Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a cooled (0° C), stirred solution of 990 mg (2.30 mmol) 3-[3-(5-bromo-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 842 μL of N,N-diisopropylethylamine and 500 μL of anhydrous dimethyl sulfoxide in 6.0 mL of anhydrous dichloromethane was added 732 mg (4.60 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 2 h. An additional 368 mg (2.30 mmol) of sulfur trioxide pyridine complex was added and, after 17 h, the mixture was poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with 1M pH 7 buffer (25 mL), brine (25 mL) and dried over Na2SO4 to give after concentration a white semisolid. This material was chromatographed on 35 g of silica gel with dichloromethane followed by 3% ethyl acetate-dichloromethane to afford 685 mg (69%) of the title compound as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 9.84 (t, 1 H, J=1.4 Hz), 7.94 (d, 1 H, J=2.5 Hz), 7.70 (dd, 1 H, J=8.9, 2.5 Hz), 6.98 (d, 1 H, J=8.9 Hz), 6.61 (br s, 1 H), 6.55 (br s, 1 H), 6.45 (t, 1 H, J=2.2 Hz), 4.21 (t, 2 H, J=6.1 Hz), 4.01 (s, 3 H), 2.88 (td, 2 H, J=6.1, 1.4 Hz) and 2.27 (s, 3 H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C17H1779BrO6S: 451.0 (M+Na). Found: 451.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[BH4-].[Na+].O.C(OCC)(=O)C>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][CH:23]([OH:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-c2noc3c2CCCC3O)ccc1-n1cnc(C)c1

Procedure:
To the 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (7.16 mg, 2.22 mmol) in THF/EtOH (v/v=1:1, 26 ml) at ° C., was added NaBH4 (101 mg, 1.66 mmol). The reaction mixture was stirred for 30 min before careful addition of water and extraction with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4 and concentrated to afford the title product which was used without further purification. 1H NMR (CDCl3) δ: 7.74 (s, 1H), 7.51 (s, 1H), 7.29-7.37 (m, 2H), 6.96 (s, 1H), 4.98 (br. s., 1H), 3.92 (s, 3H), 2.70-2.79 (m, 1H), 2.57-2.68 (m, 1H), 2.55 (br. s., 1H), 2.27-2.34 (m, 3H), 1.98-2.11 (m, 3H), 1.86-1.93 (m, 1H), 1.59 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])=[C:5]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:4]=1)#[N:2].Br[CH2:36][CH2:37][OH:38].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:36][CH2:37][OH:38])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])=[C:5]([S:31]([CH3:34])(=[O:32])=[O:33])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCCO)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (74 mg, 150 μmol) was initially charged in dry DMF (2 ml), 2-bromoethanol (75 mg, 600 μmol; 4 eq.) and triethylamine (31 mg, 300 μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 8 h. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (2×20 ml) and saturated sodium chloride solution (20 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:3). The product-containing fractions were combined and concentrated, the residue was taken up in a little acetonitrile, water was added and the mixture was lyophilized. The title compound was obtained as a colorless solid (63 mg, 78% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=1)([O-])=O>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([N:6]2[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccn(-c2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CO
Product: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-nitro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole (7 g, 27.24 mmol, 1.00 equiv) in methanol (30 mL). The mixture was treated with Pd/C (3 g) and stirred under a hydrogen atmosphere overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 6 g (97%) of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:16][S:15][CH:14]3[N:11]([C:12](=[O:17])[CH2:13]3)[C:10]=2[C:18]([O:20]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:19])=[N:5][N:4]=[N:3]1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:16][S:15][CH:14]3[N:11]([C:12](=[O:17])[CH2:13]3)[C:10]=2[C:18]([OH:20])=[O:19])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)CC2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)CC2SC1

Procedure:
The 7β-[[DL-[[[2,4-dioxo-1-imidazolidinyl)amino]carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester obtained in Example 14 is treated with trifluoroacetic acid and anisole according to the procedure of Example 8, to obtain 7β-[[DL-[[[2,4-dioxo-1-imidazolidinyl)amino]carbonyl]amino]-2-thienylacetyl]-amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, m.p. 160°-180° (dec.). The sodium salt is obtained by treating this product with an equimolar amount of sodium bicarbonate in water, filtering and freeze drying the filtrate, m.p. 200°-220° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5](CC2C=C(C=CC=2)C(OC)=O)[CH:6]=1.BrCC1C=C(C=CC=1)C(OC)=O.Br[C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:6]=1
Reactant: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: COC(=O)c1cccc(CBr)c1
Product: CCOC(=O)C(C)(C)n1cc(Br)cn1

Procedure:
The title compound was prepared using a procedure analogous to methyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzoate except that methyl 3-(bromomethyl)benzoate was replaced with ethyl 2-bromo-2-methylpropanoate. LCMS, [M+H]+=261.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13]/[C:12](=[N:14]\[C:15]([C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)=[O:16])/[N:11](COCC[Si](C)(C)C)[CH:10]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[O:16])=[N:11][CH:10]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(F)cc2F)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncc(-c2ccc(F)cc2F)s1)C12CC3CC(CC(C3)C1)C2

Procedure:
A solution of Example 200B in trifluoroacetic acid was heated at 50° C. for 3 hours then concentrated. The residue was diluted with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated to afford the title compound. MS (ESI) m/z 375 (M+H)+.
Reaction SMILES: [C:1](=O)([O:4]C)[O:2][CH3:3].C[O-].[Na+].[CH2:10]=[C:11]([OH:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:1](=[O:4])([O:2][CH3:3])[O:19][CH:11]([CH3:10])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(O)Cc1ccccc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OC(C)Cc1ccccc1
Temperature: 78 °C

Procedure:
Into a 2 liter reaction flask equipped with stirrer, thermometer, reflux condenser, heating mantle and Bidwell addition funnel is placed 222 grams of dimethyl carbonate and 24 grams of a solution of sodium methoxide in methanol. The resulting mixture is heated to reflux. Over a 30 minute period 268 grams of alpha-methylene phenylethyl alcohol having the structure: ##STR161## is added over a period of 20 minutes after bringing the mixture to reflux at 72°-76° C. At the end of the addition of the alpha-methylene phenylethyl alcohol the reaction mass is continued to be refluxed at 78° C. for a period of two hours. At the end of the two hour period, the excess methyl alcohol is taken off at 100° C. The reaction mass is then cooled and 200 ml wter is added thereto. The organic phase is then distilled on a 12" Goodloe column yielding the following fractions:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH2:35]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51]Br)=[N:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:35]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: BrCc1nn(Cc2ccccc2)c2ccccc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
To a stirring solution of 490 mg (1.08 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 12 mL DMF at 0° C. is added dropwise over 5 min 2.35 mL (1.18 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 355 mg (1.18 mmol, 1.1 equiv) of 1-Benzyl-3-bromomethyl-1H-indazole in 3 mL DMF is added. The resulting solution is stirred 4.5 h at RT and then quenched with 5 mL of H2O. The reaction mixture is then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using hexane/EtOAc 3/2 as eluent followed by lyophilization in acetonitrile/H2O afforded 620 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.86 (d, 1H, J=8.1), 7.40 (d, 1H, J=7.9), 7.33-6.88 (m, 20H), 5.43 (s, 2H), 5.00 (m, 1H), 4.25 (m, 3H), 3.85 (m,4H), 3.58 (dd, 1H, J=5.1, 16.0), 1.06 (d, 6H, J=6.6); low resolution MS (FAB)m/e 678 (MH+), 677 (M+),
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: Cc1ccc(NN)nc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(NNC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)nc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A 50-mL, 3-necked, round bottom flask, charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) in EtOAc (10 mL) was treated with 2-hydrazinyl-5-methylpyridine (0.97 g, 1.1 eq.). The mixture was cooled to −60° C. and treated with T3P (propyl phosphonic anhydride; 0.85 mL, 2.0 eq.) and DIPEA (0.5 mL, 4.0 eq.). The mixture was stirred for 30 min then poured into water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford a crude compound that was purified by column chromatography (SiO2, 60/120 mesh, MeOH:CH2Cl2 as mobile phase). The desired compound started eluting with 2.5% MeOH:CH2Cl2. Fractions containing the desired compound were combined and concentrated under reduced pressure to afford 0.130 g (yield: 40%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(5-methylpyridin-2-yl)acrylohydrazide. 1H NMR (400 MHz, CDCl3) δ, 10.38 (s, exchangeable, 1H), 9.65 (s, 1H), 8.54 (s, 2H), 8.40 (s, exchangeable, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 7.48-7.51 (d, J=10.4 Hz, 1H), 7.33-7.36 (dd, J=2 Hz, J=6 Hz, 1H), 6.61-6.63 (d, J=8.4 Hz, 1H), 6.20-6.23 (d, J=10.4 Hz, 1H), 2.15 (s, 3H); LCMS for C19H15F6N6O [M+H]+ 457.35. found 457.24 (RT 2.61 min, purity: 99.13%).
Reaction SMILES: CS([C:5]1[C:6]([CH3:16])=[C:7]([CH3:15])[C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1)(=O)=O.[C-:17]#[N:18].[K+]>CN(C=O)C>[NH2:14][C:11]1[N:9]2[N:10]=[C:5]([C:17]#[N:18])[C:6]([CH3:16])=[C:7]([CH3:15])[C:8]2=[N:13][N:12]=1
Reactant: [C-]#N
Reactant: Cc1c(S(C)(=O)=O)nn2c(N)nnc2c1C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C#N)nn2c(N)nnc2c1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
6-Methanesulfonyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.130; 1.0 g) was dissolved in DMF (30 ml) and admixed with potassium cyanide (405 mg). After stirring at 100° C. for 1 h, the mixture was dried. The residue was stirred in EA and chromatographed using a short silica gel column with EA. Fractions concentrated by rotary evaporation. 560 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17](=O)[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18]/[C:17](=[N:24]\[NH:23][C:20]([NH2:22])=[NH:21])/[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1
Reactant: Cc1coc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1cccc(Cl)c1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 162.4 %

Procedure:
To a mixture of 6-(2,3-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.15 g) and aminoguanidine hydrochloride (56 mg) were added ethanol (10 ml) and 6N hydrochloric acid (0.044 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2,3-dichlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 43) (0.16 g).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:3]=1[O:4][C:5]1[N:6]=[C:7]([O:27][CH2:28][CH2:29][CH3:30])[C:8]2[N:13]=[C:12]([C:14]3[CH:24]=[C:23]([CH3:25])[C:17]([O:18][CH2:19][C:20](O)=[O:21])=[C:16]([CH3:26])[CH:15]=3)[O:11][C:9]=2[N:10]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:67]1[CH2:78][CH2:77][CH2:76][C@H:68]1[C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70].Cl>CN(C)C=O.O>[F:1][C:2]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:3]=1[O:4][C:5]1[N:6]=[C:7]([O:27][CH2:28][CH2:29][CH3:30])[C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH3:26])[C:17]([O:18][CH2:19][C:20]([N:67]4[CH2:78][CH2:77][CH2:76][C@H:68]4[C:69]([O:71][C:72]([CH3:74])([CH3:75])[CH3:73])=[O:70])=[O:21])=[C:23]([CH3:25])[CH:24]=3)[O:11][C:9]=2[N:10]=1
Reactant: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c(C)c3)nc12
Reaction time: 16 h

Procedure:
60 mg of {4-[5-(2,5-difluorophenoxy)-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetic acid were dissolved in 1 ml of N,N-dimethylformamide, and 35 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 7 mg of 1-hydroxy-7-azabenzotriazole and 139 μl of N,N-diisopropylethylamine were added, and 5 min later 17 mg of tert-butyl L-prolinate were added. After 16 h at room temperature, 10 ml of water were added, after which the mixture was adjusted to pH 3 by addition of 2 M aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution and sodium chloride solution, dried and concentrated under reduced pressure. This gave 61 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH:11]3[CH:15]([CH2:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=O)[O:13][C:12]3=[O:27])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:27][CH2:12][CH:11]1[CH:15]([CH2:14][OH:13])[CH2:16][C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: COc1ccc(C2=C(c3ccc(OC)cc3)CC3C(=O)OC(=O)C3C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(c3ccc(OC)cc3)CC(CO)C(CO)C2)cc1
Temperature: 25 °C

Procedure:
To the cooled solution of 5,6-bis-(4-methoxy-phenyl)-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione (2.95g) in THF (30 mL) at 0° C. was added LAH (1.0 M in THF, 20 mL) and the reaction mixture was stirred at 25° C. for 16. The reaction mixture was then quenched with methanol (20 mL) and aqueous HCl (10%, 30 mL) and then extracted with diethyl ether (2×300 mL). The organic layer was dried and concentrated to yield [6-Hydroxymethyl-3,4-bis-(4-methoxy-phenyl)-cyclohex-3-enyl]-methanol.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:17]([C:30]2[CH:31]=[C:32]([CH:38]=[CH:39][C:40]([O:42]CC)=[O:41])[CH:33]=[CH:34][C:35]=2[O:36][CH3:37])=[CH:18][C:19]2[C:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[C:24]=2[CH:25]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:17]([C:30]2[CH:31]=[C:32]([CH:38]=[CH:39][C:40]([OH:42])=[O:41])[CH:33]=[CH:34][C:35]=2[O:36][CH3:37])=[CH:18][C:19]2[C:20]([CH3:28])([CH3:29])[CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[C:24]=2[CH:25]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2OCCCCCCCC(=O)OC(C)(C)C)C(C)(C)CCC3(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCCCC(=O)O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.3 %

Procedure:
A solution of 3.75 g (6.18 mmol) of ethyl 3-{3-[3-(7-tert-butoxycarbonylheptyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate obtained in Example 22(b) dissolved in 60 ml of dichloromethane was placed in a round-bottomed flask, 4.76 ml (61.8 mmol) of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 4 hours. The reaction medium was poured into water and extracted with ethyl ether, and the organic phase was decanted, dried over magnesium sulfate, filtered and evaporated. 3.4 g (100%) of the expected compound were obtained in the form of a white foam.
Reaction SMILES: [C:1]([N:8]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].S(C)C.Cl>C1COCC1>[C:1]([N:8]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)O
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@@H]1c1ccccc1
Yield: 102.4 %

Procedure:
To a stirred solution of N-Boc-5-(R)-phenyl-(2S)-proline (1.14 g, 3.91 mmol) in THF (20 ml) was added 10M-BH3.Me2S (780 ml, 7.82 mmol) at rt, and the resulting mixture was heated under reflux for 30 min. The mixture was poured into aq. 1N-HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3—MeOH (10:1) as eluent to give N-Boc-2-(S)-hydroxymethyl-5-(R)-phenylpyrrolidine (1.11 g, quant.) as a colorless oil: 1H-NMR (CDCl3) δ1.19 (brs, 9 H), 1.65 (brs, 1 H), 1.83-1.90 (m, 1 H), 1.98-2.06 (m, 1 H), 2.22-2.31 (m, 1 H), 3.75-3.86 (m, 2 H), 4.16-4.19 (m, 1 H), 4.83 (t, J=6.8 Hz, 1 H), 4.89 (brs, 1 H), 7.19-7.31 (m, 5 H); MS (ESI) m/z, 2.78 (M++H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]2[O:17][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:26]=2)[CH:12]=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COc1ccccc1C(N)=NO
Reactant: COc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3ccccc3C)c(OC)c2)n1

Procedure:
Oxalyl chloride (126 μL; 1.49 mmol; 3 eq.), Intermediate 27 (120 mg; 0.5 mmol; 1 eq.), Intermediate 1 (82 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.49 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from DCM/n-pentane afforded the title compound as a brown solid.