Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH2:15]2)[CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1cc(CC2CNCCN2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CC2CN(S(=O)(=O)c3cccs3)CCN2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a 100-mL round-bottomed flask was added 2-((2-methoxy-4-pyridinyl)methyl)piperazine (350 mg, 1.69 mmol), triethylamine (0.353 mL, 2.54 mmol), and 2-thiophenesulfonyl chloride (0.34 mL, 1.86 mmol, Aldrich, St. Louis, Mo.) in DCM (5 mL). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (10 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc to give 3-((2-methoxy-4-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (198 mg) as colorless glass.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:11]([O-])=O)[CH:8]=2)[C:3]1=[O:14].[Sn](Cl)(Cl)(Cl)Cl>CCO.O>[NH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:14])[N:2]([CH3:1])[CH2:10]2
Reactant: CN1Cc2cc([N+](=O)[O-])ccc2C1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: CN1Cc2cc(N)ccc2C1=O
Temperature: 79 °C
Reaction time: 2 h

Procedure:
The 2-methyl-5-nitroisoindolin-1-one (50 mg, 0.26 mmol) was dissolved in EtOH (1.3 ml) with heating, and tin chloride (117 mg, 0.52 mmol) added. The solution was stirred at 79° C. for 2 hours. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (aq, 100 ml), extracted with EtOAc (3×100 ml), the organics combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 5% MeOH:DCM+1% TEA to give the titled compound.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Br:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>ClCCl>[C:2]([O:19][C:17]([C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([CH2:6][Br:5])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)=[O:18])([CH3:3])([CH3:1])[CH3:4]
Reactant: O=C(O)c1cccc2ccc(CBr)cc12
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc2ccc(CBr)cc12
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Isobutylene was passed through a suspension of 7-bromomethylnaphthalene-1-carboxylic acid (10.4 g, 39.2 mmol) in dichloromethane (150 mL) in the presence of concentrated sulfuric acid (1 mL) for 3 hours, and then the mixture was stirred overnight. The resulting deep green solution was washed with a saturated solution of sodium hydrogen carbonate, dried (magnesium sulfate) and the solvent was removed under reduced pressure to give crude 7-bromomethylnaphthalene-1-carboxylic acid tert-butyl ester (11.2 g, 88.8%) as a deep green oil. This compound was directly used for the subsequent Michaelis-Becker alkylation without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([O:14]C)=[O:13])=[CH:5]2.[OH-].[K+].O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2
Reactant: COC(=O)c1cc2cc(Cl)ccc2cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc(Cl)ccc2cn1
Temperature: 80 °C
Yield: 13.4 %

Procedure:
Methyl 6-chloro-isoquinoline3-carboxylate (0.80 g, 3.6 mmol) is suspended in 95% EtOH (35 mL). KOH (0.61 g, 10.9 mmol) is added, and the reaction is heated to 80° C. When a white precipitate begins to form, 10 mL of H2O is added and all solid is redissolved. After heating for 1 hour, the reaction is cooled to rt and a white precipitate forms. The precipitate (identified as the K+ salt) is collected by vacuum filtration. The filtrate is acidified with concentrated HCl until the pH is between 4 and 5. The filtrate is loaded directly onto a column of AGW-×2 resin (H+ form) and the column is rinsed with MeOH. The product is eluted with a solution of 5% TEA in MeOH. This solution is concentrated, evaporated from MeCN three times, and the resulting solid is recrystallized from EtOH/H2O. This material is purified by preparative achiral HPLC to yield 0.10 g (13%) of 6-chloroisoquinoline-3-carboxylic acid. HRMS (FAB) calculated for C10H6ClNO2+H+: 208.0165, found 208.0164.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH2:40])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][C:46]([CH3:51])([CH3:50])[C:47]([NH2:49])=[O:48].NCCN1CC[O:58][CH2:57]C1>>[C:47]([C:46]([NH:45][C:57](=[O:58])[NH:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:42]([CH3:44])[CH3:43])=[C:32]([CH3:41])[CH:33]=1)([CH3:51])[CH3:50])(=[O:48])[NH2:49]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCN1CCOCC1
Reactant: CC(C)(N)C(N)=O
Product: Cc1cc(OCCNC(=O)NC(C)(C)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 19 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 4-(2-aminoethyl)morpholine, respectively.
Reaction SMILES: [O:1]=[C:2]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[O:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:7]1[CH2:6][CH2:5][C:4]2([O:3][C:2](=[O:1])[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=3)[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OC(=O)Nc1ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2C2(CCNCC2)O1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
tert-Butyl 2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate (6.71 g, 21.1 mmol) was dissolved in dichloromethane (50 mL), treated with trifluoroacetic acid (20 mL) and stirred at room temperature for 45 min. The reaction was concentrated under reduced pressure, re-dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was cooled in an ice-H2O bath, dissolved in ice-cold saturated brine (20 mL) and H2O (50 mL) and basified with ice-cold 35% NaOH (aq). A small amount of product (obtained from extraction with 50 mL ethyl acetate) was added to the aqueous layer to initiate crystallization. The suspension obtained was cooled in an ice-H2O bath, filtered, rinsed with ice-cold H2O and dried to afford 3.071 g spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one free base as a white crystalline solid. An additional 800 mg free base was obtained via extraction of the mother liquor with ethyl acetate (10×50 mL) and subsequent trituration of the crude free base with acetonitrile (overall yield=84%). LC/MS m/z 219.2 [M+H]+, retention time 0.58 min (RP-C18, 10-99% CH3CN/0.05% TFA); 1H-NMR (400 MHz, DMSO-d6) δ 10.17 (br s, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.87 (dd, J=8.2, 1.2 Hz, 1H), 2.89 (m, 2H), 2.82 (m, 2H), 1.84 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>C(O)(=O)C.Cl.O.C(O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccc(F)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 4-fluoroaniline (1000 mg, 9.00 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (746 mg, 10.80 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(4-fluorophenyl)hydrazono]pentane-2,4-dione (1200 mg, 60%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.Cl>C(OCC)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[OH:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccc(C(O)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 306.7 %

Procedure:
Magnesium turnings (0.39 g, 0.016 mol) were dried in a flask and then cooled under nitrogen. Anhydrous diethyl ether (3 mL) was added, followed by 4-bromotoluene (3.0 g, 1.8 mmol). The mixture was refluxed, and more anhydrous diethyl ether was added to keep the solution volume constant. The resultant Grignard solution was added dropwise to a solution of 4-bromobenzaldehyde (1.66 g, 9.0 mmol) in anhydrous diethyl ether(6 mL). The reaction was heated with reflux for 30 minutes, following which it was cooled. The cooled solution was poured into a solution of hydrochloric acid (HCl) (3.7 milliliters (mL) concentrated HCl in 17 grams of ice-water) and stirred for 1 hour (h). The resulting mixture was extracted with diethyl ether (3 times, 50 mL each), and the combined organic extracts were dried using magnesium sulfate (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica gel (petroleum ether/ethyl acetate, 90/10, v/v) afforded 1.53 grams of (4′-bromophenyl)-4-methylphenyl methanol, a yield of about 62% as a white solid. The melting point (mp) was 80-81° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:16])[C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C([Li])(C)(C)C.CN(C)[CH:24]=[O:25].Cl>C1COCC1>[OH:16][C:4]1[C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=[C:2]([CH:24]=[O:25])[CH:3]=1
Reactant: CN(C)C=O
Reactant: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2c(O)cc(C=O)cc21
Temperature: -78 °C
Yield: 67 %

Procedure:
30 g (106 mmol) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-1-ol are dissolved in 500 mL of anhydrous THF. The medium is cooled to −78° C. and 156 mL (265 mmol) of tert-butyllithium are then added dropwise. After 45 minutes at this temperature, 12.3 mL (159 mmol) of dimethylformamide are added. The mixture is warmed to room temperature and then treated with 1N hydrochloric acid solution and extracted with ethyl acetate. The residue obtained is then purified by chromatography (eluent: 9/1 heptane/ethyl acetate). A white solid is obtained (m=16.5 g; yield=67%; m.p.=144° C.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4Cl)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:23]1([CH2:29][CH2:30][OH:31])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO.C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[O:31][CH2:30][CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Reactant: OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1OCCN1CCOCC1
Yield: 6.6 %

Procedure:
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one (I-180a: 100 mg, 0.3023 mmol) was refluxed with 2-morpholin-4-yl-ethanol (60 mg, 0.4534 mmol), potassium hydroxide (68 mg, 1.2092 mmol), potassium carbonate (42 mg, 0.3023 mmol), 18-crown-ether (8 mg, 0.0302 mmol) and toluene (3 mL) at 120° C. to afford the crude product. The reaction was monitored by TLC (10% MeOH in chloroform). Purification by column chromatography on silica gel (3.5% methanol in chloroform) followed by hexane wash and ether wash afforded 8.5 mg of the product (6.6% yield).
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].[H-].[Na+].Cl[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>O1CCCC1.C(O)C.O>[N:1]([CH2:4][CH2:5][O:6][CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: [N-]=[N+]=NCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour and the ice-cooled solution treated with a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was then partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was heated under reflux for 1 hour, allowed to cool to room temperature and treated with methyl 2-(2-chlorobenzylidene)acetoacetate (286.6 g). The mixture was heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 l) for 16 hours and the resulting solid collected, washed twice with methanol, dried and recrystallised from methanol to give the title compound (78 g), m.p. 145°-146°.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+].[O-][Mn](=O)(=O)=O.[K+].[OH2:25]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([OH:25])=[O:17])=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 26 %

Procedure:
To a suspension of 1-benzenesulfonyl-4-methylbenzene (5.05 g, 21.7 mmol) in H2O (100 mL) were added NaOH (2 pellets) and KMnO4 (6.87 g, 43.5 mmol). The mixture was heated to reflux overnight. The reaction was cooled and additional NaOH (1 pellet) and KMnO4 (4 g, 25 mmol) were added. The reaction was heated to reflux for 20 h. The reaction was cooled to rt and filtered to collect the solids. The filtrate was acidified with conc. HCl. The aqueous suspension was extracted with EtOAc (4×60 mL). The combined organic layers were washed with brine (60 mL), dried (Na2SO4), filtered and concentrated to provide the title compound (1.49 g, 26%) as an ivory powder. 1H NMR (DMSO-d6): δ 8.11 (dd, J=7, 7 Hz, 4H), 7.97 (d, J=7 Hz, 2H), 7.71-7.65 (m, 3H). MS (M−H)− 261.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:30])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.17 mmol, 60 mg), n-butyl chloroformate (0.19 mmol, 24 μL) and triethylamine (0.51 mmol, 71 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. The reaction mixture was quenched with water followed by an extraction with ethylacetate. Removal of organic solvents in vacuo provided Compound A48 as a white solid (40 mg, 50%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.67 (s, 1H); 8.62 (d, 2H); 8.26 (s, 1H); 8.11 (d, 2H); 5.62 (h, 1H); 4.12 (t, 2H); 3.92 (m, 2H); 3.39 (m, 2H); 3.10 (s, 3H); 2.11 (m, 2H); 1.65 (m, 2H), 1.56 (p, 2H); 1.42 (s, 2H); 0.97 (t, 3H). Exact mass calculated for C22H27N5O5S 473.55, found 474.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:26]C(=O)OC(C)(C)C)[C:10]([NH:12][C:13]2[S:17][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=[N:15][C:14]=2[CH3:25])=[O:11])=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:26][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([NH:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=2)=[N:15][C:14]=1[CH3:25])=[O:11]
Reactant: Cc1cc(-c2nc(C)c(NC(=O)[C@H](Cc3ccc(F)cc3)NC(=O)OC(C)(C)C)s2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc(C)c(NC(=O)[C@@H](N)Cc3ccc(F)cc3)s2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of tert-butyl (S)-3-(4-fluorophenyl)-1-(4-methyl-2-(2-methylpyridin-4-yl)thiazol-5-ylamino)-1-oxopropan-2-ylcarbamate (0.061 g, 0.13 mmol) in DCM (0.0083 ml, 0.13 mmol) was added TFA (0.01 ml, 0.13 mmol). The resulting mixture was allowed to stir at rt overnight. The mixture was concentrated and the residue was purified by HPLC to give 40 mg of (2S)-2-Amino-3-(4-fluorophenyl)-N-(4-methyl-2-(2-methylpyridin-4-yl)thiazol-5-yl)propanamide 22E. 400 MHz 1H NMR (CD3OD) δ: 8.63 (d, J=8.0 Hz, 1H), 8.28 (br s, 1H), 8.22 (dd, J=8.0, 4.0 Hz, 1H), 7.31 (dd, J=8.0, 4.0 Hz, 2H), 7.09 (dd, J=8.0, 8.0 Hz, 2H), 4.51 (dd, J=8.0, 8.0 Hz, 1H), 3.30 (obscured dd, 1H), 3.23 (dd, J=16.0, 8.0 Hz, 1H), 2.80 (s, 3H), 2.43 (s, 3H). LCMS (ES+) m/z 371.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[N:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][CH2:30][CH2:31]Br.O>CC(N(C)C)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:30]([O:29][CH3:28])[CH3:31])[CH2:18][CH2:17]2)=[N:13][CH:14]=1
Reactant: Brc1ccc(OC2CCNCC2)nc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(C)N1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
5-Bromo-2-(piperidin-4-yloxy)pyridine trifluoroacetate (0.86 g) was stirred with potassium carbonate (0.838 g) in dimethylacetamide (5 ml). Bromoethyl methyl ether (0.342 ml) was is added and the mixture was heated at 80° C. for 20 minutes. After cooling the mixture was poured into water (30 ml) and extracted three times with ether. The combined extracts were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 0 to 2% 2M methanolic ammonia in dichloromethane to give the product as a colourless oil (0.71 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16].Cl.[OH-].[Na+]>CCO>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=2)[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cc1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1I
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A solution of the above phenylhydrazine (5.08 g, 22 mmol) and 4,4-dimethyl-3-oxopentanenitrile (3.06 g, 1.1 equiv.) in EtOH (100 mL) containing conc. HCl (3 mL) was refluxed for 17 h, then cooled to room temperature. The pH was adjusted to 14 with 40% aqueous sodium hydroxide solution. The aqueous mixture was extracted with EtOAc, (3×50 mL), dried (MgSO4), and concentrated to give 5-tert-butyl-2-(3-iodo-4-methyl-phenyl)-2H-pyrazol-3-ylamine (6.3 g, 86%). This material was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:25][C:26](=[O:28])[CH3:27])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)COc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
2-Methyl-8-hydroxyquinoline (0.80 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) were stirred at room temperature for 30 min. To this solution was added chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) in one portion. The resulting mixture was stirred at room temperature for 24 h. (monitored by TLC) and then poured into ice water (100 ml). The pale yellow solid thus obtained was collected and crystallized from dichloromethane and ether to afford 2-methyl-8-(2-oxopropoxy)quinoline (10a) (0.77 g, 72%). mp: 99°-100° C.; 1H-NMR (CDCl3): δ2.35 (s, 3H, 2'-CH3), 2.79 (s, 3H, 2-CH3), 4.86 (s, 2H, OCH2), 6.88-7.44 (m, 3H, Ar--H), 7.33 (d, 1H, 3-H), 8.03 (d, 1H, 4-H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][CH:21]([OH:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O>>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C:11]1([CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]1)[CH2:22][CH:21]2[OH:23]
Reactant: OC1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Reactant: C=CC(=O)OC
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(O)CC1(CCN(Cc3ccccc3)CC1)O2

Procedure:
1′-Benzyl-6-bromo-4-hydroxy-spiro[chromane-2,4′-piperidine] (3.0 g, 7.7 mmol, Intermediate 3) was treated with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, giving (E)-3-{1′-benzyl-4-hydroxy-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (3.1 g). The crude intermediate was dissolved in THF (20 ml) under N2 and p-TsOH (0.15 g, 0.79 mmol) was added. The mixture was heated to reflux. After 16 h, the mixture was poured into water and a 10% NaOH solution was added until reaching a neutral pH value. The solution was extracted with DCM, dried over Na2SO4, filtered and evaporated under vacuum. The crude mixture was purified by column chromatography using DCM/MeOH (90/10) and then hexane/AcOEt (70/30) as eluent to give (E)-3-{1′-benzyl-spiro[chromene-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (150 mg).