Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[N:9]2)[CH2:4][O:3]1.O.[OH-].[Na+].CCCCCCC>C(OC)(C)(C)C>[CH3:1][C:2]1([CH3:17])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Solvent: O
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Temperature: 62.5 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a 5 L glass flask equipped with a mechanical stirrer and thermometer was charged with 584 g (315 g after corrected by wt %, 1.28 mol) of N-[1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-acetamide and 1.2 L of purified water. The mixture was agitated at 60-65° C. for 3 h, forming a homogeneous solution. After cooling the batch to 40-45° C., 214 g (5.14 mol) of NaOH (solid) was added in portions. The mixture was agitated at 90° C. for 24 h. The mixture was cooled to 20-25° C. and extracted with 2 kg of isopropyl acetate. The combined organic phase was concentrated by distillation in vacuo (35-45° C. (batch)/P<−0.1 MPa) to give a yellow oil. The residue was diluted with 414 g of methyl tert-butyl ether and 750 g of heptane subsequently. The resulting suspension was stirred at 20-25° C. for 15 h. The solids were collected by filtration and washed with 1100 g of methyl tert-butyl ether/heptane (1/2, v/v). The solids were dried in a vacuum oven (30-35° C./P≦−0.1 MPa) for ca. 24 h to afford 215 g (68% yield in 2 steps) of 1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine as an off-white solid. 1H-NMR (400 MHz, d6-DMSO): δ 7.31 (s, 1H), 5.38 (s, 1H), 4.55 (s, 2H), 4.26-4.32 (m, 1H), 3.92-3.98 (m, 3H), 3.7-3.73 (m, 1H), 1.31 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11](=S)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:14]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH2:23]([O:22][C:20]([N:14]1[CH2:19][CH2:18][N:17]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=3[N:10]=2)[CH2:16][CH2:15]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1cccc2oc(=S)[nH]c12
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: O=C(OCc1ccccc1)N1CCN(c2nc3c([N+](=O)[O-])cccc3o2)CC1

Procedure:
A mixture of 4-nitro-3H-benzoxazole-2-thione (7.00 g, 35.7 mmol) and benzyl 1-piperazinecarboxylate (15.72 g, 71.36 mmol) in xylenes was heated at reflux temperature overnight, cooled and concentrated in vacuo to provide the title compound which was used, without further purification, in Example 8.
Reaction SMILES: C(O)(=O)C=[O:3].CON=[CH:9][C@H:10]([F:31])[C@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:12]([Br:22])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C.O>O1CCCC1>[Br:22][C@@H:12]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:10]([F:31])[CH:9]=[O:3]
Reactant: O=CC(=O)O
Reactant: CON=C[C@H](F)[C@H](OCc1ccccc1)[C@@H](Br)COCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C[C@@H](F)[C@H](OCc1ccccc1)[C@@H](Br)COCc1ccccc1
Temperature: 70 °C
Reaction time: 4.83 h

Procedure:
3.3 mL of a 50% glyoxylic acid aqueous solution was added to a solution of 662 mg of the (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal O-methyloxime in 6.6 mL of tetrahydrofuran, and the obtained mixture was then stirred at 70° C. for 4.83 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 655 mg of colorless oily (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal and a water adduct thereof.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=CC=2N=N1.[C:28]1([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([S:43]([C:46]3[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O:55]1CCC(NC)[CH2:56]1.C(N(CC)CC)C>C(Cl)Cl>[C:28]1([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([S:43]([C:46]3[CH:47]=[CH:48][C:49]([C:50]([NH:8][CH2:12][CH:13]4[CH2:14][CH2:15][O:55][CH2:56]4)=[O:51])=[CH:53][CH:54]=3)(=[O:45])=[O:44])[CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: CNC1CCOC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCOC1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
Add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.2 g, 5.0 mmol, 1.5 equiv) to a solution of 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (1.23 g, 3.26 mmol, 1 equiv), (tetrahydro-furan-3-yl)-methylamine (331 mg, 3.27 mmol, 1.0 equiv), and triethylamine (2.3 mL, 1.7 g, 17 mmol, 5.0 equiv) in anhydr CH2Cl2 (12 mL). After 1 h, rotary evaporate the reaction solution and transfer the resultant residue to a column of silica gel (235 mm×35 mm dia.) and elute (50-90% EtOAc/hex). This yields 486 mg (32.4%) of rac-4-(3-phenyl-indole-1-sulfonyl)-N-(tetrahydro-furan-3-ylmethyl)-benzamide as a yellow foam. MS (m/e): 460.96 (M+1); 459.04 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][NH2:14].[BH4-].[Na+].C(=O)(O)[O-].[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][N:14]([CH3:13])[C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a flask with 2-fluoro-5-nitrobenzaldehyde (2 g, 11.83 mmol) in MeOH (60 mL) was added methylamine (33% in EtOH, 2.94 mL, 23.65 mmol). The reaction mixture was stirred at rt for 2 h, cooled to 0° C. Sodium borohydride (0.895 g, 23.65 mmol) was added and the mixture was stirred at rt for 1 h. Solvent was removed and the residue was suspended in THF (60.0 mL) and water (30.0 mL). The mixture was treated with sodium bicarbonate (2.98 g, 35.5 mmol), cooled to 0° C., and then CBZ-Cl (2.195 mL, 15.37 mmol) was added dropwise. The mixture was stirred rt overnight. The solvent was removed and the residue was dissolved in EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 13A (3.6 g, 11.31 mmol, 96% yield) as a yellow oil. MS (ESI) (m/z): 341 (M+Na)+. 1H NMR (400 MHz, chloroform-d) δ ppm 8.04-8.28 (m, 2H) 7.28-7.50 (m, 5H) 7.21 (t, J=8.34 Hz, 1H) 5.19 (d, J=8.84 Hz, 2H) 4.51-4.68 (m, 2H) 3.01 (br. s., 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:24][C:25]#[CH:26])[C:13]([NH:15][CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]([NH3+:64])[C:60]([O:62][CH3:63])=[O:61])=[N+:50]=[N-:51].CCN(C(C)C)C(C)C>CN(C=O)C>[N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]([C:60]([O:62][CH3:63])=[O:61])[NH:64][C:17](=[O:19])[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:15][C:13](=[O:14])[CH:12]([CH2:24][C:25]#[CH:26])[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:50]=[N-:51]
Reactant: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)O
Reactant: COC(=O)C([NH3+])CCC(=O)NCCCN=[N+]=[N-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)NCCCN=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of compound 4 (11.7 g; 31 mmol) in dry DMF (100 mL) was added EDCI (7.25 g; 37.82 mmol), HOBt (5.79 g; 37.82 mmol), and the reaction mixture was stirred at room temperature for 30 min (solution A). In the meantime, to a solution of compound 9 (8.67 g: 31 mmol) in dry DMF (100 mL) kept at 0° C. was added DIEA (10.01 g; 77.7 mmol) and stirred for 30 min (solution B). Solution B was mixed with solution A and the reaction mixture was stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (300 mL) and washed sequentially with saturated sodium bicarbonate (2×75 mL), 5% HCl (2×75 mL) and brine (75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, yielding a crude product which was purified using recrystallization to yield 9 as an off white solid (8.3 g; 46% yield). NMR (CDCl3) δ 8.1 (s, 1H), 7.9 (s, 1H), 7.8 (s, 1H), 7.5 (s, 1H) 7.3 (m, 5H), 5.0 (s, 2H), 4.3 (m, 1H), 4.1 (m, 1H), 3.3 (t, 1H), 2.8 (s, 1H), 2.4 (d, 2H), 2.2 (d, 2H), 2.1 (m, 2H), 1.9 (m, 2H), 1.8 (m, 2H), 1.6 (m, 2H), 1.4 (m, 1H), 0.8 (d, 6H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([SH:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O[C:23]([C:25]1[S:26][C:27]([CH:30](O)[CH3:31])=[CH:28][CH:29]=1)=[O:24])C.Cl.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][NH2:39]>>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][NH:39][C:23]([C:25]1[S:26][C:27]([CH:30]([S:18][C:14]2[CH:13]=[C:12]([CH3:19])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)=[C:16]([CH3:17])[CH:15]=2)[CH3:31])=[CH:28][CH:29]=1)=[O:24]
Reactant: Cc1cc(S)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)c1ccc(C(C)O)s1
Reactant: COC(=O)CCN
Agent: Cl
Product: COC(=O)CCNC(=O)c1ccc(C(C)Sc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1

Procedure:
This compound is made by the general method as exemplified in Preparation 107 using 4′-tert-butyl-2,6-dimethyl-biphenyl-4-thiol and (±)-5-(1-hydroxy-ethyl)-thiophene-2-carboxylic acid ethyl ester in Step A and 3-amino-propionic acid methyl ester hydrochloride salt in Step C as the starting materials to provide (±)-3-({5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.279 g) as a white foam. MS (ES): 508.3 [M−H]−.
Reaction SMILES: [C:1]1([S:7][C:8]2[S:18][C:11]3=[N:12][CH:13]=[C:14]([CH3:17])[C:15](=[O:16])[N:10]3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19]OS([O-])=O.[K+].C(Cl)(Cl)Cl.[OH2:29]>CO>[C:1]1([S:7]([C:8]2[S:18][C:11]3=[N:12][CH:13]=[C:14]([CH3:17])[C:15](=[O:16])[N:10]3[N:9]=2)(=[O:19])=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cnc2sc(Sc3ccccc3)nn2c1=O
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cnc2sc(S(=O)(=O)c3ccccc3)nn2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
In 165 ml of methanol, 4.1 g of 2-phenylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. A dispersion of 40.3 g of OXONE® suspended in 165 ml of water was added to the methanol solution, and the resulting mixture was warmed to 60° C. and stirred for 2 hours. After cooling, chloroform was added for extraction, the organic layer was washed with a sodium thiosulfate aqueous solution, a sodium hydrogen carbonate aqueous solution and water respectively. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was recrystallized from a toluene/ethanol (1:1) mixture and thus 1.2 g of 2-benzenesulfonyl-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[Br:18]Br>O.CC(O)=O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncccc1N
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(Br)ccc1N
Reaction time: 1.5 h

Procedure:
To a suspension of ethyl 3-aminopyridine-2-carboxylate (39.96 g, 241 mmol) in water (330 ml) was added H2SO4 (8 ml) and AcOH (16 ml). To this solution was added a solution of bromine in AcOH (84 ml) at ambient temperature under vigorous stirring so that the internal temperature remained around 25° C. After all bromine was added, stirring was continued for 1.5 h then the orange suspension was filtered giving ethyl 3-amino-6-bromo-pyridine-2-carboxylate.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])[CH2:2]2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.0 g, 33.0 mmol; from Preparation B above) and triethylamine (6.8 mL, 36 mmol) were dissolved in CHCl3 (80 mL) and cooled to 0° C. N-(Benzyloxycarbonyloxy)succinimide (9.0 g, 36.1 mmol), dissolved in CHCl3 (70 mL), was slowly added 0° C. The solution was allowed to reach r.t, and was stirred at r.t overnight. CHCl3 (200 mL) was added and the solution was washed with water, then dried and evaporated. The residue was then dissolved in ether and washed with 2 M HCl in order to remove any remaining unreacted starting material. Drying and evaporation gave 10 g (88%) of the sub-title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH:10]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:36]1([C:42]2[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=2[C:44](Cl)=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(C2C=CC=CC=2)C(C(O)=O)=CC=CC=1>C1COCC1.O>[OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:17][CH:18]=2)[C:9](=[O:11])[CH:10]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: O=C(O)c1ccccc1-c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a cold (ice-bath) solution of 2-(2-hydroxyethyl)-5-(4-aminobenzyl)-1,5-benzothiazepine-4-one as prepared in Example 21 (0.865 g, 2.6 mM) in dry THF was added N,O-bis(trimethylsilyl)acetamide (1.16 ml, 5.2 mM). After 1 hour, 2-phenylbenzoyl chloride (0.570 g, 2.6 mM), prepared from 2-biphenylcarboxylic acid as described in Example 3, was added and stirring was continued for an addition hour. Water (80 ml) was added and the mixture was extracted with ethyl acetate (2×80 ml). The organic extract was dried (MgSO4), filtered and evaporated in vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 30% EtOAc in CH2Cl2) yielded the desired product as a white solid (1.1 g, 83%) m.p.116-120° C. 1H NMR (300 MHz, DMSOd6) δ7.8 (d, J=7 Hz, 1H); 5.09(d, J=15 Hz, H); 4.89(d,J=15 Hz,1H); 3.79 (m, 3H); 2.69-2.24(m, 2H); 1.71 (m, 2H); m/z (MH+)509.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)#[CH:2].C([Li])CCC.[CH3:23][O:24][C:25](=[O:40])[CH2:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31]([CH:36]=[O:37])=[CH:30][C:29]=1[O:38][CH3:39].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:23][O:24][C:25](=[O:40])[CH2:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31]([C:36](=[O:37])[C:2]#[C:1][C:3]2[CH:8]=[C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[C:6]([O:14][CH3:15])=[CH:5][C:4]=2[O:16][CH3:17])=[CH:30][C:29]=1[O:38][CH3:39]
Reactant: COC(=O)COc1c(OC)cc(C=O)cc1OC
Reactant: C#Cc1cc(-c2cccs2)c(OC)cc1OC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Li]CCCC
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)COc1c(OC)cc(C(=O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
Ex-3: A solution of 2-(5-ethynyl-2,4-dimethoxy-phenyl)-thiophene (1.0 g, 4.09 mmol) from Ex-1B in THF (35 mL) was cooled to −78° C. n-Butyllithium (4.62 mmol, 1.85 mL of a 2.5 M solution in hexanes) was added over 15 min while maintaining an internal temperature below −50° C. After aging for 15 min at −78° C., the reaction was transferred via cannula over 5 min to a cold (−78° C.) solution of (4-formyl-2,6-dimethoxy-phenoxy)-acetic acid methyl ester (1.15 g, 4.52 mmol) from Ex-3A in THF (25 mL). The resulting solution was slowly warmed to room temperature and then quenched with a saturated NH4Cl solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure The resulting crude {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-1-hydroxy-prop-2-ynyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester was dissolved in dichloromethane (50 mL), charged with pyridinium dichromate (3.00 g, 7.97 mmol) and aged at room temperature under nitrogen for 2.5 h. The reaction was then filtered through a pad of celite using additional dichloromethane and then ethyl acetate. The combined organic was concentrated under reduced pressure. Silica gel chromatography (ethyl acetate/hexane, 3:2) gave 1.0 g (49%) of the desired {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester as a yellow solid, m.p. 153–155° C. 1H-NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.60 (s, 2H), 7.41 (dd, 1H, J=3.6 and 1.5 Hz), 7.35 (dd, 1H, J=5.3 and 1.5 Hz), 7.09 (dd, 1H, J=5.3 and 3.6 Hz), 6.54 (s, 1H), 4.77 (s, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.97 (s, 6H), 3.82 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=3)=[C:10]([CH:12]=2)[NH2:11])=[CH:2]1.[CH:23](O)=O>>[C:20]([C:16]1[CH:15]=[C:14]([N:13]2[C:9]3[CH:8]=[CH:7][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[CH:12][C:10]=3[N:11]=[CH:23]2)[CH:19]=[CH:18][CH:17]=1)([OH:22])=[O:21]
Reactant: Nc1cc(-c2ccoc2)ccc1Nc1cccc(C(=O)O)c1
Reactant: O=CO
Product: O=C(O)c1cccc(-n2cnc3cc(-c4ccoc4)ccc32)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
To 13r from Example 4 (2.4 g, 8.16 mmol) is added formic acid (25 ml) and the mixture is stirred at 80° C. for 1.5 hours. After cooling the mixture is poured into ice-water. The precipitate is filtered off, washed with methanol and dried to yield 14r (0.89 g, 40%). Mp 272-274° C.
Reaction SMILES: [CH2:1]([O:17][CH:18]([CH3:23])[CH:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:21][CH2:20][CH:19]([OH:22])[CH:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)CO
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOC(C)C(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.3 %

Procedure:
In 100 ml of dry dimethylformamide, 17.67 g of 3-hexadecyloxybutane-1,2-diol was treated with 2.36 g of 60% sodium hydride under chilling with ice. To the chilled mixture was added 6.77 g of benzyl chloride, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was recovered in a conventional manner and purified by silica gel column chromatography to give 4.33 g of 1-benzyloxy-3-hexadecyloxy-2-butanol.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@H:33]1[NH:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][CH2:34][C@H:33]3[CH3:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCNC[C@H]3C)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (R)-3-methylpiperazine-1-carboxylic acid, tert-butyl ester and the product purified by HPLC.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[NH2:25][C:26]1[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=1[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:25][C:26]3[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=3[CH3:31])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Cc1nn(C)c(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2c(C)nn(C)c2C)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 371 mg, 1.00 mmol), 4-amino-1,3,5-trimethylpyrazole (375 mg, 3.00 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 150° C. for 16 hr. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 0-5% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (340 mg, 0.74 mmol, 74%) as a colorless solid.