Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O>CN(C)C(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:17]2[C:18]3[C:10]4[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:31]=[CH:32][N:33]=[C:2]([N:38]6[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]6)[CH:3]=5)[CH:30]=[CH:29][C:11]=4[CH2:12][CH2:13][C:14]=3[C:15]([C:26]([NH2:28])=[O:27])=[N:16]2)=[CH:20][CH:21]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3ccnc(Cl)c3)cc1-2
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCN(c2cc(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(F)cc3)CC4)ccn2)CC1
Temperature: 100 °C
Reaction time: 88 h

Procedure:
The material from step 1 (2.17 mmoles) and N-methyl piperazine (32.9 mmoles) were dissolved in 5.0 mL N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100° C. for 88 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was then dissolved in acetonitrile, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The solvent was stripped, then the solid residue was recrystallized from acetonitrile. Mp: 277-279° C. 1H NMR (400 MHz, d6-DMSO): δ 2.17 (s, 3H); 2.35 (t, 4H, J=5 Hz); 2.82-2.95 (m, 4H); 3.47 (t, 4H, J=5 Hz); 6.85 (d, 1H, J=5 Hz); 7.01 (s, 1H); 7.21-7.44 (m, 6H); 7.50-7.59 (m, 3H); 8.16 (d, 1H, J=5 Hz); 10.10 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 20.32, 29.69, 45.20, 46.46, 55.00, 105.43, 111.23, 115.50, 117.07, 117.30, 120.66, 121.37, 126.54, 128.60, 128.69, 129.48, 133.36, 136.82, 136.85, 137.70, 139.71, 143.19, 144.36, 148.89, 159.88, 161.37, 163.81, 164.44, 165.15. M+1=526.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(Br)cc3o2)CC1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(-c4ccc(S(C)(=O)=O)cc4F)cc3o2)CC1
Yield: 17 %

Procedure:
Following the General Procedure-1, the titled compound (21 mg) was prepared from Intermediate 10 (100 mg, 0.26 mmol) and Intermediate 3 (102 mg, 0.34 mmol) as an off-white solid. M.P.: 174-178.3° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85-7.75 (m, 3H), 7.73-7.64 (m, 2H), 7.50 (d, J 8.2, 1H), 4.15 (d, J 12.4, 2H), 3.20-3.10 (m, 4H), 3.0 (t, J 12.5, 2H), 2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.C(O)(=O)C.[CH2:23]([NH2:25])[CH3:24]>C1(C)C=CC=CC=1>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:25][CH2:23][CH3:24])=[O:4]
Reactant: CCN
Reactant: COC(=O)CC[C@H](N)C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Yield: 3.7 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 45 g of toluene. To this, 15 g (233 mmol) of acetylacetone and 5.6 g (93 mmol) of acetic acid were added. The mixture was heated for 2 hours while removing water generated by use of an ester tube at 100° C. to 110° C. The solvent was removed to obtain 7.9 g of a yellow oily substance. To the oily substance, 13.5 g (210 mmol) of 70% ethylamine was added and allowed to react for 23 hours. The same procedure as in Example 1 was performed to obtain 0.2 g of theanine (yield: 5.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(Cc2ccccc2N2CCN(c3ccncc3)CC2)cc1
Reaction time: 18 h
Yield: 2 %

Procedure:
A solution of N-(4-pyridyl)piperazine (8.15 g), 4,4′-difluorobenzophenone (13.1 g) and powdered potassium carbonate (9.12 g) was stirred at 95° C. in DMSO (100 ml) overnight. The solution was poured into water (1500 ml) to give a precipitate which was filtered, washed with water and dried. The solid (7.82 g) was stirred in trifluoroacetic acid (25 ml) under argon with triethylsilane (10 ml) for 18 hours. The solution was poured into water (315 ml), taken to pH 12 with sodium hydroxide solution and extracted with dichloromethane (2×300 ml). The combined dichloromethane extracts were washed with water, dried (Na2SO4) and evaporated to give a residue which was purified by chromatography on alumina (ICN Alumina N 32-63) using 0.5% methanol in dichloromethane as eluant. The solid obtained was recrystallised from a mixture of ethyl acetate/isohexane to give 1-(4-fluorobenzylphenyl)-4-(4-pyridyl)piperazine (350 mg) as a solid, m.p. 110-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH3:24])=[O:34]
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl isocyanate (54 mg) was added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (6/4) to give 111 mg (yield 77%) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:12])[CH2:5][CH2:4][C@@H:3]1[NH:13][CH2:14][CH2:15][CH3:16].I[CH2:18][CH2:19][CH3:20].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C(#N)C>[CH3:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:12])[CH2:5][CH2:4][C@@H:3]1[N:13]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16]
Reactant: CCCI
Reactant: CCCN[C@H]1CCc2cccc(Br)c2[C@H]1C
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CC#N
Product: CCCN(CCC)[C@H]1CCc2cccc(Br)c2[C@H]1C
Temperature: 50 °C
Yield: 19.6 %

Procedure:
To a solution of cis-1-Methyl-2-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.47 gm, 5.2 mMol) in acetonitrile (30 mL) were added 1-iodopropane (.59 mL, 5.8 mMol) and proton sponge (2.2 gm, 10.4 mMol), and the mixture was stirred at 50° C. for eighteen hours. The colorless suspension was filtered and the filtrate concentrated in vacuo to give a light yellow oil. Purification by flash chromatography (20% diethyl ether in hexane+tr. NH4OH) gave the desired compound as a colorless glass (330 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:10].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 103.4 %

Procedure:
To a stirred solution of methyl 3-chloro-4-[N′-(2-methylphenyl)ureido]phenylacetate (1.23 g, 3.70 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried over 60° C. for 2 days under a reduced pressure to give 3-chloro-4-[N′-(2-methylphenyl) ureido]phenylacetic acid (1.22 g, 100%) as colorless powder. 1H-NMR (DMSO-d6) δ .26 (s, 3H), 3.40 (s, 2H), 6.95 (t, J=7.3 Hz, 1H), 7.11 (d, J=7.6 Hz, 2H), 7.16 (d, J=7.3 Hz, 1H), 7.32 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.94 (dd, J=9.3, 1.0 Hz, 1H), 8.72 (s, 2H); MS (ESI) m/z 319 (M++1), 321 (M++3), 341 (M++Na).
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][CH3:15])[N:8]=1>CN(C)C=O>[Cl:6][C:7]1[CH:12]=[C:11]([O:2][CH3:1])[N:10]=[C:9]([S:14][CH3:15])[N:8]=1
Reactant: CO
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(SC)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.4 %

Procedure:
3.86 g of 28% sodium methoxide methanol solution was added dropwise over 20 minutes to a solution of 3.9 g of 4,6-dichloro-2-methylthiopyrimidine in 20 ml of N,N-dimethylformamide at 0° C. Then the mixture was stirred at room temperature for 7 hours. 20 g of ice was added to the mixture, then white precipitate was collected by suction filtration, and the solid was washed with water. The solid was dissolved in ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 3.18 g of 4-chloro-6-methoxy-2-methylthiopyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][CH:20]=1)[CH3:18].[CH3:30]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([NH:16][C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:28])[CH3:29])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:13])[C:6]=2[C:14]=1[F:15]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)Cn1cnc2ccc(Cl)c(F)c21
Reactant: CC(N)c1ccc(C(C)(C)C#N)cc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc([C@H](C)NC(=O)Cn2cnc3ccc(Cl)c(F)c32)ccc1C(C)(C)C#N
Yield: 159.6 %

Procedure:
To a solution of (6-chloro-7-fluoro-1H-benzimidazol-1-yl)acetic acid (100 mg, 0.44 mmol) prepared according to scheme 13, (S) (−)-2-{4-[1-aminoethyl]phenyl}-2-methylpropanenitrile (88.5 mg 0.44 mmol) prepared according to scheme 20 or 21 and DMAP (106 mg, 0.88 mmol) stirred in anhydrous DMF (2.0 mL) is added HATU (166 mg, 0.44 mmol) after 18 hours of stirring, the mixture is diluted with methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (S)-(−)-2-(6-chloro-7-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (290 mg, 53%) as a clear solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.50 (d, J=7.03 Hz, 3H) 1.69 (s, 6H) 5.03 (q, J=7.01 Hz, 1H) 5.07-5.18 (m, 2H) 7.29 (dd, J=9.37, 6.64 Hz, 3H) 7.39 (d, J=8.59 Hz, 2H) 7.44 (d, J=9.37 Hz, 1H) 7.48 (d, J=8.59 Hz, 2H) 8.14 (s, 1H) MS [M+H], calcd: 399.1. found: 399.2, [α]D=−138° (C=0.5 METHANOL)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:13]Br.O>C(O)(=O)C>[Br:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9][NH:10][CH:11]=1
Reactant: BrBr
Reactant: Clc1ccc(-c2cc[nH]n2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(-c2n[nH]cc2Br)cc1
Yield: 100 %

Procedure:
1.5 g (0.0084 mol) of 3-(4-chlorophenyl)-1H-pyrazole, prepared in the above example (19), are dissolved, at room temperature and with stirring, in 25 ml of acetic acid. 1.6 g (0.01 mol) of bromine are then run in dropwise while maintaining the temperature below 30° C. Stirring is maintained for 30 hours 30 min and then the reaction mixture is poured into water. The precipitate is filtered and washed with water and heptane. 2.1 g (0.0084 mol) (yield: 100%; melting point: 143° C.) of 4-bromo-3-(4-chlorophenyl)-1H-pyrazole are obtained.
Reaction SMILES: C([O:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])C.[Se](=O)=O.[O:16]1CCO[CH2:18][CH2:17]1>O.C(OCC)(=O)C>[CH2:17]([O:16][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:5]([CH:4]=[O:3])=[O:6])[CH3:18]
Reactant: C1COCCO1
Reactant: CCOCC(=O)c1ccccc1
Agent: O=[Se]=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccccc1C(=O)C=O

Procedure:
2 g of 2-ethoxyacetophenone are dissolved in 20 ml of dioxane, and a solution of 2 g of selenium dioxide in one ml of water is added thereto. The solution is refluxed for 10 hours. After the reaction, insoluble materials are removed by filtration, and the filtrate is concentrated. The residue thus obtained is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and then with an aqueous sodium bicarbonate solution and water. Then, said solution is dried and evaporated to remove solvent. 2.1 g of 2-ethoxyphenylglyoxal are obtained as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:24][C:25]1[N:29]=[C:28]([NH2:30])[S:27][N:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)/[C:13]([NH:30][C:28]2[S:27][N:26]=[C:25]([CH3:24])[N:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Reactant: Cc1nsc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nsc(NC(=O)/C(=N/OC2CCCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (prepared as in Example 9, 112 mg, 0.31 mmol), 3-methyl-[1,2,4]thiadiazol-5-ylamine (36 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-acetamide (57 mg, 40%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H21ClN4O4S2 [M+] 456.07, found 457 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.25-1.64 (m, 6H, 3×CH2), 1.73 (m, 2H, 2×CH of CH2), 2.00 (m, 2H, 2×CH of CH2), 2.60 (s, 3 H, ArCH3), 3.31 (s, 3 H, SO2CH3), 4.37 (m, 1 H, OCH), 7.64 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.74 (d, Jm=1.5 Hz, 1 H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.35 (s, 1 H, NH).
Reaction SMILES: [NH4+:1].[Cl-:2].C[Al](C)C.[C:7]1([CH2:17][C:18]#[N:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[ClH:2].[C:7]1([CH2:17][C:18]([NH2:1])=[NH:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: N#CCc1cccc2ccccc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cl
Product: N=C(N)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a stirred suspension of NH4Cl (1.6 g, 30 mmol) in anhydrous toluene (50 mL) was added trimethyl aluminium (2M in toluene, 15 mL, 30 mmol) at 0° C. The mixture was then warmed to room temperature and stirred for 2 h. A solution of 2-(naphthalen-1-yl)acetonitrile (1.67 g, 10 mmol) in toluene (10 mL) was added to the above reaction mixture and the reaction mixture was stirred at 80° C. for 18 h. After completion of the reaction, the reaction mixture was quenched with a suspension of silica gel in chloroform. The mixture was stirred at room temperature for 0.5 h before being filtered through a sintered funnel. The silica gel was washed with methanol. The combined filtrate was concentrated under reduced pressure to give the crude product as an off-white solid (2 g, 91%), which was used directly without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:20])=[C:8]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.CCS.[Al](Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:20])=[C:8]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)c(-c3ccncc3)c(=O)oc2c1
Agent: Br[Al](Br)Br
Solvent: ClCCl
Solvent: CCS
Product: Cc1c(-c2ccncc2)c(=O)oc2cc(O)ccc12
Temperature: 25 °C

Procedure:
To a solution of 7-methoxy-4-methyl-3-pyridin-4-yl-chromen-2-one (600 mg, 2.24 mmoL) in CH2Cl2 (10 mL) at 0° C. was added EtSH (˜1 mL) followed by AlBr3 (6.74 mmoL, 1.80 g). The mixture was slowly warm to room temperature and poured into ice sat. NaHCO3 solution. Extraction was conducted 3× with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was then purified by silica gel column chromatography using hexanes:ethyl acetate 1:1 as eluent to afford the title product as pale yellow solid.
Reaction SMILES: CS[C:3]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5]>CO.[Ni]>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:18]=[CH:17]2
Reactant: COC(=O)C(C)(SC)c1ccc2cc(OC)ccc2c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
Methyl α-methylthio-α-(6-methoxy-2-naphthyl)propionate (372 mg) was dissolved in 2 ml of methanol, and 10 ml of a methanol suspension of 5.0 cc of Raney nickel (W-II) was added, and the mixture was stirred at room temperature for 15 hours. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. Methylene chloride was added to the residue. The insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was chromatograhed on a silica gel column using benzene as an eluent to afford 212 mg of methyl α-(6-methoxy-2-naphthyl)propionate as colorless crystals in a yield of 68%. The product had a melting point (from petroleum ether) of 67° to 69° C. The IR and NMR spectra of this product coincided with those of the authentic sample.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH:2]=1.N#CBr.C([OH:19])C>>[NH:9]1[C:8]2[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]([CH:4]=[CH:5][CH:6]=[O:19])=[CH:2]1
Reactant: CCO
Reactant: Nc1ccccc1-c1cccnc1
Agent: N#CBr
Product: O=CC=Cc1c[nH]c2ccccc12

Procedure:
To a solution of 10.0 g of 2-(pyridin-3-yl)aniline (58.7 mmol) in 100 mL ethanol is slowly added 6.2 mL of cyanogen bromide (12.4 g, 118 mmol). The reaction is heated to reflux for 1 hour, monitoring by TLC (silica, hexanes:ethyl acetate 1:1) for formation of the Zincke salt. The reaction is then quenched via addition of 50 mL saturated NH4Cl, and extracted with 3×50 mL dichloromethane. The combined organic layers are washed 3×100 mL saturated NH4Cl, followed by drying over anhydrous Na2SO4 and removal of the solvent. The crude residue is further purified via column chromatography over silica, using a hexanes-ethyl acetate gradient.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:12][N:11]=[C:10]([S:21][CH3:22])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH3:24])[C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:12][N:11]=[C:10]([S:21][CH3:22])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CSc1ncc(-c2ccccc2C)c(NC(=O)OC(C)(C)C)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CI
Product: CSc1ncc(-c2ccccc2C)c(N(C)C(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 2.45 g (7.40 mmol) (2-methylsulfanyl-5-o-tolyl-pyrimidin-4-yl)-carbamic acid tert.-butyl ester in 30 ml N,N-dimethylformamide 0.44 g (11.09 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.74 ml (11.83 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. The reaction mixture was distributed between 75 ml H2O, 75 ml brine and 75 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 75 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 2.50 g (98%) methyl-(2-methylsulfanyl-5-o-tolyl-pyrimidin-4-yl)-carbamic acid tert.-butyl ester as a colorless oil, MS (TSP): 345 (M+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([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.[F:36][CH:37]([F:44])[C:38](N(OC)C)=[O:39].C1COCC1>CC(OC)(C)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:38](=[O:39])[CH:37]([F:44])[F:36])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Reactant: CON(C)C(=O)C(F)F
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)F)c(F)c2F)C[C@@H](C)O1

Procedure:
Starting materials (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 43) and 2,2-difluoro-N-methoxy-N-methylacetamide (MTBE was used as solvent instead of THF).