Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:5][C:6]([N+:20]([O-])=O)=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=1.[Sn].Cl.[OH-].[Na+]>C(O)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](/[CH:10]=[CH:9]/[C:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:5][C:6]=2[NH2:20])=[N:12]1
Reactant: COc1cc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(/C=C/c2n[nH]c3ccccc23)c(N)cc1OCCCN1CCOCC1
Temperature: 40 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
(E)-3-{2-[5-methoxy-4-(3-(morpholin-4-yl) propyloxy)-2-nitrophenyl]vinyl}-1H-indazole (0.39 g, 0.89 mmol) obtained in Step 2 was dissolved in ethanol (3.0 mL), and the solution was added with tin (0.22 g, 1.9 mmol) and concentrated hydrochloric acid (1.5 mL) under ice-cooling, followed by stirring at 40° C. for 6 hours. To the reaction mixture under ice-cooling, 6 mol/L aqueous sodium hydroxide solution was added to neutralize the mixture. Then, the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (chloroform to chloroform/methanol=9/1) to obtain (E)-2-[2-(1H-indazol-3-yl)vinyl]-4-methoxy-5-[3-(morpholin-4-yl)propyloxy]phenylamine (0.32 g, 89%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:20](O)=[O:21])[CH2:5]1)(=[O:3])[CH3:2].O[NH:24][C:25](=[NH:30])[CH2:26][CH2:27][O:28][CH3:29]>>[F:18][CH:17]([F:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:8]2[CH2:7][CH:6]([C:20]3[O:21][N:30]=[C:25]([CH2:26][CH2:27][O:28][CH3:29])[N:24]=3)[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9]2)=[CH:15][CH:14]=1
Reactant: CC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)F)cc2)C1
Reactant: COCCC(=N)NO
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(C)=O)C2)n1

Procedure:
According to General Method 6A, 153 mg (0.270 mmol, purity 50%) of the compound from Example 59A and 41.3 mg (0.297 mmol, purity 85%) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 46.6 mg (32% of theory, purity 72%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:43][CH3:44])(=[O:42])[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[OH:37].O[CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1>[CH3:44][O:43][C:34](=[O:42])[C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[O:37][CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: OCCN1CCCC1
Reactant: COC(=O)c1ccccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
To a mixture of triphenylphosphine (0.79 g, 3.0 mmol) in THF (15 ml) was successively added diisopropylazodicarboxylate (0.61 g, 3.0 mmol) followed by methyl salicylate (0.46 g, 3.0 mmol) and the resultant mixture stirred at ambient temperature for 1 h. 1-(2-Hydroxyethyl)-pyrrolidine (0.35 g, 3.0 mmol) was then added drop-wise and the reaction mixture left stirring at ambient temperature for a further 5 h. The reaction mixture was reduced in vacuo and purified by flash column chromatography [SiO2, EtOAc/MeOH (3:1, 1:1)] to give 2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester as a clear yellow oil (446 mg, 60%). (LC/MS: Rt 1.58, [M+H]+ 250.05).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoate (1.20 g, 2.7459 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (13.7 ml) and 1,4-dioxane (30 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (1.02 g, 2.4113 mmol, 88%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.[Br:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].[CH2:31]([N:33]([CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1)[CH3:32]>C(OCC)(=O)C.C(N(CC)CC)C.ClCCl>[Br:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:33]([CH2:31][CH3:32])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1
Reactant: CCN(CCCC(=O)O)c1cccc(C)c1
Reactant: Nc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CCCC(=O)Nc1ccccc1Br)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg), 1-hydroxy-7-azabenzotriazole (106 mg), dichloromethane (2 ml), 2-bromoaniline (134 μl), and triethylamine (162 μl) were added to the compound (100 mg) obtained in Step 2, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (56 mg).
Reaction SMILES: [Br:1]CCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24]1>>[Br:1][CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCBr
Reactant: O=C(OCc1ccccc1)N1CCCC(CCO)C1
Product: O=C(OCc1ccccc1)N1CCCC(CCBr)C1

Procedure:
Prepared similarly to Intermediate 26 from phenylmethyl 3-(2-hydroxyethyl)-1-piperidinecarboxylate
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][N:25]=1.O.C(#N)C>CN(C)C=O>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([Br:23])[CH:29]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Reactant: BrCc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Br)c1
Reaction time: 0.58 h
Yield: 11.6 %

Procedure:
0.023 g of sodium hydride is added to a solution of 0.081 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 2 ml of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is continued at this temperature for 35 minutes. A solution of 0.071 g of 2-bromo-4-(bromomethyl)pyridine in 1 ml of anhydrous dimethylformamide is added, followed by addition of ice-cold water after reaction for 15 minutes. The reaction mixture is placed on a cartridge 16 mm in diameter packed with 5 g of octadecyl-grafted 40-60 μm silica conditioned successively with the mixture (water/acetonitrile) (5/95) (v/v) and then the mixture (water/acetonitrile) (95/5) (v/v). The elution was performed with a linear gradient of from 5% to 95% of acetonitrile over 30 minutes then with a mixture (water/acetonitrile) (5/95) (v/v) over 10 minutes, at a flow rate of 5 ml/minute. The fractions between 90 and 100 ml are concentrated under reduced pressure. 0.015 g of 5,5-dimethyl-1-(2-bromopyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)-imidazolidine-2,4-dione is thus obtained in the form of a white foam, the characteristics of which product are as follows:
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[OH-].[Na+]>O.C(O)C.ClCCl>[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[N:2][OH:3]
Reactant: O=Cc1cccc(Cl)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: ON=Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
A solution of hydroxylamine hydrochloride (3.68 g, 53 mmol) in water (5 ml) was added to a solution of 3-chlorobenzaldehyde (5.00 ml, 44 mmol) in ethanol (20 ml). A solution of sodium hydroxide (2.64 g, 66 mmol) in water (5 ml) was added. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was given onto water/ice (150 ml). The formed precipitation was isolated by filtration and dissolved in dichloromethane (200 ml). This solution was dried over magnesium sulphate. The solvent was removed to give 3.88 g of 3-chlorobenzaldehyde oxime, which was used without further purification.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=3)[CH2:7][CH2:6]2)[C:30]([C:27]2[CH:26]=[N:25][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[CH:29][N:28]=2)=[O:31])[CH2:2][CH2:3]1
Reactant: CCCc1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1cnc(-c2cnco2)cn1
Product: CCCc1noc(N2CCC(N(C(=O)c3cnc(-c4cnco4)cn3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 5-oxazol-5-yl-pyrazine-2-carboxylic acid following a procedure analogous to that described in Example 1. LC (method 8): tR=1.48 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[C:14]#[CH:15].C1(OCC#C)C2C(=CC=CC=2)C=CC=1>[OH-].[K+].CN(C)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1[CH:13]=[CH:14][CH2:15][O:12][C:7]=1[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: C#CCBr
Agent: C#CCOc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Product: Brc1ccc2c3c(ccc2c1)OCC=C3

Procedure:
In Reaction E, 6-bromo-2-naphthol and propargyl bromide represented by graphic formulae VIII and XVII, respectively, are refluxed together in ethanoic potassium hydroxide. The resulting propargyl naphthyl ether represented by graphic formula XVIII will, when refluxed in N,N-dimethylaniline (DMA), yield 8-bromo-3H-naphtho[2,1-b]pyran represented by graphic formula XIX. See Chromenes, Chromanones and Chromones Chapter II, E. E. Schweizer and D. Meeder-Nycz, 1977, pages 43 to 70. The conversion of 8-bromo-3H-naphtho[2,1-b]pyran to 8-hydroxy-3H-naphtho[2,1-b]pyran of graphic formula XX proceeds thru a series of steps described in Organic Synthesis Vol. 49 pages 90-93, 1972. Other substituted 8-hydroxy-3H-naphtho[2,1-b]pyrans may be synthesized by replacing propargyl bromide with another reactant such as substituted 3-bromo-1-alkynes. Coupling the resulting 8-hydroxy-3H-naphtho[2,1-b]pyran with the appropriate propargyl alcohol would result in compounds represented by graphic formula IB having formula IIC as group A. ##STR9##
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([CH:21]4OCC[O:22]4)[CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[CH:21]=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccc(CCCc3cccc(C4OCCO4)c3)nc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cccc(CCCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To a solution of 2-(3-(3-(7-chloroquinolin-2-yl)propyl)phenyl)-1,3-dioxolane from Step 6 (189 mg) in THF (9.5 mL) was added a 1 to 1 mixture of acetic acid and water (6.5 mL). The reaction was heated at 63° for 2 hours. The reaction was diluted with ethyl acetate and the organic layer washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated. The residue was co-evaporated once with toluene to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][CH:19]=2)[N:14]=1.O.C(OC(C)C)(C)C>C(OCC)C>[CH:24]([O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Oc1ccc2ccc(N)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2ccc3ccc(OC(C)C)nc3n2)cc1
Temperature: 4 °C
Yield: 34.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (16.7 g), N,N'-carbonyldiimidazole (19.4 g) and 2-amino-7-isopropoxy-1,8-naphthyridine (25 g). The reaction mixture is poured into water and extracted with ethyl acetate. After concentration to dryness under reduced pressure (4 kPa), the oil produced (39 g) is stirred in the presence of diethyl ether (100 cc) to give a crystallised solid (23 g; m.p. 78° C.). The product produced is dissolved in boiling isopropyl ether (100 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with diethyl ether (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-isopropoxy-1,8-naphthyridin-2-yl)-4-methoxybenzamide (12.9 g) is produced, m.p. 82° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1>C(#N)C>[Cl:9][C:10]1[C:18]([I:1])=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cc2ccccn2n1
Solvent: CC#N
Product: Clc1nn2ccccc2c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-iodosuccinimide (1.06 g, 4.74 mmol) was added to a solution of 2-chloro-pyrazolo-[1,5-a]pyridine (27-2; 0.6 g, 3.95 mmol) in acetonitrile (18.0 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography (5-10% ethyl acetate in hexanes) provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.36-8.34 (d, J=6.8 Hz, 1 H), 7.40-7.37 (d, J=8.8 Hz, 1 H), 7.26-7.23 (m, 1 H), 6.84-6.81 (m, 1 H). MS (M+1): 279.0.
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:11]([OH:14])[CH2:12][CH3:13])[CH2:3][CH3:4].N1C=CC=CC=1.[C:21]1([P:27](Cl)(Cl)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[NH+]1C=CC=CC=1.Cl>>[CH2:3]([C@@H:2]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C@H:11]([CH2:12][CH3:13])[O:14][P:27](=[O:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:1]1)[CH3:4]
Reactant: CC[C@@H](O)c1ccccc1[C@@H](O)CC
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CC[C@@H]1OP(=O)(c2ccccc2)O[C@H](CC)c2ccccc21

Procedure:
To a solution of (R,S)-1-[2-(1-Hydroxy-propyl)-phenyl]-propan-1-ol (1.0 g, 5.15 mmol) in pyridine (1.22 g, 15.4 mmol) was added under exclusion of moisture phenyl phosphonic acid dichloride (1.0 g, 5.15 mmol). There is an exotherm and instant formation of pyridinium hydrochloride. The mixture was stirred over night. By 31P-NMR of the crude mixture there was complete conversion, and only one of two possible diastereoisomers present. After addition of HCl (5 ml of 4 N solution) the product was extracted with TBME (20 ml).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]([CH3:12])=[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]2=[N:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[CH2:9][CH2:10][C:5]2=[N:4][N:3]([CH3:2])[C:11]([CH3:12])=[C:6]2[CH2:7]1
Reactant: Cc1c2c(nn1C)CCNC2
Reactant: ClCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c2c(nn1C)CCN(CCCCl)C2
Yield: 43.2 %

Procedure:
To a mixture of 2,3-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride (2.0 g, 13.22 mmol, 1.0 eq) and K2CO3 (5.47, 39.66 mmol, 3.0 eq) in 40 mL of acetone was added 1-bromo-3-chloropropane (4.16 g, 26.44 mmol, 2.0 eq). The reaction mixture was heated to reflux for 5.0 h and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 100:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (1.3 g, 44.21%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 228.73 (M+1).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH3:11][C:12]1[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=1[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][C:12]1[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=1[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:21])=[CH:18][CH:17]=1)=[O:15]
Reactant: Cc1ccccc1C(=O)c1ccc(C(=O)O)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.288 g (1.2 mmol) of 4-(2-methylbenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]([CH3:32])[CH2:11][C@H:12]1[CH2:17][N:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:15][CH2:14][NH:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:3]([N:10]([CH2:11][C@H:12]1[CH2:17][N:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:15][CH2:14][N:13]1[C:40](=[O:42])[CH3:41])[CH3:32])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCN[C@@H](CN(C)Cc3ccccc3)C2)cc1OC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](CN(C)Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of (S)—N-benzyl-1-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-2-yl)-N-methylmethanamine dihydrochloride, (Example 42, Compound 130) (96.5 mg, 0.20 mmol) in CH2Cl2 (2 mL) at 0-5 C was treated with triethylamine (84 ul, 0.60 mmol) followed by acetyl chloride (22 uL, 0.30 mmol). The reaction mixture was allowed to warm to room temperature and stir 1 h. After this time the reaction mixture was treated with a saturated aqueous solution of NaHCO3 (1 mL). The organic portion was then dried over MgSO4, filtered, and evaporated to afford quenched with evaporated and the residue purified by silica gel flash chromatography with 100% EtOAc then 5% MeOH/EtOAc as eluant to afford product as an oil (65 mg, 72%). LC/MS (Method B) 2.57 min, [M+1]+ 452. Potency class ND.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][O:10][CH2:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]>O>[OH:8][C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[CH2:9][O:10][CH2:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:7]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc2c(c1)COCO2
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c(COCc2cc([N+](=O)[O-])ccc2O)c1

Procedure:
30 g(0.17 Mol) 6-Nitro-1,3-benzodioxan III are dissolved in 300 ml of certain alcohols. After addition of 15 ml of water 60 ml concentrated sulfuric acid is added dropwise with stirring. The solution is heated under reflux until completely converted to product with the help of a control by thin layer chromatography. After cooling the reaction mixture is mixed with about 200 ml water and the solution is concentrated to about 1/3 of its volume under vacuum. A yellow oil comes down which is extracted with ether. The ether phase is dried by sodium sulfate and the residue is filtered by silica gel with methylene chloride as elution agent. After concentration of the methylene chloride solution light yellow crystals of the corresponding 4-nitrophenol compound precipitate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[C:67]([C:68]#[N:69])=[CH:66][CH:65]=[CH:64][C:63]=3[Cl:70])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:70][C:63]1[CH:64]=[CH:65][CH:66]=[C:67]([C:68]#[N:69])[C:62]=1[N:59]1[C:55]2=[N:56][CH:57]=[N:58][C:53]([O:52][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=3)=[O:43])=[C:54]2[CH:61]=[N:60]1
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1C#N)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cccc(Cl)c1-n1ncc2c(O[C@@H](COCCO)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.611 mL, 0.61 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)propanamide (Intermediate AH1) in THF (5 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (2 mL), diluted with DCM (25 mL) and poured through a phase separator. The organic phase was reduced to give a gum. This was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)-3-(2-hydroxyethoxy)propanamide (194 mg, 61.7%, 84% ee). 1H NMR (400 MHz, DMSO) δ 3.53 (2H, m), 3.70-3.58 (2H, m), 4.05 (1H, m), 4.13 (1H, m), 4.62 (1H, t), 5.95 (1H, s), 7.92-7.86 (2H, m), 8.06-8.00 (1H, m), 8.17 (1H, m), 8.19 (1H, m), 8.42-8.38 (1H, m), 8.61 (1H, s), 8.79 (1H, d), 11.21 (1H, s). m/z (ES+) (M+H)+=514; HPLC tR=2.10 min.