Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:29]([O-:31])=[O:30])[CH2:8]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(#N)C>[C:38]1([S:44][CH2:6][C@@H:7]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:29]([O:31][C:16]([CH3:19])([CH3:17])[CH3:15])=[O:30])[CH2:8]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)OC[C@H]1CN(C(=O)[O-])CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CSc2ccccc2)C1
Temperature: 120 °C
Yield: 122.8 %

Procedure:
A 5 mL vial was charged with (3R)-3-(((methylsulfonyl)oxy)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.300 g, 0.559 mmol), potassium carbonate (0.190 g, 1.38 mmol), benzenethiol (0.070 mL, 0.69 mmol, Sigma-Aldrich, St. Louis, Mo.) and acetonitrile (2 mL). The reaction mixture was heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica, 0-30% EtOAc in hexanes) to afford tert-butyl (3R)-3-((phenylsulfanyl)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.189 g) as a white solid.
Reaction SMILES: CS(C)=O.C(=O)([O-])[O-:6].[K+].[K+].[I-].[K+].[CH:13](Br)([CH2:15][CH3:16])[CH3:14].O[C:19]1[C:28]([OH:29])=[C:27]2[C:22]([C:23](=[O:32])[CH2:24][C:25]([CH3:31])([CH3:30])[O:26]2)=[CH:21][CH:20]=1>COCCOCCOC>[CH2:14]([O:6][CH:24]1[C:23](=[O:32])[C:22]2[C:27](=[C:28]([OH:29])[CH:19]=[CH:20][CH:21]=2)[O:26][C:25]1([CH3:31])[CH3:30])[CH2:13][CH2:15][CH3:16]
Reactant: CCC(C)Br
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(=O)c2ccc(O)c(O)c2O1
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COCCOCCOC
Product: CCCCOC1C(=O)c2cccc(O)c2OC1(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
In 80 ml of dimethyl sulfoxide 4.2 g (20 millimoles) of 7.8-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 10 ml of diethylene glycol dimethylether, 4.1 g (30 millimoles) of potassium carbonate, 0.5 g of potassium iodide and 3.3 g (2.6 ml, 24 millimoles) of sec. butyl bromide are added. The reaction mixture is heated at 100° C. for 10 hours, poured onto 200 ml of crushed ice and extracted with 100 ml of carbon tetrachloride. To the aqueous phase 20 ml of 10% sodium hydroxide solution are added, the mixture is cooled to 0° C., acidified with concentrated hydrochloric acid and stirred at 0° C. for 2 hours. The product is filtered, washed twice with 20 ml of water, dried and crystallised from 90% ethanol. Thus 4.4 g of the desired compound are obtained, yield 83%, mp.: 108°-110° C.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:15]C1C=CC=CC=1CBr.COP(OC)OC>>[CH3:15][C:13]1[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Reactant: Cc1ccccc1CBr
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccccc1C)OC

Procedure:
Following the procedure of Compound 11, 2-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH3:29])[C:6]1[C:7]2[C:15]([CH3:17])([CH3:16])[CH:14]([OH:18])[N:13]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:32]I>C1COCC1>[CH2:1]([N:5]([CH2:28][CH3:29])[C:6]1[C:7]2[C:15]([CH3:16])([CH3:17])[CH:14]([O:18][CH3:32])[N:13]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1nc(C)nc2c1C(C)(C)C(O)N2c1c(C)cc(C)cc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(CC)c1nc(C)nc2c1C(C)(C)C(OC)N2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-(butyl-ethyl-amino)-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-ol] (20 mg, 0.05 mmol) in 1 ml of dry THF was treated with sodium hydride (60% in oil, 4 mg, 0.1 mmol) and then methyl iodide (0.3 ml) was added at room temperature. After stirring at room temperature for 2.5 hours, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 26 mg of crude material. After silica gel column purification with 10% ethyl acetate in hexane, 19 mg of a colorless oil of the title compound was obtained. 1H NMR (CDCl3) δ 6.92 (s, 1H), 6.89 (s, 1H), 4.48 (s, 1H), 3.1–3.3 (m, 4H), 3.11 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H), 1.4–1.52 (m, 2H), 1.2–1.4 (m, 2H), 1.10 (t, 3H), 0.90 (t, 3H) ppm.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:30])[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[CH3:16].[Sn](Cl)(Cl)(Cl)Cl>>[CH2:15]([O:17][C:18]([C:19]1[C:20](=[O:21])[O:14][C:10]2[C:11]([C:25]=1[OH:26])=[CH:12][CH:13]=[C:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]=2)=[O:30])[CH3:16]
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCOC(=O)c1c(O)c2ccc(Oc3ccccc3)cc2oc1=O
Temperature: 200 °C
Yield: 4.5 %

Procedure:
A mixture of 3-phenoxy-phenol (1.068 g, 5.73 mmol), 2-ethoxycarbonyl-malonic acid diethyl ester (3.65 mL, 17.2 mmol), and tin tetrachloride (14 μL, 0.11 mmol) was heated in a 200° C.-oil bath for 5 min; then cooled, the reaction mixture was directly purified on silica gel column chromatography (eluent: ethyl acetate in dichloromethane: 10% to 80%) to give the desired title product (84 mg, 4.4%). ESI (m/z): 327 (M+H)+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[OH:6][CH:7]([CH2:14][OH:15])[CH2:8][S:9]([CH2:11][CH2:12][NH2:13])=[O:10]>O>[OH:6][CH:7]([CH2:14][OH:15])[CH2:8][S:9]([CH2:11][CH2:12][NH:13][C:2]([NH2:3])=[O:1])=[O:10]
Reactant: N#C[O-]
Reactant: NCCS(=O)CC(O)CO
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCCS(=O)CC(O)CO
Temperature: -5 °C
Reaction time: 1 h

Procedure:
There is slowly added to an aqueous solution of potassium cyanate (5 × 10-3 mole) a solution of 5 × 10-3 mole of 2-(2,3-dihydroxy propylsulfinyl) ethylamine hydrochloride in water. This mixture is agitated for 1 hour at a temperature lower than -5° C. The mixture is then concentrated under reduced pressure and the resulting residue is taken up in methanol and filtered. The filtrate is evaporated and the residue is crystallized in a mixture of isopropanol and acetonitrile, yielding white crystals having a melting point of 102° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16](=O)[C:15](=O)[C:14]=2[C:13]1=[O:24]>>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]1[C:13](=[O:24])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21]
Reactant: O=c1ccc2c(=O)n(CCO)c(=O)c=2c1=O
Reactant: Oc1cccc(I)c1
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(I)c1

Procedure:
Alkylation of 3-iodophenol with 2-(2-hydroxyethyl)isoindoline-1,3-dione dione following method used in Example 31 gave 2-(2-(3-iodophenoxy)ethyl)isoindoline-1,3-dione. Yield (2.8 g, 71%): 1H NMR (400 MHz, CDCl3) δ 7.85-7.87 (m, 2H), 7.71-7.73 (m, 2H), 7.22-7.26 (m, 3H), 6.94 (t, J=8.4 Hz, 1H), 6.81:6.84 (m, 1H), 4.19 (t, J=5.6 Hz, 2H), 4.09 (t, J=5.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([C:11]#N)[C:5]2=[C:4]([NH2:13])[N:3]=1.C(O)=[O:15]>[Ni]>[NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([CH:11]=[O:15])[C:5]2=[C:4]([NH2:13])[N:3]=1
Reactant: N#Cc1cnc2[nH]c(N)nc(N)c1-2
Reactant: O=CO
Agent: [Ni]
Product: Nc1nc(N)c2c(C=O)cnc-2[nH]1
Temperature: 80 °C

Procedure:
About 6.0 g of Raney Ni was added to a stirred solution of about 2.0 g of Compound 12 and about 50 ml of HCOOH. The mixture was heated to about 80° C. for about 2 hours, until no starting material could be detected by TLC. The mixture was cooled to room temperature and filtered through Celite®. The filtrate was evaporated under reduced pressure, azeotroping with methanol to remove traces of HCOOH. The residue was dissolved in about 25 ml of hot water, treated with Norit®, an activated adsorption carbon commercially available from American Norit Company, Inc., and filtered through Celite®. The filtrate was neutralized with NH4OH. The light brown precipitate which resulted was filtered and dried to yield about 1.40 g of Compound 13, which was immediately used in subsequent reactions without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C(C)C>CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Brc1cncc(I)c1
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cncc(Br)c2)C1
Temperature: 55 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
A mixture of 3-bromo-5-iodopyridine (500 mg, 1.761 mmol, Aldrich), tert-butyl 3-aminopiperidine-1-carboxylate (388 mg, 1.937 mmol, Combi-blocks), Cut (33.5 mg, 0.176 mmol, Aldrich) and cesium carbonate (1148 mg, 3.52 mmol, Fluka) was capped, degassed and backfilled with argon (3×). Dioxane (2 mL) and 2-isobutyrylcyclohexanone (0.118 mL, 0.704 mmol) were added, and the reaction was heated to 55° C. After 16 h, the temperature was raised to 70° C. After 60 h at 70° C., the reaction mixture was cooled to 23° C., diluted with EtOAc (75 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 25-60% EtOAc/hexane), affording tert-butyl 3-(5-bromopyridin-3-ylamino)piperidine-1-carboxylate (375 mg, 60%). MS (ESI, pos. ion) m/z: 356.1 (M+1), 358.1 (M+3).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[O:18][CH2:17][CH2:16][CH:15]3[NH2:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31]([NH:34][CH:35]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:36][C:37](O)=[O:38])(=[O:33])=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31]([NH:34][CH:35]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:36][C:37]([NH:20][CH:15]1[C:14]2[C:19](=[C:10]([CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH:11]=[CH:12][CH:13]=2)[O:18][CH2:17][CH2:16]1)=[O:38])(=[O:33])=[O:32]
Reactant: NC1CCOc2c(CN3CCCCC3)cccc21
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCOc2c(CN3CCCCC3)cccc21
Reaction time: 8 h

Procedure:
8-Piperidin-1-ylmethylchroman-4-ylamine dihydrochloride (Step E) (28 mg, 0.11 mmol), 3-(naphthalen-2-yl-sulfonylamino)-3-phenylpropionic acid (40 mg, 0.11 mmol), HOBt (17 mg, 0.12 mmol), and DIEA (21 mg, 0.16 mmol) were dissolved in CH2Cl2 (5 mL). EDC (25 mg, 0.13 mmol) was added and the reaction was kept at 22-25° C. overnight until completed. The reaction solution was washed with dilute (˜5%) NaHCO3—H2O and H2O, then dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by column chromatography (silica gel, 0.5% Et3N in EtOAc). The compound was converted to the HCl salt in Et2O to provide the title compound as a mixture of diastereomers, as a white solid (ca. 1:1 by 1H NMR). MS (ESI) 584 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[N:34](C(OC(C)(C)C)=O)[N:33]=[CH:32]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:45][CH2:46][CH2:47][O:48][CH3:49].[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:5]=4)[N:10]=[C:9]([C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:27])[C:21]5[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=5)[CH:16]=[CH:17][CH:18]=4)[N:8]=3)=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)c4cccnc4)c3)nc2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(Nc3ccc4[nH]ncc4c3)nc(-c3cccc(NC(=O)c4cccnc4)c3)nc2cc1OC
Yield: 71 %

Procedure:
A solution of tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate in CH2Cl2 (15 mL) and TFA (2.2 mL) was stirred at RT for 1 h. The volatiles were removed in vacuo and the residue was washed with Et2O to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)nicotinamide trifluroacetate salt (0.086 g, 0.127 mmol, 71% over two steps). MS 562.4 (M+1). HPLC retention time 4.92 mins.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[N:12][CH:13]=1.[CH3:19][C:20]([CH3:22])=O>[Cl-].[Cl-].[Zn+2]>[C:5]([C:20]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[N:12][CH:13]=1)([CH3:22])[CH3:19])#[N:6]
Reactant: CC(C)=O
Reactant: C[Si](C)(C)C#N
Reactant: N#CCCCc1ccc(N)cn1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C#N)Nc1ccc(CCCC#N)nc1
Yield: 102.2 %

Procedure:
TMSCN (0.24 mL, 1.8 mmol) was added to a mixture of compound 78 (100 mg, 0.6 mmol), acetone (0.27 mL, 3.6 mmol) and ZnCl2 (10 mg, 0.08 mmol) with stirring. The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 79 (140 mg, 98%) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ8.12 (s, 1H), 7.20-7.25 (m, 1H), 7.00-7.06 (m, 1H), 2.81 (t, 2H, J=7.1 Hz). 2.32 (t, 2H, J=7.1 Hz), 1.98-2.12 (m, 2H), 1.69 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[OH-].[K+].O>CS(C)=O>[N:17]1([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1N1CCCCC1
Temperature: 90 °C
Yield: 91.8 %

Procedure:
To 1-(5-chloro-2-nitro-phenyl)-piperidine (184 mg, 0.760 mmol, as prepared in Example 3, step (a)) and imidazole (67.8 mg, 0.99 mmol) in 3 mL of DMSO was added KOH (64 mg, 1.1 mmol). The reaction was heated to 90° C. overnight. The dark solution was poured into 40 mL of water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo to give 190 mg (92%) of the title compound as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C14H16N4O2, 273.1 (M+H), found 273.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12](O)[CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.P(Br)(Br)[Br:17]>CCOCC.N1C=CC=CC=1.CCCCCC>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([Br:17])[CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCO2
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(Br)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
6.2 g of 4,4-dimethyl-6-(1-hydroxyethyl)chromane were dissolved in 3 ml of absolute ether and 20 ml of hexane and the solution was treated with 3 drops of pyridine. At a temperature of 0°-5° C. there was slowly added dropwise thereto a solution of 5.4 g of phosphorus tribromide in 20 ml of hexane. The mixture was stirred at 0° C. for a further 3 hours, poured onto ice and extracted with ether. The organic phase was washed with dilute sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. There were obtained 4.5 g of 4,4-dimethyl-6-(1-bromoethyl)chromane in the form of a reddish oil which was converted into the phosphonium bromide without further purification.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[Sn](Cl)(Cl)(Cl)Cl.[C:26]1(=O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[CH:28]=[CH:27]1.[C:38](OCC)(=[O:40])[CH3:39]>>[C:38]([O:36][C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:27][CH:28]=1)(=[O:40])[CH3:39]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CCOC(C)=O
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OC(C)=O)c2ccccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
An amount of 250 ml of octadecanol was dissolved by heating to 60° C. and 8.0 g of hydrochloric acid gas was blown thereinto little by little. Next, 44.5 g of anhydrous tin chloride and 25.0 g of 1,4-naphthoquinone were added, and the mixture was heated on a water bath of 75° C. for 2 hours. After the reaction, the product was poured into 1,000 ml of ethyl acetate, the insolubles were filtered off, and the ethyl acetate layer was washed with water. After evaporation of ethyl acetate under reduced pressure, octadecanol was recovered by vacuum distillation. The residue was dissolved in 30 ml of anhydrous acetic acid, and 2 to 3 drops of conc. sulfuric acid were added thereto, whereby vigorous heat generation occurred. After 30 minutes, ice-water was added, and the oily product separated was extracted with 500 ml of n-hexane. After washing with water and drying, the solvent ws evaporated and the residue was purified by column chromatography to obtain a thick syruppy desired product at a yield of 52%. The product was confirmed by NMR, Mass spectra.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=O.[CH3:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][C:20]([CH:1]([C:3]2[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:4]=2)[C:3]2[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:19][CH:18]=1
Reactant: CN(C)c1ccccc1
Reactant: CN(C)c1ccc(C=O)c(C(=O)O)c1
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
In another known process for the preparation of CVL there are three steps. The first step comprises the interaction of the methyl ester of 2-formyl-5-dimethylaminobenzoic acid with two equivalents of N,N-dimethylaniline to obtain the methyl ester of 2-[bis(4-dimethylaminophenyl)-methyl]-5-dimethylaminobenzoic acid. After isolation, this benzoic acid is oxidized in the second step and finally in the third step the oxidized product is saponified and the lactone ring is closed to obtain the 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide (CVL).
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.CN1C[CH2:22][O:21]CC1.[OH2:24]>>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:22]([OH:21])=[O:24])=[CH:9][CH:8]=1
Reactant: O
Reactant: CN1CCOCC1
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 95 °C
Reaction time: 9 h
Yield: 96 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (2.8 g; 10 mmol), N-methylmorpholine (24 ml) and water (16 ml) is heated at 95° C., under stirring for 9 h. The reaction mixture is worked up as described in example 1a to give 2-(4-methoxyphenyl)-propionic acid (1.79 g; 9.6 mmol; yield 96%), m.p. 56°-57° C. (In this experiment, N-methyl-morpholine acts as weak base as well as dipolar aprotic diluent).
Reaction SMILES: FC(F)(S(O[C:17]1[CH:18]=[C:19]2[C@@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:36]#[C:37][C:38]([OH:41])([CH3:40])[CH3:39])[CH:28]=3)[O:23][C:20]2=[CH:21][CH:22]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.CN(C=O)C.C(NC(C)C)(C)C.[C:55]([CH:57]1[CH2:59][CH2:58]1)#[CH:56]>O.[Cu]I>[NH2:35][C:32]1[O:33][CH2:34][C@:30]2([C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:36]#[C:37][C:38]([CH3:40])([OH:41])[CH3:39])[CH:28]=3)[O:23][C:20]3[C:19]2=[CH:18][C:17]([C:56]#[C:55][CH:57]2[CH2:59][CH2:58]2)=[CH:22][CH:21]=3)[N:31]=1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc1O2
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3CC3)ccc1O2
Temperature: 80 °C

Procedure:
A 0.5-2 mL vial was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (106 mg, 0.167 mmol), and copper(i) iodide (3.19 mg, 0.017 mmol). The vial was flushed with Ar (g), then DMF (669 μL, 0.167 mmol), diisopropylamine (469 μL, 3.35 mmol), and ethynylcyclopropane (70.8 μL, 0.836 mmol) were added in sequence to give a yellow solution. The vial was sealed and heated overnight in at 80° C. The mixture was diluted with water (15 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 0-50% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-4-(2′-amino-7-(cyclopropylethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol as a tan solid after evaporation from DCM/hexanes.