Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][C:10]([C:18]#[C:19][Si](C)(C)C)=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.C(OCC)(=O)C>[C:18]([C:10]1[N:11]=[C:12]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=2)[N:9]=1)#[CH:19]
Reactant: COc1ccc(Cn2nc(C#C[Si](C)(C)C)nc2N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1nc(N2CCCC2)n(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.7 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-3-((trimethylsilyl)ethynyl)-1H-1,2,4-triazole (95 mg, 268 μmol, Eq: 1.00) and sodium hydroxide sol. 1N (0.1 ml) in methanol (3 ml) was stirred for 18 hours at 25° C. The mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 3-ethynyl-1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazole (83 mg/110%) as a yellow oil. MS: m/e=283.4 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[Br:14][C:4]1[CH:5]=[C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(C)(C)C#N)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)(C)C#N)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-methoxy-phenyl)-2-methyl-propionitrile (17.5 g, 0.10 mol) in TFA (80 mL) was cooled to 0° C. N-bromosuccinimide (17.8 g, 0.10 mol) was added in small portions keeping the temperature below 5° C. The orange solution was stirred for 2 h/25° C. and evaporated to dryness. Water (200 mL) was added and the mixture was stirred vigorously for 1 h. The crude product was filtered off and recrystallized from boiling MeOH. The pure product was isolated as white needles. Yield: 19.3 g (76%). GCMS: >99%
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1CNC(=O)C1.[Br:23][Br-]Br>O1CCCC1.S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH:14]([Br:23])[CH3:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCC(=O)c1ccc2c(c1)CCN2C(C)=O
Agent: O=C1CCCN1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(C(=O)C(C)Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a solution of 1-acetyl-5-propionylindoline (1.65 g) in tetrahydrofuran (150 ml) were added concentrated sulfuric acid (5 drops) and pyrrolidone hydrotribromide (4.14 g), and the mixture was stirred at room temperature for 16 hours. The insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1.78 g of 1-acetyl-5-(2-bromopropionyl)indoline melting at 140°-142° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH:3]=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC>[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[C:26]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=3)[CH:3]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2cc(-c3cccc4c3oc3ccccc34)ncn2)cc1

Procedure:
tert-Butyl N-[4-(6-chloropyrimidin-4-ylamino)-phenyl]carbamate (compound C1) (10.1 g, 31 mmol) and 4-dibenzofurane boronic acid (9.96 g, 47 mmol) are heated in dimethoxyethane (500 mL) under an inert atmosphere with dichloro-bis(tricyclohexylphosphine)-palladium(II) (2.28 g, 3.1 mmol) and an aqueous Na2CO3-solution (32.8 g in 310 mL of water) for 4 h at 80° C. After evaporation and extraction of the residue, the product is purified by crystallization.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][CH2:12][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][O:15][CH3:16].CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][CH2:12][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:14][O:15][CH3:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC[C@@H](CNc1ccc(C#N)c(Br)c1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 78.1 %

Procedure:
To a solution of 2-bromo-4-fluorobenzonitrile (0.2 g, 1 mmol) in DMSO (3 mL) was added (R)-tert-butyl 1-amino-3-methoxypropan-2-ylcarbamate (0.22 g, 1.08 mmol) and DIPEA (0.267 mL, 1.5 mmol). The mixture was heated at 100° C. for 15 h, and was diluted with EtOAc and washed with 1N HCl and Sat. NaHCO3. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-(3-bromo-4-cyanophenylamino)-3-methoxypropan-2-ylcarbamate (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2Br)=[N:11][N:12]=1.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:33]2[CH:34]=[CH:35][S:31][CH:32]=2)=[N:11][N:12]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4Br)o3)n2)cc1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4-c4ccsc4)o3)n2)cc1
Temperature: 25 °C
Yield: 14.6 %

Procedure:
A solution of 4-[5-amino-6-[5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (50 mg, 0.108 mmol), thiophen-3-ylboronic acid (13.8 mg, 0.108 mmol), cesium carbonate (107 μL of 2M aqueous solution) and dichloropalladium; triphenylphosphane (7.55 mg, 0.0108 mmol) in dioxane (2 mL) was heated at 110° C. in the microwave for 1 h. The reaction mixture was cooled to room temperature and filtered. The filtrated was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (7.4 mg, 17% yield); 1H NMR (400 MHz, DMSO) d 2.97 (m, 6H), 7.09 (m, 1H), 7.53 (m, 2H), 7.60 (m, 2H), 7.64 (m, 2H), 7.71-7.76 (m, 3H), 8.01 (m, 2H), 8.07 (m, 1H) and 8.95 (s, 1H) ppm; MS (ES−) 469.22
Reaction SMILES: C(OC(=O)NCC1C=CC2N(CCCCO)C(CN3C4C(=CC=CC=4)C(=O)N(C4CC4)C3=O)=NC=2C=1)(C)(C)C.[C:40]([O:44][C:45]([NH:47][CH2:48][C:49]1[CH:82]=[CH:81][C:52]2[N:53]([CH2:70][CH2:71][CH2:72][CH2:73][O:74]C(=O)C(C)(C)C)[C:54]([CH2:56][N:57]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:60]([O:67][CH3:68])=[CH:59][C:58]3=[O:69])=[N:55][C:51]=2[CH:50]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>O>[C:40]([O:44][C:45](=[O:46])[NH:47][CH2:48][C:49]1[CH:82]=[CH:81][C:52]2[N:53]([CH2:70][CH2:71][CH2:72][CH2:73][OH:74])[C:54]([CH2:56][N:57]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:60]([O:67][CH3:68])=[CH:59][C:58]3=[O:69])=[N:55][C:51]=2[CH:50]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: COc1cc(=O)n(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCOC(=O)C(C)(C)C)c2ccccc12
Agent: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCCCO
Solvent: O
Product: COc1cc(=O)n(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCO)c2ccccc12
Yield: 85 %

Procedure:
The procedure for the preparation of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(4-hydroxy-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed starting from 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-(4-methoxy-2-oxo-2H-quinolin-1-ylmethyl)-benzoimidazol-1-yl]-butyl ester (280 mg, 0.474 mmol). After neutralization more water was added and the resulting white precipitate collected by filtration, which was washed with water (thrice) and diethyl ether (thrice) to yield 204 mg (85%) of [1-(4-hydroxy-butyl)-2-(4-methoxy-2-oxo-2H-quinolin-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](SC)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.O1CCOCC1.O.[C:26]12([CH2:36][NH2:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.O>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([NH:37][CH2:36][C:26]34[CH2:35][CH:30]5[CH2:29][CH:28]([CH2:34][CH:32]([CH2:31]5)[CH2:33]3)[CH2:27]4)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)c1cnc(NCC23CC4CC(CC(C4)C2)C3)nc1
Temperature: 110 °C
Yield: 23.1 %

Procedure:
To a solution of 2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (50 mg, 0.19 mmol) in 4/1 dioxane/water (0.6 mL) in a sealed tube was added 1-adamantanemethyl amine (250 μL, 1.4 mmol). The solution was heated at 110° C. for 18 h, cooled, diluted with 3% HCl and then poured into water to form a precipitate. The solids were collected by filtration, washed with water and dried. Trituration of the solids with ethyl acetate at about 70° C., followed by a hot filtration and washing with hexane, afforded 16.7 mg (24% yield) of the titled product as a white solid. API-MS m/z 381 (MH)+, 379 (M−H)−.
Reaction SMILES: C(N(CC)C(C)C)(C)C.O[C@@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>C(Cl)Cl>[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]
Reactant: O=C1OCC[C@H]1O
Reactant: Fc1ccc2c(c1Cl)CCN2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Temperature: -40 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −40° C., N,N-diisopropylethylamine (34.1 mL, 196 mmol) was added dropwise to a solution of solution of (R)-dihydro-3-hydroxyfuran-2(3H)-one (10.0 g, 98 mmol) in CH2Cl2 (100 mL). Trifluoromethanesulfonic anhydride (17.3 mL, 103 mmol) was added dropwise to this solution maintaining the internal temperature of the reaction mixture below −40° C. Upon completion of addition, the mixture was stirred at −40° C. for 1 h. A solution of 4-chloro-5-fluoroindoline (27.6, 147 mmol) in CH2Cl2 (40 mL) was added dropwise to this solution maintaining the internal temperature of the reaction mixture below −40° C. The reaction was allowed to warm up to −20° C. and was kept at this temperature for 48 h. The reaction mixture was washed with saturated aqueous sodium bicarbonate (2×), brine, dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 0-40% ethyl acetate in hexane gave (S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one as a white solid (22.9 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 7.07-7.02 (m, 1H), 6.50 (dd, J=3.6, 8.6 Hz, 1H), 4.88 (dd, J=9.0, 11.4 Hz, 1H), 4.44-4.39 (m, 1H), 4.29-4.22 (m, 1H), 3.60-3.54 (m, 1H), 3.28 (dd, J=8.6, 17.8 Hz, 1H), 3.07-2.92 (m, 2H), 2.43-2.28 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=256.1; tR=1.54 min.
Reaction SMILES: [Br:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[O:14][C:10]=3[CH:9]=2)=[C:4]([N+:22]([O-])=O)[CH:3]=1>CO.C(Cl)Cl.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[O:14][C:10]=3[CH:9]=2)=[CH:19][C:20]=1[Cl:21]
Reactant: CSc1nc2ccc(CNc3cc(Cl)c(Br)cc3[N+](=O)[O-])cc2o1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CSc1nc2ccc(CNc3cc(Cl)c(Br)cc3N)cc2o1
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a stirred solution of 4-bromo-5-chloro-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline (451 mg, 1.06 mmol) in methanol (80 mL) and DCM (80 mL) was added palladium on activated charcoal (100 mg). The mixture was stirred under hydrogen for 2 h, filtered and concentrated under reduced pressure to give 4-bromo-5-chloro-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine as a light yellow solid (415 mg, 98.6%). 1H NMR (300 MHz, DMSO-d6) δ 7.57-7.60 (m, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 6.41 (s, 1H), 5.64 (t, 1H), 5.03 (s, 2H), 4.40 (d, J=6.0 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 399 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:27](Cl)(=[O:29])=[O:28])=[CH:15][CH:14]=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:32][CH:31]=1)(=[O:28])=[O:29]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (0.48 mmoles, 85 mg), NaH (1.2 mmoles, 48 mg), 2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride (0.53 mmoles, 0.19 g) and THF (3 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from methanol and water provided 46 mg (20%) of a white crystalline solid, m.p. 120-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([NH2:17])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1.O(Cl)Cl.[P]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]#[N:17])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1
Reactant: CC(C(N)=O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: ClOCl
Agent: [P]
Product: CC(C#N)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 74776.6 %

Procedure:
2.84 g (0.01 mmole) of 2-[3-chloro-4-(4-chloropyrazol-1-yl) phenyl] propionamide and 1 g (7 mmoles) of phosphorus oxy chloride are heated to 100° C. for one hour. The reaction mixture is cooled, washed with sodium carbonate solution and water, concentrated and distilled. 1.99 g (75%) of 2-[3-chloro-4-(4-chloropyrazol-1-yl) phenyl] propionitrile (b.p. 107°-109° C./10-2 mm Hg) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61](C)C)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].COC(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH3:61])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1

Procedure:
This compound was made in an analogous manner to methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate, substituting (S)-2-(methoxycarbonylamino)propanoic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amide coupling. LCMS-ESI+: calculated for C46H46N8O7: 822.91; observed [M+1]+: 823.58.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])=[CH:11][CH:10]=[C:9]([N+:20]([O-])=O)[CH:8]=2)([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]([O:16][CH3:17])[O:18][CH3:19])=[CH:11][CH:10]=[C:9]([NH2:20])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cc1c(C(C)(C)C)[nH]c2cc([N+](=O)[O-])ccc12)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(Cc1c(C(C)(C)C)[nH]c2cc(N)ccc12)OC
Reaction time: 16 h
Yield: 62.8 %

Procedure:
To a solution of 2-tert-butyl-3-(2,2-dimethoxy-ethyl)-6-nitro-1H-indole (611 mg, 2 mmol) in methanol was added palladium hydroxide on carbon (100 mg). The flask was evacuated and purged with hydrogen gas three times. The reaction was stirred under hydrogen for 16 h and filtered through a pad of Celite, which was rinsed with methanol. The organic solution was combined and concentrated in vacuo and the residue was purified via flash chromatography to give the desired product (347 mg, 63% yield).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O-:4])=[O:3].[F:22][CH:23]([F:26])[CH2:24]I.C(NC(C)C)(C)C>CN(C)C=O.ClCCl>[F:22][CH:23]([F:26])[CH2:24][N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:6][C:5]=2[N+:2]([O-:4])=[O:3])[CH2:13][CH2:14]1
Reactant: FC(F)CI
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: NS(=O)(=O)c1ccc(NC2CCN(CC(F)F)CC2)c([N+](=O)[O-])c1
Temperature: 85 °C

Procedure:
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide hydrochloride (0.100 g), 1,1-difluoro-2-iodoethane (0.063 mL) and diisopropylamine (0.156 mL) were stirred together in N,N-dimethylformamide (3 ml) and heated to 85° C. The reaction was diluted with dichloromethane (50 mL) and washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel (GraceResolve 12 g) and eluted using a gradient of 0.5% methanol/dichloromethane to 3% methanol/dichloromethane over 30 minutes to give the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=[CH:16]4)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:32]([O:34][CH3:35])=[O:33].O>O1CCOCC1>[C:23]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:12]=[CH:11][C:7]1[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=1)[CH2:1][N:2]([C:32]([O:34][CH3:35])=[O:33])[CH2:3][CH2:4]3)[CH:22]=[CH:21]2)#[N:24]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc2cc(C=Cc3ccc4c(c3)CCNC4)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Reaction time: 16 h

Procedure:
A solution of Example 42J (650 mg, 1.53 mmol) in dioxane (30 mL) at room temperature was treated with 10% K2CO3 (10 mL) and methyl chloroformate (700 mg) and stirred for 16 hours. The mixture was treated with water and extracted with dichloromethane. The combined extracts were washed sequentially with 5% HCl, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)[C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1>[C].[Pd].CO>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: CN(C)CCN(C(=O)C=Cc1ccc2c(c1)OCO2)[C@H]1CC[C@H](C)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCN(C(=O)CCc1ccc2c(c1)OCO2)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,4-methylenedioxycinnamamide (Example 81), 60 ml of methanol, and 0.05 g of 10% palladium-carbon, a reaction similar to that conducted in Example 76 was carried out. As a result, 0.91 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-(3,4-methylenedioxyphenyl)propionamide (a compound of the present invention) was obtained as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>CN(C=O)C>[Cl:21][CH2:20][CH2:19][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[NH2:11]
Reactant: ClCCBr
Reactant: Nc1nc(N)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2ncn(CCCl)c2n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 72 %

Procedure:
10 g (66.6 mmol) 2,6-diaminopurine were suspended under argon in 300 ml DMF and 21.6 g (156.5 mmol) potassium carbonate and 24 ml 1-bromo-2-chloroethane were added. The mixture was stirred for 64 hours at room temperature. The light yellow suspension was filtered and the solids were washed with 30 ml DMF and subsequently triturated with 100 ml water for 30 minutes. The mixture was filtered and the solids were washed with 50 ml water and dried in vacuo to give 10.15 g (72%) of the desired product as a white solid.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30]Br>CN(C=O)C.CCOC(C)=O>[F:21][C:18]([F:19])([F:20])[CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:2]([C:3]2([C:4]([O:6][CH3:7])=[O:5])[CH2:30][CH2:29]2)=[O:1])=[CH:9][CH:10]=1
Reactant: BrCCBr
Reactant: COC(=O)CC(=O)c1ccc(OCCCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)c2ccc(OCCCC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
To a solution of Intermediate 14A (6.0 g, 19.7 mmol) in DMF (197 mL) was added K2CO3 (8.18 g, 59.2 mmol) followed by 1,2-dibromoethane (2.6 mL, 30 mmol). The reaction mixture was stirred at rt for 2 days. The reaction was reduced in volume in vacuo, then diluted with EtOAc, washed with a 1:1 solution of sat'd aq NaCl and water, dried over anhydrous MgSO4, filtered and concentrated. The product was isolated by silica gel chromatography (220 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 14B (4.2 g, 61%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.45-1.49 (m, 2H), 1.56-1.61 (m, 2H), 2.03-2.14 (m, 2H), 2.26-2.39 (m, 2H), 3.60 (s, 3H), 4.09 (t, J=6.05 Hz, 2H), 6.90-6.94 (m, 2H), 7.86-7.93 (m, 2H).