Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[F:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncccc1F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of 9.59 g of 2-chloro-3-fluoropyridine in 6 ml of ethanol there was added 6 ml of hydrazine monohydrate, and the mixture was stirred at 60° C. for 3 days. The solution was adsorbed onto 50 g of NH silica gel and purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (403 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][C:12]2([C:17]([OH:19])=O)[CH2:14][CH2:15][CH2:16][CH:11]2[C:10]1=[O:20].C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40]>C1COCC1>[F:35][C:36]([F:48])([F:49])[C:37]1[CH:38]=[C:39]([NH:40][C:17]([C:12]23[CH2:14][CH2:15][CH2:16][CH:11]2[C:10](=[O:20])[N:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:13]3)=[O:19])[CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1CC2(C(=O)O)CCCC2C1=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC2(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2C1=O
Temperature: 75 °C
Yield: 55 %

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylic acid (86 mg, 0.3 mmol) and diisopropylethyl amine (104 μL, 0.6 mmol) in THF, methanesulfonyl chloride (32 μL, 0.4 mmol) was added. The mixture was treated with 3,5-bis(trifluoromethyl)aniline (137 mg, 0.6 mmol) and heated at 75° C. for 3 h. After evaporating the solvent, the crude product was applied on C18 preparative HPLC column and eluted with acetonitrile/water solvent system (5-80% acetonitrile gradient with 0.1% TFA). After neutralization and solvent evaporation of the combined product containing fractions, 80 mg of N-(3,5-bis(trifluoromethyl)phenyl)-2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxamide was obtained (53% yield). 1H NMR (400 MHz, CDCl3) δ□1.72-1.84 (m, 1H), 1.94-2.04 (m, 1H), 2.09 (s, 3H), 2.18 (s, 3H), 2.24-2.40 (m, 4H), 3.43 (d, 1H, J=11 Hz), 3.52-3.58 (m, 1H, 4.06 (d, 1H, J=11 Hz), 7.00-7.17 (m, 3H), 7.61 (s, 1H) 8.13 (s, 2H), 8.61 (s, 1H). LC-MS: Rt (retention time)=2.99 min, MS: (ES) m/z 485 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:33]1[CH2:37]OC[CH2:34]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:3]=1[CH:18]([CH2:34][CH2:33][CH3:37])[C:19]([O:21][CH3:22])=[O:20]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1C(C)(C)C)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1C(C)(C)C)CCC3
Yield: 46.1 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.067 g; 0.211 mmol), LHMDS 1N in THF (0.232 mL; 0.232 mmol), 1-iodopropane (0.031 mL; 0.317 mmol) in DMF (0.85 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.035 g (46%) of the title compound as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[CH2:11]([Li])CCC.COS(OC)(=O)=O.[Cl-].[NH4+]>C(OCC)C>[CH3:11][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: [Li]CCCC
Reactant: c1csc(-c2cccs2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: Cc1ccc(-c2cccs2)s1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a stirred solution of 32.0 grams (0.193 mole) of 2,2'-bithienyl in 150 mL of diethyl ether was cooled to -5°0 C., and 90.5 mL (0.226 mole--2.6M in hexanes) of n-butyllithium was added slowy dropwise. Upon completion of addition the reaction mixture was stirred at -5° C. for one hour, and then a solution of 27.8 grams (0.220 mole) of dimethylsulfate in 75 mL of diethyl ether was added very slowly dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 18 hours. After this time the reaction mixture was poured into 350 mL of an aqueous 10% ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined extracts were washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 30.0 grams of 5-methyl(2,2'-bithienyl); b.p. 108°-113° C./1.9 mm.
Reaction SMILES: [CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:29])[CH3:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[OH-].[Na+].C(OC(=O)C1C=CC(C#CC2C=CC3C(NC4CC4)CCC(C)(C)C=3C=2)=CC=1)C>C(O)C.O1CCCC1>[CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:28])[CH3:29])[CH2:5][CH3:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C(C)C)c2)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3NC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(Cc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (600.0 mg,1 5.0 mmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55° C. for 9 hours. Work-up followed by crystallization of the solid residue from hot CH3CN afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:13]C(OCC1C=CC=CC=1)=O)=[CH:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH2:13])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2
Reactant: COC(=O)C(=CC1CC2CCC1C2)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)CC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
In a flask was placed 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-2-yl-acrylic acid methyl ester (491 mg, 1.49 mmol) and methanol (15 mL). To this mixture added 10% palladium on activated carbon (60 mg) and the flask was fitted with a balloon filled with hydrogen. The mixture was allowed to stir at 25° C. for 1 h and then filtered through celite and concentrated in vacuo to afford 2-amino-3-bicyclo[2.2.1]hept-2-yl-propionic acid methyl ester (206 mg, 70%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]4[CH2:41][CH2:40]4)=[O:38])[N:35]=3)[CH:32]=2)=[C:24]([F:44])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:22]([NH:21][C:7]([C:6]5[C:2](=[O:1])[N:3]([C:15]6[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=6)[N:4]([CH2:10][C:11]([F:12])([F:13])[F:14])[CH:5]=5)=[O:8])=[CH:23][C:24]=4[F:44])=[CH:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: O=C(O)c1cn(CC(F)(F)F)n(-c2ccccc2)c1=O
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)c1cn(CC(F)(F)F)n(-c2ccccc2)c1=O
Yield: 77.6 %

Procedure:
Using 3-oxo-2-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (210 mg, 0.72 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (170 mg, 0.52 mmol), HATU (280 mg, 0.72 mmol), diisopropylethylamine (200 mg, 1.6 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (240 mg, 77%) was obtained as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C([NH+](CC)CC)C>C1COCC1>[C:13]([N:1]1[CH:5]=[N:4][N:3]=[N:2]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1cnnn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirring suspension of 1H-tetrazole (7.0 g, 0.1 mol) and triethylamine (15 ml, 0.12 mol) in anhydrous THF (300 ml), in a bath maintained at 0° C., was added benzoyl chloride (99%, 12.8 ml, 0.11 mol) slowly over 30 min. When addition was complete, the mixture was stirred for an additional 45 min. A precipitate formed, identified as triethylammonium hydrochloride (using NMR spectroscopy), was removed by filtration through a pad of Celite 545. The solvent was removed under reduced pressure while the bath temperature was maintained below 30° C. A residual oil was obtained. Crystallization of the residual oil in hexanes yielded N-benzoyltetrazole as colorless crystals. The crystals were removed by filtration, washed with hexanes (2×15 ml) and dried under vacuum for approximately 15 hours at room temperature. Yield: 15 g, 86%; m.p. 56-58iC; 1H NMR, (CDCl3) δ 9.43 (s, 1H), 8.26-8.22 (d, J=, 2H), 7.79-7.54 (m, 3H); 13C NMR, (CDCl3) 162.9, 143.7, 136.3, 132.7, 129.7 and 129.5. HRMS: (FAB) for C8H7N4O (MH+) 175.0620, found 175.0627.
Reaction SMILES: [F:1][C:2]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([C:15]([O:17]CC)=[O:16])=[C:12]([CH3:14])[N:13]=2)[N:6]=[N:5]1.O.[OH-].[Li+]>O1CCCC1.O>[F:26][C:2]([F:1])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)[N:6]=[N:5]1
Reactant: CCOC(=O)c1sc(-c2cn(CC(F)(F)c3ccccc3)nn2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cn(CC(F)(F)c3ccccc3)nn2)sc1C(=O)O
Yield: 84 %

Procedure:
To a solution of ethyl 2-(1-(2,2-difluoro-2-phenylethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate (0.13 g, 0.34 mmol) in a mixture of tetrahydrofuran (8 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.05 g, 1.24 mmol). The reaction mixture was heated to reflux for 17 hours. The solvent was removed in vacuo, and the residue was neutralized to pH 4˜5 with 10% hydrochloric acid. The resulting precipitate was collected by filtration and dried to afford the title compound as a white solid (0.10 g, 84%): MS (ES+) m/z 349.1 (M+1).
Reaction SMILES: [CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[CH:50]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[O:48][N:47]=1>>[C:51]([C:49]1[O:48][N:47]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[CH:50]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)on5)c5ccccc54)cn23)CC1)(C(C)C)C(C)C

Procedure:
Intermediate 14e was reacted with (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (WO 2006/091671, which is incorporated herein by reference in its entirety) in an analogous manner to that described in Example 14 step f to give the title compound. LCMS (Method 3): Rt: 5.43 min, m/z 717 [MH+].
Reaction SMILES: CO[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[S:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1.B(Br)(Br)[Br:19]>C(Cl)Cl.O>[Br:19][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[S:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: BrB(Br)Br
Reactant: COCCc1ccc2sc(S(N)(=O)=O)cc2c1
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
To a solution of 5-(2-methoxyethyl)-2sulfamoylbenzo[b]thiophene (8.3 g, 0.031 mol) in 550 ml of methylene chloride at -78° C. was added dropwise under nitrogen, 100 ml of a solution of boron tribromide (BBr3) (lM in hexane, 0.1 mol). The reaction was stirred at room temperature overnight (15 hours) following the addition. The mixture was cooled and diluted with 100 ml of cold water. The aqueous phase was separated and extracted 2X with methylene chloride. The original organic phase and the extracts were combined, dried, filtered and concentrated to dryness to yield 8.3 g (86%) of product with m.p. 118°-120° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[CH:9][CH:10]=1.[Br:18]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:18][C:8]1[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1nccs1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nccs1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
t-Butyl 2-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (6.70 g, 26.8 mmol) synthesized in Example (1f) was dissolved in tetrahydrofuran (100 mL) and cooled to 0° C. With stirring under nitrogen atmosphere, N-bromosuccinimide (4.79 g, 26.9 mmol) was divided into 5 parts to be added every 10 minutes, followed by further stirring at 0° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and extraction was carried out with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-16%) to afford the desired compound (7.55 g, yield 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]=[S:27]>CS(C)=O.O>[CH3:24][C:23]1[C:18]([C:16]([NH:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:28](=[O:29])[O:30][CH2:31][CH3:32])=[S:27])=[N:7][CH:6]=2)=[O:17])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)N=C=S
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3ncccc3C)c2)cn1
Yield: 77 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (1.84 g, 5.75 mmol) in DMSO (20 mL) was added dropwise with stirring under ice-cooling ethyl isothiocyanatoformate (0.75 mL, 6.35 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (25%→40% ethyl acetate-hexane) to give the title compound (2.00 g, 77%) as a white solid.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:18]([OH:20])=[O:19])[CH2:11][C@@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(O)C>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:8][C@@:9]1([C:18]([O:20][CH2:22][CH3:23])=[O:19])[CH2:11][C@@H:10]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)C[C@@H]1c1ccccc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@]1(N)C[C@@H]1c1ccccc1

Procedure:
The title compound was prepared by standard methods, by esterifying commercially available (1S,2R)-1-[(tert-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid with ethanol and subsequent Boc detachment with trifluoroacetic acid.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])C>O1CCCC1>[CH:3]1([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[O:15][CH:20]([CH3:21])[C:19]([OH:23])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Oc1cccc(C2CCCCC2)c1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Oc1cccc(C2CCCCC2)c1)C(=O)O
Reaction time: 16 h

Procedure:
11 g of a 55% oily sodium hydride dispersion are deoiled with petroleum ether in an atmosphere of nitrogen, and 500 cc of dry tetrahydrofuran are then added. 44 g of 3 -cyclohexyl-phenol in 500 cc of dry tetrahydrofuran are added dropwise within approximately 30 minutes while stirring. 46 g of 2-bromopropionic acid ethyl ester are then added dropwise while stirring. The reaction mixture is heated to 60° for 1 hour and is then allowed to stand at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is divided thrice between methylene chloride and water. The aqueous phases are again extracted twice with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate and concentrated. The residue is boiled at reflux for 2 hours in a solution of 50 g of potassium hydroxide in 900 cc of methanol and 100 cc of water. The reaction solution is concentrated to a great extent by evaporation, acidified to pH = 2 with 2 N hydrochloric acid and extracted thrice with methylene chloride. The organic phases are washed once with water, combined, dried over anhydrous sodium sulphate and concentrated. Recrystallization of the residue from petroleum ether yields 2-(3-cyclohexyl-phenoxy)propionic acid having an M.P. of 81°-82°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH2:20])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2)n1
Yield: 94.3 %

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine [0.7 g, Intermediate (4)], 2-(4-chlorophenyl)-ethylamine (0.66 g) and sodium bicarbonate (0.88 g) in EtOH (25 ml) is heated at 80° C. for three hours, poured into water (400 mL) and the solid is filtered and air dried affording (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-chlorophenyl)-ethyl]amine [1.1 g, Intermediate (14)]. MS: 299 (M+H). 1H NMR (CD3)2SO]: δ 8 (d, 2H, J=3 Hz); 7.4 (2H, d, J=3 Hz); 6.05 (1H, s); 4 (3H, s): 3.6-3.7 (2H, m); 2.95 (2H, t).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1[OH:21].O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:21][C@@H:13]2[CH2:12][O:16][C@@H:15]3[C@H:17]([OH:20])[CH2:18][O:19][C@H:14]23)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A solution of p-toluenesulfonyl chloride (24.8 g, 130 mmol) in pyridine (150 mL) was added to a stirred solution of isomannide (40) (19.0 g, 130 mmol) in pyridine (150 mL) over 1 hour at 0° C. then stirred at ambient temperature for 1 hour. The mixture was poured onto iced-water (1 L) then extracted with dichloromethane (3×300 mL). The organic phase washed with brine (300 mL), dried (MgSO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 50:50 gave monotosylate (50) (23.4 g, 60%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(=O)C.[K+]>C(O)CCC.O>[F:11][C:12]1[C:17]([C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1ncnc2cc[nH]c12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: Fc1ncccc1-c1ncnc2cc[nH]c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.500 g, 3.26 mmol), 2-fluoropyridin-3-ylboronic acid (0.688 g, 4.88 mmol) and potassium acetate (0.959 g, 9.77 mmol) in 1-butanol (25 mL) and water (5 mL) was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2Cl2(PtBu2Ph)2 (0.0243 g, 0.0391 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 60 min. The brown solution was concentrated in vacuo to a solid residue. The residue was treated with 3:1 CHCl3:IPA (100 mL) and water (70 mL). The mixture was sonicated and the layers separated. The aqueous phase was extracted with 3:1 CHCl3:IPA (50 mL). The combined organic extracts were washed with water (3×70 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 0.74 g crude product as a yellow solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 80% to 100% EtOAc in CH2Cl2, to provide 4-(2-fluoropyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (0.51 g, 73% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 215 [M+H]+.