Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])[C:5]2=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1)CCC>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.O1CCOCC1>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:10]1[C:5]2[N:6]([C:2]([C:30]3[CH:35]=[N:34][CH:33]=[CH:32][N:31]=3)=[CH:3][N:4]=2)[N:7]=[CH:8][CH:9]=1
Reactant: Cc1ccncc1-c1ccnn2c(I)cnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccncc1-c1ccnn2c(-c3cnccn3)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
A microwave vial was charged with a mixture of 3-iodo-8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine, TFA (66 mg, 0.147 mmol), 2-(tributylstannyl)pyrazine (162 mg, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (33.9 mg, 0.029 mmol), and dioxane (4 mL) was stirred at RT for 5 min. under nitrogen. The resulting mixture was heated to 114° C. for 15 h in microwave. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep. HPLC to give 18.2 mg (30%) product. 1H NMR (400 MHz, CD3OD) δ ppm 9.86 (1H, d, J=1.76 Hz), 8.97 (1H, s), 8.86 (2H, dd, J=16.12, 5.29 Hz), 8.66-8.79 (1H, m), 8.59 (1H, d, J=2.52 Hz), 8.56 (1H, s), 8.10 (1H, d, J=6.04 Hz), 7.54 (1H, d, J=4.78 Hz), 2.57 (3H, s); LC (Conditions B & C): >95% purity. LC/MS: Rt=1.05 min. LC/MS (Condition A): 289.12.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.CN(C)C=O.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>C(Cl)(Cl)Cl>[C:25]1(=[O:35])[N:29]([CH2:2][CH2:3][CH2:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ICCCC1c2ccccc2C=Cc2ccccc21
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCC1c2ccccc2C=Cc2ccccc21

Procedure:
5-(3-Iodopropyl)-5H-dibenzo[a,d]cycloheptene, 1.8 g. (0.005 mole), is dissolved in 10 ml. of dimethylformamide. The solution is stirred while 930 mg. (0.0051 mole) of potassium phthalimide is added. When the addition is complete, the mixture is heated to 85°-90° C. for 40 minutes, then cooled, diluted with chloroform and poured into water. The chloroform layer is separated and the aqueous layer extracted further with chloroform. Evaporation of the chloroform gives the product as an oily crystalline solid. Several recrystallizations from isopropyl alcohol gave product, m.p. 125.5°-131.5° C.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]([C:17]([CH3:24])([CH3:23])[C:18](OCC)=[O:19])[S:13](=[O:16])(=[O:15])[NH2:14])=[CH:7][C:6]=1[CH3:25]>CO.C(OCC)(=O)C>[Br:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[S:13](=[O:16])(=[O:15])[NH:14][C:18](=[O:19])[C:17]2([CH3:24])[CH3:23])=[CH:7][C:6]=1[CH3:25]
Reactant: CCOC(=O)C(C)(C)N(c1cc(C)c(Br)c(C)c1)S(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(N2C(C)(C)C(=O)NS2(=O)=O)cc(C)c1Br
Yield: 90.7 %

Procedure:
A 2 M solution of sodium methoxide in methanol (4 ml, 8 mmol) was added to a solution of ethyl 2-[N-(4-bromo-3,5-dimethyl-phenyl)-N-sulfamoyl-amino]-2-methyl-propanoate (100 mg, 0.254 mmol) in methanol (12 ml), and the mixture was irradiated with microwaves at 65° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer was sequentially washed with water and saturated brine and concentrated under reduced pressure to give 5-(4-bromo-3,5-dimethyl-phenyl)-4,4-dimethyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-3-one (80 mg, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=3)=[CH:33][CH:34]=2)[N:5]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(CCl)cc2)nc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCCc3ccc(CC)cn3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 2-[2-(4-chloromethylphenoxy)ethyl]-5-ethylpyridine (414 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-1H-pyrazol-4-yl]propionate (520 mg, yield: 77%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]1=2)=[O:11].Cl.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](O)=[O:38])=[CH:31][CH:30]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:27].[Cl:27][C:25]1[CH:24]=[CH:23][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH2:18][N:12]([C:10](=[O:11])[CH2:9][NH:8][C:37](=[O:38])[CH2:36][CH2:35][C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)[C:13]=2[CH:26]=1
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(O)CCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCc1ccncc1)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
Triethylamine (0.8 mL) was added to a stirred mixture of 10-(aminoacetyl)-8-chloro-10,11-dihydrodibenz-[b,f][1,4]oxazepine (0.77 gram) and 4-pyridinepropanoic acid, monohydrochloride (0.50 gram) in dimethylformamide (10 mL) at room temperature under a nitrogen atmosphere. After 5 minutes, the mixture was cooled to 5° C. in an ice bath, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (0.56 gram) was added. The reaction was stirred at room temperature under a nitrogen atmosphere for 60 hours, partitioned between saturated aqueous sodium bicarbonate (100 mL) and ethyl acetate (75 mL), and filtered. The layers of the filtrate were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The ethyl acetate extracts were combined, washed with aqueous saturated sodium bicarbonate (2×100 mn), water (100 mL), and brine (100 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 9:1 ethyl acetate:ethanol. The purified product was taken up in ethyl acetate and treated with 9.5M HCl in ethanol to pH 1. The precipitated product was collected by filtration and dried in vacuo at 80° C. Yield: 0,233 gram (19%). Analysis calculated for C23H20ClN3O3 ×1 HCl: C, 60.27; H, 4.62;N, 9.17; Cl, 15.47. Found: C, 59.88; H, 4.66;N, 8.99; Cl, 15.58.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14][NH2:15])=[CH:3][N:2]=1>C(O)C.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:3][N:2]=1
Reactant: NCC/C=C/c1cncc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: NCCCCc1cncc2ccccc12
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A solution of 1 g of (E)-4-(4-isoquinolinyl)-3-buten-1-amine in 20 mL of ethanol was hydrogenated over 0.12 g of 10% Pd/C at room temperature and atmospheric pressure. After 8 hours, the catalyst was removed by filtration and the filtrate was concentrated to yield 0.893 g of 4-isoquinolinebutanamine.
Reaction SMILES: ClC1C=C(C(=NO)CC2C=CC(SC)=CC=2)C=CC=1OC.C(OC(=O)C)(=O)C.[Cl:29][C:30]1[CH:31]=[C:32]([C:38]2[C:42]([C:43]3[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=O)=O)=[CH:45][CH:44]=3)=[C:41]([CH3:53])[O:40][N:39]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].OOS([O-])=O.[K+]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:38]2[C:42]([C:43]3[CH:48]=[CH:47][C:46]([S:49][CH3:52])=[CH:45][CH:44]=3)=[C:41]([CH3:53])[O:40][N:39]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(-c2noc(C)c2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Agent: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1Cl
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2noc(C)c2-c2ccc(SC)cc2)cc1Cl
Yield: 26 %

Procedure:
3-(3-Chloro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole was prepared in 26% yield from 1-(3-chloro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one oxime from Step 5 and acetic anhydride by the method described in Example 4, Step 1 and then oxidized to 3-(3-chloro-4 methoxyphenyl)-5-methyl-4-[4-methylsulfonylphenyl]isoxazole with Oxone® by the method described in Example 5, Step 4: Mass spectrum: MLi+=384. High resolution mass spectrum Calc'd. For C18H16ClNO4S: 378.0567. Found: 378.0573.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:13]([CH3:14])=[N:12][N:11]([C:15]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:18]=[CH:17][N:16]=3)[C:10]2=[O:27])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC.O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:13]([CH3:14])=[N:12][N:11]([C:15]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:18]=[CH:17][N:16]=3)[C:10]=2[O:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CC1=NN(c2nccc(-c3ccccn3)n2)C(=O)C1Sc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COc1c(Sc2ccc(Cl)cc2)c(C)nn1-c1nccc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
To a solution of 4-(4-chloro-phenylsulfanyl)-5-methyl-2(4-pyridin-2yl-pyrimidin-2-yl)-2,4-dihydro-pyrazol-3-one (0.344 g, 0.869 mmol) in acetone (10 mL) was added potassium carbonate (ca. 3 g) and iodomethane (0.130 g, 0.912 mmol). The suspension was heated to reflux and stirred for 2 hours. The suspension was allowed to cool to room temperature, and water (100 mL) was added. The mixture was extracted with diethyl ether (50 mL), and the organic phase was washed with brine (50 mL), dried (magnesium sulfate), filtered and concentrated to afford a white solid. Flash chromatography over silica (methylene chloride/2M ammonia in methanol, two columns) provided 0.007 g (2%) of the product as a white solid. 1H NMR analysis was consistent with the assigned structure.
Reaction SMILES: Br.Br.[CH3:3][C:4]1([NH2:9])[CH2:6][C:5]1([CH3:8])[NH2:7].[F:10][C:11]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:12]=1[CH2:13][O:14][C:15]1[N:20]2[N:21]=[C:22]([CH3:27])[C:23]([C:24](O)=[O:25])=[C:19]2[CH:18]=[C:17]([CH3:28])[CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.ClCCl>[NH2:7][C:5]1([CH3:8])[CH2:6][C:4]1([NH:9][C:24]([C:23]1[C:22]([CH3:27])=[N:21][N:20]2[C:15]([O:14][CH2:13][C:12]3[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:11]=3[F:10])=[CH:16][C:17]([CH3:28])=[CH:18][C:19]=12)=[O:25])[CH3:3]
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: CC1(N)CC1(C)N
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC3(C)CC3(C)N)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
29 mg (0.11 mmol) of rac-1,2-dimethylcyclopropane-1,2-diamine dihydrobromide (described in: W. v. d. Saal et al. Liebigs Annalen der Chemie 1994, 569-580) were initially charged in a 96-well deep-well multititre plate. A solution of 33.2 mg (0.1 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A in 0.4 ml of DMF/dichloromethane (1:1, v/v) and a solution of 49.4 mg (0.13 mmol) of HATU in 0.4 ml of DMF/dichloromethane (1:1, v/v) were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Subsequently, the mixture was heated to 60° C. and shaken at this temperature for 7 h. Then the solvent was evaporated off completely. The residue was dissolved in 0.8 ml of DMF and filtered, and the target compound was isolated by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 2.3 mg (5% of theory) of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:7]=1[C:8]#[N:9].CSC>ClCCCl>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:7]=1[CH2:8][NH2:9]
Reactant: N#Cc1cc(Cl)ccc1OCc1ccccc1Br
Solvent: CSC
Solvent: ClCCCl
Product: NCc1cc(Cl)ccc1OCc1ccccc1Br
Temperature: 65 °C
Yield: 60 %

Procedure:
To a stirred solution of 2-(2-Bromo-benzyloxy)-5-chloro-benzonitrile Example 348A (1.52 g, 4.71 mmol) in DCE (50 mL) under argon was added BH3 DMS (30.0 mL, 18.8 mmol). The reaction mixture was heated at 65° C. for 14 h and then cooled to room temperature. The mixture was quenched with 1N HCl solution slowly (25 mL). This solution was then mixed with 1N NaOH solution (30 mL), and extracted with EtOAc (3×80 mL). The combined EtOAc extracts were washed with saturated NaHCO3 solution (1×40 mL) and brine (1×40 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 0.92 g (60%) of crude 2-(2-Bromo-benzyloxy)-5-chloro-benzylamine Example 348B which was used as is without further purification. HPLC Rt=2.87 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=326
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C#N)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)C#N)cc1
Yield: 83.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.5 g, 4.84 mmol) was reacted with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanenitrile (1.87 g, 7.26 mmol) to afford the desired product (1.45 g, 82%) as a brown solid: ESI MS m/z 361 [C21H16N2O2S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.Cl.Cl.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[CH2:20][CH2:19]1>>[OH:32][CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][CH:18]([NH:17][C:11]([C:5]3[NH:6][C:7]4[C:3]([CH:4]=3)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)=[O:13])[CH2:23][CH2:22]2)[CH2:31][CH2:30]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Br)cccc2[nH]1

Procedure:
This compound is synthesized from 4-Bromo-1H-indole-2-carboxylic acid and amine 21 analogously to the method described for 194 (see example 156).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21]C(C)(C)[O:23][C@@H:19]2[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]2[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]2)[CH2:17]1.C(N(CC)C(C)C)(C)C.[C:55]([C:59]1[CH:60]=[C:61]([NH2:66])[C:62]([NH2:65])=[CH:63][CH:64]=1)([CH3:58])([CH3:57])[CH3:56].C([O-])(O)=O.[Na+]>CN(C)C=O>[NH2:66][C:61]1[CH:60]=[C:59]([C:55]([CH3:57])([CH3:56])[CH3:58])[CH:64]=[CH:63][C:62]=1[NH:65][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@H:18]2[CH2:17][C@@H:16]([N:11]3[CH:10]=[N:9][C:8]4[C:12]3=[N:13][CH:14]=[N:15][C:7]=4[NH:6][CH2:5][C:4]3[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=3[O:2][CH3:1])[C@H:20]([OH:21])[C@@H:19]2[OH:23])[CH:37]([CH3:38])[CH3:39])[CH2:29]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@@H](O)[C@H]2O)c(OC)c1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.19 g, 3.13 mmol) added to a solution of 3-{3-[{[(3aR,4R,6R,6aS)-6-{6-[(2,4-dimethoxybenzyl)amino]-9H-purin-9-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl}{isopropyl)amino]cyclobutyl}propanoic acid (1.30 g, 2.09 mmol) and N,N-Diisopropylethylamine (1.20 ml, 6.89 mmol) and 4-tert-butylbenzene-1,2-diamine (0.411 g, 2.50 mmol) in N,N-Dimethylformamide (12.9 ml). The reaction was stirred for 2 hours, NaHCO3 (saturated) was added and the mixture extracted with EtOAc (3×) and the combined organics was dried over MgSO4 filtered and concentrated. The residue was purified by flash chromatography (DCM→DCM/7N NH3 in MeOH 95:5) to yield the desired amide (1.4 g) as a solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(N2CCNCC2)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)N1CCN(c2ccc(I)cc2)CC1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a mixture of 1-(4-iodophenyl)piperazine (1.44 g, 5 mmol) and acetone (1.47 mL, 20 mmol) in DCE/THF (45 mL/15 mL) was added NaBH(OAc)3 (1.38 g, 6.5 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction as quenched with sat. NaHCO3 (10 mL) and H2O (20 mL), and was then extracted with EtOAc (2×60 mL), dried over MgSO4 and concentrated to give the crude title compound as a light yellow solid (1.396 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 3.12-3.07 (m, 4H), 2.65 (p, J=6.5 Hz, 1H), 2.56-2.52 (m, 4H), 0.98 (d, J=6.4 Hz, 6H); MS ESI 330.9 [M+H]+, calcd. for [C13H19IN2+H]+ 331.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([O:22]CC)=O)[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][NH2:37]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:36][NH2:37])=[O:22])[CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1

Procedure:
Synthesized according to General Procedure C: 6{10} (2.02 g, 4.26 mmol, 1 equiv.), anhydrous hydrazine (0.40 mL, 12.8 mmol, 3 equiv.), ethanol (8.6 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{10} (3.00 g, 81%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H), 7.45-7.44 (m, 4H), 7.37-7.33 (m, 4H) 7.31-7.27 (m, 2H), 6.92 (d, 1H, J=2.0 Hz), 6.87 (d, 1H, J=8.0 Hz), 6.77 (dd, 1H, J=2.0, 8.0 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 3.84 (br s, 2H), 3.39 (s, 2H), 3.06 (s, 2H), 2.48 (br s, 4H), 2.37 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 148.6, 148.1, 137.3, 137.3, 131.1, 128.4, 128.3, 127.7, 127.6, 127.3, 127.2, 122.0, 116.0, 114.6, 71.3, 71.1, 62.3, 60.5, 53.6, 52.8.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[C:19]([CH3:34])[CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:35])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[C:19]([CH3:34])[CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)ccc1-c1c(C)n(C)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.04 mmol, 22 mg) in ethanol (2 mL) was added aqueous 1.0 N sodium hydroxide (0.5 mL) at room temperature. The mixture was stirred for 2 h at room temperature. The ethanol was removed under reduced pressure and the residue was diluted with water (10 mL). The aqueous solution was washed with diethyl ether (20 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×15 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 20 mg (93% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C23H21Cl2N3O5 [(M-H)+2Na] 548.0725, found 548.0733.