Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:9]1)=[O:7])(C)(C)C.F[C:22](F)(F)[C:23](O)=O.C(Cl)(=O)CC.C(N(CC)CC)C>C(Cl)Cl>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:10]2[CH2:9][N:8]([C:6](=[O:7])[CH2:22][CH3:23])[CH2:11]2)=[N:13][CH:14]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cn2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CC(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 3-(5-nitro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (1.22 g, 4.36 mmol) in CH2Cl2 (100 ml) was treated with trifluoroacetic acid (TFA) (15 ml) and then stirred at room temperature for 2 h. After concentration, the raw mixture was digested in CH2Cl2 and washed with saturated aqueous NaHCO3. The aqueous phase was extracted with CH2Cl2 (×3), the combined organic layers dried over Na2SO4 and evaporated. The raw material was next dissolved in THF (80 ml) and the solution cooled to 0° C. Propionyl chloride (460 μl, 5.26 mmol) and triethylamine (735 μl, 5.28 mmol) were next added, the mixture allowed to reach 20° C. and stirred for a further 12 h. It was then diluted with CH2Cl2 and washed successively with 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4) and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 49:1) to afford the title compound (880 mg, 85% for two steps) as a brown oil.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22]>CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])=[CH:10][CH:9]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COC(=O)/C=C/c1ccc(S(F)(F)(F)(F)F)cc1

Procedure:
Diazonium salt 1 reacted with methyl acrylate in the presence of Pd(OAc)2 in 95% EtOH to give methyl trans-3-[4-(pentafluorosulfanyl)phenyl]prop-2-enoate 3 in 85% isolated yield with no cis isomer being observed, as seen in FIG. 2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:50](Cl)([O:52]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCCCCC>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[C:50]=[O:52]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N=C=O)cc2)C1=O)NC(=O)OC(C)(C)C
Yield: 78.9 %

Procedure:
A solution of 2.0 g (3.6 mmol) of N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and 2.0 mL of triethylamine (14 mmol) in 40 mL of methylene chloride under a nitrogen atmosphere was cooled to -10° C. and treated with 2.12 g (7.15 mmol) of triphosgene in one portion. An exotherm occurred. The reaction was stirred at room temperature for 1.5 hours when no starting amine was detected by thin layer chromatography on silica (hexanethyl acetate (1:1)). The reaction mixture was diluted with 40 mL of hexane and filtered. The filtrate was passed over 150 g of silica gel and eluted with hexane/ethyl acetate (1:1) to give 1.65 g (2.84 mmol, 79%) of the product. 1H NMR (400 MHz, CDCl3): δ 1.34 (s, 6H), 1.39 (s, 9H), 1.84 ((m, 1H), 2.40 (m, 1H), 2.49 (dd, 1H), 2.52 (m, 1H), 4.51 (m, 1H), 4.88 (d, 1H), 5.25 (d, 1H), 5.34 (br s, 1H), 6.71 (d, 1H), 7.20 (m, 12H).
Reaction SMILES: Cl[C:2]1[C:3]([N:15](C)[CH:16]2[CH2:20][CH2:19][C:18]3([CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30]([OH:32])=O)#[N:28].[CH3:33]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:33][C:2]1[C:3]([NH:15][CH:16]2[CH2:24][CH2:25][C:18]3([CH2:21][N:22]([C:30](=[O:32])[CH2:29][C:27]#[N:28])[CH2:23][CH2:17]3)[CH2:19][CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCCNC2)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)CC#N)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 5-chloro-N4-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(7-azaspiro[4.5]decan-2-yl)pyrimidine-2,4-diamine (0.18 g, 0.479 mmol), 2-cyanoacetic acid (60.5 mg, 0.711 mmol) in a mixture of DCM (20 mL) and DMF (5 mL) were added HATU (335.2 mg, 0.882 mmol) and Et3N (169.4 mg, 1.674 mmol). After addition, the reaction mixture was stirred at rt overnight, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), then dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as a beige solid (83 mg, 39.1%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=4)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(-c3cccc(C#N)c3)c2n1C
Temperature: 140 °C
Yield: 38.5 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (100 mg, 0.27 mmol), 3-cyanobenzeneboronic acid (51 mg, 0.35 mmol), Pd(PPh3)4 (31 mg, 0.03 mmol) and Cs2CO3 (175 mg, 0.54 mmol) in dioxane (3 mL) and H2O (1.5 mL) was heated for 30 min by microwave irradiation at 140° C. The reaction solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford 422 as a white solid (41 mg, 39%). LCMS (Method K): RT 3.08 min [M+H]+ 395. 1H NMR (DMSO-d6, 400 MHz): δ 8.03 (1H, s), 7.97 (1H, s), 7.94-7.91 (1H, m), 7.82-7.80 (1H, m), 7.72-7.66 (3H, m), 7.32 (2H, bs), 7.26 (1H, dd, J=8.0, 7.5 Hz), 7.07 (1H, dd, J=7.5, 1.0 Hz), 5.65 (1H, dq, J=7.0, 7.0 Hz), 3.29 (3H, s), 1.60 (3H, d, J=7.0 Hz)
Reaction SMILES: C[O-].[Na+].[S:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.O>CN(C)C=O>[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[C:5]1\[S:4][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]\1=[O:14]
Reactant: O=C1CSc2ccccc2N1
Reactant: O=Cc1ccc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2S/C1=C\c1ccc[nH]1
Temperature: 120 °C

Procedure:
Sodium methoxide (0.28 g, 5.2 mmol) was added to a solution of 2H-1,4-benzothiazin-3(4H)-one (0.60 g, 4 mmol) and pyrrol-2-carboxaldehyde (0.49 g, 5.2 mmol) in dry N,N-dimethylformamide (3.5 ml) (hereinafter “DMF”). The mixture was heated at 120° C. for 6.5 h, allowed to cool and poured into water (60 ml). The precipitate was collected by filtration and washed with water. The precipitate was dissolved in ethyl acetate and the insoluble black residue was filtered out. The filtrate was concentrated, then chromatographed on a silica column using a gradient of 100% dichloromethane to (100:1) dichloromethane:ethanol as the mobile phase. The first eluted product was the (E)-isomer.
Reaction SMILES: [C:1]([C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2)#[CH:2].[Cl:11][C:12]1[N:17]=[C:16](I)[C:15]([OH:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:12]1[N:17]=[C:16]2[CH:2]=[C:1]([C:3]34[CH2:10][CH2:9][CH2:8][N:7]3[CH2:6][CH2:5][CH2:4]4)[O:19][C:15]2=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: C#CC12CCCN1CCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Clc1ccc2oc(C34CCCN3CCC4)cc2n1
Yield: 77 %

Procedure:
7a-Ethynyl-hexahydro-1H-pyrrolizine from Example 15b (225 mg, 1.66 mol, 6-chloro-2-iodo-3-pyridinol (509 mg, 2.0 mmol), copper(I) iodide (60 mg, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (58 mg, 0.08 mmol) and triethylamine (0.280 mL, 2.0 mmol) were combined in a similar fashion as that described in Example 15c. The crude product was chromatographed (silica gel; CHCl3 /MeOH, 97.5:2.5) to afford a waxy tan solid (335 mg, 77%): 1H NMR (CDCl3, 300 MHz) δ 1.88-1.97 (m, 6H), 2.21-2.33 (m, 2H), 2.67-2.79 (m, 2H), 3.19-3.26 (m, 2H), 6.70 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H); MS (CI/NH3) m/z: 263 (M+H)+.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][N:5]([CH3:7])[CH3:6].O.CN(C)C>CO>[OH:3][CH2:1][CH2:2][N+:5]([CH3:7])([CH3:6])[CH3:4].[CH2:2]=[O:3]
Reactant: C1CO1
Reactant: CN(C)C
Solvent: O
Solvent: CO
Product: C=O
Product: C[N+](C)(C)CCO

Procedure:
45% by weight choline base in methanol was prepared by the reaction of ethylene oxide with a methanolic solution of 1:1 trimethylamine/water. The trimethylamine content of the stock solution as prepared was 19 ppm. Sufficient paraformaldehyde to give solutions containing 0.05%, 0.1%, 0.5%, and 1% by weight of paraformaldehyde, and sufficient ethylenediamine to give a reference solution containing 0.15% by weight ethylenediamine (the usual stabilizer for methanolic choline base), when mixed with 15 g of solution, were weighed into 20 ml screw-cap sample vials (one vial for each stabilizer concentration and analysis period), and 15 g of the stock solution added to each vial. The samples were mixed by agitation of the vials, and stored in the dark at ambient temperature (approximately 25° C.) until analysis. Vials were opened, and samples analyzed at two-week intervals for trimethylamine content, and the color noted (each vial was analyzed only once, and the sample discarded after opening, to avoid repeated exposure to air of the longer-term samples). The trimethylamine content was determined by extraction of a 10 mL sample into chloroform, development of the color by reaction with picric acid solution, and spectrophotometric comparison with standard solutions of trimethylamine treated identically. Table 1 shows the trimethylamine (TMA) content versus time for the samples over a period of eight weeks.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CN(C)c1cccc(B(O)O)c1
Product: CN(C)c1cccc(-c2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-(dimethylamino)phenylboronic acid in analogy to Example 1b): MS (ISP): 499.1 and 501.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>C(Cl)Cl.CO>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][C:2]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)=[CH:35][CH:34]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)N(C)C)n3)cc2)CC1
Yield: 32 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 32% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 8.35 (d, 1H J=8.2 Hz), 8.05 (s, 1H), 7.46 (s, 2H, J=8.2 Hz), 7.38 (t, 1H, J=7.8 Hz), 7.29 (d, 1H, J=7.5 Hz), 7.21 (d, 2H, J=8.2 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.01 (s, 1H), 3.45 (s, 2H), 3.11 (s, 3H), 3.04 (s, 3H), 2.43 (bs, 8H), 2.27 (s, 3H); MS (ESI): 480.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH:21]([CH:23]1[CH2:25][CH2:24]1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:32])CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH:21]([CH:23]1[CH2:25][CH2:24]1)[F:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(O)C1CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(F)C1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg (0.55 mmol) of [7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazin-8-yl](cyclopropyl)methanol (prepared as outlined in Example 3, Step A) in 3.5 mL of dichloromethane was cooled to −78° C. and 0.406 mL (3.31 mmol) of (diethylamino)sulfur trifluoride (DAST) was added. The reaction mixture was stirred at −78° C. for 1 h, then warmed to ambient temperature and stirred overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The aqueous phase was extracted with three portions of dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated. Purification by HPLC (Gilson, YMC C-18, 10 to 90% acetonitrile/water gradient) gave the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.C(N(CC)CC)C.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>C1(C)C=CC=CC=1>[OH:9][CH2:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([N:1]2[C:20](=[O:21])[C:19]3[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]2=[O:22])[CH2:3]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@H]1CCC[C@H](CO)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](CO)C1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
Racemic trans 3-amino-cyclohexyl-methanol (0.65 g, 3.925 mmol) was taken up in toluene (25 mL) and triethylamine (1.6 mL, 11.5 mmol). Phthalic anhydride (0.581 g, 3.925 mmol) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was allowed to cool to RT before being washed with H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and evaporated. The remaining solid was purified by SiO2 chromatography (40 g SiO2, hexanes/EtOAc 0 to 40%) to give 0.749 g of racemic trans-2-(3-hydroxymethyl-cyclohexyl)-isoindole-1,3-dione as a white solid (73% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)C.[NH2:21][NH2:22]>C(#N)C>[CH3:18][O:17][C:9]1[CH:8]=[C:7]([C:6]2[CH2:5][C:4](=[O:3])[NH:21][N:22]=2)[CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[O:15][CH3:16]
Reactant: CCOC(=O)CC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: NN
Solvent: CC#N
Product: COc1cc(C2=NNC(=O)C2)cc(OC)c1OC
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a stirred solution of 3-oxo-3-(3,4,5-trimethoxyphenyl)-propionic acid ethyl ester (2.82 g, 10 mmol) in dry acetonitrile (15 mL) was added to anhydrous hydrazine (640 mL, 20 mmol) at room temperature. After 1 hour, the mixture was heated to reflux for 16 hours. The mixture was diluted with acetonitrile (20 mL) and the solid was filtered. The solid was washed with acetonitrile (10 mL) and dried under nitrogen to afford 2.2 g of title compound (k).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N+:41]([O-:43])=[O:42])[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2-c2ccccc2[N+](=O)[O-])cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 125 °C

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (25 mg, 0.53 mmol), 1-fluoro-2-nitrobenzene (14 mg, 0.13 mmol), and potassium carbonate (18.2 mg, 0.13 mmol) were combined in acetonitrile (1.0 mL) and heated via microwave at 125° C. for 30 h. The reaction was concentrated, dissolved in methylene chloride, and washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Purification by column chromatography afforded 20.4 mg (65%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]1=2)(=[O:22])=[O:21]
Reactant: Ic1cnc2c(c1)NCCN2
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Product: O=S(=O)(c1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was dissolved in anhydrous pyridine. 2,5-difluorobenzene sulfonyl chloride (1.0 eq) was added and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography to give the title compound as a pale yellow solid (13% yield). M.p. 187-188° C., LCMS: m/z=437.73 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.29-3.33 (m, 2H), 3.83 (t, J=4.8 Hz, 2H), 5.08 (bs, 1H), 7.11-7.19 (m, 1H), 7.26-7.33 (m, 1H), 7.58-7.63 (m, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=C[C:13]([NH2:17])=[CH:14][CH:15]=2)C=C1C(OC)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-:23].[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1.CO.O>>[C:4]([O:3][C:1]([NH:8][C:16]1[CH:11]=[C:28]2[C:13](=[CH:14][CH:15]=1)[NH:17][C:25]([C:26]([OH:23])=[O:27])=[CH:24]2)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2cc(N)ccc2n1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 60 °C
Yield: 96 %

Procedure:
A solution of N—BOC-5-amino-2-(methoxycarbonyl)indole (57 mg, 0.2 mmol, 1.0 equiv) in THF—CH3OH—H2O (2.4 mL) was treated with aqueous 1 N LiOH (0.24 mL, 0.24 mmol, 1.2 equiv). The reaction mixture was warmed at 60° C. for 2 h. The solvent was concentrated under a N2 stream and H2O (3 mL) was added. This solution was treated with 10% aqueous HCl until the mixture was acidic. The insoluble solid was collected by centrifugation and washed with H2O (2×3 mL). Drying the solid afforded the title compound (53 mg, 96%) as a white solid: mp 235-250° C. (decomp.); 1H NMR (acetone-d6, 400 MHz) δ 10.74 (br s, 1H, COOH), 8.26 (br s, 1H, NH), 7.95 (br s, 1H, NH), 7.43 (d, 1H, J=8.9 Hz, C6-H), 7.42 (s, 1H, C3-H), 7.39 (dd, 1H, J=8.9, 1.9 Hz, C7-H), 7.13 (dd, 1H, J=2.1, 0.8 Hz, C4-H), 1.49 (s, 9H, C(CH3)3); IR (neat) νmax 3351, 1698, 1536, 1236, 1177 cm−1; FABHRMS (NBA-NaI) m/z 299.1003 (M++Na, C14H16N2O4 requires 299.1008).
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[F:6][C:7]([F:19])([F:18])[C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH:1]1([N:4]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]([C:7]([F:6])([F:18])[F:19])=[N:5]2)[CH2:3][CH2:2]1
Reactant: NNC1CC1
Reactant: CCOC(=O)C(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)c1cc(C(F)(F)F)nn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 5,5,5-trifluoro-2,4-dioxopentanoate at 100° C. for 2 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 9:1). tR: 1.23 min (LC-MS 2); ESI-MS: 249.2 [M+H]+ (LC-MS 2); Rf=0.34 (hexane/EtOAc 9:1).
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].Cl[S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>ClCCl>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][S:6]([N:9]1[CH2:2][CH2:3][O:4][C:10]1=[O:11])(=[O:8])=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CN(C)CCN
Reactant: OCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNS(=O)(=O)N1CCOC1=O
Reaction time: 0.75 h
Yield: 67.3 %

Procedure:
A solution of 2-chloroethanol (2.00 g, 24.84 mmol) in dichloromethane (15 mL) was added to a solution of chlorosulfonyl isocyanate (3.52 g, 24.8 mmol) in dichloromethane (15 mL) This mixture was slowly added to a 0° C. solution of N1,N1-dimethylethane-1,2-diamine (2.19 g, 24.8 mmol) and triethylamine (3.81 mL, 27.3 mmol). The reaction was stirred for 45 minutes, diluted with dichloromethane, washed with saturated ammonium chloride, concentrated and purified by silica gel chromatography. The isolated material was dissolved in methylene chloride and triethylamine (3.81 mL, 27.3 mmol) and stirred for 5 hours. The reaction mixture was washed with water and the organic layer was concentrated to give crude N-(2-(dimethylamino)ethyl)-2-oxooxazolidine-3-sulfonamide (3.96 g, 67.24% yield).