Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[N:8][CH:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[CH2:30]([O:32][C:33](Cl)=[O:34])[CH3:31].C(Cl)(Cl)Cl>>[CH3:13][C:9]1[N:8]([C:33]([O:32][CH2:30][CH3:31])=[O:34])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[N:10]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N=C(C)N(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]

Procedure:
To a solution of 5-ethoxycarbonyl-2,6-dimethyl-4-(2'-nitrophenyl)-dihydropyrimidine (756 mg, 2.49 millimole) and triethylamine (374 mg, 3.7 millimole) in 30 ml of chloroform ethyl chlorocarbonate (406 mg, 3.74 millimole) was added dropwise with stirring in ice and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 2% aqueous NaOH solution and water, dried and evaporated to remove the solvent. The obtained oil (730 mg) was purified on silica gel by column chromatography and eluted with 1% MeOH/CHCl3 to obtain the title product as crystals. The crystals were recrystallized from acetone-n-hexane to obtain colorless prisms (m.p. 130°-131.5°, 290 mg, 31% yield).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2[CH:45]=[CH:46][CH:47]=[N:48]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:48][CH:47]5[CH2:45][CH2:46]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and cyclopropylamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.61 (m, 2H) 0.70 (dd, J=7.07, 2.27 Hz, 2H) 1.31-1.48 (m, 2H) 1.51-1.70 (m, 4H) 1.71-1.91 (m, 4H) 2.81 (dt, J=7.14, 3.63 Hz, 1H) 3.17 (s, 3H) 3.93 (s, 3H) 4.03 (q, J=7.07 Hz, 2H) 4.46 (t, J=11.62 Hz, 1H) 7.40-7.55 (m, 2H) 7.90 (s, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H) 8.37 (d, J=3.79 Hz, 1H). [M+H] C25H30F2N6O3 calc'd for, 501. found 501.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C@H:49]([NH2:51])[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:51][C@@H:49]([C:45]2[S:44][CH:48]=[CH:47][N:46]=2)[CH3:50])=[O:42])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: C[C@@H](N)c1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4nccs4)cc3OC)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (31 mg, yield 71%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH3:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[CH2:15]([NH2:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[ClH:2].[CH3:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:1][CH:3]([OH:5])[CH2:4][NH:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCN
Reactant: ClCC1CO1
Reactant: CSc1ccccc1O
Product: CCCCCCCCNCC(O)COc1ccccc1SC
Product: Cl
Yield: 18 %

Procedure:
Reaction of the epichlorhydrin derivative of 2-(methylthio)phenol (14 g., 0.071 mole) with n-octylamine (9.04 g., 0.07 mole) according to the procedure of Example 2(b) and crystallization of the crude product from methanol-ether affords an 18% yield of analytically pure 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol hydrochloride, m.p. 105.5°-107.5° (corr.).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([O:16][CH:17]([O:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1)[CH3:18])[CH3:15].CN(C)[CH:31]=[O:32]>CCCCCC.C1COCC1>[CH2:14]([O:16][CH:17]([O:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[C:21]=1[CH:31]=[O:32])[CH3:18])[CH3:15]
Reactant: CN(C)C=O
Reactant: CCOC(C)Oc1ccc2c(c1)OCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C)Oc1ccc2c(c1C=O)OCO2
Temperature: -78 °C
Yield: 96 %

Procedure:
n-Butyllithium (18.6 ml of a 2.5M solution in hexane, 46.5 mmol) and N,N,N',N'-tetramethylethylenediamine (5.38 g, 46.3 mmol), respectively, were added (using a syringe) to a stirred solution of 5-(1-ethoxyethoxy)-1,3-benzodioxole (8.9 g, 42.4 mmol) in dry THF (100 ml) in a nitrogen atmosphere at -78° C. The resulting solution was allowed to attain room temperature and then cooled to -78° C. A solution of N,N-dimethylformamide (3.70 g, 50.6 mmol) in dry THF (20 ml) was added using a syringe, and the reaction mixture was allowed to attain room temperature. The resulting mixture was quenched with water and extracted with diethyl ether (3times). The combined ether layers were washed with water (2 times), dried over Na2SO4, filtered and evaporated in vacuo to to yield 5-(1-ethoxyethoxy)-4-formyl-1,3-benzodioxole (9.7 g, 96% yield; compound No. 2) as a pale yellow solid, m.p. 48°- 50° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(C)COC)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
A mixture of ethyl {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (580 mg), tetrahydrofuran (3 mL), ethanol (3 mL) and 1M aqueous sodium hydroxide solution (3 mL) was stirred at room temperature for 4 h. Water and 1M hydrochloric acid (3 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (510 mg, 93%) as a brown amorphous solid. MS 520 (MH+).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[C@H:30]12[CH2:36][C@H:33]([NH:34][CH2:35]1)[CH2:32][N:31]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C(N(CC)C(C)C)(C)C.CC#N>CN1C(=O)CCC1>[C:40]([O:39][C:37]([N:31]1[CH2:32][CH:33]2[CH2:36][CH:30]1[CH2:35][N:34]2[C:2]1[CH:29]=[CH:28][C:5]([C:6](=[O:7])[NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:11]=2)=[CH:4][N:3]=1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1
Temperature: 115 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 6-chloro-N-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)nicotinamide (intermediate E) (30 mg, 0.071 mmol), (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (43 mg, 0.212 mmol) and N,N-diisopropylethylamine (59.2 mg, 80.0 μL, 0.456 mmol) in NMP (500 μL) was stirred at 115° C. in a sealed tube overnight. The reaction mixture was transferred to a vial with CH3CN, then concentrated under a stream of nitrogen. The crude product was purified using preparative reverse-phase HPLC. The product 5-{5-[(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamoyl]-pyridin-2-yl}-2,5-diaza-bicyclo-[2.2.1]-heptane-2-carboxylic acid tert-butyl ester (28 mg, 68%) was obtained as a white solid. MS calcd. for C32H32ClN5O4 [(M+H)+] 586.2, obsd. 586.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:16]([C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)=[C:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=2)(O)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:43]>CO.O.O1CCOCC1>[ClH:43].[ClH:43].[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:17]2[NH:18][CH:19]=[C:15]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[C:16]=2[C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:31][CH:32]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2(O)CCN(Cc3ccccc3)CC2)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2[nH]cc(C3=CCNCC3)c2-c2ccncc2)cc1
Yield: 80 %

Procedure:
249 mg (0.689 mmol) of 4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in Example 9 above] were dissolved in a mixture of 2.5 ml of methanol and 2.5 ml of water, after which 2.43 ml (9.646 mmol) of a 4 N solution of hydrogen chloride in dioxane were added to the solution. The resulting mixture was heated under reflux for 11 hours, after which the reaction mixture was concentrated by evaporation under reduced pressure and the residual solid was washed with hot isopropanol to give 216 mg (yield 80%) of the title compound as a pale yellow powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:18].[CH2:19]=O>C(O)=O.O.[OH-].[Na+].C(O)C>[CH3:19][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:18]
Reactant: C=O
Reactant: O[C@@H]1Cc2ccccc2C[C@H]1CC1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: CN1CCCCC1C[C@@H]1Cc2ccccc2C[C@H]1O
Temperature: 0 °C

Procedure:
trans-1,2,3,4-Tetrahydro-3-(2-piperidinylmethyl)-2-naphthalenol from Part D (21.5 g, 0.088 M) is dissolved in 20 ml 35% formaldehyde solution and 50 ml 98% formic acid. The mixture is heated overnight on a steam bath. The solution is taken to near dryness in vacuo. The residue is dissolved in water and basified with 50% NaOH solution. The material is extracted into chloroform, dried and the solvent is removed leaving a brown oil which shows a strong peak in the carbonyl region on the IR. This is dissolved in ethanol, NaOH solution is added and the mixture is heated for a few minutes on a steam bath. After diluting with ice water the mixture is extracted twice with ether. The ether extracts are dried and the solvent is removed leaving 23 g (quant) of the title compound.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CO)cs1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCc1csc(NC(=N)N)n1
Yield: 96 %

Procedure:
To a solution of 2-guanidino-4-hydroxymethylthiazole (0.86 g) in pyridine (6 ml) is gradually added methanesulfonyl chloride (0.6 g) under ice cooling, and the resultant mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuum, and the residual oil is chromatographed on a column of silica gel, which is eluted with methanol. The eluate is concentrated in vacuum to give 2-guanidino-4-(methanesulfonyloxymethyl)thiazole (1.2 g) as an oil. The yield is 96%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[C:4]([Br:10])[CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Br:10])[CH:3]=1)[CH2:8][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCc1cc(Br)cc(Br)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Br)cc(Br)c1
Temperature: 120 °C
Yield: 84.4 %

Procedure:
A mixture of 1,3-dibromo-5-(bromomethyl)benzene (1.1 g, ˜3.3 mmol) and potassium phthalimide (0.62 g, 3.3 mmol) in DMF (10 ml) was heated at 120° C. for 2 hours. After cooled down, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 2-(3,5-dibromobenzyl)isoindoline-1,3-dione (1.1 g, 83%) was obtained as white solid.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:14]>C(Cl)Cl>[ClH:12].[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([O:15][C:13]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:14])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Oc1cccc(C(F)(F)F)c1
Reactant: CCC(CC)N1CCNCC1
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)Oc2cccc(C(F)(F)F)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a stirred mixture of 1-(1-ethylpropyl)piperazine (175p1, 1.0 mmol) and dry DCM (10 ml) was added 3-trifluoromethylphenyl chloroformate (250 mg, 1.1 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and the residue was dissolved in a 0.5 N HCl solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 330 mg (86%) of the title compound as a solid. M.p. 260-261° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:41]([Cl:43])[Cl:42]>C(O)(=O)C>[NH3:1].[CH2:41]([Cl:43])[Cl:42].[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc(OCCCN2CCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N
Product: c1ccc(NCc2ccc(OCCCN3CCCC3)cc2)nc1
Reaction time: 16 h

Procedure:
A solution of 4-(3-Pyrrolidin-1-yl-propoxy)-benzaldehyde (0.51 g), 2-aminopyridine (0.24 g), and acetic acid (0.13 mL) in DCM (7 mL) was treated with sodium triacetoxyborohydride (650 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (10 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–4% 2 M methanolic ammonia/DCM) gave the title compound as an off white solid (500 mg). 1H NMR (400 MHz, CDCl3): 8.09 (m, 1H), 7.39 (m, 1H), 7.26 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.58 (m, 1H), 6.36 (m, 1H), 4.79 (m, 1H), 4.41 (d, J=5.5, 2H), 4.01 (t, J=6.3 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.54 (m, 4H), 2.04–1.96 (m, 2H), 1.79 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([OH:17])[CH2:4][CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.O>[N:20]([CH2:5][CH2:4][CH:3]([OH:17])[C:2]([F:19])([F:18])[F:1])=[N+:21]=[N-:22]
Reactant: Cc1ccc(S(=O)(=O)OCCC(O)C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCC(O)C(F)(F)F
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of 4-toluenesulfonic acid 4,4,4-trifluoro-3-hydroxybutyl ester (1.30 g, 4.36 mmol) in DMSO (7 mL) was treated with sodium azide (0.306 g, 4.71 mmol) at is ambient temperature and then heated at 50° C. for 23 h. The mixture was diluted with cold water and extracted with diethyl ether. The combined organic extracts were washed (brine), dried, and evaporated without heat to give the product as a yellow oil (0.737 g, 100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[N:3]([CH2:1][CH3:2])[CH2:11][CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)c1cccc(OCCCBr)c1
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a solution of 3-(diethylamino)phenol (0.0104 g, 0.631 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.640 mL, 6.30 mmol) followed by Cs2CO3 (0.313 g, 0.961 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0314 g, 17.4%). EI-MS m/z 286(M+H+) Rt (1.59 min).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][C:11]1[CH:12]=[C:13]([CH:30]=[C:31]([CH3:33])[CH:32]=1)[C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17]1)=[O:15].Cl[CH2:35][CH2:36][C:37](Cl)=[O:38].Br.Br.[CH2:42]([N:49]1[CH2:54][C@@H:53]2[CH2:55][C@H:50]1[CH2:51][NH:52]2)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:18]2[CH2:17][N:16]([C:14](=[O:15])[C:13]3[CH:30]=[C:31]([CH3:33])[CH:32]=[C:11]([CH3:10])[CH:12]=3)[CH2:21][CH2:20][N:19]2[C:37](=[O:38])[CH2:36][CH2:35][N:52]2[CH2:51][C@@H:50]3[CH2:55][C@H:53]2[CH2:54][N:49]3[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: Cc1cc(C)cc(C(=O)N2CCNC(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: O=C(Cl)CCCl
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CCN3C[C@@H]4C[C@H]3CN4Cc3ccccc3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
To a cooled solution of CH2Cl2 (10 mL) containing diisopropylethylamine (0.275 mL, 2.0 mmol) and [3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine (Enantiomer B) (Example 4) (305 mg, 0.84 mmol) was added chloropropionyl chloride (0.075 mL, 0.8 mmol). The reaction mixture was allowed to warm to room temperature. After 20 minutes, (1S,4S)-2-benzyl-2,5-diazabicyclo(2.2.1)heptane 2HBr (297 mg, 0.85 mmol) and diisopropylethylamine (0.275 mL, 2.0 mmol) were added and the mixture was left over night, after which the reaction mixture was concentrated. The product was purified by flash chromatography on flash grade silica gel, eluting with 30:1:0.1 CH2Cl2 /MeOH/NH3 to give a foamy solid (140 mg, 0.23 mmol, 29%), High Res. MS:[M+1]+ calcd. for C34H39Cl2N4O2 605.2450; Found, 605.2465.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2)(=O)=O.[OH-].[K+]>O1CCCC1.C(O)C.O>[OH:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OS(C)(=O)=O)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.2 %

Procedure:
Ethyl 7-[(methylsulfonyl)oxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (11.74 g) was suspended in a mixture of tetrahydrofuran (300 mL) and ethanol (150 mL). A solution of potassium hydroxide (85%, 6.8 g) in water (100 mL) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was concentrated and 1M hydrochloric acid (130 mL) was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (8.39 g, 93%) as a brown solid. MS 349 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl.[CH2:36]([O:38][C:39](=[O:42])[CH2:40][NH2:41])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])[N:14]=[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:41][CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:42])=[O:29])=[CH:31][CH:32]=3)[N:12]=2)=[CH:33][CH:34]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)OCC)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg, 0.21 mmol) in DCM (3 mL) was added glycine ethyl ester HCl (44 mg, 0.32 mmol), HATU (120 mg, 0.32 mol) and iPr2NEt (0.11 mL, 0.63 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed under vacuum and the residue was purified by silica gel column (EtOAC/Hexanes=40% to 60%) to give ethyl 2-(4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate (100 mg, 81%) as a white solid.