Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[N:20]=3)[C:6](=[O:30])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][CH3:40].N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[N:20]=3)[C:6](=[O:30])[N:5]([CH2:38][CH2:39][CH3:40])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCCc3nc(-c4ccccn4)no3)c(=O)c21
Reactant: CCCI
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCn1c(=O)n(CCCCc2nc(-c3ccccn3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (40 mg, 0.09 mmol) in DMF (3 ml) was treated with potassium carbonate (15 mg, 0.11 mmol) and 1-iodopropane (19 mg, 0.11 mmol). The mixture was heated at 40° C. for 3 h then at 70° C. for a further 3 h. The mixture was cooled and degassed by the successive application of vacuum and nitrogen gas. The mixture was then treated with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and morpholine (0.1 ml, 1.2 mmol) and then stirred overnight. The mixture was evaporated and partitioned between chloroform (2 ml) and water (2 ml). The aqueous phase was extracted with further chloroform (2 ml) and the combined organics evaporated and the residue dissolved in methanol (2 ml). The solution was applied to a 1 g aminopropyl SPE and eluted with methanol and then with 5% acetic acid in methanol. Product-containing fractions were pooled and evaporated and the product further purified by MDAP to reveal 8-chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (1.4 mg) as a white solid.
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[I-:10].[Na+]>C(#N)C>[C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3]([I:10])[CH3:4]
Reactant: CCOC(=O)OC(C)Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)OC(C)I
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 51.5 %

Procedure:
1-Chloroethyl ethyl carbonate (5.0 g, 32.8 mmol) was dissolved in 125 mL acetonitrile. Sodium iodide (22.1 g, 147.5 mmol) was added and stirred at 60° C. for 1.5 hours. The reaction was evaporated, diluted with ether and filtered. The filtrate was evaporated to a dark red oil, to afford 1-iodoethyl ethyl carbonate (4.12 g, 51% yield). N016 (2.07 g, 11.3 mmol) and freshly made 1-iodoethyl ethyl carbonate (4.12 g, 16.9 mmol) were dissolved in 15 mL acetonitrile and stirred at room temperature overnight. The reaction was evaporated, diluted with ethyl acetate, washed with 0.2N Na2S2O3 and brine, dried over magnesium sulfate and evaporated. Chromatography was performed using 50% ethyl acetate/hexanes to yield a colorless oil (890 mg, 28% yield). 1H NMR (400 MHz, d-DMSO) δ 6.28 (dq, J=2.6, 5.6 Hz, 1H), 4.76 (dt, J=2.9, 5.7 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.97-3.86 (m, 1H), 3.55-3.31 (m, 4H), 1.96-1.77 (m, 4H), 1.47 (d, J=5.5 Hz, 3H), 1.17 (dt, J=18.4, 7.1 Hz, 3H). LC tr=2.98 minutes (C-18 column, 5 to 95% acetonitrile/water over 6 minutes at 1.7 mL/min with detection 254 nm, at 23° C.). ES(pos)MS m/z 300 (M+Na calcd for C10H19N3O6 requires 300).
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][C:25]([OH:27])=O)[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:25](=[O:27])[CH2:24][CH2:23][CH:20]2[CH2:19][CH2:18][N:17]([C:9](=[O:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:22][CH2:21]2)[CH:32]=[CH:31][C:30]=1[Cl:35]
Reactant: Clc1ccccc1Cl
Reactant: O=C(O)CCC1CCN(C(=O)c2ccccc2)CC1
Solvent: COc1ccccc1
Product: O=C(CCC1CCN(C(=O)c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
In Example 1 the 9.9 g of anisole and the 15.7 g of 3-(1-benzoyl 4-piperidyl) propionic acid are substituted by 185 ml of 1,2 dichlorobenzene and 35 g of 3-(1-benzoyl 4-piperidyl) propionic acid respectively. The reaction is effected at 100° C. and without solvent. 51.1 g of crude 1-(3,4-dichlorophenyl) 3-(1-benzoyl 4-piperidyl) 1-propanone in the form of an oil which crystallizes slowly are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][N:31]=3)=[O:29])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][N:31]=3)=[O:29])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 4-phenyl-2-(5-phenylpyridine-2-carboxamido)benzoate (0.11 g), followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the obtained residue. After adjusting the pH to 6.5 with a saturated aqueous solution of sodium bicarbonate, the organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 90 mg of 4-phenyl-2-(5-phenylpyridine-2-carboxamido)benzoic acid as a white solid.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O>CCCCC>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([O:4][CH:1]([CH3:3])[CH3:2])=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCC
Product: CC(C)OC(=S)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 ml of isopropanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 11.2 grams (0.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours at room temperature and then allowed to stand overnight. The next morning the reaction mixture was poured into 200 ml of water and the product extracted with 50 ml pentane. The pentane extract was washed twice with water, once with 10% NaHCO3, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave a semi-solid. The semi-solid was slurried in cold pentane and filtered. The filter cake was air dried and weighed 4.0 grams (20% crude yield) and melted at 62°-64° C. The product had a strong band at 1525 cm-1 and a sharp NH band at 3300 cm-1 in its infrared spectrum.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:15][NH:16][CH2:17][CH2:18][C:19]#[N:20]>>[C:19]([CH2:18][CH2:17][N:16]([CH3:15])[S:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])#[N:20]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CNCCC#N
Product: CN(CCC#N)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In operating analogously to Preparation V, starting with 2-(trifluoromethyl)benzenesulphonyl chloride and 3-(methylamino)propionitrile, the expected product is obtained as a yellow oil (yield=98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.OO.C([O-])([O-])=[O:32].[K+].[K+]>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:32])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C(N)=O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 2, 25 mg, 0.062 mmol) in 2 mL DMSO at 0° C. was added lint of 30% H2O2 (aq). A catalytic amount of K2CO3 was added and the reaction was stirred at 50° C. for 60 min. The reaction mixture was diluted with MeOH and the product was purified by reverse phase HPLC. The fractions containing the product were collected and diluted with EtOAc, washed with aq NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.23 (d, 2H), 7.84 (d, 2H), 7.78 (m, 2H), 7.58 (m, 3H), 7.28 (d, 2H), 7.08 (d, 2H), 6.23 (broad s, 1H), 5.82 (broad s, 1H), 3.72 (s, 3H). LCMS: m/z 420 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[OH:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=1)[CH:6]=[CH:5]2
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: Clc1ccc2cc(Br)ccc2n1
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc3cc(Br)ccc3n2)cc1

Procedure:
was prepared from 6-bromo-2-chloroquinoline and ethyl 2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The compound had a melting point of 85° C.
Reaction SMILES: C(NCC)C.[Li]CCCC.[C:11]([Si:15]([CH3:28])([CH3:27])[N:16]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]1=[O:26])([CH3:14])([CH3:13])[CH3:12].Br[CH2:30][CH2:31][CH:32]([Br:34])[CH3:33].[NH4+].[Cl-]>C1COCC1>[Br:34][CH:32]([CH3:33])[CH2:31][CH2:30][CH:18]1[CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:16]([Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:28])[CH3:27])[C:17]1=[O:26]
Reactant: CC(Br)CCBr
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC(Br)CCC1C(=O)N([Si](C)(C)C(C)(C)C)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To diethylamine (4.32 g, 59.0 mmol) in 22 mL of THF at 0° C. was added nBuLi (2.5 M in hexanes; 50.6 mmol, 20.2 mL). After 15 minutes the solution was added via cannula to a −50° C. solution of 1-(tert-Butyl-dimethyl-silanyl)-4-phenyl-azetidin-2-one (11.0 g, 42.2 mmol) in 110 mL of THF. After stirring for 20 minutes, 1,3-dibromobutane was added and the solution was stirred for 1 hour. Saturated aqueous NH4Cl was added and the mixture was warmed to room temperature and extracted once with ether. The extract was dried with MgSO4, concentrated and chromatographed (9:1 hexanes/EtOAc) to give 11.4 g (68%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ comp, 10H), 4.21 (d, J=2.5 Hz, 1H), 4.16 (d, J=2.5 Hz, 1H), 4.08 (m, 1H), 3.02 (m, 1H), 1.80–2.10 (comp, 4H), 1.67 (d, J=6.6 Hz, 3H), 0.90 (s, 9H), 0.18 (s, 3H), −0.22 (s, 3H); Mass spectrum m/e calcd for M+H=396.2. Found 396.0 (base), 316.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(=O)(O)[O-].[Na+].O>O1CCOCC1>[CH2:14]([O:13][C:11]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (15 g, 0.10 mol), benzyl chloroformate (17 ml, 0.12 mol) and sodium bicarbonate (25 g, 0.50 mol in dioxane (120 ml) and water (100 ml) was stirred at room temperature for 48 hours. Water was added and the mixture was extracted with methylene chloride; the organic layer was washed with brine and dried over magnesium sulfate. Upon evaporation, the title compound was obtained as a colorless liquid (21.7 g, 0.093 mol, yield 93%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[CH:63]=[CH:62][C:61]([S:64](Cl)(=[O:66])=[O:65])=[CH:60][CH:59]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:61]1[CH:60]=[CH:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[CH:63][CH:62]=1)(=[O:66])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(NC(C)=O)cc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (32 mg) was reacted with 4-acetylamino-benzenesulfonyl chloride to give (S)-2-({(S)-7-(4-acetylamino-benzenesulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure E. This product (20 mg) was hydrolysed according to General Procedure B to give the title compound (3 mg). LCMS (m/z): 931.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[CH3:27][Si:28]([CH3:38])([CH3:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>O>[O:1]=[C:2]1[C@H:7]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([Si:28]([CH3:27])([CH3:38])[CH3:37])[CH:30]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3]1
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cccc([Si](C)(C)C)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 85.7 %

Procedure:
A dry 250 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet was charged with 2.08 g of t-butyl (2R, 3S)-(-)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (Aldrich), 1.43 g of 3-(trimethylsilyl)benzyl bromide (Yamakawa, T., et al, J. Med. Chem., 1990, 33, 1430), and 45 mL of anhydrous THF. The solution was cooled to -78° C. and was treated with 6.17 mL of 1 M sodium bis(trimethylsilyl)amide/THF (Aldrich) via syringe through a rubber septum. The solution was stirred at -78° C. for 3.5 h and was then poured into 150 mL of water. The resulting mixture was extracted with EtOAc (4×50 mL). The combined EtOAc extracts were washed with saturated brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a light yellow oil. The crude material was purified by flash chromatography on silica gel (9:1 hexane:EtOAc) to afford 2.6 g (88%) of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(trimethylsilyl)benzyl)-4-morpholinecarboxylate as a white powder, m.p. 88-90° C.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:26])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([CH:24]=[CH2:25])[O:18]1.CCN(CC)CC>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[CH3:22][C:21]1([CH3:23])[C:17]([CH3:26])([CH3:16])[O:18][B:19](/[CH:24]=[CH:25]/[C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:20]1
Reactant: Brc1ccc(CCN2CCOCC2)cc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2ccc(CCN3CCOCC3)cc2)OC1(C)C
Temperature: 80 °C
Yield: 76.8 %

Procedure:
To a mixture of 4-(4-bromophenethyl)morpholine (731 mg, 2.71 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.5 mL, 2.95 mmol, 1.1 eq.) and toluene (10 mL) in a 20 mL microwave vial was added Et3N (0.76 mL, 5.4 mmol, 2 eq.), followed by Pd(PtBu3)2 (14 mg, 0.027 mmol, 1 mol %). The resulting mixture was purged with argon, then capped and heated at 80° C. (oil temp.) for 2 h. After cooling to rt, it was quenched with sat. NaHCO3 (10 mL), H2O (10 mL), extracted with EtOAc (30 mL×2) and dried (Na2SO4). After evaporation of the solvents, the residue was purified by Biotage column system (EtOAc/hex gradient: 0-100%) to give (E)-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenethyl)morpholine as a white solid (714 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.0 Hz, 2H), 7.38 (d, J=19.0 Hz, 1H), 7.19 (d, J=7.8 Hz, 2H), 6.13 (d, J=18.3 Hz, 1H), 3.75 (t, J=4.4 Hz, 4H), 2.84-2.77 (m, 2H), 2.63-2.56 (m, 2H), 2.53 (br, pseudo s, 4H), 1.32 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[CH3:18].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]>>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:9]2[C:4]3[C:3]([CH3:18])=[C:2]([Cl:1])[S:17][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: Cc1c(Cl)sc2ncnc(NC3CCNCC3)c12
Reactant: COc1ccccc1CCl
Product: COc1ccccc1CN1CCC(Nc2ncnc3sc(Cl)c(C)c23)CC1

Procedure:
The title compound was prepared (115 mg, 85%) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95 mg, 0.336 m. mol) and 1-(chloromethyl)-2-methoxybenzene (58 mg, 0.37 m. mol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3):δ 8.40 (s, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 6.95 (m, 1H), 6.85 (d, 1H), 5.35 (d, 1H), 4.25 (m, 1H), 3.85 (s, 3H), 3.60 (s, 2H), 2.90 (m, 2H), 2.50 (s, 3H), 2.35 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m/z: Calculated: 402.94; Observed: 403.2 (M++1).
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[O:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5].Cl.[NH2:15][CH2:16][CH2:17][SH:18].[OH-].[Na+]>Cl.O>[CH3:1][N:2]([CH2:6][C:7]1[O:11][C:10]([CH2:12][S:18][CH2:17][CH2:16][NH2:15])=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5]
Reactant: NCCS
Reactant: C#CCN(C)Cc1ccc(CO)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCN(C)Cc1ccc(CSCCN)o1
Temperature: 0 °C
Reaction time: 7 h
Yield: 791.4 %

Procedure:
A solution of 5-{[N-methyl-N-(2-propynyl)amino]methyl}-2-furanmethanol (40.0 g; 223 mmoles) [prepared in Step A] in 100 ml of ice-cold concentrated HCl was added to a cold (5°) stirred solution of cysteamine hydrochloride (27.9 g; 24.6 mmoles) in 125 ml of concentrated hydrochloric acid. The solution was allowed to stand at 0° for 21/2 days, and then at ambient temperature for 7 hours to complete the reaction. The reaction mixture was cooled in an ice-water bath, diluted with 200 ml of water, made strongly alkaline with 40% aqueous NaOH, and then extracted with three portions of methylene chloride. The combined organic phase was dried, filtered, and evaporated under reduced pressure to give the product as a thick oil (46.4 g). A rapid vacuum distillation of the oil yielded the title compound, bp 136°-140°/0.2 mm Hg.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)[C@@H:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[CH3:30][CH:31]([CH3:35])[C:32](Cl)=[O:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[C@@H:10]([NH:12][C:32](=[O:33])[CH:31]([CH3:35])[CH3:30])[CH3:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Product: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(C)C)cc1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine (7a, 20 mg, 50 μmol) and 2-methylpropanoyl chloride (16 mg, 150 nmol). Yield 18 mg (78%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH3:30])[C:9]=2[C:8]1=[O:20]
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccnc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 99.4 %

Procedure:
In a similar manner to Reference Example 5, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 3; 300 mg) was reacted with 2-methylphenylboronic acid (116 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (278 mg, 99%).
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.ClCCl.[Pd]>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(C2=CCCC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
1-(1-Cyclopentenyl)-4-nitro-benzene (225 mg, 1.19 mmol) in methanol (10 mL) and dichloromethane (2.5 mL) was treated with 10% Pd/C (70 mg) and stirred under H2 atmosphere for 1 h at room temperature. The reaction was filtered and concentrated in vacuo to provide 4-cyclopentylaniline (180 mg, 94% yield). 1H NMR (400.0 MHz, MeOD) δ 7.01 (d, J=8.2 Hz, 2H), 6.73-6.70 (m, 2H), 2.88 (dd, J=2.3, 17.3 Hz, 1H), 2.00-1.95 (m, 2H), 1.80-1.75 (m, 2H), 1.70-1.64 (m, 2H), 1.56-1.49 (m, 2H).