Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH:18]=[C:17]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)CC1=Cc2c(cccc2-c2ccc(C(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
50 g (150 mmole) 7-(4′-tert-Butyl-phenyl)-2-(2,2-dimethyl-propyl)-indan-1-one were dissolved in 180 ml toluene in a 500 ml-roundbottom flask equipped with a reflux condenser. 6.22 g (1.1 eq.) sodium borohydride were added. Then 26.1 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 4 h at 50° C. Another 3.11 g sodium borohydride and 10.3 g methanol were added and the mixture was stirred at 50° C. overnight. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 300 ml of toluene. After addition of 1 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and recrystallization from 500 ml ethanol afforded 35.3 g (74%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.47 (s, 4H, aromatic), 7.34 (d, 1H, aromatic), 7.25 (d, 1H, aromatic), 7.16 (t, 1H, aromatic), 6.72 (s, 1H, C═CH), 3.44 (s, 2H, benzylic), 2.36 (s, 2H, CH2-t-Bu), 1.37 (s, 9H, Ph-t-Bu), 0.96 (s, 9H, CH2-t-Bu) ppm.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:32]3[CH2:33][O:30][CH2:31]3)[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C2COC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (21 mg, 0.046 mmol, racemic intermediate from Example 2, Step 1), oxetan-3-one (from Synthonix, 3.6 mg, 0.050 mmol), and triethylamine (20 μL, 0.14 mmol) in methylene chloride (0.32 mL) was added resin of sodium triacetoxyborohydride (40 mg, 0.091 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was filtered and concentrated and then purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2 mg, 9.9%). The product was isolated as a racemic mixture. LCMS calculated for C22H28ClN6O2 (M+H)+: m/z=443.2; Found: 443.1.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][C:15](=[O:35])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[C:24]([Cl:33])=[C:23]([F:34])[CH:22]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([O:14][C:15](=[O:35])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([F:34])[C:24]([Cl:33])=[C:25]([C:27]#[CH:28])[CH:26]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1cc(CCCCNC(=O)OCc2ccccc2)cc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(CCCCNC(=O)OCc2ccccc2)cc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
K2CO3 (2.76 g, 20 mmol, 2 eq.) was added to a solution of 4a (4.50 g, 10.36 mmol, 1 eq.) in degassed MeOH (200 mL). The suspension was stirred at room temperature for 30 min. before concentration. The residue was partitioned between EtOAc (200 mL) and brine (200 mL). The EtOAc layer was separated and washed further with brine (100 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (0-50%, EtOAc in heptane) to afford 5a as a colorless oil (3.60 g, 96%).
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH2:24]>>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH:24][C:3]1[CH:2]=[C:1]([NH:17][C:14]2[CH:13]=[C:12]([CH3:11])[NH:16][N:15]=2)[N:10]=[C:1]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: NCC1CCCO1
Reactant: N#CC=Cc1ccccc1
Product: Cc1cc(Nc2cc(NCC3CCCO3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 164 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and (tetrahydrofuran-2-yl)methanamine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:8]([NH:9][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:22][CH:23]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
To a solution of phenylethylamine (14.0 g, 14.6 mL, 0.11 mol) and DIEA (20.1 mL, 0.11 mol in DCM (500 mL) at 0° C. was added 4-(trifluoromethyl)benzoyl chloride (17.2 mL, 0.11 mol) dropwise. After the addition was completed, the reaction mixture was stirred at 0° C. and warmed up itself to RT for 16 h. An off-white solid precipitated was observed. The off-white solid was collected by filtration. The solid was then washed with DCM (2×50 mL), and dried under vacuum to give the title compound as a white solid. MS (ESI, positive ion) m/z: 294 (M+H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][O:32]COC)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Br)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[O:24][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:22][C:21]=1[CH2:31][OH:32])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](OCc1oc(-c2ccccc2)nc1CO)(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-tert-butyldiphenylsilyloxymethyl-4-methoxymethoxymethyl-2-phenyl-1,3-oxazole (20.0 g) and chloroform (250 mL) added dropwise trimethylsilyl bromide (25.0 g) at −40° C. The reaction mixture was stirred at −40° C. for 30 min, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give [5-(tert-butyldiphenylsilyloxymethyl)-2-phenyl-1,3-oxazol-4-yl]methanol. Recrystallization from hexane-ethyl acetate gave colorless crystals (10.2 g, yield 56%). melting point: 95-96° C.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[O:16].[CH:29](N1CCCCC1)=[O:30].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([CH:29]=[O:30])=[CH:20][C:21]=1[NH:22][C:23](=[O:28])[C:24]([F:25])([F:26])[F:27])=[O:16]
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: O=CN1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1sc(C=O)cc1NC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 1.6M n-BuLi solution in hexane (12 mL) was added dropwise to a solution of diisopropylamine (2.9 mL) in THF (30 mL) at −78° C. The reaction mixture was stirred at 0° C. for 10 min and then cooled to −78° C., and a solution of 3-(2,2,2-trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester (1.5 g) in THF (15 mL) was added. The reaction mixture was stirred at −78° C. for 30 min and then 1-formylpiperidine (4 g) was added, and the mixture was again stirred at this temperature for 1.5 h. Subsequently, saturated ammonium chloride solution was added and the reaction mixture was allowed to reach room temperature. The aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. The product with the molecular weight of 281.0 (C9H6F3NO4S) was obtained in this way; MS (ESI): 282 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:35]=[CH:34][C:33]([CH2:36]OS(C)(=O)=O)=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:33]2[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1ccc(Cl)nc1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3ccc(Cl)nc3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with methanesulfonic acid 6-chloro-pyridin-3-ylmethyl ester (described in Journal of Organic Chemistry (1999), 64(23), 8576-8581) gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[OH:18])[CH3:2].S(=O)(=O)(O)[OH:20]>[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[OH:18])(=[O:20])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1nnc2ccc(CC)cc2c1O
Agent: [Cr+6]
Agent: [O-2]
Product: CCOC(=O)c1nnc2ccc(C(C)=O)cc2c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of ethyl 6-ethyl-4-hydroxycinnolin-3-yl carboxylate (5.0 g.) in concentrated sulphuric acid (30 ml.) was stirred at 10° C. as chromium trioxide (6.0 g.) was added. The solution was stirred at room temperature for 5 hours and then was poured onto cracked ice. The resulting aqueous solution was extracted with ethyl acetate (4 × 250 ml.), and the combined extracts were shaken with excess sodium bisulphite solution to extract ketonic material as the bisulphite compound. The aqueous bisulphite solution was washed with ethyl acetate (2 × 250 ml.), and then treated with excess 40% v/v formaldehyde in water and sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate (3 × 250 ml.) and the combined extracts were dried (MgSO4), and filtered. Evaporation of the filtrate yielded a solid residue which on recrystallisation from a mixture of ethanol and ether gave ethyl 6-acetyl-4-hydroxycinnolin-3-yl carboxylate, m.p. 250°-252° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1CBr
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of 2-(4-Methoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.41 g, 5.09 mmol), N-bromosuccinimide (951 mg, 5.34 mmol) and benzoyl peroxide (62 mg, 0.25 mmol) in carbon tetrachloride (20 mL) was refluxed for 15 h before it was cooled to room temperature and partitioned between dichloromethane and water, the organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (1.71 g): MS: (+) m/z 355.96, 357.96 (M+1, 79Br/81Br).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)[N:17]=[C:18]([C:19]3[CH:34]=[CH:33][C:22]([NH:23][CH2:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:26])=[CH:21][CH:20]=3)[C:11]=12.[BH4-].[Na+]>CO>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:35]3[CH2:36][CH2:37][C@@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:39][CH2:40]3)[N:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([NH:23][CH2:24][CH:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[OH:26])=[CH:33][CH:34]=3)[C:11]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NCC(=O)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NCC(O)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A solution of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1-phenyl-1-ethanone diacetate (0.050 g, 0.000077 mol) in anhydrous methanol (5 mL) was cooled to 0° C. and sodium borohydride (0.018 g, 0.0000477 mol) was added at once. The mixture was allowed to warm up to ambient temperature while stirring under an atmosphere of nitrogen for three hours. The reaction was quenched by dropwise addition of acetic acid, the reaction mixture was concentrated under reduced pressure and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1 M ammonium acetate over 25 min, 21 mL/min) to yield cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1-phenyl-1-ethanol diacetate (0.035 g, 0.000054 mol) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[C:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)#[N:29]>CN(C=O)C>[Cl-:1].[C:28]([C:30]1[CH:31]=[N+:32]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH:33]=[CH:34][CH:35]=1)#[N:29]
Reactant: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: N#Cc1cccnc1
Solvent: CN(C)C=O
Product: N#Cc1ccc[n+](Cc2ccc(NC(=O)C3=Cc4cc(-c5ccccc5)ccc4CC3)cc2)c1
Product: [Cl-]
Temperature: 70 °C
Reaction time: 24 h
Yield: 28.4 %

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg), and to the mixture was added 3-cyanopyridine (133 mg). The mixture was stirred at 70° C. for 24 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 3-cyano-1-[4-(7-phenyl-3,4-dihydro-naphthalene-2-carboxamido)benzyl]pyridinium chloride (Compound 22) (58 mg) as pale orange crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13]>ClCCl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:12](=[O:13])[CH2:11][Cl:10]
Reactant: COC(CN)OC
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(CNC(=O)CCl)OC
Yield: 62.7 %

Procedure:
A mixture of 105.1 grams (g) (1.0 moles) of aminoacetaldehyde dimethyl acetal, 80 g (1.0 moles) of a 50% aqueous solution of sodium hydroxide, and 200 ml dichloromethane are placed in a 1 liter flask fitted with a stirrer and thermometer. To this is added 113.0 g (1.0 moles) of chloroacetyl chloride dropwise with rapid stirring at 0°-10° C. After the addition is complete, the reaction is allowed to rise to room temperature and is stirred for 1 hour. Next the mixture is washed with 100 ml water, 100 ml sodium carbonate solution and 100 ml water, followed by drying and evaporation to give 113.8 g (63% yield) of the title compound, m.p. 33°-36° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:13]=[C:14]([CH2:21][OH:22])[C:15]([CH2:19][OH:20])=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C>ClCCl.ClCCl.CS(C)=O>[CH3:18][C:17]1[CH:16]=[C:15]([CH:19]=[O:20])[C:14](=[CH:13][C:12]=1[CH3:11])[CH:21]=[O:22]
Reactant: Cc1cc(CO)c(CO)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C=O)c(C=O)cc1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
To a solution of oxalyl chloride 2M in dichloromethane (DCM) (26.5 mL, 53.0 mmol, 2.2 molar equivalents) cooled to −78° C. was added dropwise a solution of dimethylsulfoxide (DMSO) (7.5 mL, 105.8 mmol; 4.4 molar equivalents) in DCM (10 ml). The solution was stirred at −78° C. for 5 min and 4,5-dimethylbenzene-1,2-dimethanol (4.0 g, 24.1 mmol, 1.0 molar equivalent) dissolved in a mixture of DCM-DMSO (2 ml-4 ml) was added dropwise. The solution was stirred for 1 h at −78° C. and triethylamine (20 mL) was slowly added at −78° C. The reaction mixture was stirred 10 minutes at −78° C. and slowly warmed up to room temperature. Ice-cold water (100 ml) was added to the reaction mixture and the aqueous layer extracted with DCM (3×100 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated in vacuum to give a brown oil. Purification by column chromatography on silica gel (eluent: hexane-ethyl acetate 8/2) gave the title compound as white needles (3.2 g, 82%). 1H NMR (300.13 MHz, CDCl3) (ppm) 2.42 (s, 6H) 7.73 (s, 2H) 10.50 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].[NH4+:15].[Cl-].C[CH2:18][O:19][C:20]([CH3:22])=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:2]1[CH:3]=[C:4]([CH:5]=[CH:22][C:20]=1[O:19][CH3:18])[C:8]#[N:15])[OH:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: [NH4+]
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, to a suspension of 3.57 g of 5-chloroisatin in THF (100 ml) was added 865 mg of NaH under ice cooling and the reaction mixture was stirred for one hour. Thereafter, the solution prepared beforehand was added dropwise. The solution was stirred at the same temperature for two hours, then, a saturated aqueous solution of NH4Cl and EtOAc were added and liquid separation was performed; the organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/1 to MeOH/CHCl3=1/9; v/v) to obtain 460 mg of the title compound (colorless solid).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:25][NH:26][CH3:27].[CH2:28]=O>C(O)(=O)C>[CH3:25][N:26]([CH2:28][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:27]
Reactant: O=C(CCCCS(=O)(=O)c1ccccc1)N1CCc2ccoc2C1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)CCCCS(=O)(=O)c1ccccc1)CC2
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.300 g (0.863 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-5-phenylsulfonylpentan-1-one in 20 ml of acetic acid, 0.117 ml (1.29 mmol) of 50% aqueous dimethylamine and 0.105 ml (1.29 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 20 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 1N aqueous sodium hydroxide 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 (chloroform to chloroform/methanol=50/1) to yield the desired product.