Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:27]([C:26]1[C:22]([C:16]2[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[N:23][O:24][C:25]=1[CH3:30])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCCNC(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
N-t-butyloxycarbonyl-1,4-diaminobutane (985 mg, 5.23 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.43 g, 5.23 mmol) were converted to 2.23 g of the title compound by the procedure of Preparation 1 except that the reaction time was about 18 hours. (100%). EA calculated for: C20H25N3O4ClF: C, 56.41; H, 5.92; N, 9.87. Found: C, 56.12; H, 5.75; N, 9.67. MS(FD) m/z 426 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=O)[C:7]=2[N:17]=1.C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=[CH:26][N+:23]([O-:25])=[O:24])[C:7]=2[N:17]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc2c(n1)c(C=O)c1n2CCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2CCCC1

Procedure:
550 mg (2.39 mmol) of the compound obtained in Step C dissolved in 25 ml of nitromethane are heated at 120° C. for 3 hours in the presence of 460 mg (5.97 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. The organic phase is dried over magnesium sulphate, filtered and evaporated. After washing with a pentane/diethyl ether mixture, the title compound is obtained in the form of a brown solid.
Reaction SMILES: [CH2:1]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.C1(N(C2CCCCC2)[C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[C:30](C)[CH:29]=2)CCCC1>C1COCC1>[CH2:1]([N:7]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC1CCCCC1
Reactant: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCN(C(=O)c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C. to 5° C.) stirred solution of N-n-hexyl-N-cyclohexyl amine (4.40 g, 24 mmol) and triethylamine (2.5 g, 24 mmol) in dry THF (50 mL) is added dropwise a solution of acid chloride (5.0 g, 23 mmol) in THF (20 mL). The reaction is stirred at room temperature overnight and worked up in the same manner as for 4-bromo-3-methylbenzoic acid N-cyclopentyl-N-cyclohexyl amide. The crude product is purified by either recrystallization or by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[S:11][C:12]3[CH2:23][CH2:22][CH2:21][CH2:20][C:13]=3[C:14]=2[C:15](OCC)=[O:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][NH2:25]>>[CH:1]1([C:7]([NH:9][C:10]2[S:11][C:12]3[CH2:23][CH2:22][CH2:21][CH2:20][C:13]=3[C:14]=2[C:15]([NH:25][CH3:24])=[O:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2
Reactant: CN
Product: CNC(=O)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2

Procedure:
The product of Example 13 and methylamine were processed as in Examples 29A and 29B to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.20-1.40 (m, 3H), 1.45-1.61 (m, 2H), 1.65-1.73 (m, 1H), 1.78-1.89 (m, 6H), 1.97-2.06 (m, 2H), 2.37 (tt, J=11.6, 3.7, 3.6 Hz, 1H), 2.64-2.73 (m, 4H), 2.98 (d, J=5.1 Hz, 3H), 5.94 (s, 1H), 12.17 (s, 1H); MS (DCI/NH3) m/z 321 (M+H)+; anal. calculated for C17H24N2O2S: C, 63.72; H, 7.55; N, 8.74. Found: C, 63.47; H, 7.45; N, 8.55.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25]3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CO>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25]3)[C:13]([C:30]([F:32])([F:33])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Yield: 56 %

Procedure:
A solution of 1-(2-((2-((6-methoxypyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)cyclopropanecarboxamide A73 (0.229 g, 0.505 mmol) in EtOAc (20 mL) was stirred over 10% Pd/C (wetted with ca. 53% water, 0.150 g) under an atmosphere of hydrogen for 16 hours. The mixture was filtered through Celite and the solvent was removed in vacuo. Purification by column chromatography (Biotage Isolera, 40 g SiO2, 0-80% EtOAc in petroleum benzine 40-60° C.) gave an off-white solid contaminated with alkyne starting material. The solid was dissolved in EtOAc (20 mL) and MeOH (10 mL) and stirred over 10% Pd/C (wetted with ca. 53% water, 0.130 g) for 16 hours under an atmosphere of hydrogen. The mixture was filtered through Celite and the solvent was removed in vacuo to give the title compound 64 as a white solid (0.130 g, 56%). LCMS-D: rt 3.51 min; m/z 458 [M+H]+.
Reaction SMILES: [C:1]1(C)[C:2](S(O)(=O)=O)=[CH:3][C:4](S(O)(=O)=O)=[CH:5][CH:6]=1.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1S(=O)(=O)O
Product: O=[N+]([O-])c1ccccc1-c1ccccc1
Yield: 87 %

Procedure:
5 parts of toluene-2,4-disulfonic acid was adsorbed to 6 parts of diatomaceous earth the same as in Example 1 to prepare solid catalyst. The solid catalyst was added to 300 parts of nitrobenzene and heated at a temperature not exceeding 120°C under reduced pressure to remove water as an azeotropic mixture with nitrobenzene. Thus 100 parts of nitrobenzene was distilled off with water. Thereafter, 15 parts of biphenyl was added to the dried mixture and one part of fuming nitric acid was added dropwise with stirring to the mixture cooled to 3° to 5°C in 30 minutes. The nitration reaction and post-treatment were conducted in the same manner as in Example 1, whereby mononitrobiphenyl was obtained with p/o ratio of 1.3. Yield was 87%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:63]=[CH:62][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44](COS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:37][CH:36]=1.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:44]2[C:45](=[O:46])[N:40]([CH2:39][C:38]3[CH:62]=[CH:63][C:35]([F:34])=[CH:36][CH:37]=3)[N:41]=[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)[CH:43]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 78.8 %

Procedure:
Following the procedure of Example 1 (10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 78.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1C1C=CC=CC=1P(C1C=CC=CC=1C1C=CC=CC=1C)C1C=CC=CC=1C1C=CC=CC=1C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:14]3[O:13][CH:17]=[CH:16][CH:15]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Br)c2C1=O
Reactant: OB(O)c1ccco1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(c1ccccc1-c1ccccc1C)c1ccccc1-c1ccccc1C
Solvent: O
Solvent: COCCOC
Product: CC1Cc2cccc(-c3ccco3)c2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Using a method similar to Example 22, 33.7 g (0.15 mol) of (2), 18.5 g (0.165 mol) of furanylboronic acid and 34.9 g (0.33 mol) of sodium carbonate were placed in 570 ml of dimethoxyethane and 180 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. 675 mg (3 mmol) of palladium acetate and 1.83 g (6 mmol) of tris(o-tolylphenyl)phosphine were added and the reaction mixture was stirred for 2 hours at 80° C. After addition of 450 ml of water, the mixture was extracted 4 times with 300 ml each time of diethyl ether, the ether phase was washed twice with 200 ml each time of water and dried over magnesium sulfate. Removal of the solvent gave 27.06 g of (23) as an oil.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:12]I.[H-].[Na+]>[Pd]>[CH3:12][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C1=Cc2ccccc2NN=C1
Reactant: CI
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Product: CN1N=CC=Cc2ccccc21

Procedure:
The bromide 20 available from references 9 and 10 was reacted with trimethylsilyacetylene in the presence of a palladium catalyst to provide trimethylsilyl analog 52. This product was methylated with methyl iodide/sodium hydride to give the N-methyl benzodiazepine 54 (XLi 351). This was subjected to fluoride-mediated desilation to furnish 53 (XLi 350) and 55 (XLi 352).
Reaction SMILES: C[Sn](C)(C)[C:3]1([F:18])[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])=[CH:5][CH:4]1[F:17].[CH3:21][C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)=[N:25][N:26]=1>>[CH3:21][C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:3]3([F:18])[CH:8]=[CH:7][C:6]([N:9]4[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]4=[O:16])=[CH:5][CH:4]3[F:17])=[CH:29][N:28]=2)=[N:25][N:26]=1
Reactant: C[Sn](C)(C)C1(F)C=CC(N2C[C@H](CO)OC2=O)=CC1F
Reactant: Cc1nnc(-c2ccc(Br)cn2)o1
Product: Cc1nnc(-c2ccc(C3(F)C=CC(N4C[C@H](CO)OC4=O)=CC3F)cn2)o1

Procedure:
The same procedure as in Example 1 was conducted by using (R)-3-(4-trimethylstannyl-3,4-difluorophenyl)-2-oxo-5-oxazolidinylmethanol and 2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine as a starting material, to prepare the title compound.
Reaction SMILES: [NH:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:2][CH2:3][C:4]#[N:5].[CH:10]1([CH:13]=O)[CH2:12][CH2:11]1>>[C:4]([CH2:3][CH2:2][N:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:13][CH:10]1[CH2:12][CH2:11]1)#[N:5]
Reactant: N#CCCNCCC#N
Reactant: O=CC1CC1
Product: N#CCCN(CCC#N)CC1CC1

Procedure:
The title compound was prepared from 3,3'-iminodipropionitrile and cyclopropanecarboxaldehyde by the method described in Example 1 in comparable yield. 1H NMR (CDCl3, 200 MHz) 2.86 (t, J=7.0 Hz, 4H), 2.42 (t, J=7.0 Hz, 4H), 2.39 (d, J=7.2 Hz, 1H), 0.75 (m, 1H), 0.45 (m, 2H), 0.06 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([CH3:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[O:13]1[CH2:37][CH:14]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]3[O:36][CH2:35]3)=[CH:28][CH:27]=2)([CH3:25])[CH3:24])=[CH:19][CH:18]=1>CO>[OH:13][CH:14]([CH2:37][NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:12])[N:5]([CH3:10])[C:6]([CH3:9])([CH3:8])[CH2:7]1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([OH:36])[CH2:35][NH:1][CH:2]3[CH2:3][C:4]([CH3:12])([CH3:11])[N:5]([CH3:10])[C:6]([CH3:8])([CH3:9])[CH2:7]3)=[CH:28][CH:27]=2)([CH3:24])[CH3:25])=[CH:19][CH:18]=1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: CO
Product: CN1C(C)(C)CC(NCC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CNC4CC(C)(C)N(C)C(C)(C)C4)cc3)cc2)CC1(C)C

Procedure:
To 100 ml of methanol were added 12 g of 4-amino-1,2,2,6,6-pentamethylpiperidine and 11 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then reacted in a similar manner to that described in Example 1, giving the desired compound in the form of white crystals melting at 141°-143° C. The compound had an Rf value of 0.64 on thin layer chromatography on silica gel developed with a 1:3:1 by volume mixture of methanol, ethyl acetate and triethylamine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[C:29]([C:31]3[CH:40]=[C:39]4[C:34]([CH2:35][CH2:36][NH:37][CH2:38]4)=[CH:33][CH:32]=3)[N:28]=[C:27]([NH2:41])[N:26]=2)[CH2:21][CH2:20]1>>[NH2:41][C:27]1[N:28]=[C:29]([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][N:37]([C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([O:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:9][CH:10]=4)=[O:16])[CH2:38]3)=[CH:33][CH:32]=2)[CH:30]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[N:26]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccc(Oc5ccccc5)cc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 4-phenoxyphenyl isocyanate (Aldrich, Cat. #478970) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=536.2.
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].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O[CH2:66][CH2:67][CH2:68][C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70]>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][CH2:66][CH2:67][CH2:68][C:69]([O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:70])[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: O=C(CCCO)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.6 %

Procedure:
To a solution of 4-isopropyl-6-hydroxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g; 2.08 mmol) in THF containing (Ph)3P (550 mg; 2.09 mmol) and DEAD (360 mg; 2.07 mmol) was added benzyl 4-hydroxybutyrate (410 mg;2.099 mmol) and the resulting mixture was stirred at room temperature for 15 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) to afford 870 mg (64%) of 4-isopropyl-6-[3-(phenylmethyloxycarbonyl)propoxy]-2-(1-phenyl-3-trifluoro methylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)3CO2CH2Ph) as a solid, m.p. 99°-101° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[NH2:22])C(OC(C)(C)C)=O)C.Cl.CCOCC>CO.O1CCOCC1>[C:20]([C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][CH:17]=1)[NH:22][C:4](=[O:3])[CH2:5][NH:6]2)#[N:21]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)NCC(=O)N2
Yield: 99 %

Procedure:
N-Boc-2-amino-5-cyanophenylglycin ethyl ester (2.6 g, 8.17 mmol) in MeOH (20 mL) was treated with 4M HCl in dioxane (20 mL) at rt for 16 hours. To the mixture was added Et2O until no more solid appeared. The solid was collected, washed with Et2O, and dried by air to give the product (1.4 g, 82%). 1H NMR (CD3COCD3) δ 7.02 (d, J=8.4 Hz, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 3.89 (s, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH:11]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:34]([C:7]1[CH:8]=[C:9]2[C:14]([CH2:13][CH2:12][CH:11]([NH:17][C:18](=[O:19])[O:20][CH2:21][CH3:22])[CH:10]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:15][CH:16]=1)#[N:35]
Reactant: CCOC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.58 h

Procedure:
8-(3,4-Dichlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (250 mg, 0.475 mmol), zinc cyanide (139 mg, 1.187 mmol) and tetrakistriphenyl palladium (82 mg, 0.071 mmol) in dimethylformamide (5 mL) were heated in the microwave at 120° C. (100 W) under stirring for 35 min. The solvent was evaporated in vacuo and the crude product was partitioned between ethyl acetate (40 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate one more time (20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product (460 mg) was purified by flash chromatography (dichloromethane to dichloromethane:methanol=100:1, silica gel). Yield: 109 mg (0.270 mmol, 57%, colorless solid).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]1([CH3:7])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cccs1
Temperature: 25 °C
Yield: 344.3 %

Procedure:
Sodium carbonate (5 ml., 2M aqueous solution) followed by 2-methylphenylboronic acid (0.294 g, 2.4 mmol) were added to a solution of 2-bromothiophene (0.542 g, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg) in toluene (5 ml) and ethanol (5 ml) under nitrogen. The mixture was refluxed for 2 hours, cooled to room temperature and extracted with ethyl acetate (2×50 ml). The combined organic layers was dried over MgSO4 and evaporated. The residue was flash chromatographed on silica gel using hexane as eluent to afford 1.2 g of 2-(2-tolyl)thiophene as a colorless gum.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[N:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:35]([C:32]2[CH:33]=[CH:34][NH:30][N:31]=2)=[O:36])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=C(O)c1cc[nH]n1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc[nH]n3)c2F)c1
Reaction time: 8 h
Yield: 49.4 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 1H-pyrazole-3-carboxylic acid (9.01 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.016 g, 50%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.11 (br. s., 1H), 7.79 (d, 1H), 7.62 (t, 1H), 7.36-7.46 (m, 4H), 6.75 (d, 1H), 4.59-4.69 (m, 2 H). LCMS m/z 404.9 (M+1).
Reaction SMILES: [O:1]1C(=O)C[CH2:3][C:2]1=O.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:22](=[S:23])[N:21]([C:24]3[CH:25]=[C:26]([CH3:32])[C:27]([C:30]#[N:31])=[N:28][CH:29]=3)[C:20](=[O:33])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:22](=[S:23])[N:21]([C:24]3[CH:25]=[C:26]([CH3:32])[C:27]([C:30]#[N:31])=[N:28][CH:29]=3)[C:20](=[O:33])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cc(N2C(=O)C3(CCC3)N(c3ccc(O)cc3)C2=S)cnc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2C(=O)C3(CCC3)N(c3ccc(OCCO)cc3)C2=S)cnc1C#N
Temperature: 85 °C
Yield: 70.8 %

Procedure:
Dihydrofuran-2,5-dione (604 mg, 6.87 mmol) in DMF (5 mL) was added to a mixture of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile (500 mg, 1.37 mmol) and potassium carbonate (378 mg, 2.74 mmol) in DMF (10 mL) and the resulting mixture was heated to 85° C. overnight. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous was extracted further with EtOAc (2×) and the combined organics were washed with water, then brine. The organics were dried over sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (50 to 100% EtOAc/hexanes) afforded 396 mg of 5-(5-(4-(2-hydroxyethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, 1H), 8.14 (d, 1H), 7.33 (d, 2H), 7.13 (d, 2H), 4.92 (t, 1H), 4.11-4.05 (m, 2H), 3.78-3.73 (m, 2H), 2.63-2.5 (m, 5H), 2.49-2.37 (m, 2H), 2.00-1.90 (m, 1H), 1.56-1.51 (m, 1H). LCMS [M+1]+ 409.0.