Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:11][C:12]1[C@@H:17]([C@H:18]([CH2:20][OH:21])[OH:19])[O:16][C:14](=[O:15])[C:13]=1[OH:22])[CH:7]([CH2:9][OH:10])[OH:8].[CH2:23](Br)[CH:24]=[CH2:25]>O>[CH2:6]([O:11][C:12]1[C@@H:17]([C@H:18]([CH2:20][OH:21])[OH:19])[O:16][C:14](=[O:15])[C:13]=1[O:22][CH2:25][CH:24]=[CH2:23])[CH:7]([CH2:9][OH:10])[OH:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCOC1=C(OCC(O)CO)[C@@H]([C@@H](O)CO)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 152.4 %

Procedure:
Under an argon atmosphere, water and sodium hydrogen carbonate (1.42 g) were added to 3-O-glyceryl ascorbic acid (1.42 g) obtained in Example 1, and the mixture was stirred at room temperature for 30 minutes. To the mixture, allyl bromide (2.45 g) was added, and the resultant mixture was heated up to 60° C. and stirred for 2 hours. Thereafter, the mixture was concentrated under reduced pressure, then, dissolved in methanol. Then, the resultant solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 6.70 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:10/3/0.4), and concentration was performed under reduced pressure to obtain to obtain 3-O-glyceryl-2-O-allyl ascorbic acid (2.51 g).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH3:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4](=[O:15])(=[O:14])[N:3]=1.C(NC1C=CC=CC=1)C.[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:62]=[CH:63][CH:64]=2)[O:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)C2N(C)C3C=CC=CC=3S(=O)(=O)N=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:62]=[CH:63][CH:64]=2)[O:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)[C:2]2[N:7]([CH2:8][CH3:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:4](=[O:15])(=[O:14])[N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCN1C(Cl)=NS(=O)(=O)c2ccccc21
Reactant: COc1ccc(CN(CCCOc2cccc(CN3CCCCC3)c2)C2=NS(=O)(=O)c3ccccc3N2C)cc1
Solvent: CCNc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCN1C(N(CCCOc2cccc(CN3CCCCC3)c2)Cc2ccc(OC)cc2)=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A 0.8 g quantity of 3-chloro-4-ethyl-1,2,4-benzothiadiazine-1,1-dioxide in the form of white crystals prepared in the same manner as in Reference Example 4 with the exception of using N-ethylaniline in place of N-methylaniline was added to a solution of 1.2 g of the N-[3-[3-(piperidinomethyl)phenoxy]propyl]-4'-methoxybenzylamine obtained in Example 1, (iii) in 12 ml of chloroform, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was purified in the same manner as in Example 1, giving 1.67 g of 3-[N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-4'-methoxybenzylamino]-4-ethyl-1,2,4-benzothiadiazine-1,1-dioxide (yield 88% ). This compound was converted to an oxalic acid salt in the same manner as in Example 1 to obtain 1.81 g of a compound 15 in the form of white crystals as listed in Table 1 (yield 92% ). M.p.: 85°~90° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:31]([Mg]Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH2:31]([C:28]1[CH:29]=[C:24]([O:23][C@@H:11]2[CH2:12][C@@H:13]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[C@@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH2:10]2)[N:25]=[CH:26][N:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cc3ccccc3)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (0.264 g, 0.559 mmol) and ferric acetylacetonate (0.0395 g, 0.112 mmol) in THF (9 mL) was added a 1.00 M solution of benzylmagnesium bromide in THF (2.52 mL) and the mixture was stirred overnight. The reaction was quenched using NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to afford the title compound as a clear oil. (0.254 g, 86%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[CH:6]([C:19]([OH:21])=[O:20])[C:5]2=O)[CH2:3][CH2:2]1.C[N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O>C(O)(C)C>[CH3:15][O:14][C:12]1[C:11]([N:24]2[CH2:25][C@@H:26]3[C@@H:27]([CH2:3][CH2:2][CH2:1][NH:4]3)[CH2:28]2)=[C:10]([F:17])[CH:9]=[C:8]2[C:7]([C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:13]=12)=[O:18]
Reactant: CN1CCCC1=O
Reactant: COc1c(F)c(F)cc2c1N(C1CC1)C(=O)C(C(=O)O)C2=O
Solvent: CC(C)O
Product: COc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-methoxy quinolone-3-carboxylic acid (100 grams), (S,S) Diazabicyclo nonane (60 grams) and 1,8-Diazabicyclo[5.4.0.]undec-7-ene(DBU) (10.gms) were added to N-Methylpyrolidinone (250 ml) and the reaction mixture was slowly heated to the 60–70° C. temperature and stirred till the reaction was substantially completed. 5% aqueous isopropyl alcohol was added to the reaction mass, and pH was adjusted towards basic with caustic lye. Then the reaction mass was filtered, through clarifying filter, washed with 5% aqueous isopropyl alcohol. Combined total filtrate and adjusted pH to 7.0 to 7.2 with aqueous Hcl. and isolated at a temperature of 10–15° C. to afford moxifloxacin. Moxifloxacin then treated with Hydrochloric acid in 10% aqueous methanol to yield corresponding hydrochloride salt. (Wet weight: 115 grams)
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\C1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3C=COC=3CO2)=CC=1)(=O)=O)[CH3:2].Br[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([N:48]([C:53]1[C:62]([C:63]([O:65][CH3:66])=[O:64])=[C:61]2[C:56]([C:57]3[CH2:69][CH2:68][O:67][C:58]=3[CH:59]=[N:60]2)=[CH:55][CH:54]=1)[C:49]([O:51][CH3:52])=[O:50])(=[O:47])=[O:46].C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C>>[CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([N:48]([C:53]1[C:62]([C:63]([O:65][CH3:66])=[O:64])=[C:61]2[C:56]([C:57]3[CH2:69][CH2:68][O:67][C:58]=3[CH:59]=[N:60]2)=[CH:55][CH:54]=1)[C:49]([O:51][CH3:52])=[O:50])(=[O:47])=[O:46])[CH3:2]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c3c(cnc12)OCC3
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)N(C(=O)OC)c1ccc2c3c(cnc2c1C(=O)OC)OCC3
Temperature: 60 °C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 9, starting from methyl 7-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,2-dihydro-furo[2,3-c]quinoline-6-carboxylate (Intermediate 21) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 11) and heating at 60° C. for 1 hour.
Reaction SMILES: O.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C1OC1C.II>C1COCC1.C1CCCCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[CH:10][C:11]3[C:12]([C:7]=2[CH:8]=1)=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3
Reactant: Clc1ccc(C=Cc2ccc(Br)cc2)cc1
Agent: CC1CO1
Agent: II
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc2ccc3ccc(Br)cc3c2c1
Reaction time: 24 h
Yield: 100.9 %

Procedure:
A 2 L vessel equipped with a pyrex inner water-cooled jacket was charged with 5.16 g (17 mmol) of 1-bromo-4-[2-(4-chlorophenyl)vinyl]benzene from Step 1, 2 L of cyclohexane, 25 mL of THF, 25 mL of propylene oxide and 6.7 g (26 mmol) of iodine. The stirring solution was degassed by bubbling nitrogen and was exposed to UV light for 24 hrs by inserting a 450 W medium pressure mercury lamp in the inner. The reaction was quenched with 10% Na2S2O3 and aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over Na2SO4 and volatiles were removed under reduced pressure. The residue was swished in a minimal amount of ethyl acetate to afford approx. 5 g of 3-bromo-6-chlorophenanthrene as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([OH:27])([C:24](O)=[O:25])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:29][CH2:30][N:31](C(C)C)C(C)C.C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([OH:27])([C:24]([NH:31][CH2:30][CH3:29])=[O:25])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)[C@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)[C@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-hydroxy-cyclohexanecarboxylic acid, 64c, (0.040 g, 0.090 mmol) was dissolved in DMF (3 mL), then iPr2NEt (0.047 mL, 0.271 mmol) and ethanamine (0.135 mL of 2 M solution, 0.271 mmol) was added, followed by HATU (0.080 g, 0.210 mmol). The reaction was stirred at room temperature for another 2 hours. The solution was evaporated and the product was purified by Preparatory HPLC to afford 10 mg of (1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-N-ethyl-1-hydroxy-cyclohexanecarboxamide, 779.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9].[O:13]1CCC[CH2:14]1>>[CH2:8]([N:10]([CH2:11][CH3:12])[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13])[CH3:9]
Reactant: C1CCOC1
Reactant: Nc1ccccc1
Reactant: CCNCC
Product: CCN(CC)C(=O)Nc1ccccc1
Reaction time: 0.5 h

Procedure:
0.93 g of aniline is added to 3.26 g of 2,4-carbonyldioxy-2,5-diphenylthiophene-1,1-dioxide in 25 ml of dry tetrahydrofuran. The mixture is left to stand for 30 minutes at 20° C., 0.73 g of diethylamine is added and the mixture is left to stand for a further 40 minutes. After distilling off the tetrahydrofuran, the residue is taken up in chloroform and the chloroform solution is washed successively with aqueous 1N hydrochloric acid and twice with aqueous sodium carbonate solution and water. After drying over magnesium sulfate and evaporating under reduced pressure, 1.4 g of slightly yellowish crystals which, as the crude product, have a melting point of 81°-85° C. (melting point quoted in the literature of 85° C.) remain.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH2:25][CH3:26])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40](O)=[O:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([C:40]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH2:25][CH3:26])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:41])[CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: Cl
Product: CCC1(C)C(=O)N(C2CCN(C(=O)c3cc(OCc4ccccc4)ccc3C)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B9) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclo hexane/EA=6:4) to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Into a round bottom flask was combined (R)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (5.0 g, 0.018 mol), palladium on C (0.3 g, 0.003 mol) and methanol (200 mL, 5 mol) (about 80 mL EtOAc was added to dissolve the reactants). The reaction mixture was stirred under hydrogen balloon at room temperature for 40 min. The mixture was filtered over celite, MeOH was removed and a solid was obtained (4.02 g). MS m/z=232.4 (M+1).
Reaction SMILES: C(Cl)CCl.C1C=C[C:8]2N(O)N=[N:11][C:9]=2[CH:10]=1.CCN(CC)CC.[C:22]([O:26][C:27]([NH:29][CH:30]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:31]([OH:35])[C:32]([OH:34])=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(N)CC1>C(Cl)Cl>[CH:9]1([NH:11][C:32](=[O:34])[CH:31]([OH:35])[CH:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:10][CH2:8]1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)O
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
EDC (8.3 g, 43.3 mmol), HOBT (6.6 g, 43.1 mmol) and Et3N (7 ml, 50.2 mmol) were added to a mixture of 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (10.6 g, 35.9 mmol) and cyclopropylamine (3.3 ml, 47.6 mmol) in DCM (300 mL) at 5° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. After cooling to 5° C. more cyclopropylamine (2 ml, 28.5 mmol), EDC (5 g, 26.1 mmol), HOBT (4 g, 26.1 mmol) and Et3N (3.5 ml, 25.1 mmol) were added, the mixture was allowed to warm to room temperature and the stirring was continued overnight. DCM (300 mL) was added, followed by washing with 0.5 M aqueous HCl solution, brine and drying with MgSO4. The crude product was recrystallized from methyl-tert-butylether, the crystals obtained were washed with n-pentane and dried providing the title compound (10.2 g, 85%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.C(O)(C)C.C(=O)=O.[N:16]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[C:17]=[O:18]>C1COCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:17]([NH:16][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:4][CH2:3]1
Reactant: O=C=NC1CCCCC1
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N[C@H]1CC[C@H](NC(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of trans-1,4-diaminocyclohexane (6.15 g, 0.054 mol) in dry THF (500 mL) was cooled to −40° C. in a cooling bath (isopropyl alcohol/dry ice) under inert atmosphere. Isocyanatocyclohexane (6.75 g, 0.054 mol) in dry THF (100 mL) was added slowly under heavy stirring. The resulting mixture was stirred for another 24 h at room temperature. The precipitating white solid was filtrated, suspended in water and acidified to pH 2 (HCl). The emerging clear solution was again filtrated and the filtrate was brought to pH 8 (NaOH) whereupon trans-1-(4-aminocyclohexyl)-3-cyclohexylurea precipitated as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=O.CCO.[NH2:11][C:12]([NH2:14])=[S:13]>>[CH:5]1([C:3]2[N:11]=[C:12]([NH2:14])[S:13][CH:2]=2)[CH2:7][CH2:6]1
Reactant: NC(N)=S
Reactant: O=C(CBr)C1CC1
Solvent: CCO
Product: Nc1nc(C2CC2)cs1

Procedure:
To a 100 mL round-bottomed flask was added 2-bromo-1-cyclopropylethanone (7.9 g, 48 mmol), EtOH (70 mL, 1202 mmol), and thiourea (2.6 mL, 48 mmol). The solution was stirred at reflux for 6 hours. The reaction solution was cooled and concentrated under reduced pressure. The reaction mixture was diluted with water (200 mL), neutralized with NaHCO3, and extracted with EtOAc (3×100 mL). The organic extract was washed with saturated sodium chloride (1×100 mL), water (1×100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 4-cyclopropylthiazol-2-amine. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient (5%→50% n 2 M NH3.MeOH in DCM), to provide 4-cyclopropylthiazol-2-amine (3.2 g, 48% yield), m/z (%): 141.3 (100%, M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]([C:39]1C=[CH:43][CH:42]=[CH:41][C:40]=1O)([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Oc4ccccc4C(C)(C)C)cc3)c2cc1OC
Yield: 92.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(tert-butyl)phenol (39 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (74 mg, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:14])=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][C:9]3=[O:13])[CH:7]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccc(F)c(N2CCCC2=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCN1c1cc(NCc2ccc(Cl)cc2)ccc1F
Yield: 44.1 %

Procedure:
A solution of 1-(5-amino-2-fluoro-phenyl)-pyrrolidin-2-one (0.34 g, 1.8 mmol), 4-chlorobenzaldehyde (0.25 g, 1.8 mmol) and sodium triacetoxyborohydride (0.75 g 3.6 mmol) was stirred in dry dichloromethane (25 ml) overnight. The reaction was quenched with water (25 ml) and the dichloromethane layer separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2) eluting with ethyl acetate/dichloromethane (1:10) to afford the title compound as a yellow oil (253 mg, 44%). HPLC retention time 4.4 min, Mass spectrum (ES+) m/z 319 (M+H).
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:16]=1[C:17]#[N:18]>CN(C)C(=O)C.CCOCC>[Br:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([S:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1Br
Reactant: SC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: N#Cc1c(Br)cccc1SC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of adamantanethiol (1.01 g) in N,N-dimethylacetamide (20 mL) at room temperature was added NaH (0.24 g, 60% in mineral oil) and the reaction was stirred for 10 minutes. 2-Fluoro-6-bromobenzonitrile (1 g) was added and the mixture was heated to 80° C. for 1 hour. The reaction mixture was cooled and diluted with ether (400 mL), and the mixture was washed three times with 1M NaOH solution and once with brine, then dried over sodium sulfate, filtered and concentrated to yield the crude product which was taken on to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[O:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:33][Mg]Br.C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C@:29]([CH3:33])([OH:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A stirred solution of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (21.4 mg, 0.048 mmol) in THF (0.5 ml) was degassed (3×) and placed under nitrogen after being cooled to 0° C. in an ice bath. Methylmagnesium bromide 3.0 M in diethyl ether (0.16 ml, 0.480 mmol) was added to the reaction mixture. After 20 minutes, the reaction mixture was removed from the bath and allowed to warm to room temperature. After 1 hour, the reaction mixture was transferred via pipette into saturated aqueous NaHCO3 (15 ml) before being partitioned between EtOAc (30 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×15 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a colorless residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 80% acetonitrile/water+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C25H22ClN3O4 463.13 observed m/e: 464.12 (M+H)+ (Rt 1.19/2 min); 1H NMR δ (ppm) (CD3OD): 8.00 (s, 1H), 7.74-7.78 (m, 4H), 7.71 (d, J=7.4 Hz, 2H), 7.49 (t, J=7.7 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 5.60 (qt, J=5.1 Hz, 1H), 5.00 (t, J=5.2 Hz, 1H), 4.13-4.19 (m, 2H), 4.07 (d, J=4.8 Hz, 1H), 3.70 (d, J=8.1 Hz, 1H), 3.54 (d, J=8.1 Hz, 1H), 1.32 (s, 3H).