Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:17]([OH:22])[CH2:18][CH2:19][CH2:20][OH:21].OCCCOCC1C=CC=C(C)C=1C(OC(C)(C)C)=O>>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][O:22][CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: Cc1cccc(CBr)c1C(=O)OC(C)(C)C
Reactant: OCCCCO
Agent: Cc1cccc(COCCCO)c1C(=O)OC(C)(C)C
Product: Cc1cccc(COCCCCO)c1C(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(4-hydroxybutoxymethyl)-6-methylbenzoate is prepared from tert-butyl 2-bromomethyl-6-methylbenzoate and butane-1,4-diol in analogy to the synthesis of tert-butyl 2-(3-hydroxypropoxymethyl)-6-methylbenzoate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([NH:14][C:15]1[C:16]([C:22]([O:24]CC)=O)=[N:17][C:18]([Br:21])=[CH:19][CH:20]=1)(=[O:13])[CH3:12]>C1COCC1>[Br:21][C:18]1[N:17]=[C:16]2[C:15](=[CH:20][CH:19]=1)[NH:14][C:11](=[O:13])[CH:12]=[C:22]2[OH:24]
Reactant: CCOC(=O)c1nc(Br)ccc1NC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(O)c2nc(Br)ccc2[nH]1
Reaction time: 1 h

Procedure:
To a solution of KHMDS (0.5 M in toluene, 27 ml, 14 mmol) at −78° C. was slowly added a solution of ethyl 3-acetamido-6-bromo-pyridine-2-carboxylate (1.3 g, 4.5 mmol) in THF (20 ml). Stirring was continued for 1 h at this temperature then the cooling bath was removed. Ethyl acetate followed by water was added at ambient temperature, then the phases were separated. The yellow aqueous phase was treated with HCl (1 M) until a colorless solid was formed. Filtration and washing of the solid with water followed by drying afforded 6-bromo-4-hydroxy-1H-1,5-naphthyridin-2-one as a colorless solid. The compound is exclusively present in the tautomer shown.
Reaction SMILES: [CH3:1][C:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4](O)[O:3]2.[Br-].[C:14]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CCC)[CH:19]=CC=C[CH:15]=1>>[CH3:1][C@@:2]1([OH:3])[CH2:8][CH2:7][C@@H:6]([CH2:5][CH:4]=[CH:15][CH2:14][CH3:19])[C:9]1([CH3:11])[CH3:10]
Reactant: CC12CCC(CC(O)O1)C2(C)C
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCC=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Yield: 69.4 %

Procedure:
Using the procedure of Example 7, 5 g of 1,8,8-trimethyl-2-oxa bicyclo [3,2,1] octan-3-ol and 15 g of triphenyl propyl phosphonium bromide were reacted and the product was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 4 g of (1R,S) 1,2,2-trimethyl-3-(2-pentenyl)-cyclopentanol.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH:14]=[CH2:15])[S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:10]1[CH:11]=[N:12][C:8]([S:5](=[O:7])(=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:13][CH:14]=[CH2:15])=[N:9]1)=[O:20])[CH3:17]
Reactant: CCN(CC)C(=O)Cl
Reactant: C=CCN(CC=C)S(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)S(=O)(=O)c1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 6.9 g. 3-diallylsulphamoyl-1,2,4-triazole, 4.5 g. diethylcarbamoyl chloride, 6 ml. triethylamine and 25 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 1.5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The solid residue was recrystallized from petroleum ether, b.p. 60° - 80°C., to give 1-diethylcarbamoyl-3-diallylsulphamoyl-1,2,4-triazole, m.p. 49° - 51°C. Elemental analysis satisfactory.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[NH2:17]>C(O)(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC(C)O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Temperature: 25 °C

Procedure:
4-Chloro-6-iodoquinazoline (5.7 g, 19.7 mmol) and 3-chloro-4-(3-fluorobenzyloxy)aniline (4.9 g, 19.7 mmol) was refluxed in isopropanol (150 mL) overnight. The mixture was cooled to room temperature. The solid product was precipitated, filtrated and dried in vacuum. The product 1405-174 was pure enough and used without further purification. (7.4 g, 74.2%): LC-MS: 506 [M+1]+, 1H NMR (DMSO-d6): δ 5.29 (s, 2H), 7.18 (m, 1H), 7.33 (m, 3H), 7.48 (m, 1H), 7.66 (m, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.94 (s, 1H), 9.29 (s, 1H).
Reaction SMILES: [P:1]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:46])([O:8][C:9]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[C:32]([F:33])=[C:31]([C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:21]3[NH:22][C:23]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[N:24][C:20]=3[CH:19]=2)=[CH:14][N:13]=1)([CH3:11])[CH3:10])([O:3]CCC#[N:7])=[O:2].[OH-].[NH4+]>CO>[P:1]([O-:3])([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:46])([O:8][C:9]([C:12]1[N:13]=[CH:14][C:15]([C:18]2[C:32]([F:33])=[C:31]([C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:21]3[NH:22][C:23]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[N:24][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)([CH3:10])[CH3:11])=[O:2].[NH4+:7]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)(OCCC#N)OCCOCCOC)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)([O-])OCCOCCOC)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a solution of 2-cyanoethyl 2-(5-(2-(3-ethylureido)-6-fluoro-7-((R)-tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl 2-(2-methoxyethoxy)ethyl phosphate (30) (734 mg, 1.106 mmol) in MeOH (20 mL) at 23° C. was added ammonium hydroxide (430 μL, 11.04 mmol). After stirring for 16 hours, more ammonium hydroxide (1 mL) was added. After a further 4 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH (7 mL) and purified via preparative HPLC, 7 injections Using a Waters XBridge C18 5 μm OBD column (19×100 mm) eluting with a 10-90% aqueous MeCN with 0.1% NH4OH buffer, gradient over 15 min at 20 mL/min flow rate. Product fractions were pooled, frozen and lyophilized to give ammonium (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl 2-(2-methoxyethoxy)ethyl phosphate (X) (443 mg, 0.7010 mmol, 63.38%) as a white solid. ESMS (M+1)=611.5; 1H NMR (300.0 MHz, CD3OD) δ 8.86 (d, J=1.0 Hz, 2H), 7.30 (d, J=6.3 Hz, 1H), 5.24 (t, J=7.6 Hz, 1H), 4.23 (dd, J=7.0, 14.8, 1H), 4.13-4.05 (m, 2H), 3.94 (dd, J=7.2, 15.0 Hz, 1H), 3.72-3.64 (m, 4H), 3.56-3.51 (m, 2H), 3.35 (s, 3H), 3.34-3.28 (m, 2H), 2.52-2.42 (m, 1H), 2.12-2.00 (m, 2H), 1.90 (d, J=1.6 Hz, 6H), 1.89-1.74 (m, 1H) and 1.22 (t, J=7.2 Hz, 3H) ppm. Elemental Analysis Calculated for C26H39FN7O8P (corrected for 4.73% w/w water, as determined by the Karl-Fischer oven method): C, 47.41; H, 6.49; N, 14.88; F, 2.89; P, 4.71. Found: C, 47.71; H, 6.27; N, 14.08; F, 2.93; P, 5.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([OH:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)(=O)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([O-:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=S(=O)([O-])c1ccccc1

Procedure:
3.790 g of Donepezil is dissolved in 70 ml of ethyl acetate. A solution (35 ml) of benzenesulfonic acid (1.852 g) in acetone is slowly added drop-wisely. The solid precipitated is filtered under suction to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=1)=O)C.[BH4-].[Na+]>C1COCC1.CO>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=[C:6]([CH2:4][OH:3])[N:11]2[N:12]=1)=[O:17])[CH3:20]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OCC)n2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(CO)n2n1
Reaction time: 1 h

Procedure:
To a stirring suspension of the product of Step 2, (0.88 g, 2.5 mmol) in THF (40 mL) and MeOH (5 mL) was added sodium borohydride (1.02 g, 27 mmol). After 1 h the reaction was quenched by the addition of ca. 50 mL water and stirred 1 h to allow formation of a precipitate. The solid was rinsed with water (3×10 mL) and dried in vacuo to give the alcohol, 1-ethyl-3-(5-hydroxymethyl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-urea as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19]C(=O)OC(C)(C)C)[S:9][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12]>FC(F)(F)C(O)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([C:10]1[S:9][C:8]([NH2:19])=[N:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Compound 185 (286 mg, 0.770 mmol) was dissolved in trifluoroacetic acid (2 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added to the resulting residue, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:4) to afford the entitled Compound 186 (208 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1([NH2:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with Phenylamine to produce 4-Chloro-3-nitro-N-phenyl-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.Cl.[N+]([O-])([O-])=O.[Na+].[I-:30].[K+]>C(OCC)(=O)C.O>[I:30][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: COc1ccc(-c2ccc(N)cc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ccc(I)cc2-c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 53.9 g. of 4'-amino-4,4"-dimethoxy-1,1':2',1"-terphenyl in 79 ml. of hydrochloric acid and 120 ml. of water was cooled by means of an external ice bath to about 0° C. A solution of 13.11 g. of sodium nitrate in 100 ml. of water was added over a ten minute period. After stirring an additional ten minutes, a solution of 29.9 g. of potassium iodide in 100 ml. of water was added over a 30 minute period. The solution was allowed to stand overnight without stirring. The reaction was then heated on a steam bath for 30 minutes. After cooling, two liters of ethyl acetate were added. The layers were separated and the aqueous layer was extracted four times each with 500 ml. of ethyl acetate. The combined organic extracts were washed four times each with 250 ml. of a 10% aqueous sodium thiosulfate solution, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography over silica gel to provide 35.12 g. of the desired iodo intermediate.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-])=O.Cl>C(O)C>[F:13][CH:2]([F:1])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH2:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)F
Agent: Cl
Solvent: CCO
Product: Nc1ccc(F)cc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of the above 2-(difluoromethyl)-4-fluoro-1-nitrobenzene (5.9 g, 31 mmol) in ethanol (0.10 L), stannous chloride dihydrate (28 g, 0.12 mol) and concentrated hydrochloric acid (20 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction, ethanol was distilled off under reduced pressure and a 5M aqueous sodium hydroxide solution was added under ice-cooling to make it basic. Thereafter, it was extracted with diethyl ether and after it was successively washed with water and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, 1:4, v/v) to give the title compound (3.0 g, 60%) as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[C@@H:21]([NH2:26])[CH2:22][CH2:23][CH:24]=[CH2:25].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:12]=1[C@@H:21]([NH:26][C:28](=[O:29])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCC[C@H](N)c1cc(C(F)(F)F)ccc1Br
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To DIPEA (7.48 mL, 42.8 mmol) and (1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-amine (4.4 g, 14.3 mmol) in DCM (20 mL) was added benzyl chloroformate at 0° C. The reaction was stirred at room temperature for 2 hours and was quenched with water. The organic was washed with 10% aqueous KOH and the aqueous was back-extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to yield benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (5.8 g, 13.1 mmol). 1H NMR (500 MHz, CDCl3) δ7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 7.1 (m, 1H), 5.83 (m, 1H), 5.3 (b, 1H), 5.15 (m, 3H), 2.22 (m, 1H), 2.18 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccccc4C#N)cc32)N=C1N
Temperature: 120 °C
Yield: 13.3 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 2-cyanophenylboronic acid (15.3 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative HPLC twice to give pure 2-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.83 mg, 13%). 1H-NMR (MeOD): 2.48-2.60 (m, 2H), 3.33 (s, 3H), 5.26 & 5.88 (m, 1H), 7.17 (m, 1H), 7.37-7.60 (m, 9H), 7.70 (m, 1H), 7.81 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]([CH2:14][O:15][CH3:16])[O:11][C:10]3[CH:17]=[C:18]([S:21]([N:24](CC4C=CC(OC)=CC=4)[C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:23])=[O:22])[CH:19]=[CH:20][C:9]2=3)=[C:4]([C:39]#[N:40])[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]([CH2:14][O:15][CH3:16])[O:11][C:10]3[CH:17]=[C:18]([S:21]([NH:24][C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:22])=[O:23])[CH:19]=[CH:20][C:9]2=3)=[C:4]([C:39]#[N:40])[CH:3]=1
Reactant: COCC1CN(c2ccc(Cl)cc2C#N)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1CN(c2ccc(Cl)cc2C#N)c2ccc(S(=O)(=O)Nc3nccs3)cc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a solution of 4-(4-chloro-2-cyanophenyl)-N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (170 mg, 0.28 mmol) in dichloromethane (10 mL) was added trifluroacetic acid (0.7 mL, Spectrochem) at 0° C. and the mixture was allowed to stir at room temperature for 4 h. The volatiles were removed under reduced pressure and the residue was basified (pH˜10) with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude material which was further purified by column chromatography (silica gel 100-200 mesh, 0-2% methanol in dichloromethane) to obtain 4-(4-chloro-2-cyanophenyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (70 mg, 51.5%) as an off white solid. m/z (ESI) 476.8 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.13 (d, J=2.5 Hz, 1H), 7.84 (dd, J=8.8, 2.5 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.35-7.04 (m, 3H), 6.80 (d, J=4.6 Hz, 1H), 6.57 (d, J=8.5 Hz, 1H), 4.46 (d, J=4.6 Hz, 1H), 3.80-3.76 (m, 1H), 3.65-3.57 (m, 3H), 3.29 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][C@H:35]1[O:40][C@@H:39]([CH3:41])[CH2:38][NH:37][CH2:36]1>CN1C(=O)CCC1>[CH3:41][C@H:39]1[O:40][C@@H:35]([CH3:34])[CH2:36][N:37]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[S:10][C:11]4[C:17]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=4[N:13]=3)=[O:7])=[CH:4][N:3]=2)[CH2:38]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(N4C[C@@H](C)O[C@@H](C)C4)nc3)nc12

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and cis-2,6-dimethyl-morpholine in NMP. ES-MS m/e (%): 506 (M+Na+, 31), 484 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.[Cl-].[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:8]1(=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CCC1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
2-methylpropane-2-sulfinamide (4.32 g, 35.7 mmol) and titanium(IV) ethoxide (16.3 g, 71.3 mmol) were added sequentially to a solution of cyclobutanone (2.5 g, 35.7 mmol) in THF (102 ml) at 22° C. The mixture was stirred at 60° C. for 5 h. The reaction mixture poured over a stirring saturated aqueous sodium chloride solution (60 mL). Celite was added to the suspension and it was filtered through a pad of Celite, washing with ethyl acetate (300 mL). The filtrate was washed with brine and the organic layers were combined and dried with anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, yielding an oil which was purified on silica gel (Biotage, 25 g column, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product N-cyclobutylidene-2-methylpropane-2-sulfinamide (4.6 g, 27 mmol, 74% yield) consistent by NMR. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.59-3.22 (m, 2H), 3.21-3.03 (m, 2H), 2.12 (t, J=8.2 Hz, 2H), 1.24 (s, 9H).
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:25])[C:4]1[N:8]=[C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[CH3:10])[O:6][N:5]=1.Cl>CO>[CH3:25][N:3]([CH3:2])[C:4]1[N:8]=[C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[CH3:10])[O:6][N:5]=1
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N(C)C)no1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CC(c1cccc(C(O)c2ccccc2)c1)c1nc(N(C)C)no1
Yield: 103.1 %

Procedure:
To sodium brohydride suspended (0.177 g, 4.7 mmol) in methanol (15 ml) under cooling with ice was slowly added dropwise 3-dimethylamino-5-(1-(3-benzoylphenyl) ethyl)-1,2,4-oxadiazole (1.45 g, 4.5 mmol) in methanol (15 ml). After the mixture was stirred under cooling with ice with 1 h, 1N-HCl was added to the mixture, then the mixture was adjusted at pH 6. The mixture was evaporated under reduced pressure to a residue, which was extracted with dichloromethane. The extracts were washed with saturated NaCl aq., dried with anhydrous magnesium sulfate, and evaporated under reduced pressure to a residue, which was chlomatographed to afford 3-dimethylamino-5-(1-(3-(α-hydroxybenzyl)phenyl)ethyl)- 1,2,4-oxadiazole (1.50 g, 99% yield) as oily substance: NMR(CDCl3)δ1.45(d, 3H), 2.27(d, 1H), 3.00(s, 6H), 4.20(q, 1H), 5.80(d, 1H), 7.20-7.45 m(m, 9H) ppm; IR(neat) 3375, 1600, 1405 cm-1.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:9]([CH3:13])[CH2:10][C:11]#[CH:12])[CH:7]=[CH2:8].[C:14](=[O:16])=[O:15].O>CCCCCC.O1CCCC1.CO>[CH2:10]([N:9]([CH3:13])[CH2:6][C:7]#[C:8][C:14]([OH:16])=[O:15])[CH:11]=[CH2:12]
Reactant: O=C=O
Reactant: C#CCN(C)CC=C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(C)CC#CC(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (16.4 mL, 2.5M in n-hexane) was slowly added to allyl-methyl-prop-2-ynyl-amine (4.5 g, 46 mmol) in 50 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at −78° C., then dry carbon dioxide was passed through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 4.1 g of 4-(allyl-methyl-amino)-but-2-ynoic acid: mass spectrum (m/e): M−H 152.