Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])(=[O:6])=[O:5])=[N+:2]=[N-:3].S(Cl)([Cl:18])=O>>[N:1]([S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:18])=[O:11])(=[O:6])=[O:5])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NS(=O)(=O)c1cccc(C(=O)O)c1
Product: [N-]=[N+]=NS(=O)(=O)c1cccc(C(=O)Cl)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
11.3 grams (50 milimoles) of 3-(azidosulfonyl) benzoic acid and 31 grams (261 milimoles) of thionyl chloride were added to a 200 ml. round bottom flask equipped with a magnetic stirrer, nitrogen sparge, reflux condenser and heating mantle. The mixture was stirred for 3 hours at 65° C. and then the excess thionyl chloride was stripped under vacuum. A 75 percent yield of 3-(azido-sulfonyl) benzoyl chloride was obtained and identified by spectroscopic analysis. Said benzoyl chloride was a straw-yellow liquid that slowly crystallized at room temperature and had a melting point of 41° C. and a refractive index of ND24.5 = 1.5751.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-])=O.[H][H]>CO.[Pd]>[NH2:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[C:3]([NH:2][CH3:1])=[O:13]
Reactant: CNC(=O)c1ccncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccncc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-methyl-3-nitroisonicotinamide (0.878 g) in methanol (50 mL) was added Pd/C (10% Pd in carbon, 100 mg, 11 wt %) under argon. A hydrogen balloon was used as the hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The methanol phase was combined, concentrated and the crude was purified by silica gel chromatography to obtain the desired product (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Oc1ccc(Cl)cc1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccc(Cl)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 352(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:23])[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:17])[C:12]([C:24]#[N:25])=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.N>C1COCC1.CO>[NH2:25][C:24]1[C:12]2[C:13](=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:11]=2)[N:15]([CH3:23])[C:16](=[O:17])[C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To the product of Step A EXAMPLE 91 (100 mg) in THF (1 mL) was added 2 mL of NH3 in methanol (7 M). The reaction stirred for 3.5 hours at room temperature before it was concentrated. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3. The solution was dried (Na2SO4) and concentrated to afford the title compound. HPLC/MS: 488.0 (M+1), 490.0 (M+3); Rt=4.05 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.Br[C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>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.O>[F:34][C:27]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[N:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30]
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)O)c(F)c4)ccc3=O)ccnc2c1
Reaction time: 0.33 h
Yield: 65.1 %

Procedure:
To a 5 ml CEM microwave tube was added 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (0.1 g, 0.3 mmol), 4-bromo-2-fluorobenzoic acid (0.08 g, 0.5 mmol), sodium carbonate (0.10 g, 0.9 mmol), dichlorobis(triphenylphosphine)-palladium(II) (30 mg, 0.05 mmol), and DMF (4 mL)-water (0.4 mL). The vial was sealed and placed in CEM microwave for 20 min at 130° C., with 100 Watts of power via Powermax. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated (toluene was added in order to removed most of DMF). The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, isocratic 5% MeOH in DCM with 1% AcOH, Flow=30 mL/min). The peak at 30 min was collected to afford the desired product as white solid (85 mg). MS (ESI pos. ion) m/z (M+1): 436.2. Calc'd exact mass for C23H18FN3O5: 357.41. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.86 (s, 3 H) 4.70 (s, 4 H) 6.96-7.04 (m, 2 H) 7.13 (d, J=9.79 Hz, 1 H) 7.25-7.30 (m, 1 H) 7.69-7.73 (m, 1 H) 7.75 (s, 1 H) 7.86 (s, 1 H) 7.87-7.95 (m, 2 H) 8.12 (d, J=9.79 Hz, 1 H) 8.64 (d, J=5.26 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH2:13](O)[CH3:14].Cl>O>[OH:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:6]([O:8][CH2:13][CH3:14])=[O:7])=[CH:9][C:10]=1[CH3:11]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: Cl
Solvent: O
Product: CCOC(=O)c1cc(C)c(O)c(C)c1

Procedure:
A mixture of 500 mg (3 mmol) of 4-hydroxy-3,5-dimethylbenzoic acid, 20 ml of absolute ethanol and a catalytic amount of anhydrous HCl was heated at reflux for 2 h. The mixture was then poured into excess cold water and the resultant precipitate was filtered. The precipitate was washed with water and dried in-vacuo to give the title compound as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:16]([F:33])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[C@@H:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:10]1)=O)(C)(C)C.[ClH:34]>C(O)C>[ClH:34].[NH2:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:16]([F:33])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[C@@H:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:10]1
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OC[C@@H]4C)C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OC[C@@H]4C)C[C@H]1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (3S)-10-(cis-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (0.6 g) in ethanol (8 ml) and ethanolic hydrochloride solution (10 ml) was stirred for 1.5 hours at room temperature and then concentrated. To the residue was added ethanol and the resulting precipitate was collected by filtration to give the title compound (0.44 g) as yellowish powder, mp 285° C. (decompd.).
Reaction SMILES: [OH-].[K+].C(O)CO.[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:23]=[CH:22][C:21]([O:24]C)=[CH:20][N:19]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(=O)C>[CH2:7]([C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=2)[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[C@H]1CC[C@H](c2ncc(OC)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CC(=O)O
Product: CCCCC[C@H]1CC[C@H](c2ncc(O)cn2)CC1
Reaction time: 3 h

Procedure:
KOH (9.5 g, 0.17 mol) and ethylene glycol (100 ml) were added to 2-(trans-4-pentylcyclohexyl)-5-methoxypyrimidine (7.4 g, 0.028 mol) prepared in the same manner as in Example 1, followed by heating the mixture under reflux with stirring for 3 hours, cooling the resulting material, adding glacial acetic acid (30 ml) thereto, further adding water (100 ml), filtering the reaction mixture under suction through a filter, sufficiently washing the residue on the filter with water, three times recrystallizing the residue from ethanol and removing ethanol under reduced pressure to obtain 2-(trans-4-pentylcyclohexyl)-5-hydroxypyrimidine (4.9 g, 0.020 mol) having a melting point of 190.0°~191.1° C.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[NH2:30]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:30][C:24]3[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[Cl:22])=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(C(=O)NCC3CCCCC3)c(C(F)(F)F)n2)c(Cl)c1

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-dioxan (1 ml) was added 2-chloro-4-methylphenylamine (Aldrich) (109 mg) the mixture was stirred at reflux for 24 hours using a Radleys Greenhouse Parallel Synthesiser. The dioxan was removed using a nitrogen blow down unit The residue was taken up into methanol (0.5 ml) and dimethylsulfoxide (0.5 ml) and purified using mass directed auto-preparative system to give the title compound) (24 mg)
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])[CH2:2][CH3:3].[C:12]1([S:18][CH2:19]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([S:18][CH2:19][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:3])[NH:8][S:7]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCSc1ccccc1
Reactant: CCCC1NS(=O)(=O)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCC1NS(=O)(=O)N(CSc2ccccc2)C1=O
Yield: 627.4 %

Procedure:
To a mixture of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.1 g, 28.65 mmol) suspended in 210 ml of toluene was added tetrabutylammonium bromide (0.92 g, 2.86 mmol) and phenylthiomethyl chloride (4.93 g, 2.86 mmol) and the resulting mixture was refluxed for 18 hours. The mixture was cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (20% ethyl acetate in hexane) to afford 5.39 g (63%) of 2-phenylthiomethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =propyl; R3 =H).
Reaction SMILES: CC(C)([O-])C.[Na+].[C@@H:7]12[CH2:13][NH:12][C@@H:11]1[CH2:10][N:9]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.I[C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[CH:45][C:44]([S:48]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:50])=[O:49])=[CH:43]2>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:51]1([S:48]([C:44]2[CH:45]=[N:46][C:47]3[C:42]([CH:43]=2)=[CH:41][CH:40]=[CH:39][C:38]=3[N:12]2[CH2:13][CH:7]3[CH:11]2[CH2:10][N:9]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8]3)(=[O:50])=[O:49])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(I)cccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CC2CN(c3cccc4cc(S(=O)(=O)c5ccccc5)cnc34)C2C1
Temperature: 60 °C

Procedure:
A solution of sodium t-butoxide (49 mg, 0.51 mmol) and (1S,5S)-benzyl 3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (98 mg, 0.24 mmol) in toluene (3 mL) was stirred under nitrogen. To this was added tri-t-butylphosphine (25 mg, 0.05 mmol), palladium (II) acetate (6.9 mg, 0.03 mmol) and 8-iodo-3-(phenylsulfonyl)quinoline (80 mg, 0.202 mmol). The mixture was then heated at 60° C. for 2 h before partitioning between CH2Cl2 and water. The mixture was filtered through Celite and the organic phase was separated. The water phase was extracted twice with CH2Cl2 and the combined extracts dried (Na2SO4), filtered and concentrated in vacuo to provide the crude material, which was purified by flash chromatography to give the title compound.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][N:26]3[CH:33]=2)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]2[N:26]([CH:33]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([O:14][CH2:13][CH2:12][CH2:11][O:10][S:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=4)(=[O:8])=[O:9])=[CH:22][CH:21]=3)[N:24]=2)[CH:27]=1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Reactant: Cc1ccc(S(=O)(=O)OCCCO)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(OCCCOS(=O)(=O)c4ccc(C)cc4)cc3)cn2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 45.1 %

Procedure:
To a solution of 554 mg (corresponding to 2.40 mmol) of 1,3-propanediol mono-p-toluenesulfonate in 10 mL of tetrahydrofuran, 260 mg (corresponding to 1.08 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine and 636 mg (corresponding to 2.42 mmol) of triphenylphosphine were added. Further, 5 mL of N,N-dimethylformamide was added thereto to completely dissolve the contents. To the reaction mixture, 0.48 mL (corresponding to 2.42 mmol) of diisopropylazodicarboxylate was added. After the resulting mixture was stirred at room temperature for 23 hours, the reaction solution was concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform/ethyl acetate=19/1), further purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name: manufactured by Japan Analytical Industry Co., Ltd.); column: two of JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), and further purified again by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=35/65) to obtain 220 mg (corresponding to 0.487 mmol) of 6-methoxy-2-[4′-(3″-p-toluenesulfonyloxypropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1, Step 7).
Reaction SMILES: [F:1][C:2]1([F:29])[C@@H:19]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:18][CH2:17][C@@:16]2([CH3:27])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:28].[CH2:30](OC=C)[CH3:31]>>[F:29][C:2]1([F:1])[C@@H:19]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:18][CH2:17][C@@:16]2([CH3:27])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:28][CH:30]=[CH2:31]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](OC5CCCCO5)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: C=COCC
Product: C=CO[C@H]1CC[C@H]2[C@@H]3CC=C4C(F)(F)[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4 g of 4,4-difluoro-3β-(2-tetrahydropyranyloxy)androst-5-en-17β-ol in 50 ml of vinyl ethyl ether, there is added 0.25 g of mercuric acetate. The mixture is stirred at room temperature for 24 hours, quenched with triethylamine, and then poured into dilute aqueous potassium carbonate solution. The aqueous mixture is extracted three times with 100-ml portions of diethyl ether and the combined organic extracts are washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent is then removed under reduced pressure and the residue is purified by flash chromatography to give 4,4-difluoro-3β-(2-tetrahydropyranyloxy)-17β-ethenyloxyandrost-5-ene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].CN(C)C=[O:35].O.O=O>Cl.[Pd](Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:9][CH2:10][CH2:11][C:12](=[O:35])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=O
Solvent: O
Product: CC(=O)CCCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 24 h

Procedure:
A mixture of [(4-benzyloxy-benzenesulfonyl)-pent-4-enyl-amino]-acetic acid tert-butyl ester (compound of formula XVI, 89 g, 200 mmol), cuprous chloride (19.8 g, 200 mmol), palladium (II) chloride (6.9 g, 39 mmol), dimethylformamide (541 ml) and water (293 ml) was treated with oxygen gas under vigorous stirring. After about 24 hours, an additional 4 g of cuprous chloride and 2 g of palladium (II) chloride were added, and stirring was continued for 2 days. The mixture was diluted with 1M hydrochloric acid, extracted 3 times with ethyl acetate, and the organic phase was washed 5 times with water, dried over sodium sulfate, filtered and concentrated, giving 83 g of [(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester (compound of formula XVII) as a colorless syrup.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:22].[Na+].OO>C1COCC1.O>[C:7]1([CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][OH:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: C=CCOCCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of 2-allyloxyethylbenzene (5. g; 30.8 mmol) dissolved in THF (75 ml) is slowly added a 0.5M THF solution of 9-BBN [9-borabicyclo [3.3.1]nonane] (68 ml; 34 mmol) and the reaction mixture warmed to room temperature and stirred for 4 hours. The reaction mixture is then cooled to 0° C. and 5 ml H2O is added followed by slow addition of 6N NaOH (30 ml; 7.2 g/30 ml). After stirring for 5 minutes, 30% H2O2 (20 ml) is added over 15 min. The reaction mixture warms significantly but is kept from refluxing. After addition is complete, it is stirred for 15 minutes allowing the mixture to come to room temperature. It is then diluted with. Et2O, washed with H2O 2×, Na2S2O3 2×, NaHCO3 and brine, dried (MgSO4) and concentrated to dryness. The residue is purified by column chromatography using Et2O to obtain 3-(2-phenylethoxy)-1-propanol which is used directly in Step C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[CH:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1>O1CCCC1>[C:7]([CH:9]=[CH:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC(CC=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CC=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium tert-butoxide, 1M in tetrahydrofuran (3694 μl, 3.69 mmol) at 0° C. was added dropwise by syringe a solution of diethyl cyanomethylphosphonate (570 μl, 3.52 mmol) in 5 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and then cooled to 0° C. again. This solution was treated with tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (701 mg, 3.52 mmol) in 2 ml tetrahydrofuran dropwise by syringe and then allowed to warm to room temperature. After stirring overnight the gelatinous mixture was quenched with water (20 ml) and extracted with ethyl acetate (2×20 ml); the organic layers were washed with brine (20 ml), dried with magnesium sulfate, filtered and concentrated. The liquid residue was flash chromatographed to give the title compound as a 1:1 mixture of E/Z isomers.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: F[C@@H]1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-ds) 6 ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])#[N:2].[C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[NH4+].C(O)(=O)CC>CCCCCCC.O>[C:1]([C:3](=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])#[N:2]
Reactant: CCCCC(CC)COC(=O)CC#N
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: O
Solvent: CCC(=O)O
Product: CCCCC(CC)COC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Into a 500 ml four-neck round-bottom flask, equipped with a mechanical stirrer, a thermometer and a condenser is charged with 62.2 g (0.32 mol) of 2-Ethylhexyl cyanoacetate (EHCA) and 81.0 g (0.45 mol) of Benzophenone (BP) (molar ratio EHCA:BP=0.71:1) and 27.7 g (0.36 mol) of ammonium acetate and 81.0 g (1.1 mol) of propionic acid and 81.0 g of heptane. The mixture is heated under stirring. When the temperature reach 110° C., a mixture of propionic acid, water, heptane is distilled off over a period of 5 hours at normal pressure. Heptane phase is returned back to the flask. Then the reactant is cooled to 90° C., and 100 ml of hot water is added to the reaction mixture. The mixture is kept at 85° C. for 10 minutes, and then transferred to a funnel for separation. To a flask equipped with a column 256.0 g of crude 2-ethylhexyl 2-cyano-3,3-diphenylacrylate solution is added. Rectification is carried out at 1 mbar. 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate is distilled out at 210° C. (vapor). After distillation, light yellow 2-ethylhexyl 2-cyano-3,3-diphenylacrylate is obtained. Reaction yields are as indicated in table 1 and assume recycle of unreacted benzophenone and 2-EHCA.