Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[CH:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>C1COCC1>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH:29]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2]#[N:3])=[CH:31][CH:32]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N#CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(C=CCCCCCC#N)cc1
Yield: 71.1 %

Procedure:
This compound was synthesized from 6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) and p-anisaldehyde (2.72 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the products (3.26 g, 71%) as a colorless liquid (bp: 143-146° C./0.05 torr). IR: 2285 cm-1 ; 1H-NMR: 1.50 (m, 6H), 2.30 (m, 4H), 3.80 (s, 3H), 5.50 (m, 1H), 6.30 (d, 1H), 7.05 (q, 4H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][BH:12][O:11]1.C(N(CC)CC)C>C(OCC)C.[H-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2]>[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][B:12](/[CH:5]=[CH:4]/[CH2:3][CH2:2][C:1]([O:7][CH3:8])=[O:6])[O:11]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CCCC(=O)OC
Agent: [Zr+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CC/C=C/B1OC(C)(C)C(C)(C)O1
Temperature: 65 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Methyl pent-4-ynoate (5.0 g, 44.6 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.42 g, 58.0 mmol) were mixed, zirconocene chloride hydride (1.18 g, 4.46 mmol) and triethylamine (0.622 ml, 4.46 mmol) were added and the mixture was stirred at 65° C. overnight. The reaction solution was left to cool and then diluted with diethyl ether, and the precipitated white solid was removed by filtration through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate) to afford the title compound (5.36 g, 50.1%).
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[ClH:3].[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([Cl:5])=[O:30])[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Reaction time: 1.5 h

Procedure:
Thionyl chloride (12.7 cc) is added in the course of 5 minutes, with stirring at a temperature of 4° C., to a suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (9.77 g) in methylene chloride (250 cc), and stirring is continued for 90 minutes at a temperature of 20° C. The clear yellow solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and dried to constant weight under reduced pressure (5 mm Hg; 0.67 kPa) at 50° C. to give 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (10.2 g) in the form of a yellow paste.
Reaction SMILES: [Mg].II.Br[CH:5]1[CH2:8][CH2:7][CH2:6]1.C[C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.[BH4-].[Na+]>C(OCC)C.O1CCCC1.CO>[CH:5]1([CH:16]([C:14]2[CH:15]=[CH:10][C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=3)=[CH:12][CH:13]=2)[NH2:17])[CH2:8][CH2:7][CH2:6]1
Reactant: BrC1CCC1
Reactant: Cc1cc(C#N)ccc1-c1ccc(C(F)(F)F)cc1
Agent: II
Agent: [BH4-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: NC(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C1CCC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 27.1 %

Procedure:
Magnesium (1.86 g, 77.4 mmol) was suspended in diethyl ether (70 mL) and to the suspension was added iodine (17.8 mg, 0.07 mmol). Bromo-cyclobutane (10 g, 70 mmol) was added slowly and the mixture was refluxed for 3 h. To a solution of 4′-(trifluoromethyl)biphenyl-4-carbonitrile (300 mg, 1.21 mmol) (prepared as in Example 1.25 Step A, using 4-bromobenzonitrile) in tetrahydrofuran (3 mL) was added this prepared Grignard (334 mg, 6.06 mL in diethyl ether, 6.06 mmol) at 0° C. under nitrogen. The resulting mixture was heated in a microwave at 100° C. for 1 hr. After that time, methanol (5 mL) and sodium borohydride (91.8 mg, 2.43 mmol) were carefully added at 0° C. After stirring for 5 minutes, the reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were concentrated. Purification by column chromatography (0-6% methanol/dichloromethane) gave cyclobutyl(4′-(trifluoromethyl)biphenyl-4-yl)methanamine (0.100 g, 27%) as a yellow solid. 1H NMR (400 MHz, CD3OD, δ): 7.84 (d, J=8.0, 2 H), 7.77 (dd, J=8.0, J=8.0, 4 H), 7.53 (d, J=8.0, 2 H), 4.27 (d, J=10.4, 1 H), 2.98-2.92 (m, 1H), 2.08-2.06 (m, 1H), 1.86-1.80 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1
Reactant: Oc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2F)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of 2,4-difluorophenol (10 g, 77 mmol), PPh3 (30.2 g, 115 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (30.9 g, 154 mmol) in THF (400 mL) was added DEAD (18.3 mL, 115 mmol) at 0° C. dropwise. After the addition was completed, the resulting mixture was allowed to stir at 40° C. for 16 h. The mixture was poured into water and extracted with EtOAc (3×400 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product. Purification by flash silica gel chromatography, eluting with 80:1 PE:EtOAc, gave tert-butyl 4-(2,4-difluorophenoxyl)piperidine-1-carboxylate as an oil (20 g, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:27]=1)=[CH:15]2
Reactant: N#Cc1cccc(C=O)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3-Cyanobenzaldehyde (0.262 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.0 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2S4. The solvent was evaporated to give a white solid. Recrystallization from methanol gave the product (500 mg), mp 154-155° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:31](O)=[O:32])=[N:11][C:12]([CH2:16][C:17]2([N:22]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=[CH:23]3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:43]([O:50][CH2:51][CH2:52][NH:53][CH3:54])([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O.C(OCC)(=O)C>[Si:43]([O:50][CH2:51][CH2:52][N:53]([CH3:54])[C:31]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([N:22]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=[CH:23]3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:32])([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45]
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reaction time: 1 h
Yield: 87 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (404) (250 mg, 0.56 mmol) in dimethylformamide (5 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.69 mmol) followed by [2-(tert-butyl-dimethylsilanyloxy)-ethyl]methyl-amine (8a) (320 mg, 1.69 mmol) and HATU (320 mg, 0.84 mmol) and stirring was continued for 1 h (TLC, ethyl acetate, Rf=0.5). Water (30 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The organic part was washed with water (2×100 mL) and brine (2×50 mL). The organic phase was thereafter dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 30-40% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) (300 mg, 87%) as a light yellow sticky solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH2:11][CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([Cl:17])=[CH:16][C:8]=2[N:7]=1)([OH:5])[CH3:4].[CH2:19]([SH:21])[CH3:20].C[O-].[Na+]>CO>[Cl:17][C:15]1[C:14]([Cl:18])=[CH:13][C:9]2[N:10]([CH2:11][CH3:12])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:21][CH2:19][CH3:20])=[N:7][C:8]=2[CH:16]=1
Reactant: CCS
Reactant: CCn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSCC(C)(O)c1nc2cc(Cl)c(Cl)cc2n1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-propan-2-ol (161 mg) in methanol (5 mL) at room temperature was added a solution of ethanethiol (37 mg) and sodium methoxide (0.144 mls of 25 wt % in MeOH). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, and dried over Na2SO4. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[CH:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[O:25][CH3:24])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)N(C)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.5 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione with 230 μl (1.5 mmol) of 2-methoxybenzoyl chloride, and after purification, 500 mg (70%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-2-methoxy-N-methylbenzamide are obtained in the form of a white solid with a melting point of 96° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O.O1CCCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[N:18][N:17]=2)=[CH:14][CH:15]=1
Reactant: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)O)cc3)s2)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of methyl 4-[5-[4-(6-methoxy-n-hexyloxy)-phenyl]-1,3,4-thiadiazol-2-yl]benzoate (179.6 g), sodium hydroxide (25.3 g), water (250 ml), methanol (1 L), and tetrahydrofuran (750 ml) was heated under refluxing for 1 hour then cooled to room temperature and poured into water (7 L). The pH of the stirred mixture was adjusted to 2.0 with 6N-hydrochloric acid and the precipitate collected by filtration, washed thoroughly with water, followed by acetonitrile, then dried under hi-vacuum at 50° C. to give 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid (167 g) as a yellow powder.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](=[O:30])[NH:18][CH:19]=[C:20]3[C:25]=2[NH:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[S:21]3)=[CH:12][CH:11]=1>O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:17](=[O:30])[NH:18][CH:19]=[C:20]3[C:25]=2[NH:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[S:21]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2c3c(c[nH]c2=O)Sc2ccccc2N3)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=c1[nH]cc2c(c1-c1ccc(O)cc1)Nc1ccccc1S2

Procedure:
To 10 parts pyridine hydrochloride heated to 170° under a stream of nitrogen is added 0.5 parts of 4-(4-methoxyphenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one in one portion. The reaction mixture is refluxed for 45 minutes, cooled, water is added and the solid which forms is collected and dried to yield 4-(4-hydroxyphenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, m.p. greater than 300°.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].Br[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.O>O1CCCC1>[CH2:3]([O:7][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCO
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCOCc1ccc(C(=O)O)cc1

Procedure:
To the suspension of sodium hydride (1.390 g, 95%, 55 mmol) in tetrahydrofuran (150 ml), But-3-en-1-ol (3.966 g, 4.7 ml, 55 mmol) was added. After the reaction mixture was refluxed for 30 min, 4-Bromomethyl-benzoic acid (5.376 g, 25 mmol) was added and the reaction was kept to reflux for additional 10 h. After cooling down, water (100 ml) was added and the tetrahydrofuran was removed under vacuum. This resulting aqueous solution was adjusted with 6N HCl to pH 2 at 5° C. to generate white precipitate, which was then collected by filtration. The recrystallization of this crude product from hexane/ether yielded pure 4-But-3-enyloxymethyl-benzoic acid as colorless crystal (4.15 g, 80.5%). 1H-NMR (400 MHz, d6-DMSO): 7.91 (d, J=8.2, 2 arom. H); 7.41 (J=8, 2 arom. H); 5.81 (m, —CH═CH2); 5.10 (2 d-like, —CH═CH2); 4.53 (s, —OCH2—C6H4); 3.49 (m, CH2═CH—CH2CH2O); 2.32 (m, CH2═CH—CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.14 (—C═O); 143.72; 135.49; 129.73; 129.28 (2 arom. C); 127.08 (2 arom. C); 116.46; 71.13; 69.18.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].O[N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:17]
Reactant: COCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
2-methoxyethanol (2.00 g, 26.3 mmol), N-hydroxyphthalimide (4.72 g, 28.9 mmol, 1.1 eq., and triphenylphosphine (7.58 g, 28.9 mmol, 1.1 eq.) were dissolved in 85 mL of dry THF and then the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (6.91 g, 34.2 mmol, 1.3 eq.) was dissolved in 15 mL of dry THF and was added slowly to the above mixture. The reaction was stirred in the ice bath for 10 minutes and then the ice bath was removed. The reaction then was allowed to stir at room temperature under N2 overnight. The reaction was done by LC/MS and was concentrated to an oil. It was then purified by flash column chromatography using hexane/ethyl acetate 70/30 to give 2-(2-methoxyethoxy)isoindoline-1,3-dione (2A, 5.19 g, 89.2% yield). ESI-MS: m/z 222.3 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.CC([O-])(C)C.[K+].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](=[O:24])[CH3:23].Cl>C1COCC1.C(OCC)(=O)C.O>[CH2:8]([O:7][C:5](=[O:6])[C:4](=[O:10])[CH2:23][C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)=[O:24])[CH3:9]
Reactant: CC(=O)c1ccco1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)c1ccco1

Procedure:
To a solution of 16 g oxalic acid diethyl ester in 350 ml THF, 10.1 g KOt-Bu were added at 0° C. Then 10 g 1-furan-2-yl-ethanone in 50 ml THF were added dropwise. After 1 h the reaction mixture was diluted with 300 ml ethyl acetate and 200 ml water. This solution was acidified with diluted hydrochloric acid to pH 5. The organic layer was separated, washed with 150 ml water, dried over MgSO4, filtered and concentrated under reduced pressure to yield a white solid.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=2)=[CH:8][CH:7]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[C:24]1([C:23]#[C:22][C:20]2[CH:21]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])=[CH:11][CH:10]=3)[CH:17]=[C:18]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:19]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(OCC#Cc2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of {4-[3-(3,5-bis-phenylethynyl-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester (0.26 g, 0.51 mmol) in THF (5.6 ml) and methanol (1.1 ml) was added a ice-cold solution of LiOH (1 M, 5.6 ml). The reaction mixture was stirred at 0° C. for 45 min., after which water (37 ml) and aqueous HCl (1M, 7.5 ml) were added. The mixture was extracted with ethyl acetate (2×25 ml), and the combined organic phases were dried and evaporated to give the title compound in 240 mg (96%) yield.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13](C(=O)C)[CH2:12][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(F)cc3)nn2Cc2ccccc2)C1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-c2nn(Cc3ccccc3)c3c2CNCC3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A mixture of 1-[1-Benzyl-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (6e) (6.9 g, 20 mmol), ethanol (73 ml) and 10N aqueous HCl (137 ml) was stirred at 80° C. for 2 h and then overnight at room temperature. The mixture was concentrated in vacuo and the product was filtrated off and washed with a small amount of cold water to give 4.87 g of 1-Benzyl-3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; hydrochloride (7b).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]([N:21]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:20])[CH2:14][CH2:13][CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[CH3:39][N:38]([CH3:40])[C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:21]([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([CH3:29])[CH3:30])=[CH:26][CH:27]=2)[C:19]([CH:15]2[C:16]3[C:11](=[CH:10][C:9]([OH:8])=[CH:18][CH:17]=3)[CH2:12][CH2:13][CH2:14]2)=[O:20])=[CH:33][CH:34]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(OCc4ccccc4)ccc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(O)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.9 %

Procedure:
To a solution of 6-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) in methanol (8.6 mL) were added 10% palladium-carbon (0.09 g) and ammonium formate (0.44 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was filtrated, and the solvent was evaporated. The obtained crude crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to give N-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.23 g). melting point: 169-171° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:28]=[CH:27][C:24](C=O)=[CH:23][CH:22]=2)[CH:5]=[CH:6][CH:7]=1.OO.S(=O)(=O)(O)[OH:32]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:22]=[CH:23][C:24]([OH:32])=[CH:27][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3cccc(F)c3)ccc2c1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(O)cc3)c(-c3cccc(F)c3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
Charge a 100 mL round-bottom flask with 4-[2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-benzaldehyde (2.5 g, 6.71 mmol) and ethyl acetate (5 mL). At room temperature add 2 mL of 35% hydrogen peroxide. To this solution slowly add 2 mL of concentrated sulfuric acid. The mixture warms to approximately 40° C. and returns to room temperature where it is stirred for 2 hours. Dilute the reaction with water and ethyl acetate (100 mL) and dry the organic layer over sodium sulfate, filter and concentrate in vacuo. Purify the crude product using radial chromatography eluting with CH2Cl2 to yield 540 mg (22%) of the title compound: mass spectrum (ion spray) m/z=359 (M−H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[CH2:34][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 78 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.