Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5]1.[CH3:23][O:24][CH2:25]Cl>O1CCCC1>[CH3:23][O:24][CH2:25][N:10]1[C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[N:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:6][CH2:5][C:4]1=[O:3]
Reactant: COCCl
Reactant: COc1ccc2c(c1)NC(=O)CCN2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN1C(=O)CCN(c2ccccc2)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 86.8 %

Procedure:
Under argon atmosphere, 60% sodium hydride (1.12 g) was suspended in tetrahydrofuran (10 ml), a solution of 2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (5.0 g) in tetrahydrofuran (50 ml) was added thereto under ice-cooling, and the mixture was stirred for 40 minutes at same temperature. After ice bath was removeded, methoxymethyl chloride (2.25 g) was added, the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into ice-water, extracted with methylene chloride. The organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 5.05 g of the titled compound as yellow-brown crystals (Yield: 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.C(O)(=[O:14])C.C(OCC)(=O)C.OO>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:14])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: CC(=O)O
Agent: OO
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cc(Br)cnc1F
Temperature: 35 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of 1.36 g (6.18 mM) of 5-bromo-2-fluoro-3-pyridineboronic acid in a mixture of 9.5 ml of ethanol, 2.3 ml of acetic acid and 1.3 ml of ethyl acetate is prepared. 2.2 ml of 30% hydrogen peroxide are added to the solution. The reaction mixture is stirred at a temperature of 35° C. for 3 hours and then cooled and extracted with ethyl ether. The organic phases are washed with a solution of ferrous ammonium sulfate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solid residue is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (9/1; v/v) as the eluent to give the desired product in the form of a white solid with a yield of 62%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14]O)=[CH:5][CH:4]=1.O1CCCC1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH2:14][C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(-c2oncc2CO)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2oncc2CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a mixture of 5-(4-methylthiophenyl)-4-isoxazolylmethanol (7.35 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionyl chloride (5.93 g) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(4-methylthiophenyl)isoxazole (7.70 g, yield 97%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio) and recrystallized from diethyl ether-hexane to give a colorless prism. melting point: 73–74° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5](=[CH:9]N(C)C)[C:6](=O)[CH3:7])[CH3:2].Cl.[N:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[N:22][N:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[C:6]=1[CH3:7])=[O:13])[CH3:2]
Reactant: NNc1ccncc1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccncc2)c1C
Yield: 76 %

Procedure:
Dissolve 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (0.550 g, 2.96 mmol), pyridin-4-yl-hydrazine hydrochloride (0.454 g, 3.12 mmol) and triethylamine (0.435 mL, 3.12 mmol) in ethanol (12 mL) and reflux for 2 hr. Evaporate the mixture then dilute with saturated sodium bicarbonate and extract 3 times with ethyl acetate. Dry (sodium sulfate) the solution, filter and concentrate. Purify using silica gel chromatography, eluting with 50:50 ethyl acetate:hexane to give 5-methyl-1-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester as a tan solid (0.520 g, 76%). MS (ES): m/z=232 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:18]2[CH:19]=[C:14]([Cl:13])[N:15]=[CH:16][N:17]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2c(Cl)nc3ccccc32)ncn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the solution of 2-Chloro-1H-benzoimidazole (3.0 g, 19.67 mmol) in 10 mL DMF at 0° C. under argon atmosphere is added with sodium hydride (60% dispersion in mineral oil, 1.18 g, 29.5 mmol) portion wise. After 20 minutes, 4,6-dichloro-pyrimidine (3.3 g, 22.1 mmol) is added. The resulting reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction mixture is treated with 120 mL water and extracted three times with 100 mL dichloromethane. The organic extracts are washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% EtOAc/hexanes to 20% EtOAc/hexanes gradient), affords the title compound as a white powder: Rf=0.35 (20% EtOAc/hexanes); 1H NMR 400 MHz (DMSO-d6) δ 9.26 (s, 1H), 8.25 (s, 1H), 7.80-7.72 (m, 2H), 7.43-7.37 (m, 2H); MS m/z 265.1 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1.Cl>CN(C=O)C.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[N:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 13.3 %

Procedure:
Sodium hydride (0.653 g, 60% in mineral oil, 16.338 mmol) was suspended in DMF (10 mL) under argon, and 4-fluorophenol (0.915 g, 8.169 mmol) added in two portions. The mixture was stirred for 20 minutes then ethyl 6-chloro-3-pyridinecarboxylate (1.515 g, 8.169 mmol) was added together with additional DMF (4 mL) added to aid solubility. The mixture was heated to 80° C. for 2.5 h. The reaction mixture was allowed to cool to room temperature and water (30 mL) was added. The solution was acidified to pH 3 with 2M HCl and extracted with ethyl acetate (×3). The combined ethyl acetate layers were dried and concentrated to produce a brown oil. The crude product was purified by chromatography. Elution with a 0-25% Et2O/petroleum ether gradient gave the title compound as a colourless oil (0.284 g). δH (CDCl3, 400 MHz) 8.81 (1H, dd), 8.28 (1H, dd), 7.11 (4H, m), 6.95 (1H, d), 4.37 (2H, q), 1.38 (3H, t). MS (ES): MH+ 262.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>[Cu]=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: O=[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Nc1nc(Cl)cc(-c2ccccn2)n1)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
200 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 0.22 ml 2-(tributylstannyl)pyridine, 55 mg of copper oxide and 81 mg of tetrakis(triphenylphosphine)palladium were added in turn to degassed toluene, and the mixture was stirred at 110° C. for 4 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 63 mg of the objective compound as colorless oil.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[NH:37][NH2:38])[CH:30]=[CH:29][N:28]=1>>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:38]2)[CH:30]=[CH:29][N:28]=1
Reactant: NNc1cccc2ccncc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Product: CN(C)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4ccncc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and isoquinolin-8-yl-hydrazine according to the method described for example 91. MS: M=473.3 (M+H)+
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([OH:13])(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[C:7]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of K2CO3 (4.17 g, 30.2 mmol) and pent-4-enoic acid (3.01 g, 29.2 mmol) in DMF (25 mL) was stirred at room temperature for 5 minutes. Benzyl bromide (3.55 mL, 29.3 mmol) was added from a syringe over 3 minutes, and the resulting white suspension was stirred at room temperature for 23 hours, then diluted with water (150 mL) and extracted with EtOAc (3×50 mL). The combined extract was washed with saturated brine (30 mL) and concentrated under vacuum to leave the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 2.30-2.41 (m, 2H) 2.42-2.50 (m, 2H) 4.96 (dddd, J=10.2, 1.7, 1.4, 1.0 Hz, 1H) 5.03 (dq, J=17.3, 1.6 Hz, 1H) 5.11 (s, 2H) 5.82 (tdd, J=17.0, 10.4, 6.3 Hz, 1H) 7.25-7.38 (m, 5H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)[Cl:27]>O=S(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([Cl:27])=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2O1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Cl)cc2O1
Yield: 94 %

Procedure:
4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (15a) (3.35 g, 9.24 mmol) was dissolved in SOCl2 (50 mL) and DCM (20 mL) and stirred at room temperature for 2 hr. The volatiles were removed to give 3.3 g of a yellow solid (94% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 1.51 (s, 6 H) 2.91 (s, 2 H) 3.06 (s, 3 H) 7.10 (d, J=8.56 Hz, 2 H) 7.30 (s, 1 H) 7.35 (s, 1 H) 7.93 (d, J=8.56 Hz, 2 H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18]([NH:12][CH2:11][CH:10]([O:13][CH3:14])[O:9][CH3:8])=[O:19]
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CNC(=O)c1cc([N+](=O)[O-])ccc1Cl)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
Thionyl chloride (14 mL, 192 mmol) was added-dropwise to a solution of 2-chloro-5-nitrobenzoic acid (10 g, 49.6 mmol) in chloroform (150 mL) at 0° C. The mixture was heated to reflux for 4 h then cooled to r.t., concentrated in vacuo and dried under high vacuum to yield 2-chloro-5-nitrobenzoyl chloride (10 g, 91.7%) as a solid. Under nitrogen, triethylamine (19 mL, 136 mmol) was added slowly to a solution of aminoacetaldehyde dimethyl acetal (5.43 mL, 50.0 mmol) in dry DCM (20 mL) at 0° C. 2-Chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) was slurried in dry DCM (30 mL) and added over a period of 30 minutes. The mixture was allowed to warm to r.t. and stirred overnight then partitioned between water and DCM. The organic phase was washed with saturated sodium bicarbonate solution, water and brine then dried over sodium sulfate and concentrated. The crude product was triturated with petroleum ether then diethyl ether and finally purified by column chromatography on silica gel (60-120 mesh) eluting with ethyl acetate/petroleum ether (2% to 40% gradient) to afford 2-chloro-N-(2,2-dimethoxy-ethyl)-5-nitro benzamide (8.3 g, 63%) as a yellow solid.
Reaction SMILES: P(O[CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:30]3[N:29]=[C:27]([NH2:28])[NH:26][C:24](=O)[C:23]=3[N:22]=[CH:21]2)[CH2:17][C@@H:16]1[OH:31])(OP(OP(O)(O)=O)(O)=O)(=O)O.[P:32]([O:44]C[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)([O:35][P:36]([O:39][P:40]([OH:43])([OH:42])=[O:41])([OH:38])=[O:37])(=[O:34])[OH:33]>>[CH:27]1[N:29]=[C:30]2[N:20]([C@@H:18]3[O:19][C@H:15]([CH2:14][O:43][P:40]([O:39][P:36]([O:35][P:32]([OH:44])([OH:34])=[O:33])([OH:38])=[O:37])([OH:42])=[O:41])[C@@H:16]([OH:31])[CH2:17]3)[CH:21]=[N:22][C:23]2=[C:24]([NH2:26])[N:28]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1

Procedure:
200 nM dGTP; 200 nM dCTP;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25].[I-:26].[Na+]>C(C(C)=O)C>[I:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1c(OCCCCl)ccc2c1OC(CCC(=O)OCC)CC2
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OCC)CC2

Procedure:
Ethyl 7-(3-chloropropoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoate (3.2 g, 9.042 mmol) and sodium iodide (13.6 g, 9.042 mmol) were added to 200 ml of methyl ethyl ketone and the reaction mixture was heated to reflux overnight. The solvent was removed under vacuum and 100 ml water was added. The solution was extracted 3 times with ethyl acetate. The combined extracts were dried and filtered, and the solvent was removed under vacuum to give the product as a brown oil.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: c1ccc(C(Nc2ccncc2)c2ccccc2)cc1
Reaction time: 20 h
Yield: 30.8 %

Procedure:
24.7 Grams (0.1 mole) of diphenylbromomethane and 29.4 grams (0.3 mole) of 4-aminopyridine in 500 milliliters of toluene were heated under reflux with stirring for 20 hours. The solid formed was filtered off and the toluene was extracted with 2 N hydrochloric acid. The acid extracts were combined with the solid material and the solid was taken into solution by the addition of water and methanol. The alcoholic solution was basified with 5 N sodium hydroxide and extracted with toluene. After drying over magnesium sulphate, the solvent was removed and 8.01 grams of the title compound were obtained as the crude crystalline base, m.p. 148°-50° C. The base was converted into its hydrochloride by solution in the minimum quantity of 2-propanol and addition of a solution of hydrogen chloride in dry ether. The hydrochloride was obtained as a colourless solid, m.p. 237°-9° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([N:13](OC)[CH3:14])[N:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[C:20]([F:26])=[CH:19][C:18]=2[CH3:27])[C:4]1=[O:28])[CH3:2].[H][H]>CO.[Pd]>[NH2:23][C:21]1[C:20]([F:26])=[CH:19][C:18]([CH3:27])=[C:17]([N:5]2[CH2:6][C:7]3[CH:12]=[N:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=3[N:3]([CH2:1][CH3:2])[C:4]2=[O:28])[CH:22]=1
Reactant: [H][H]
Reactant: CCN1C(=O)N(c2cc([N+](=O)[O-])c(F)cc2C)Cc2cnc(N(C)OC)cc21
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)N(c2cc(N)c(F)cc2C)Cc2cnc(NC)cc21
Yield: 77.8 %

Procedure:
1-Ethyl-3-(4-fluoro-2-methyl-5-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (3.2 g, 8.2 mmol) and Pd/C (0.3 g) were combined in MeOH (60 ml) and subjected to hydrogen (45 psi) at 50° C. overnight. The reaction mixture was filtered, concentrated in vacuo and purified by column chromatography to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.1 g, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.71 (s, 1 H), 6.88 (d, J=12.0 Hz, 1 H), 6.64 (d, J=8.4 Hz, 1 H), 6.38 (m, 1 H), 5.99 (s, 1 H), 5.01 (s, 2 H), 4.51 (d, J=13.6 Hz, 1 H), 4.29 (d, J=13.6 Hz, 1 H), 3.76 (m, 2 H), 2.75 (d, J=4.8 Hz, 3 H), 1.91 (s, 3 H), 1.14 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 330.2 [M+H]+.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][CH:2]=[C:1]([NH:22][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:10]2=[CH:9][CH:8]=1
Reactant: Nc1cccc2ccccc12
Reactant: Oc1cccc2ccccc12
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc2c(Nc3cccc4ccccc34)cccc2c1
Temperature: 220 °C
Yield: 93 %

Procedure:
144 parts of α-naphthol, 143 parts of α-naphthylamine and 15 parts of triphenyl phosphite are mixed and heated to 220° C. The elimination of water commences at this temperature and has ended when the internal temperature reaches 250° C. 18 parts of water are removed in the course of 10 hours. After distilling off excess α-naphthol and α-naphthylamine, 250 parts of 1,1'-dinaphthylamine, of melting point 97° - 102° C, are obtained at 256° - 257°/5 mm Hg. This corresponds to a yield of 93% of theory.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[C-:29]#[N:30].[Na+]>CN1C(=O)CCC1.[Ni](Br)Br>[C:29]([C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1)#[N:30]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(C#N)cc(N2CCOCC2)c1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol), sodium cyanide (24.5 mg, 0.5 mmol), nickel(II) bromide (54.6 mg, 0.25 mmol) in NMP (0.5 mL) was stirred for 10 minutes at 200° C. with microwave. After removal of the solid, the rediue was purificated by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-cyano-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (39 mg, 40%) as a white solid: LC/MS m/e calcd for C23H25N3O3 (M+H)+: 392.5, observed: 392.2.
Reaction SMILES: Br[C:2]1[N:19]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:18])([F:17])[CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:4]2[N:3]=1.C([N:22](S(F)(F)F)[CH2:23][CH3:24])C>C(Cl)(Cl)Cl>[F:17][C:10]([F:18])([CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:9]1[N:4]2[N:3]=[C:2]([NH:19][C:5]3[CH:24]=[C:23]4[C:8]([C:9]([CH3:10])=[N:4][NH:22]4)=[CH:7][CH:6]=3)[N:19]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(c1cccc2nc(Br)nn12)C1CCOCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2cc(Nc3nc4cccc(C(F)(F)C5CCOCC5)n4n3)ccc12
Temperature: 50 °C
Yield: 79 %

Procedure:
2-Bromo-5-(difluoro(tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine. (Diethylamino)sulfur trifluoride (4.26 mL, 32.2 mmol) was added to a stirred solution of (2-bromo-[1,2,4]triazolo[1,5-c]pyridin-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (2 g, 6.45 mmol) in chloroform (40 mL) in a high pressure flask under nitrogen. The flask was sealed and heated at 50° C. for 16 h. The reaction was quenched with methanol (1 mL). The resulting mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate. The organics were washed with brine and then dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was purified using flash chromatography (5-50% ethyl acetate in hexane), to give the desired product (1.7 g, 5.12 mmol, 79% yield) as a light yellow solid. MS (ESI) m/z 334.2 [M+2]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 3-fluoro-4-nitrophenol (2.96 g, 18.81 mmol) in DMF (18.81 mL) was added 1-(chloromethyl)-4-methoxybenzene (2.55 mL, 18.81 mmol) and potassium carbonate (5.20 g, 37.6 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The mixture was diluted with EtOAc (100 mL), washed with water, and the aqueous layer was back-extracted with EtOAc (25 mL). The combined organic layers were washed with 1 M aqueous NaOH (20 mL) and then with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The yellow solid was triturated with ether (20 mL), and the solid was collected, rinsing with ether (5 mL). The title compound was obtained as a yellow solid (4.39 g, 84% yield).