Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:29][C:28]([F:32])([F:31])[F:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: NCC(F)(F)F
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCC(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.56 g, 1.44 mmol) in CH3CN, was added neat 2,2,2-trifluoroethylamine (0.236 g, 1.74 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3 h). The reaction was quenched with saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of 1:1 EtOAc and hexanes, providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(2,2,2-trifluoroethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.576 g, 81% yield). 1H NMR (500 MHz, CDCl3) δ 2.00 (6H, s), 2.04 (s, 3H), 3.87-3.90 (m, 1H), 4.03-4.11 (m, 1H), 4.20-4.26 (m, 2H), 4.36 (s, 1H), 5.07 (t, 1H, J=9.6 Hz), 5.27 (t, 1H, J=9.8 Hz), 5.73 (d, 1H, J=8.5 Hz), 6.75 (s, 2H).
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].CI>CN(C=O)C>[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (2.6 g, 6.98 mmol) in dry DMF (75 ml) was added NaH (0.35 g, 8.38 mmol 60% in mineral oil) and the resulting mixture was stirred for 1 hr. Methyl iodide (521 μl, 8.38 mmol) was added and the stirring was continued for an additional 1 hr. The reaction mixture was quenched with water (50 ml) followed by extraction with diethyl ether (2×50 ml). The combined organic phases were washed with saturated aqueous ammonium chloride, dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (40 ml) and TFA (25 ml) was added. The resulting mixture was stirred for 18 hrs. at room temperature and evaporated in vacuo. To the residue was added water (10 ml) and the pH was adjusted to 9 by addition of 1 N sodium hydroxide. The aqueous phase was extracted with diethyl ether (2×25 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo affording 2.5 g crude product which was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording a slowly crystallizing oil which was washed with diethyl ether (10 ml), filtered off and dried in vacuo at 50° C. afforded 0.9 g (45%) of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[C:16]2=[O:31]>C(O)CCC>[CH3:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:30])[C:23]=1[N:17]1[C:16](=[O:31])[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([NH:12][C:2]3[N:11]=[C:10]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[CH:14]=2)[C:18]1=[O:22]
Reactant: Cc1cccc(C)c1N1C(=O)c2ccc(N)cc2C1=O
Reactant: Clc1ncc2ccccc2n1
Solvent: CCCCO
Product: Cc1cccc(C)c1N1C(=O)c2ccc(Nc3nc(-c4ccccc4)c4ccccc4n3)cc2C1=O
Yield: 42.5 %

Procedure:
A mixture of 2-chloroquinazoline (0.62 g, 2.6 mmol) and 5-amino-2-(2,6-dimethylphenyl)isoindoline-1,3-dione (0.69 g, 2.6 mmol) in n-butanol (10 mL) was heated at 120° C. until all of the butanol had evaporated. Additional butanol (10 mL) was added and the process repeated twice. After the reaction mixture was cooled, water was added (20 mL). A precipitate which formed was collected by suction filtration. N,N-Dimethylacetamide (5 mL) was added to dissolve the solid which was purified by preparative reverse-phase HPLC to give 2-(2,6-dimethylphenyl)-5-[(4-phenylquinazolin-2-yl)amino]-1H-isoindole-1,3(2H)-dione (0.26 g, 21%). 1H NMR (400 MHz, DMSO-d6): δ10.88 (s, 1H), 8.80 (m, 1H), 8.42 (m, 1H), 7.96 (m, 1H), 7.90 (m, 2H), 7.85 (m, 1H), 7.81 (m, 2H), 7.65 (m, 3H), 7.50 (m, 1H), 7.32 (m, 1H), 7.25 (m, 2H), 2.10 (s, 6H). MS (EI) for C30H22N4O2: 471.0 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[CH2:21][CH3:22])=[O:13])[CH3:22]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CCc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1CC
Yield: 33.6 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-ethylaniline (1.40 g, 11.6 mmol) in 12 mL of pyridine. The crude product was recrystallized from acetonitrile-DMF to yield 1.0 g of the title compound, mp 255°-256° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure BH above and using 3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(NC(N)=S)cc1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(Nc2ccc(C)c(O)c2)n1
Yield: 65 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 1-(3-hydroxy-4-methylphenyl)thiourea (100 mg, 0.59 mmol) and ethyl 3-bromopyruvate (0.074 mL, 0.59 mmol) in dry DMF (2.4 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 65% yield (105 mg).
Reaction SMILES: Cl[C:2]1[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:3]=2[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5])[CH2:25][CH2:24]1
Reactant: O=C(OCC(F)(F)F)c1ccc(OCC(F)(F)F)nc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc(OCC(F)(F)F)ccc2C(=O)OCC(F)(F)F)CC1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (0.71 g, yellow oil) from 2,2,2-trifluoroethyl 2-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (0.75 g, 2.04 mmol, Step-1 of Amine-37) and 1-methylpiperazine instead of morpholine by the similar manner in Step-2 of Amine-37.
Reaction SMILES: Cl.C([O:6][C:7](=[O:37])[CH2:8][N:9]([S:19]([C:22]1[CH:31]=[C:30]2[C:25]([C:26]([Cl:36])=[CH:27][N:28]=[C:29]2[NH:32][C:33]([NH2:35])=[NH:34])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(C)(C)C>C(C(O)=O)(F)(F)F.C1(C)C=CC=CC=1>[Cl:36][C:26]1[C:25]2[C:30](=[CH:31][C:22]([S:19]([N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH2:8][C:7]([OH:37])=[O:6])(=[O:20])=[O:21])=[CH:23][CH:24]=2)[C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[N:28][CH:27]=1
Reactant: COc1cccc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1cccc(CN(CC(=O)O)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-methoxybenzyl)glycine t-butyl ester hydrochloride (95 mg, 0.167 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was dissolved in EtOAc and stirred at room temperature for 1 h. The resulting precipitate was collected by filtration, washed with Et2O and dried to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-methoxybenzyl)glycine (65 mg, 0.128 mmol) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[NH:13])[NH2:12])[CH:5]=[CH:6][C:7]=1[F:8].[OH:14]/[CH:15]=[C:16](/[CH2:21][C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1)\[C:17](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][CH2:10][C:11]1[NH:12][CH:17]=[C:16]([CH2:21][C:22]2[CH:23]=[N:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=2)[C:15](=[O:14])[N:13]=1
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Reactant: N=C(N)CCc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(F)c(Br)c3)nc2=O)cn1
Temperature: 130 °C
Yield: 42.8 %

Procedure:
The mixture of 3-(3-bromo-4-fluorophenyl)propanimidamide (3.28 g, 13.38 mmol), methyl (2Z)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (1.5 g, 6.69 mmol) and K2CO3 (2.77 g, 20.07 mmol) in NMP (20 mL) was heated with a microwave reactor at 130° C. for 2 h. The mixture was purified with a reverse phase Biotage to provide the title compound (1.2 g, 40.6% yield). LCMS: rt=2.52 min, [M+H+]=419
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]([OH:23])[C:20]([OH:22])=O)=[O:16])[N:9]=2)=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][CH2:42][NH2:43]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH:19]([OH:23])[C:20](=[O:22])[NH:43][CH2:42][CH2:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCc1ccccn1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCCc1ccccn1)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with 2-(pyridin-2-yl)ethylamine; ESI-MS [M+H]+: 565.2
Reaction SMILES: [C:1]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][N:15]=1)(=O)[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4]C=1.I.[OH2:23]>>[C:16]1([C:13]2[O:12][C:11]([C:1]3[CH:2]=[CH:7][C:6]([OH:23])=[CH:5][CH:4]=3)=[N:15][N:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)c2nnc(-c3ccccc3)o2)cc1
Reactant: O
Agent: I
Product: Oc1ccc(-c2nnc(-c3ccccc3)o2)cc1
Temperature: 130 °C

Procedure:
3.5 g (13.89 mmol) of 2-(p-anisoyl) 5-phenyl 1,3,4-oxadiazole and 100 mL of concentrated HI aqueous solution was mixed under nitrogen and refluxed at 130° C. for 12 hours. The mixture was cooled down to room temperature and 100 mL of deionized water was added. The precipitate was collected by filtration and dried under vacuum, p-(5-phenyl-1,3,4-oxadiazole-2-yl)phenol was obtained. 1H-NMR (acetone-d6, ppm): δ 9.26 (s, 1H), δ 8.15 (m, 2H), δ 8.06 (d, 2H), δ 7.62 (m, 3H), δ 7.07 (d, 2H); mp 256.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([C:14]([OH:16])=[O:15])[NH:4][C:5](N(C)CCCC=C)=[O:6].[CH3:19][C:20]([NH2:27])([CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])[CH3:21]>>[CH3:19][C:20]([NH:27][C:5]([NH:4][C@H:3]([C:14]([OH:16])=[O:15])[C:2]([CH3:1])([CH3:17])[CH3:18])=[O:6])([CH3:21])[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]
Reactant: C=CCCCN(C)C(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=CCCCC(C)(C)N
Product: C=CCCCC(C)(C)NC(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
N-{[(1,1-Dimethylhex-5-enyl)amino]carbonyl}-3-methyl-L-valine was prepared according to the procedure for 3-methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valine (Steps 4-5) by using 2-methylhept-6-en-2-amine instead of N-methylpent-4-en-1-amine in Step 4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[C:10]([O:24][CH3:25])[C:9]([Cl:26])=[C:8]([CH3:27])[C:7]=1[C:28](=[O:30])[CH3:29].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:26][C:9]1[C:8]([CH3:27])=[C:7]([C:28](=[O:30])[CH3:29])[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:11]([O:12][CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[C:10]=1[O:24][CH3:25]
Reactant: C1COCCN1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCCBr)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCCN2CCOCC2)c1OCCC(C)c1ccc(F)cc1
Yield: 88.6 %

Procedure:
Example 22a (40 mg, 0.08 mmol) was reacted with morpholine (0.2 mL, 2.29 mmol) as described under General Procedure G and the crude mixture was purified by flash chromatography (silica-gel, DCM/EtOAc/MeOH 1:0:0, 9:8:2) to afford the title compound (36 mg, 88%) as yellow/brown oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.00 (t, J=6.4 Hz, 2H), 3.94 (t, J=6.7 Hz, 2H), 3.83 (s, 3H), 3.72-3.69 (m, 4H), 3.07-2.95 (m, 1H), 2.46 (s, 3H), 2.45-2.40 (m, 6H), 2.18 (s, 3H), 2.02-1.99 (m, 2H), 1.88-1.79 (m, 2H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 508.3 (M+H+)
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 84.9 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.0.740 mmol), benzylamine (0.5 mL, 4.6 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 207 mg of the product 189. 1H NMR (CDCl3) δ 8.56 (s, 1H), 7.50-7.20 (m, 5H), 5.15-4.95 (m, 2H), 4.35-4.05 (m, 2H), 2.85-2.55 (m, 1H), 2.25-2.05 (m, 1H), 1.90-1.05 (m, 15H); MS: m/z 330 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC.C1CCCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCCCC1
Product: COc1ccc2c(c1)C(O)(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 20 g (0.123 mol) of 6-methoxy-1-indanone in 500 mL of ether cooled to -20° C. was added 72 mL (0.129 mol) of 1.8M phenyllithium in cyclohexane/ether and the mixture was stirred at room temperature for 1 h. An additional (10 mL) phenyllithium solution was added and stirred at room temperature for 1 h. To the reaction mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×250 mL), and the organic layer was dried over sodium sulfate and concentrated in vacuo to afford 32.3 g of crude (contains solvent) 6-methoxy-1-phenyl-indan-1-ol.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][CH2:46][CH2:47][C:48]1[CH:57]=[CH:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[N:49]=1>C1COCC1>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26]([NH:45][CH2:46][CH2:47][C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:49]=2)=[O:27])=[CH:18]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1ccc2ccccc2n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1ccc2ccccc2n1
Temperature: -22 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a stirred solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (1.59 g, 4.0 mmole) in dry THF (50 mL) at -22° C. was added N-methylmorpholine (0.644 g, 6.3 mmole) and isobutyl chloroformate (0.632 g, 4.6 mmole). The mixture was stirred at -22° C. for 1 hour and then a solution of 2-(2-aminoethyl)quinoline (0.690 g, 4.0 mmole) in dry THF (15 mL) was added. After stirring at this temperature 4 hours the reaction mixture was allowed to stir at room temperature 15 hours. The solvent was removed in vacuo and the residue was taken up in EtOAc and washed with 5% citric acid (2×50 mL), water (2×50 mL), 5% NaHCO3 (3×50 mL), water (2×50 mL), and brine (2×50 mL). The organic phase was dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed on silica gel, eluting with EtOAc-n-hexane. The oil obtained was triturated with cold Et2O, yielding the product as an amorphous white solid, (0.38 g, 17%); 1H NMR (CDCl3) δ1.41-1.88 (17H, m), 3.00-3.04 (2H, m), 3.40 (2H, q, J 9.59 Hz), 3.68-3.70 (2H, m), 4.70 (1H, s), 5.43 (1H, br s), 6.90 (1H, d, J 2.23), 6.96-7.22 (4H, m), 7.45-7.55 (2H, m), 7.63-7.70 (2H, m), 7.78 (1H, d, J 8.06), 7.89 (2H, d, J 8.10), 8.03 (1H, d, J 8.46).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]3[O:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(B(O)O)o1
Reactant: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3ccnc(Cl)c3)cc2)o1

Procedure:
A mixture of 4-chloro-N-(2-chloro-4-pyridinyl)benzenesulfonamide (D3) (350 mg, 1 mmol), 5-methylfuran-2-boronic acid (150 mg, 1.2 mmol), sodium carbonate (230 mg, 2.2 mmol) and dichlorobis(triphenylphosphine) palladium(0) (20 mg, 15 mol %) in 1,2-dimethoxyethane (3 ml) and water (1 ml) was microwaved at 120° C. for 20 min. The reaction mixture was partitioned between ethyl acetate (5 ml) and water (5 ml) and the organic phase was dried and evaporated. Purification by column chromatography eluting with 5-50% ethyl acetate in hexanes afforded the title compound (D4), MS (ES+) m/e 349, 351 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([C:11]([O:13]C)=O)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18]>CCO>[OH:18][CH2:17][CH:16]([NH:15][C:3]([C:5]1[C:10]([C:11]([NH:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18])=[O:13])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4])[CH2:19][OH:20]
Reactant: NC(CO)CO
Reactant: COC(=O)c1cccnc1C(=O)OC
Solvent: CCO
Product: O=C(NC(CO)CO)c1cccnc1C(=O)NC(CO)CO
Yield: 124.6 %

Procedure:
Pyridine-2,3-dicarboxylic acid dimethyl ester (2 g, 10.25 mmol) was dissolved in EtOH (5 mL). 2-Amino-1,3-propanediol (1.87 g, 20.5 mmol) was added and the mixture was heated under reflux for 6 h. After cooling the solvent was evaporated and the residue was purified by silica gel chromatography (CHCl3 /MeOH, 7:4) to afford the title compound (4 g, 75%).
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([OH:33])[CH:5]=1)([CH3:3])[CH3:2].[C:34]1([CH2:40][O:41][C:42](=[O:49])[C:43]([CH3:48])([CH3:47])[CH2:44][CH2:45]O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:29])([F:30])[F:31])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:45][CH2:44][C:43]([CH3:48])([C:42]([O:41][CH2:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:49])[CH3:47])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Reactant: CC(C)(CCO)C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCC(C)(C)C(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
A mixture of 4-isopropyl-6-hydroxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (7 g; 14.55 mmol), 4-hydroxy-2,2-dimethylbutyric acid phenylmethyl ester (3.88 g;17.46 mmol), DEAD (3.04 g; 17.46 mmol) was dissolved in 180 ml of THF at 00C and then (Ph)3P (4.575 g; 17.46 mmol) was added at 0° C. The above mixture was stirred overnight at room temperature and concentrated in vacuo, and the residue was purified by column chromatography (2×, silica gel; 12-33% ethyl acetate/hexane;methylene chloride/hexane, 1/4-30/1) to afford 3.65 g (37%) of 4-isopropyl-6-[3-methyl-3-(phenylmethyloxycarbonyl)butoxy]-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3 (2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)2 C(CH3)2CO2Ph) as a solid.