). The product was characterized by GC, GC-MS, 13C and 1H NMR.
Reaction SMILES: [NH2:1][C@@:2]([C:17]1[CH:22]=[C:21]([Br:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])([CH3:16])[C:3]([F:15])([F:14])[C:4]([CH3:13])([O:6][CH2:7][C:8](OCC)=[O:9])[CH3:5].CCCCCCC>C(OCC)(=O)C>[Br:23][C:21]1[C:20]([F:24])=[CH:19][C:18]([F:25])=[C:17]([C@:2]2([CH3:16])[C:3]([F:15])([F:14])[C:4]([CH3:13])([CH3:5])[O:6][CH2:7][C:8](=[O:9])[NH:1]2)[CH:22]=1
Reactant: CCOC(=O)COC(C)(C)C(F)(F)[C@](C)(N)c1cc(Br)c(F)cc1F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)c(F)cc2F)C1(F)F
Yield: 62.6 %

Procedure:
Prepared in an analogous manner as described for intermediate A22A from (R)-ethyl 2-(4-amino-4-(5-bromo-2,4-difluorophenyl)-3,3-difluoro-2-methylpentan-2-yloxy)acetate (intermediate A22B) (16.1 g; 37.4 mmol). After silica gel column chromatography with heptane and ethyl acetate the (R)-5-(5-bromo-2,4-difluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (9.0 g, 23.4 mmol, 63% yield) was obtained as an off-white solid. MS (ISP): m/z=384.2 [(M+H)+] and 386.1 [(M+2+H)+].
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]2[C:18]2[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34]>CC#N>[CH3:37][O:36][C:32](=[O:35])[CH:33]=[CH:34][C:21]1[CH:20]=[CH:19][C:18]([CH:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:23][CH:22]=1
Reactant: C=CC(=O)OC
Reactant: O=S(=O)(Oc1ccc(C2c3ccccc3CCCC2c2ccccc2)cc1)C(F)(F)F
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2c3ccccc3CCCC2c2ccccc2)cc1

Procedure:
Prepared by Heck coupling 8c and methyl acrylate in accordance with the general method described in Example IV. Yield (14%); APcI m/z: 424 (M+H+CH3CN+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([CH2:11][CH3:12])[CH2:9][CH:8]([CH2:13][S:14]([OH:17])(=[O:16])=O)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(Cl)Cl.CN(C=O)C>[CH2:24]([N:26]([CH2:27][CH3:28])[S:14]([CH2:13][CH:8]1[CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:10]([CH2:11][CH3:12])[CH2:9]1)(=[O:16])=[O:17])[CH3:25]
Reactant: CCNCC
Reactant: CCOC(=O)C1CC(CS(=O)(=O)O)CC1CC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CC(CS(=O)(=O)N(CC)CC)CC1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
A solution of (3-(ethoxycarbonyl)-4-ethylcyclopentyl)methanesulfonic acid (3.18 g, 12.03 mmol) in DCM (10 mL) and DMF (10 mL) was cooled to about 0° C. Oxalyl chloride (24.1 mL, 48.1 mmol) was added dropwise while the temperature was kept at about 0° C. After the addition was complete, the reaction mixture was warmed to ambient temperature and stirred for about 1 h. The solvent was removed under reduced pressure. The residue was dissolved in DMF (10 mL) and then added dropwise to a solution of TEA (2.51 mL, 18.03 mmol) and diethylamine (0.937 mL, 9.02 mmol) in DMF (10 mL) at about 0° C. The reaction mixture was stirred at ambient temperature for about 16 h. The solvent was removed under reduced pressure. The material was purified by silica gel (120 g) chromatography eluting with a gradient of 10-60% EtOAc in heptane to provide ethyl 4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate (0.570 g, 30%) as a yellow oil: LC/MS (Table 1, Method b) Rt=2.60 min; MS m/z: 320 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.C(N(CC)CC)C.[SH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C(OCC)(=O)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[N:11][CH:10]=1
Reactant: Sc1ccccn1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(Sc2ccccn2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution of 250 mg (0.432 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4), 0.090 ml (0.65 mmol) triethylamine and 59 mg (0.52 mmol) 2-mercaptopyridine in 4 ml tetrahydrofuran was deoxygenated by three freeze-thaw cycles. After addition of 15 mg (0.022 mmol) bis(triphenylphosphine)palladium(II) chloride the reaction mixture was heated at reflux over night. Cooling to room temperature was followed by dilution with ethyl acetate and washing with saturated aqueous sodium carbonate solution and brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 210 mg (87%) of the title compound as a light yellow amorphous mass.