Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=S.[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:31])=[C:13]([C@@:15]2([NH:23]C(=O)OC(C)(C)C)[C@:19]([F:22])([CH2:20][OH:21])[CH2:18][O:17][CH2:16]2)[CH:14]=1)(=[O:7])[CH3:6].FC(F)(F)C(O)=O.C(N(CC)CC)C.[C:46]([N:54]=[C:55]=[S:56])(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:31])=[C:13]([C@@:15]2([NH:23][C:55]([NH:54][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[S:56])[C@:19]([F:22])([CH2:20][OH:21])[CH2:18][O:17][CH2:16]2)[CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(F)c([C@]2(NC(=O)OC(C)(C)C)COC[C@@]2(F)CO)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: NC(N)=S
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(F)c([C@]2(NC(=S)NC(=O)c3ccccc3)COC[C@@]2(F)CO)c1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 82.8 %

Procedure:
Scheme 2, step I, (deprotection and thiourea formation): A solution of tert-butyl N-[(3S,4S)-3-(5-acetamido-2-fluoro-phenyl)-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]carbamate (2.70 g, 6.99 mmol) in dichloromethane (40 mL) and trifluoroacetic acid (8.00 mL, 106 mmol) is stirred at ambient temperature for 150 minutes. The reaction is concentrated under reduced pressure and azeotroped with toluene. The residue is dissolved in tetrahydrofuran and treated with triethylamine (1.10 mL, 7.89 mmol) and benzoyl isothiocyanate (1.00 mL, 7.41 mmol). The reaction is stirred at ambient temperature for 16.5 hours and is then quenched with a solution of saturated sodium bicarbonate in water, extracted with ethyl acetate and dichloromethane consecutively. The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with methanol/dichloromethane (0:10) to methanol/dichloromethane (1:10) to give the title compound (2.60 g, 83%). ES/MS (m/e): 450 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH2:8]([NH2:11])[CH:9]=[CH2:10].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:8]([NH:11][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH:9]=[CH2:10]
Reactant: O=Cc1ccoc1
Reactant: C=CCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCNCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.019 g (62.64 mmol) of 3-furaldehyde and 5.37 g (94.0 mmol) of allylamine in 100 ml of methanol was stirred at room temperature for 0.5 hours. To this reaction mixture, 4.74 g (125 mmol) of sodium borohydride was added portionwise under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into an aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to yield N-allyl-3-furylmethylamine.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14](O)=[O:15])[C:5]1=[O:17])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([Cl:20])=[O:15])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)c(C(=O)O)cc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)n1c(=O)c(C(=O)Cl)cc2ccccc21

Procedure:
A solution of 3.88 g of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid and 5.0 ml of thionyl chloride in 50 ml of toluene was stirred at 100° C. for 5 hours. After toluene was distilled off under vacuum, toluene was again added to the residue. The solvent was again distilled off under vacuum to give 4.22 g of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([OH:22])=O)=[O:14])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].CN(C(ON1N=[N:44][C:39]2[CH:40]=[CH:41][CH:42]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CCC1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:22])[NH:44][CH:39]2[CH2:40][CH2:41][CH2:42]2)=[O:14])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)O)n(-c2ccccc2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1

Procedure:
To a solution of 4.5 g 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 105 ml DMF were added 4.4 g HATU and 1.9 ml DIPEA. After 10 minutes 1.0 ml cyclobutylamine was added and after 30 minutes the reaction mixture was concentrated. The residue was taken up in dichloromethane and extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 4:1 as eluent. Yield: 3.2 g colorless oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([NH2:28])=O)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl-].O>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]#[N:28])[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: NC(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
To a solution of 2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-3-carboxamide (0.147 g) in N,N-dimethylformamide (5 mL) was added cyanuroyl chloride (0.061 g) under ice-cooling, m and the mixture was warmed to room temperature and stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30, volume ratio), and recrystallized from hexane-diethyl ether to give the title compound (0.093 g, yield 66%) as colorless crystals. MS: 468 (MH+). melting point 114-116° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4](C(OCC)=O)=[C:3]1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1cc(C)cn1C
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To 50 grams of a solution of 20% ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate (10 grams, 40 mmoles) in toluene containing 2.4 ml of absolute ethanol (1.9 grams, 41 mmoles) were added, dropwise, over 20 minutes, 8.6 ml of 96% sulfuric acid (15 grams, 160 mmoles, containing 0.63 gram, 35 mmoles of water). During the addition, the temperature of the reaction mixture rose to about 50° C., and the mixture became heterogeneous. The reaction mixture was then heated in an oil bath at 75°-80° C. for 75 minutes with stirring. Gas evolution was observed. The reaction mixture was then diluted with 25 ml of toluene and cooled to 5° C. Then 75 ml of ice water was added in one portion with vigorous stirring. After five minutes, the organic layer was separated and dried with magnesium sulfate. Gas chromatographic analysis indicates the toluene contained 9% ethyl 1,4-dimethylpyrrole-2 -acetate. The toluene was removed by vacuum distillation at 100 mm of mercury followed by vacuum distillation of the residue at 1 mm of mercury to give a fraction which weighed 5.5 grams. This corresponds to a 78% yield of ethyl 1,4-dimethylpyrrole-2-acetate.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24]>>[C:54]([O:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:20])[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:24])=[CH:48][CH:49]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 81 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].CN[C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1NC.IC1C=CC=CC=1>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(C)cc1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: Ic1ccccc1
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 868.7 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), N-ethyl-p-toluenesulfonamide (240 mg, 1.20 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %), iodobenzene (112 μL, 1.00 mmol) and toluene (1 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting pale brown suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash-chromatography on silica gel (2×15 cm, hexane-ethyl acetate 4:1, 15 mL fractions). Fractions 10-17 provided 244 mg (89% yield) of the desired product.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([CH:18]=[N:19][C:20]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]2[C:21]=1[CH:22]=[N:23][C:24]([CH3:31])=[N:25]2)([OH:17])[CH2:4][C:5](C1C=CC(Cl)=CC=1OC)([CH3:7])[CH3:6].B(Br)(Br)Br.[C:38]([O-:41])(O)=O.[Na+].Cl[CH2:44][Cl:45]>>[Cl:45][C:44]1[CH:6]=[CH:5][C:4]([CH:18]([C:3]([OH:17])([CH2:4][C:5]([CH3:7])=[CH2:6])[C:2]([F:33])([F:32])[F:1])[NH:19][C:20]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]3[C:21]=2[CH:22]=[N:23][C:24]([CH3:31])=[N:25]3)=[C:3]([O:41][CH3:38])[CH:2]=1
Reactant: O=C([O-])O
Reactant: ClCCl
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F
Agent: BrB(Br)Br
Agent: [Na+]
Product: C=C(C)CC(O)(C(Nc1ccc(F)c2nc(C)ncc12)c1ccc(Cl)cc1OC)C(F)(F)F
Reaction time: 2.5 h
Yield: 26 %

Procedure:
3.1 g (6.4 mmol) of (rac) 1,1,1,-trifluoro-4-(4-chloro-2-methoxyphenyl)-2-[(8-fluoro-2-methyl-quinazol-5-yl)iminomethyl]-4-methyl-pentan-2-ol is introduced into 50 ml of dichloromethane and 128 ml of a 1 M solution of boron tribromide in dichloromethane is added in drops at −75° C. It is allowed to reach −20° C. within 2.5 hours. Then, the reaction mixture is added to 300 ml of a saturated NaHCO3 solution, stirred for 15 more minutes, the phases are separated, the aqueous phase is extracted with dichloromethane, the combined organic phases are washed with saturated NaHCO3 solution and saturated NaCl solution and dried with sodium sulfate. After the solvent is removed in a rotary evaporator, the crude product is chromatographed on silica gel (eluant: hexane/ethyl acetate 3:1 to 1:1). Then, it is purified again by means of HPLC. 650 mg (26%) of the desired product is obtained as a yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:13][C:14]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH3:24])[C:15](OCCCCCC)=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[CH2:26]([O:25][C:14]([O:13][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:24])[CH2:15][OH:16])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCOC(C)(CO)OCCCCCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 96.1 %

Procedure:
To a mixture of LiAlH4 (3.44 g, 90.5 mmol) in Et2O (200 mL) is added a solution of ester 3 (29.5 g, 82.3 mmol) in Et2O (100 mL). After addition, the mixture is refluxed for 6 hours. The reaction mixture is cooled to 0° C. and quenched with ethyl acetate (20 mL) and H2O (20 mL). The mixture is added to saturated potassium sodium tartrate (300 mL) and stirred at 23° C. for 12 hours. The mixture is extracted with Et2O (2×200 mL) and the combined organic layers are dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propan-1-ol 4 (20.6 g, 94%) as a colorless oil: Rf(15% EtOAc/hexane)=0.20; IR (thin film, cm−1) 3430, 2955, 2929, 2859, 1467, 1378, 1244, 1155, 1112, 1064, 876; 1H NMR (600 MHz, C6D6) δ 3.58 (d, J=6.6 Hz, 2H), 3.43 (t, J=6.6 Hz, 4H), 1.58 (t, J=6.6 Hz, 1H), 1.53 (m, 4H), 1.36 (s, 3H), 1.34-1.22 (m, 12H), 0.88 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, C6D6) δ 101.0, 66.2, 61.3, 32.5, 30.9, 26.8, 23.4, 21.3, 14.6.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:22][CH2:23][CH2:24][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=CCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.63 mL (4.6 mmol) of triethylamine was added and dissolved in a suspension of 0.73 g (4.2 mmol) of ascorbic acid in acetonitrile (9 mL). After the above crude product of (4,8,12-trimethyltridec-3-enyl)tosylate was added at room temperature, the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]3[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=3)[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)c1cc(F)cc(F)c1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3cc(F)cc(F)c3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.442 mmol) was reacted with N-(2-azidoethyl)-3,5-difluorobenzamide (0.100 g, 0.442 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(3,5-difluorobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), δ 7.39 (m, 3H), δ 6.88 (t, J=4.8 Hz, 1H), δ 6.43 (s, 1H), δ 6.38 (bs, 2H), δ 4.55 (s, 2H), δ 3.93 (s, 2H), δ 2.56 (t, J=5.1 Hz, 2H), δ 2.24 (s, 2H), δ 1.55 (m, 14H), δ 1.23 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.3, 164.2, 161.9, 150.3, 149.3, 148.2, 137.6, 122.4, 111.0, 110.8, 107.3, 107.1, 106.8, 106.6, 85.5, 49.3, 40.4, 29.9, 29.5, 29.1, 28.7, 28.2, 27.9, 27.5, 25.4 ppm; HRMS (ESI) calcd for C24H31F2N7O3 (M+) 503.2456. found 503.2458, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-3,5-difluorobenzamide hydrochloride (0.115 g, 59% yield). 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), δ 7.42 (d, J=2.0 Hz, 2H), δ 7.29 (t, J=2.40 Hz, 1H), δ 6.51 (s, 1H), δ 4.84 (t, J=4.8 Hz, 2H), δ 3.96 (q, J=13.2, 4.8 Hz, 2H), δ 2.89 (t, J=7.2 Hz, 2H), δ 2.49 (t, J=7.2 Hz, 2H), δ 1.79 (m, 2H), δ 1.75 (m, 2H), δ 1.44 (m, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 164.5, 164.4, 127.6, 126.9, 110.6, 110.6, 110.3, 108.5, 107.1, 106.8, 106.6, 52.5, 39.5, 30.4, 27.9, 27.8, 27.6, 24.0, 23.8, 23.1 ppm; FIRMS (ESI) calcd for C19H23F2N7O (M+) 403.1932. found 403.1926.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19](=[O:22])[CH:20]=[CH2:21].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:21][CH2:20][C:19]([O:18][CH3:17])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCC(C(=O)c1ccc(Cl)s1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7.35 g (27.1 mmol) of 2-(3-chlorophenyl)-1-(5-chlorothiophen-2-yl)ethanone (Example 63, Step A) and acrylic acid methyl ester (2.81 mL, 31.2 mmol) in DCM (60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.05 mL, 27.1 mmol) in DCM (10 mL) slowly at 0° C. over 20 min. Then the reaction was allowed to warm to ambient temperature. After being stirred at 25° C. for two days, the reaction mixture was diluted with DCM and washed with 2N HCl, water and sat. aq. NaCl solution. The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light yellow oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a pre-packed silica gel column (220 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provided the title compound as a light-yellow oil. Mass Spectrum (ESI) m/z=357 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([NH:17][OH:18])=[NH:16])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=O>>[ClH:19].[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][CH2:13][CH2:14][C:15]3[N:16]=[C:23]([C:22]4[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=4)[O:18][N:17]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: N=C(CCCC1CCN(C2CCCC2)CC1)NO
Product: Cl
Product: Clc1ccc(-c2nc(CCCC3CCN(C4CCCC4)CC3)no2)cc1Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 3, starting from 4-(1-cyclopentylpiperidin-4-yl)-N-hydroxybutyramidine and 3,4-dichlorobenzoyl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1>>[CH:18]1([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[N:3][C:2]([C:35]5[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]6[C:36]=5[CH:37]=[CH:38][NH:39]6)=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cc(C#N)cc3[nH]ccc23)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CC4)CC3)cc2n1
Product: N#Cc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C5CC5)CC4)cc3n2)c2cc[nH]c2c1
Yield: 21.7 %

Procedure:
A mixture of 2-chloro-6-(4-cyclopropyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-H-indole-6-carbonitrile (273 mg) were reacted using Suzuki coupling method B, to give the title compound (55 mg) as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:39][CH3:40])=[C:7]([CH:28]=[C:29]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:30]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][NH:22][CH2:23][CH2:24]C(C)C)([CH3:4])([CH3:3])[CH3:2].C(C=O)=O.[NH4+:45].[OH-].Cl>CCO>[C:1]([C:5]1[C:6]([O:39][CH3:40])=[C:7]([CH:28]=[C:29]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:30]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[C:21]1[NH:45][CH:24]=[CH:23][N:22]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [NH4+]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CNCCC(C)C)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: Cl
Agent: O=CC=O
Agent: [OH-]
Solvent: CCO
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2-c2ncc[nH]2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of the product from Example 30, Part A (50 mg, 0.10 mmol) in EtOH (2 ml) was added glyoxal (57 uL, 0.50 mmol) and concentrated aqueous NH4OH (70 uL, 0.50 mmol). The resulting mixture was stirred at room temperature for 16 h. To the mixture was added 1 N aq. HCl until pH=7, and the mixture was partitioned between H2O (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 5% MeOH in CH2Cl2 as the eluent to give the title compound (27 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1 H) 11.40 (d, J=1.84 Hz, 1 H) 9.98 (s, 1 H) 7.89 (d, J=8.82 Hz, 1 H) 7.66-7.76 (m, 2 H) 7.38 (t, J=2.21 Hz, 2 H) 7.23-7.31 (m, 2 H) 7.06-7.21 (m, 3 H) 5.63 (dd, J=8.09, 1.84 Hz, 1 H) 3.78 (s, 3 H) 3.07 (s, 3 H) 1.37 (s, 9 H).