Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:49]([N:51]=[C:52]=NCCCN(C)C)C.O1CCCC1.CNC>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:49][N:51]([CH3:52])[C:34](=[O:35])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:32][CH2:31]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CN(C)C(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and 2M dimethylamine tetrahydrofuran solution (0.29 mL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (102 mg, yield 60%) as a pale-yellow amorphous solid.
Reaction SMILES: Br[C:2]1C=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1C=CC(C(=O)C)=CC=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][N:37]=[CH:4][CH:5]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)c1ccncc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccncc4)ccc3c1)n2C1CCCCC1
Yield: 62 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-pyridin-4-yl-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (68 mg, 62% yield). MS: 449.19 (M+H+); HPLC Procedure A, retention time=7.98 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH3:14])[N:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>O1CCOCC1>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1)=[N:3][C:4]([C@@H:13]([NH2:15])[CH3:14])=[CH:5]2
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: C[C@H](N)c1cc2cccc(Cl)c2c(N2CCN(C)CC2)n1
Temperature: 25 °C

Procedure:
A solution of (S)-(9H-fluoren-9-yl)methyl 1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate 69 (250 mg, 0.539 mmol, 1.0 eq) and 1-methylpiperazine (108 mg, 1.079 mmol, 2.0 eq) in 1,4-dioxane (5 mL) was stirred at reflux overnight. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3.3% MeOH-DCM) to afford the product (S)-1-(8-chloro-1-(4-methylpiperazin-1-yl) isoquinolin-3-yl)ethanamine 95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].[CH3:27][O:28][C:29](=[O:42])[CH:30](I)[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].S([O-])(O)(=O)=O.[K+]>C1COCC1>[CH3:27][O:28][C:29](=[O:42])[CH:30]([N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1)[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: COC(=O)C(I)CCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 349.6 %

Procedure:
A suspension of 0.313 g (0.100 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 5A) in 10 ml of THF was treated at 0° C. with 0.135 g (0.120 mmol) of potassium tert-butylate. After 10 min, 0.394 g (0.110 mmol) of (rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-iodo-butyric acid methyl ester (intermediate 1) was added. The reaction was stirred 1 h at 0° C., 15 h at RT and then neutralized with cold 10% aq. potassium hydrogensulfate solution and extracted with diethyl ether (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane/ethyl acetate 1:1 to 2:3) to yield 0.19 g (35%) of the titled compound as light yellow viscous oil. MS: 543.3 (MH+, 2Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18]1([CH2:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:24]([NH:25][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
Combined 6-chloronicotinoyl chloride (1.76 g, 10.00 mmol) and DCM (20 mL) and cooled in an ice-bath then triethylamine (2.09 mL, 15.0 mmol) and phenylmethanamine (1.072 g, 10.00 mmol) were added. The reaction was then stirred at room temperature for 3 hours before being diluted in DCM (30 ml), washed with 1N aqueous HCl (50 ml), saturated aqueous sodium bicarbonate (50 ml), brine (50 ml), dried over Na2SO4, and concentrated to give the title compound (2.19 g, 89%) as a light beige solid which was used without further purification. MS m/z [M+H]+ 247.1.
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[O:4][CH2:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CC1(C)C(C)(C)OB([C:22]2[CH:39]=[CH:38][C:25]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:24][CH:23]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.O>[O:10]1[CH2:11][CH2:12][N:7]([C:6]2[CH2:5][O:4][C:3](=[O:13])[C:2]=2[C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:38][CH:39]=2)[CH2:8][CH2:9]1
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: O=C1OCC(N2CCOCC2)=C1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCC(N2CCOCC2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 10.4 %

Procedure:
To a stirred solution of 3-bromo-4-morpholinofuran-2(5H)-one (300 mg, 1.20 mmol) in 2:1 toluene/H2O (8 mL) were added 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (480 mg, 1.33 mmol), Cs2CO3 (1.54 g, 4.23 mmol) and Pd(dppf)Cl2 (197.5 mg, 0.24 mmol). The reaction mixture was then refluxed for 4 h, filtered and the filtrate was partitioned between water and EtOAc. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 40% EtOAc in hexanes to afford 4-morpholino-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (50 mg, 10%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.6 Hz, 1H), 8.04-7.96 (m, 2H), 7.82-7.76 (m, 1H), 7.70-7.67 (m, 1H), 7.65-7.59 (m, 1H), 7.17 (d, J=7.2 Hz, 2H), 7.05 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 4.91 (s, 2H), 3.60 (bs, 4H), 3.19 (bs, 4H). MS: M+H: m/z=403.1; M+Na: m/z=425.2 HPLC: 90%, (Condition-J).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:20])=[C:4](Cl)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1.[ClH:21]>C(O)C.[Zn]>[Cl:21][C:18]1[C:6]2[CH2:7][C@H:8]([C:15]([OH:17])=[O:16])[C@H:9]([C:11]([F:14])([F:13])[F:12])[O:10][C:5]=2[CH:4]=[C:3]([Cl:20])[C:2]=1[Cl:1]
Reactant: Cl
Reactant: O=C(O)C1=Cc2cc(Cl)c(Cl)c(Cl)c2OC1C(F)(F)F
Agent: [Zn]
Solvent: CCO
Product: O=C(O)[C@H]1Cc2c(cc(Cl)c(Cl)c2Cl)O[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6,7,8-trichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (0.28 g, 0.81 mmol, prepared as described in WO98/47890, in ethanol (10 mL) was treated with concentrated HCl (5 mL) and zinc powder (1.21 g, 18.5 mmol). The mixture was stirred at room temperature for 3 hours, filtered, and concentrated in vacuo. The residue was extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a white solid (0.31 g) which was a 3:2 mixture of cis and trans isomers. The isomers were separated by reverse phase HPLC to obtain the desired cis isomer as a white solid (0.11 g, 39%): mp 207.3-208.5° C. 1H NMR (acetone-d6/300 MHz) 7.23 (s, 1H), 5.17-5.31 (m, 1H), 3.58-3.72 (m, 1H), 3.19 (dd, 1H, J=17.9 Hz, 6.5 Hz), 3.10 (dd, 1H, J=17.9 Hz, 7.7 Hz) 19F NMR (acetone-d6/282 MHz) −74.6 (d, J=7.2 Hz). ESHRMS m/z 346.9270 (M−H, Calc'd 346.9256). Anal. Calc'd for C11H6Cl3F3O3: C, 37.80; H, 1.73; Cl, 30.43. Found: C, 37.66; H, 1.75; Cl, 30.71.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: CCCCOP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCCOP(=O)(CCC(N)C(=O)O)Oc1ccccc1
Yield: 74.6 %

Procedure:
Next, 0.64 g (1.19 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[butyl(phenyl)phosphono]butanoate was dissolved in 20 mL of a solvent mixture of methanol and water at 3:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced for 75 minutes. The palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated. The residue was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min, and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[butyl(phenyl)phosphono]butanoic acid (0.28 g, yield 75%) as a colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:16]=2)[CH2:9][CH2:8]1>C1COCC1>[NH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:12]([NH:11][CH2:10][CH:7]3[CH2:9][CH2:8]3)[S:13][CH:14]=2)=[CH:22][N:21]=1
Reactant: N#Cc1ccc(-c2csc(NCC3CC3)n2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-c2csc(NCC3CC3)n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
Add lithium aluminum hydride (75 mg, 2.0 mmol) portionwise over 1 minute to a solution of 5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine-2-carbonitrile (340 mg, 1.3 mmol) in THF (20 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 10 min at room temperature. Quench the mixture successively with water (0.1 mL) and 1N NaOH (0.1 mL). Add sodium sulfate to absorb residual water, filter through Celite®, wash with DCM (30 mL) and concentrate in vacuo. Purify the residue by chromatography on silica gel (12 g) eluting with DCM/2M ammonia in methanol (97:3) to obtain the title compound (180 mg, 52%). MS (ES+) m/z: 261.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30]>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: CC(C)OCCBr
Product: CC(C)OCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21

Procedure:
Using ((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester and 2-(2-bromo-ethoxy)-propane, the title product was prepared in the same manner as described for example 1a (69%). Pink, viscous oil. MS: m/e=411(M+H+).
Reaction SMILES: [C:1](OC1C2C(=CC=CC=2)N(CCC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:28](=[O:42])[C:27]2=[O:43]>>[C:1]([O:43][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=2)[N:29]([CH2:33][CH2:34][CH2:35][N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)[C:28]1=[O:42])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Reactant: O=C1C(=O)N(CCCN2CCOCC2)c2ccc(Cl)cc21
Product: O=C(OC1C(=O)N(CCCN2CCOCC2)c2ccc(Cl)cc21)c1ccccc1

Procedure:
This compound was prepared in a similar way to 2-oxo-1-propylindolin-3-yl benzoate from 5-chloro-1-(3-morpholinopropyl)indoline-2,3-dione. 1H-NMR δ 8.07 (dd, 2H), 7.63 (dd, 1H), 7.53 (dd, 2H), 7.42 (s, 1H), 7.33 (dd, 1H), 7.6.92 (d, 1H), 6.09 (s, 1H), 3.84 (m, 2H), 3.76 (m, 4H), 2.50 (m, 6H), 1.97 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccccc3C(F)(F)F)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([OH:28])([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)(O)CC(=O)O
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (15 mg, 49.7%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-hydroxy-3-methylbutanoic acid.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]1[C:23]2[CH:24]=[C:25]([CH3:33])[C:26]([CH:28]=[CH:29][C:30]([OH:32])=[O:31])=[CH:27][C:22]=2[O:21][N:20]=1)([CH3:3])[CH3:2].O.NN>CO.Cl>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]1[C:23]2[CH:24]=[C:25]([CH3:33])[C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:27][C:22]=2[O:21][N:20]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1C=CC(=O)O
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1CCC(=O)O
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of the above-mentioned 3-[3-[2-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]ethyl]-5-methylbenzisoxazol-6-yl]acrylic acid (75 mg, 0.15 mmol) in MeOH (0.8 mL) was added hydrazine monohydrate (0.15 mL, 3.1 mmol). The mixture was heated reflux for 4 hours, cooled to room temperature, diluted with ice-water and 1M HCl, and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the titled compound as a brown oil (57 mg, yield 78%).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[N+:13]([C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][C:22]([N+]([O-])=O)=[CH:23][CH:24]=3)[CH:19]([CH:32]3[O:36][CH2:35][CH2:34][O:33]3)[C:18]=2[CH:17]=1)([O-:15])=[O:14].CN(C)C=O>C(Cl)Cl>[SH:10][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[C:18](=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:28][CH:27]=3)[CH:19]([CH:32]3[O:36][CH2:35][CH2:34][O:33]3)[C:20]=2[CH:21]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(C1OCCO1)c1cc(S)ccc1-2
Reaction time: 0.5 h

Procedure:
For a period of 0.5 hours, 10 parts of sodium sulfide nonahydrate was added to a solution of 6 parts of 2-(2,7-dinitro-9-fluorenyl)-1,3-dioxolane in 300 parts of dimethylformamide contained within a 1 liter flask at room temperature. The mixture was then stirred for 20 hours, diluted with 1000 parts of methylene chloride, and washed with water in the amount of 4 parts water: 1000 parts methylene chloride.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1.[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]([OH:18])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Cc1ccnc(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccnc(C(O)c2cc(F)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 2-bromo-4-methylpyridine (334 μl, 3 mmol) under ice cooling and the mixture was stirred at room temperature for 60 minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise to the resulting brown solution. The temperature of the reaction mixture was raised gradually to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. After drying the solvent, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (456 mg, 65%) was obtained as needle crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])(=[O:4])=[O:3].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH2:28])[N:21]=1>ClCCl>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:16]([NH:15][S:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:13])=[O:14])=[O:17])[N:21]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CS(=O)(=O)c1ccccc1CS(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.0 g of the product from Example 10 in 30 ml dry dichloromethane was added 1.2 g of 4,6-dimethoxy-2-aminopyrimidine and the yellow homogeneous solution was stirred at room temperature overnight. The desired product, which had precipitated, was collected by filtration, washed with 1-chlorobutane, and dried in vacuo. The yield of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-(methylsulfonyl)phenylmethanesulfonamide, m.p. 180°-182° C., was 2.4 g of white solid.
Reaction SMILES: [CH2:1](N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1)[C:2]1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59](=[O:67])[CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.C1(C2(C(N=C=S)=O)CC2)C=CC=CC=1>>[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59]([C:60]2([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH2:2][CH2:1]2)=[O:67])=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Agent: O=C(N=C=S)C1(c2ccccc2)CC1
Product: O=C(NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)C1(c2ccccc2)CC1
Yield: 41 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 1-phenylcyclopropanecarbonyl isothiocyanate, title compound 192d was obtained in 41% yield. Characterization of 192d is provided in table 18.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:23][C:22]2[C:21]3[C:20]([O:24][CH:25]4[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][C:14]=2[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH2:10][C@@H:11]1[CH2:23][C:22]2[C:21]3[C:20]([O:24][CH:25]4[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:29][CH2:30]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][C:14]=2[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of tert-butyl N-(4-[[(12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (240 mg, 0.43 mmol, 1.00 equiv) in 4 mL of THF was added TBAF (223 mg, 0.85 mmol, 2.00 equiv) and the resulting solution was stirred overnight at 25° C. in an oil bath. The reaction was then quenched with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to provide tert-butyl N-(4-[[(12S)-12-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (172 mg, 90%) as yellow oil. MS: m/z 448 (M+H)+.