Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[NH:8][C:7]2=[O:16].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:26][C:27](O)=[O:28].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([F:30])([F:31])[F:17])[CH2:13][CH2:14]1)[NH:8][C:7]2=[O:16]
Reactant: O=C1NC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
A mixture of 7-bromospiro[isoindoline-1,4′-piperidin]-3-one (194 mg, 0.69 mmol), 3-(2-(trifluoromethyl)phenyl)acrylic acid (100 mg, 0.46 mmol), EDCI (181 mg, 0.92 mmol), HOBt (124 mg, 0.92 mmol) and i-Pr2NEt (1 mL) was stirred at rt overnight. The mixture was washed with 5% aq HCl, and the organic layer was concentrated to give a residue which was purified by preparative HPLC to afford (E)-7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[isoindoline-1,4′-piperidin]-3-one (5 mg, 2%). 1H NMR (400 MHz, CDCl3): δ=1.53 (m, 2H), 2.98 (m, 3H), 3.42 (m, 1H), 4.23 (m, 1H), 4.50 (m, 1H), 4.93 (m, 1H), 6.80 (m, 1H), 7.33 (m, 1H), 7.40 (m, 1H), 7.50 (m, 1H), 7.65 (m, 3H), 7.77 (m, 1H), 7.95 (m, 1H), 8.50 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[NH:27]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][C:33](=[O:35])[CH3:34])(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonamide (hereinafter referred to as starting compound B, 500 mg), acetic anhydride (5 mL), pyridine (10 mL) and DMF (20 mL) was heated with stirring at 55° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with aqueous saturated sodium hydrogencarbonate solution and water successively. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)acetamide (58 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[C:4]([NH2:20])[N:3]=1
Reactant: CCCCCCCCCCCCCCCCCCI
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 l) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2Cl2. The product containing fraction were evaporated to yield the product (11 g). 1H NMR (DMSO-d6) δ0.84 (t, 3, CH2); 1.22 [m, 32, O--CH2 --CH2 --(CH2)16 --]; 1.86 (m, 2, O--CH2CH2 --); 3.25 (m, 2, O--CH2 --); 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H); 4.38 (t, 1, 2'H); 5.08 (d, 1, 3'-OH); 5.48 (t, 1, 5'-OH); 5.75 (s, 2, 6-NH2); 5.84 (d, 1, 1'-H); 6.8 (s, 2, 2-NH2); and 7.95 (s, 1, 8-H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].[OH-].[Na+]>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][S:33]([CH2:32][CH2:31][CH2:30][Cl:29])(=[O:35])=[O:34])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(NS(=O)(=O)CCCCl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-amine (0.15 g, 0.49 mmol) in ethyl acetate (18 mL), cooled to 0° C., was added triethylamine (0.274 mL, 1.37 mmol) then 3-chloro-1-propanesulfonyl chloride (0.070 mL, 0.576 mmol), and the reaction mixture allowed to warm to room temperature. After stirring for 1 h, the reaction was basified with 1N sodium hydroxide (2.5 mL), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to yield the title compound as an oil. This crude product was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:19]([N:8]1[C:7](=[O:23])[C:6]([NH:5][CH2:4][CH2:3][CH2:2][O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:9]1(=[O:18])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccnc2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 46.5 %

Procedure:
A mixture of 4-[(3-bromopropyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.120 g, 0.29 mmol), 3-hydroxypyridine (0.028 g, 0.29 mmol) and K2CO3 (0.207 g, 1.49 mmol) in MeCN (2 mL) was heated in a microwave reactor at 140° C. for 30 mins. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 35-85% EtOAc in hexane mixture as eluant, to give the title compound (0.056 g, 45%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.28-8.22 (m, 2H), 7.54-7.50 (m, 2H), 7.50-7.42 (m, 3H), 7.24-7.20 (m, 1H), 7.16-7.12 (m, 1H), 5.68 (t, 1H), 3.92 (t, 2H), 3.14-3.08 (m, 2H), 1.90-1.82 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.8, 154.7, 142.8, 137.9, 135.2, 131.8, 129.9, 128.8, 125.2, 124.1, 121.3, 107.5, 66.3, 61.8, 42.1, 29.0, 27.8; Mass Spectrum: M+H+ 416.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCCOC2C=CC(C(O)=O)=CC=2)C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(OCCCCc2ccccc2)cc1
Reactant: CCOC(=O)CCCCCc1ccccc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1ccc(OCCCCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCc1ccccc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of p-(4-phenylbutoxy)benzoyl chloride prepared from 1 g of p-(phenylbutoxy)benzoic acid and 2 ml of oxalyl chloride in methylene chloride was added to a solution of 0.6 g of ethyl 6-(o-aminophenyl)hexanate obtained in Reference Example 17 in 10 ml of pyridine at temperature less than -30° C. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. Toluene was added to the residue. The mixture was washed with diluted hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The systems was concentrated under reduced pressure to obtain 1.0 g of oily ethyl 6-[o-[p-(4-phenylbutoxy)benzamido]phenyl]hexanate.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][N:7]=1.[C:18](OC(=O)C)(=[O:20])C.NC1C=CC=CC=1CCC1C=CC=CN=1>C(O)=O>[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[NH:1][CH:18]=[O:20])=[N:7][CH:8]=1)[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(CCc2ccccc2N)nc1
Agent: Nc1ccccc1CCc1ccccn1
Solvent: O=CO
Product: CCc1ccc(CCc2ccccc2NC=O)nc1

Procedure:
Reaction of 2-(o-aminophenethyl)-5-ethylpyridine with acetic anhydride and formic acid according to the procedure described in Example 2b for 2-(o-aminophenethyl)pyridine provides the formylated product 5-ethyl-2-(o-formamidophenethyl)pyridine which can be crystallized from isopropyl ether, m.p. 62°-63.5°C. (corr.).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].C(N(C(C)C)CC)(C)C.Cl[C:20]([O:22][CH3:23])=[O:21]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH3:5])[C:20](=[O:21])[O:22][CH3:23]
Reactant: COC(=O)Cl
Reactant: CNc1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N(C)c1ccccc1Br
Reaction time: 8 h

Procedure:
2-Bromo-N-methylaniline (1.00 g, 5.37 mmol) and diisopropylethylamine (2.0 ml, 11.50 mmol) were dissolved in dichloromethane (50 mL) and cooled in an ice bath. Methyl chloroformate (1.0 ml, 12.94 mmol) was added dropwise and the reaction stirred overnight. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[CH:22][CH:21]=1)=[O:10]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Oc1cccc(F)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2cccc(F)c2)cc1
Yield: 98.3 %

Procedure:
To a stirred solution 2-(3-Fluoro-phenoxy)-nicotinic acid (0.250 g, 1.07 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.195 grams, 1.18 mmole) and 1-hydroxybenzotriazole hydrate (0.173 grams, 1.28 mmole) in dry dimethylformamide (15 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.173 grams, 1.28 mmole) and stirred over night. The mixture was diluted with 300 ml water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica. Recrystalization from ethyl acetate/hexane gave a solid (0.400 g). M.P. 106-108° C.; Anal. calcd. for C22H21N2O3F: C, 69.46; H, 5.56; N, 7.36. Found: C, 69.05; H, 5.68; N, 7.25.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>N1C=CC=CC=1.C(Cl)Cl>[C:31]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)=[CH:26][CH:25]=1)(=[O:32])[CH2:30][CH2:29][CH3:28]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)OC(=O)CCC)o2)cc1
Reaction time: 23 h
Yield: 142.1 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 8) (200 mg, 0.52 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added n-butyryl chloride (0.16 mL, 1.56 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (10 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic extracts were washed with NaHCO3 (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange viscous oil, which was purified by flash chromatography over silica gel (15-25% EtOAc in hexanes) to provide the title compound as a colourless solid (194 mg, 71%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.00 (dm, J=8.8 Hz, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (dm, J=8.8 Hz, 2H), 6.72 (d, J=8.8 Hz, 1H), 5.57 (pentet, J=5.9 Hz, 1H), 5.18 (d, J=8.0 Hz, 1H), 5.02 (dd, J=5.7, 8.0 Hz, 1H), 2.55 (t, J=7.4 Hz, 2H), 2.32 (dt, J=2.6, 7.4 Hz, 2H), 2.30 (s, 3H), 1.77 (sextet, J=7.4 Hz, 2H), 1.63 (sextet, J=7.4 Hz, 2H), 1.36 (d, J=6.5 Hz, 3H), 1.03 (t, J=7.4 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](Cl)=[N:8][OH:9])=[N:4][O:5][N:6]=1.Cl.Cl.[NH2:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:8][OH:9])[NH:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[N:4][O:5][N:6]=1
Reactant: CS(=O)(=O)NCCN
Reactant: Nc1nonc1C(Cl)=NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)NCCNC(=NO)c1nonc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (9.7 g, 60 mmol) was stirred in ethanol (460 mL) and N-(2-aminoethyl)methanesulfonamide dihydrochloride (19 g, 109 mmol) was added slowly in portions and the temperature rose to 25° C. After cooling back to 0° C., triethylamine (53 mL, 380 mmol) was added dropwise over 15 minutes and the reaction was stirred for an additional 15 minutes. The solution was washed with water (300 mL) and brine (300 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the desired product (16 g, 100%). LCMS calculated for C6H13N6O4S (M+H)+: m/z=265.1. 1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.07 (m, 1H), 7.18 (m, 1H), 6.37 (s, 2H), 3.36 (m, 2H), 3.15 (m, 2H), 2.87 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=O.[CH3:18][NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2)(=[O:22])=[O:21].N1CCCCC1>C(O)C>[CH3:18][NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:15]\[C:7]1[NH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:6]=1[CH2:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])(=[O:22])=[O:21]
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN(C)C)CCCC3)C(=O)N2
Yield: 70 %

Procedure:
3-(3-Dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (71 mg, 0.3 mmol), 5-methylaminosulfonyloxindole (68 mg, 0.3 mmol) and piperidine (0.03 ml) in 1 ml of ethanol was stirred at 60° C. for over night. The mixture was cooled and the solids collected by vacuum filtration and washed with ethanol to give (93 mg, 70% yield) of 3-[1-[3-(3-dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[CH:9]=2)[N:3]=1.[CH:18]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1)=O.C(O)(=O)C.Cl>CO>[Cl:16][C:14]1[CH:15]=[C:8]([NH:7][C:4]2[N:3]=[C:2]([NH:1][CH2:18][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:22][CH:21]=3)[NH:6][N:5]=2)[CH:9]=[C:10]([Cl:17])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(Cl)cc(Nc2n[nH]c(N)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CNc2nc(Nc3cc(Cl)c(C#N)c(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
To a solution of 4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-benzonitrile (60 mg, 223 μmol) in MeOH (3.5 ml) was added tert-butyl 4-formylbenzoate (55.2 mg, 268 μmol) followed by acetic acid (21.0 mg, 20 μl, 349 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (32.2 mg, 349 μmol) was added and the stirring was continued for 4 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and let stand. The resulting suspension was filtered to collect the solid. Purification by super fluid chromatography and trituration from acetonitrile afforded a white solid as desired product (54.5 mg, 53% yield). MS +m/z: 459 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ncc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3S)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 494 [M+1]+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:14]1[CH:19]=[CH:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1>>[N:5]1([CH2:1][CH:2]([OH:4])[CH2:3][N:14]2[CH2:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[CH2:18][CH2:19]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: c1ccc2c(c1)ccn2CC1CO1
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Product: OC(CN1CC=C(c2c[nH]c3ccccc23)CC1)Cn1ccc2ccccc21
Yield: 47.6 %

Procedure:
A methanolic solution of 1-N-glycidylindole (0.52 g, 3.0 mmole) from example 4 and 3-(4-tetrahydropyridinyl)indole (0.59 g, 3.0 mmole) was refluxed under nitrogen for 24 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as a yellow colored solid (0.53 g, 47% yield). Treatment with a 0.25M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][N:14]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C1COCC1.CCOCC>[Br:24][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(-c3ccc(F)cc3)cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1cc(Br)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
Step 3 A solution of tert-butyl 6-(4-fluorophenyl)-1H-indole-1-carboxylate (187.8 mg, 0.603 mmol) in THF (4 mL) was treated with N-bromosuccinimide (118 mg, 0.663 mmol) and stirred at rt. After 18 h, the solution was diluted with ether, washed with 2×10 mL aqueous sodium bisulfite (ca. 1.5 M), then with NaHCO3 (aq), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 90:10 hexane-EtOAc) provide tert-butyl 3-bromo-6-(4-fluorophenyl)-1H-indole-1-carboxylate as a white glassy foam (134 mg, 57%). 1H NMR (400 MHz, chloroform-d) δ 8.39 (1H, br. s.), 7.59-7.68 (3H, m), 7.54-7.59 (1H, m), 7.48-7.53 (1H, m), 7.14 (2H, t, J=8.7 Hz), 1.67 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH2:14])[S:11][N:10]=2)=[CH:5][CH:4]=1.C[Al](C)C.[CH3:19][C@@H:20]1[CH2:22][C@H:21]1[C:23](OCC1C=CC=CC=1)=[O:24].N#N>ClCCl.CC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([NH:14][C:23]([C@@H:21]3[CH2:22][C@H:20]3[CH3:19])=[O:24])[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(N)sn2)cc1
Reactant: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1ccc(-c2cc(NC(=O)[C@@H]3C[C@H]3C)sn2)cc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
To a stirred suspension of 3-(4-methoxyphenyl)isothiazol-5-ylamine (5.0 g, 24.3 mmol) in anhydrous dichloromethane (230 mL), cooled to 0-5° C., is added trimethylaluminum (2.0 M in toluene, 12.1 mL, 24.2 mmol) by syringe. The solution is stirred 5 min, and benzyl (R,R)-2-methylcyclopropanecarboxylate (4.6 g, 24.21 mmol) is added with the aid of anhydrous dichloromethane (10 mL). The mixture is then warmed to 40-45° C. with N2 flow (needle bleed valve) to slowly remove solvent. After 2 h, most of the dichloromethane has been removed, and the internal temperature rises to about 50° C. The solution is stirred further for 3 h, cooled, and quenched cautiously with dropwise addition of water followed by 0.1 N HCl under a good N2 stream. The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL). The organic layer is dried over potassium carbonate, filtered, and evaporated to a low volume. The resulting suspension is diluted with hexanes and the solid filtered to afford 5.9 g of crude product which is re-suspended in MTBE (100 mL), warmed to mild reflux for 1 h, and cooled to room temperature. After standing 1 h, the solid was filtered and dried (20 mm Hg, 40° C.) to afford (R,R)—N-[3-(4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide (5.2 g, 75%). 1H NMR (DMSO-d6) 7.86 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 1.62 (m, 1H), 1.34 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 1.09 (m, 1H), 0.80 (m, 1H); ES-MS m/e 289 (m+H).