Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=[O:3])C.[P:5]([O:14][CH2:15][CH2:16][Cl:17])([O:10][CH2:11][CH2:12][Cl:13])[O:6][CH2:7][CH2:8]Cl>C(Cl)CCl>[P:5]([O:14][CH2:15][CH2:16][Cl:17])([O:10][CH2:11][CH2:12][Cl:13])[O:6][C:7](=[O:3])[CH3:8]
Reactant: CC(=O)Cl
Reactant: ClCCOP(OCCCl)OCCCl
Solvent: ClCCCl
Product: CC(=O)OP(OCCCl)OCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The same equipment and procedure as in Example 1 was employed. The reaction flask was charged with 100 ml ethylene dichloride and 85 g acetyl chloride (1.1 mole). The addition of 270 g (1.0 mole) tris (β-chloroethyl) phosphite was commenced dropwise and continued for one hour during which there was a slow exotherm to 35° C. After addition of the triphosphite the reaction continued with a self-maintained exotherm at about 40° C. for three hours and then a slow return to ambient temperature while stirring overnight. The pink acetyl bis(β-chloroethyl) phosphite was isolated by rotary evaporatory at 50° C. and 15 torr. The yield was 261 g; acid number 2; purity by infrared analysis was about 75%.
Reaction SMILES: [C:1](O)(=O)C.Cl.[NH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][CH:10]=1.C(=O)CC>CO>[CH2:1]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:9]=2[CH2:8][CH2:7][NH:6]1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(=O)O
Agent: Cl
Solvent: CCC=O
Solvent: CO
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3
Temperature: 75 °C

Procedure:
Acetic acid was added dropwise to a solution of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (200 mg) in 7 mL methanol until the pH=4. Propionaldehyde (0.2 mL) was added and the mixture was heated at 75° C. in a sealed tube for 1 h. The tube was cooled to rt and unsealed. The solvent was evaporated to yield 190 mg of 2,3,4,9-tetrahydro-1H-β-carbolin-6-ol.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([Cl:22])=[CH:17][CH:16]=3)=[O:12])[C@H:6]([NH:23][C:24]([C:26]2[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=2)=[O:25])[CH2:5]1)(O)=[O:2].Cl.[CH2:37]([NH2:39])[CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[ClH:22].[Cl:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([C:1](=[O:2])[NH:39][CH2:37][CH3:38])[CH2:5][C@H:6]1[NH:23][C:24]([C:26]1[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=1)=[O:25])=[O:12])=[CH:21]2
Reactant: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 87.9 %

Procedure:
(1S,2R,4S)-4-Carboxy-N1-[(5-chloroindol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine (150 mg) was dissolved in N,N-dimethylformamide (3 ml), to which N-ethylamine hydrochloride (119 mg), 1-hydroxybenzotriazole monohydrate (79 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg) and triethylamine (326 μl) were added, and the mixture was stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to conduct extraction with dichloromethane. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=47:3). The thus-obtained white solid was dissolved in dichloromethane, to which 1N ethanol solution (171 μl) of hydrochloric acid was added. The solvent was distilled off under reduced pressure, and methanol and diethyl ether were added to the residue to collect precipitate formed by filtration, thereby obtaining the title compound (74 mg) as white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:24][CH3:25])[C:16]2=[O:26])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[C].[Pd]>[CH2:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:16]1=[O:26])[CH3:25]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) and 10% palladium-carbon (0.83 g) in EtOH (250 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.42 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:20]=[C:13]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])[C:12]([OH:21])=[CH:11][CH:10]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[CH:25][CH:24]=[C:23]2[O:21][C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:20][C:13]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Propyl 5-(2,4-difluorophenyl)salicylate (179 mg), 4-chloro-6,7-dimethoxyquinoline (70 mg), and 4-dimethylaminopyridine (110 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (30 mg, yield 10%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])=[O:7].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:9]1=[O:17])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2C1C(=O)c1ccco1
Product: CC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccccc21
Yield: 73 %

Procedure:
Acetylation of 3-(2-furoyl)-2-oxindole with acetic anhydride, substantially according to the procedure of Example 1, afforded a 73% yield of the title compound, m.p. 137.5°-138.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)[O:28][B:27](B2OC(C)(C)C(C)(C)O2)[O:26]1.CC(O[K])=O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)=[CH:3][C:2]([B:27]([OH:28])[OH:26])=[CH:7]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[K]
Solvent: C1COCCO1
Product: Cn1cc(B(O)O)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 32.9 %

Procedure:
To a solution of 5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 252a (1 g, 2.64 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2 g, 7.92 mmol) in dioxane (40 mL) was added PdCl2(dppf) (215 mg, 0.26 mmol) and CH3COOK (776 mg, 7.92 mmol). The mixture was stirred at 100° C. for 6 h under argon atmosphere. After reaction the mixture was filtered and evaporated in vacuo. The residue was purified by reverse phase combiflash eluting with 0.3% NH4HCO3 in 1:3 water/CH3CN to give 143a as a white solid (300 mg, 33%). MS: (M+H)+ 346.
Reaction SMILES: Br[C:2]1[C:3]2[O:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[Cu](C#N)[C:12]#[N:13].CN(C)C=O>C(OCC)C.[Cu](I)I>[O:10]1[C:3]2[C:2]([C:12]#[N:13])=[CH:7][N:6]=[CH:5][C:4]=2[CH:8]=[CH:9]1
Reactant: N#C[Cu]C#N
Reactant: Brc1cncc2ccoc12
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cncc2ccoc12
Temperature: 25 °C

Procedure:
Combine 7-bromofuro[3,2-c]pyridine (4.673 g, 23.5 mmol), copper cyanide (4.21 g, 47.1 mmol), copper iodide (8.96 g, 47.1 mmol), and anhydrous dimethylformamide (100 mL) and at 130° C. for 30 hours. Cool to room temperature, dilute with diethyl ether and wash with 15% aqueous ammonium hydroxide. Extract combined aqueous layers with diethyl ether, wash combined organic layers with 15% aqueous ammonium hydroxide, and brine, dry over magnesium sulfate, and concentrate. Purification using flash chromatography, eluting with hexane: ethyl acetate gives the tide compound as a white solid.
Reaction SMILES: BrC1C=CC(O)=CC=1.IC1C=CC(I)=CC=1C(O)=O.C([O-])([O-])=O.[Cs+].[Cs+].OS(O)(=O)=O.[Br:31][C:32]1[CH:48]=[CH:47][C:35]([O:36][C:37]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:38]=2[C:39]([OH:41])=O)=[CH:34][CH:33]=1>CCOC(C)=O.C1(C)C=CC=CC=1>[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[O:36][C:37]3[C:38](=[CH:42][C:43]([I:46])=[CH:44][CH:45]=3)[C:39](=[O:41])[C:47]=2[CH:48]=1
Reactant: O=C(O)c1cc(I)ccc1Oc1ccc(Br)cc1
Agent: O=C(O)c1cc(I)ccc1I
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1c2cc(Br)ccc2oc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 84.9 %

Procedure:
A RBF equipped with a reflux condenser was charged with 4-bromophenol (15.5 g, 89.4 mmol), 2,5-diiodobenzoic acid (25.700 g, 68.7 mmol), EtOAc (0.337 ml, 3.44 mmol), and toluene (100 mL). Cs2CO3 (44.8 g, 137 mmol) was carefully added portion-wise. After stirring at RT for 1 min, the mixture was heated to 50° C. for 40 min and then heated to 100° C. for 20 hrs. The reaction mixture was allowed to cool to RT. The mixture was filtered through Celite and the solids were washed with EtOAc. The filtrate was diluted with water (200 mL), acidified with 2N HCl (300 mL), and extracted with EtOAc (4×500 mL). The organic extract was washed with brine and dried over sodium sulfate. The organic fraction was concentrated under reduced pressure to afford crude 2-(4-bromophenoxy)-5-iodobenzoic acid (31.1 g) as a tan oil that solidified upon standing. Step 2: H2SO4 (73.3 ml, 1375 mmol) was added to 2-(4-bromophenoxy)-5-iodobenzoic acid (28.800 g, 68.7 mmol) at rt. The resulting dark mixture was heated to 60° C. for 45 minutes. The brown solution was poured slowly onto ice-water (1 L) with stirring. The resulting tan precipitant was collected by filtration, washed with water a 1 N solution of NaOH, again with water, and dried under reduced pressure to afford 2-bromo-7-iodo-9H-xanthen-9-one (23.4 g) as a tan solid that was used without further purification.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH3:11][O:12][C:13]1[CH:18]=[C:17]2[C:16](=[CH:15][C:14]=1[O:19][CH3:20])[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]2([CH3:10])[CH3:3]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)C(C)(C)CCC2(C)C
Temperature: 60 °C
Yield: 44.3 %

Procedure:
2,5-dichloro-2,5-dimethylhexane (2.2 g, 12 mmol), 1,2-dimethoxybenzene (1.38 g, 10 mmol), anhydrous 1,2-dichloroethane (10 mL) and anhydrous AlCl3 (200 mg) were combined in a 100 mL Schlenk flask under Ar. The mixture was heated at 60° C. for 6 h before quenching with ice water. The layers were then separated, and the aqueous layer extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The remaining residue was purified by flash column chromatography (hexanes/Ethyl acetate=10:1) to afford the title compound (1.1 g, 35% yield). 1H NMR (CDCl3): 1.27 (s, 12H), 1.67 (s, 4H), 3.86 (s, 6H), 6.77 (s, 2H); 13C NMR (CDCl3): 32.07, 34.22, 35.42, 56.01, 109.37, 137.23, 147.05.
Reaction SMILES: C(OC(N[C@H]1CC[C@H](C(O)=O)CC1)=O)C1C=CC=CC=1.[Br:21][C:22]1[N:23]=[C:24]([C@H:32]2[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]2)[N:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[C:26]=12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH:47]([F:49])[F:48]>CN(C)C=O>[Br:21][C:22]1[N:23]=[C:24]([C@H:32]2[CH2:37][CH2:36][C@H:35]([NH:38][CH2:46][CH:47]([F:49])[F:48])[CH2:34][CH2:33]2)[N:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[C:26]=12
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N)CC1
Reactant: FC(F)CBr
Agent: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](NCC(F)F)CC1
Temperature: 60 °C

Procedure:
Using the procedures described in example 17 (trans)-4-(benzyloxycarbonylamino)cyclohexanecarboxylic acid was used to prepare (trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexanamine. The latter compound (0.217 mmol, 67.1 mg) was dissolved in N,N-dimethylformamide, potassium carbonate (0.651 mmol, 90 mg) was added followed by 2-bromo-1,1-difluoroethane (0.217 mmol, 17.47 μl, 31.5 mg) and the reaction mixture was stirred in the micro wave at 60° C. After one hour another amount of 2-bromo-1,1-difluoroethane (0.217 mmol, 17.47 μl, 31.5 mg) was added and the reaction mixture was stirred in the micro wave at 60° C. for another hour. The reaction mixture was filtered, the filter was rinsed with acetonitrile and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, gradient dichloromethane/methanol 10/0 to 9/1) to give (trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)-N-(2,2-difluoroethyl)cyclohexanamine (39.8 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1)[NH2:5].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:21])[CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(F)cc(Oc2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc(F)cc(Oc2cccnc2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-5-(pyridine-3-yloxy)aniline (330 mg) in acetic acid (5.0 ml), 160 mg of phthalic anhydride was added, the reaction solution was stirred overnight at 100° C. The reaction solution was cooled, followed by adding a saturated aqueous sodium bicarbonate solution and extracting the mixture with chloroform. The combined organic layers were washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel chromatography to yield the title compound as a white solid.
Reaction SMILES: C(S)C(O)C(O)CS.[CH:9]1([N:15]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[S:20][C:21]([S:24]C#N)=[CH:22][N:23]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].Br[C:40]([CH3:47])([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42]>CO>[CH2:44]([O:43][C:41](=[O:42])[C:40]([S:24][C:21]1[S:20][C:19]([NH:18][C:16]([N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:17])=[N:23][CH:22]=1)([CH3:47])[CH3:46])[CH3:45]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O=C([O-])[O-]
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: CO
Product: CCOC(=O)C(C)(C)Sc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An equimolar mixture of 1,4-dithiothreitol (DTT) and 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea (prepared as described in Step 1) in MeOH (4 mL/mmol) was stirred in a nitrogen atmosphere at room temperature for 2 h. Addition of K2CO3 (3 equiv) and ethyl 2-bromo-2-methylproprionate (1.1 equivalents). The reaction mixture was stirred at room temperature over night and quenched with water. Addition of CH2Cl2. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were concentrated in vacuo. The crude product was dissolved in MeCN and purified by reverse phase preparative (HPLC method 1) to give 2-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-2-methyl-propionic acid ethyl ester as an oil. This material was dissolved in MeOH and treated with 20 equivalents of 1N NaOH and stirred over night at room temperature. MeOH was removed by evaporation. Addition of 1N HCl to pH<1 caused precipitation. The precipitate was isolated by filtration, washed with water and dried to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:18]=[C:17]4[N:19]([C:28]5[CH:33]=[CH:32][C:31]([C:34]6([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]6)=[CH:30][CH:29]=5)[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:21][C:16]4=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>C(Cl)(Cl)Cl.C1COCC1.CO.C(OCC)(=O)C>[N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:18]=[C:17]4[N:19]([C:28]5[CH:29]=[CH:30][C:31]([C:34]6([NH2:38])[CH2:37][CH2:36][CH2:35]6)=[CH:32][CH:33]=5)[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:21][C:16]4=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4ccccc4)nc4ccc(-c5cccc(N6CCOCC6)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1(c2ccc(-n3c(-c4ccccc4)nc4ccc(-c5cccc(N6CCOCC6)c5)nc43)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a stirred solution of tert-butyl (1-{4-[5-(3-morpholin-4-ylphenyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (67 mg, 0.11 mmol) in CHCl3/THF/MeOH (1:1:1, v/v/v, 3 mL), was added 4M HCl in ethyl acetate 1˜5 mL at rt. The mixture was stirred for 2 h at rt and ethyl acetate added. The solid was collected by filtration. The solid was dried to give the titled compound (54 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])#[N:12]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11]#[N:12])(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1C#N

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 2-cyanobenzenesulphonyl chloride (0.24 g).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[CH:8])(=[O:4])[CH:2]=[CH2:3].[CH2:9]([N:21]=[N+:22]=[N-:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:9]([N:21]1[CH:8]=[C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:23]=[N:22]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCOC(=O)C=C
Reactant: CCCCCCCCCCCCN=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)OCc1cn(CCCCCCCCCCCC)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Propargyl acrylate (13 g, 0.118 mmoles), dodecyl azide (22.3 g, 0.118 mmoles) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (0.75 g, 2 mmoles) are dissolved in DMF (200 ml) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture is poured into water wherefrom the product precipitated as a white crystalline solid (33.5 g; yield 95%; mp 50-52° C.). 1H NMR (CDCl3, δ ppm) 7.78 (broad, 1H), 6.42 (d, 1H), 6.16 (dd, 1H), 5.82 (d, 1H), 5.30 (s, 2H), 4.32 (t, 2H), 1.92 (t, 2H), 1.28 (m, 20H), 0.88 (t, 3H). 13C NMR (CDCl3, δ ppm) 165.7, 142.4, 131.1, 127.9, 123.5, 57.6, 57.5, 50.2, 31.7, 30.1, 29.4, 29.3, 29.2, 29.1, 28.8, 26.3, 22.4, 13.9.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@H:5]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@@H:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[Na+]>O1CCCC1.O>[C:19]([O:18][C:16]([NH:15][C@@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C@H:6]([OH:23])[C@@H:5]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:4]([OH:34])=[O:3])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)[C@H](NCc1ccc(OC)cc1)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN[C@@H](C(=O)O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
9 g of 4(S)-tert-butoxycarbonylamino-3(S)-hydroxy-2(R)-(4-methoxybenzylamino)-5-phenyl-pentanoic acid ethylester are dissolved in 300 ml of tetrahydrofuran and 22 ml of 1 N aqueous sodium hydroxide solution are added. The reaction mixture is stirred for 16 hours at room temperature and diluted with 300 ml of water. Tetrahydrofuran is evaporated and the aqueous solution is washed with ethyl acetate. Acidification with 1N HCl leads to a white precipitate which is filtered off and dried (m.p.: 203°-206°).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.B.C1COCC1.[NH2:19]S(O)(=O)=O.[OH-].[Na+]>C1COCC1>[O:4]1[CH2:3][CH:2]([CH2:1][NH2:19])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]1=2
Reactant: NS(=O)(=O)O
Reactant: C=C1COc2ccccc2OC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCC1COc2ccccc2OC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Methylene-3,4-dihydro-2H-benzo[b][1,4]dioxepine (5.00 g, 30.8 mmol) was dissolved in dry THF (100 mL). Borane-THF (1.0 M in THF, 10.3 mL) was added at 0° C. The reaction was stirred at RT for 5 hours. Aminosulfonic acid (6.97 g, 61.6 mmol) was added. The reaction was heated to reflux overnight. The reaction was cooled to room temperature and aqueous sodium hydroxide (3.0 M, 100 mL) was added. The solution was extracted with ethyl acetate (3×100 mL). The combined organic solution was dried over MgSO4. The solution was concentrated under vacuum and purified by chromatography (2% to 8% methanol in dichloromethane) to yield ((3,4-dihydro-2H-benzo[b][1,4]dioxepin-3-yl)methyl)amine as a colorless oil.