Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:14][CH:13]2[CH2:12][O:11][C:10]3=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClCCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:10][OH:15])[CH2:14][CH:13]2[CH2:12][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1OCC2C[C@]12c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC1C[C@@]1(CO)c1ccc(Cl)c(Cl)c1
Yield: 98.4 %

Procedure:
BMS (10.9 mL, 115 mmol) was added to (1S)-1-(3,4-dichloro-phenyl)-3-oxabicyclo[3.1.0]hexan-2-one (14 g, 57.6 mmol) in dry tetrahydrofuran (140 mL), under nitrogen atmosphere. The reaction mass was refluxed for 5 hours and monitored by TLC (dichloromethane (100%)). The reaction was quenched with 10% potassium carbonate solution. The aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 14 g (98.5%) of desired product. 1H NMR δ(300 MHz,CDCl3): 0.9-0.98 (1H,m), 1.17 (1H,m), 1.48 (1H,m), 3.23-3.42 (2H,m) 3.92-4.03 (2H,m) 7.10-7.13 (1H,m), 7.24-7.27 (1H,m), 7.38 (1H,m,).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH2:31])[CH3:30])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanamine (54 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H17ClFN6O2 (M+H)+: m/z=427.1. found: 427.1.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)=[CH:13][C:12]=1[NH:32][C:33](=[O:50])[C:34]1[CH:39]=[C:38]([S:40]([F:45])([F:44])([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:46](O)([CH3:48])[CH3:47])[CH:35]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)=[CH:13][C:12]=1[NH:32][C:33](=[O:50])[C:34]1[CH:39]=[C:38]([S:40]([F:45])([F:44])([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:46]([F:7])([CH3:48])[CH3:47])[CH:35]=1
Reactant: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C(C)(C)F)cc(S(F)(F)(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., a solution of 27 μl (0.203 mmol) of diethylaminosulphur trifluoride (DAST) in 0.5 ml of anhydrous dichloromethane was added to a solution of 100 mg (0.169 mmol) of the compound of Example 148 in 3.5 ml of anhydrous dichloromethane. After the reaction mixture had been stirred at −78° C. for 1 h, 1 ml of saturated aqueous sodium bicarbonate solution was added and the mixture was warmed to RT. Using an Extrelut cartridge NT3 (from Merck, Darmstadt, Germany), the mixture was freed from salts and aqueous components. After concentration, the residue obtained was separated into its components by preparative HPLC (Method 36). Evaporation of the product fractions and drying of the residue under high vacuum gave 50 mg (50% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[F:16][C:12]1[N:11]=[C:10]([CH2:9][O:8][C:4]2[N:3]=[C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: Fc1cccc(COc2cncc(Cl)n2)n1
Product: Fc1cccc(COc2cncc(N3CCNCC3)n2)n1

Procedure:
Following the general procedure for the preparation of I-3b above, 2-chloro-6-(6-fluoro-pyridin-2-ylmethoxy)-pyrazine (100 mg, 0.42 mmol) and piperazine (360 mg, 4.17 mmol) were reacted to give the title compound (3-B). The crude material was purified by preparative TLC using 5% methanol/methylene chloride with 1% NH4OH as the eluant to yield 23 mg of the title product (3-B).
Reaction SMILES: [OH:1]C1C=C(O)C=CC=1CC(O)=O.[CH2:13]1[CH2:18][CH2:17][CH:16]([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:15][CH2:14]1>C(OCC)(=O)C.CCCCCC>[CH:22]1([NH:21][C:20](=[O:1])[NH:19][CH:16]2[CH2:15][CH2:14][CH2:13][CH2:18][CH2:17]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)Cc1ccc(O)cc1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
1.5 g of 2,4-dihydroxyphenylacetic acid (1.8 mole) was dissolved in 20 mL of 50:50 v/v ethyl acetate and hexane. Then 1.5 mL of DCC (˜1.4 mmole) was added and the reaction continued for 1 hr at room temperature under argon that was bubbled into the solution. A white precipitate of dicyclohexyl urea formed during the reaction. After 3 hr, the urea precipitate was removed and 1.8 mL (5.6 mmol) of oleylamine (C18-content 80-90%; Fisher), was initially dissolved in 10 mL of hexane in the presence of 4-dimethylaminopyridine (0.5 g) and added to the reaction product of the 2,4-dihydroxyphenylacetic acid and DCC. The reaction continued at room temperature for 1 hr and then stored at −20° C. for one week.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.Cl[CH:23]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([S:38][CH3:39])[N:33]=1)[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>C1COCC1>[CH3:39][S:38][C:34]1[N:33]=[C:32]([CH:23]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:37]=[CH:36][N:35]=1
Reactant: CSc1nccc(C(Cl)c2cccc(C#N)c2)n1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(C(c2cccc(C#N)c2)C(c2cccnc2)c2cccnc2)n1
Reaction time: 1 h

Procedure:
To the solution of 3-(pyridin-3-ylmethyl)pyridine (1.24 g, 7.26 mmol) in THF (32 mL) at −78° C. was added LDA (4.4 mL, 1.8 M) and stirred for 1 h. 3-{chloro[2-(methylthio)pyrimidin-4-yl]methyl}benzonitrile (2.0 g, 7.25 mmol) in THF (5 mL) was added. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give (±)-3-{1-[2-(methylthio)pyrimidin-4-yl]-2,2-dipyridin-3-ylethyl}benzonitrile. LRMS m/z (M+H) Calcd: 410.5, found: 410.1. Step D
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][NH:20][CH2:21][CH:22]1[CH2:25][NH:24][CH2:23]1>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:24]3[CH2:25][CH:22]([CH2:21][NH:20][CH3:19])[CH2:23]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CNCC1CNC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(CNC)C3)nc21
Temperature: 5 °C
Yield: 26.9 %

Procedure:
A suspension of 0.81 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid, 0.9 g (9.0 mmole) of N-methyl-3-azetidinemethanamine and 30 mL of acetonitrile was refluxed for six hours. The reaction was cooled to 5° C. The filtered solids were washed with acetonitrile, ether, and dried in vacuo. The dried solid was suspended in 70 mL of water and made basic to pH 11.0 after filtering through a fiber glass pad to clarify, the filtrate was acidified to pH 7.4 with 1.0M hydrochloric acid. The resulting precipitate was removed by filtration, washed successively with water, 2-propanol, ether and dried in vacuo to give 270 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-azetidinyl]-4-oxo-1,8 -naphthyridine-3-carboxylic acid, mp 180°-182° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[CH2:7][C:8]#[N:9].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]#[N:9])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: N#CCC(=O)c1ccco1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(=CC#N)c2ccco2)cc1
Yield: 92.5 %

Procedure:
To a mixture of 3-(2-furyl)-3-oxopropanenitrile (5.29 g), p-toluenesulfonyl chloride (9.00 g) and dichloromethane (60 mL) was added dropwise triethylamine (5.99 g) under ice-cooling. After stirring under ice-cooling for 1.5 hrs, the mixture was diluted with dichloromethane (100 mL). The mixture was washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9:1→3:1) to give the title compound (10.48 g) as a mixture of (E)-form and (Z)-form (3:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
1.12 g (5 mmol) of 2-bromo-5-fluoro-nitrobenzene were dissolved in 50 ml THF. At a temperature of −45° C. 15 ml of a 1M vinyl magnesium bromide solution in THF were added under nitrogen in such a way that the temperature did not exceed −40° C. After complete addition the dark solution was stirred for 30 min at −40° C. The reaction mixture was quenched with 10 ml aqueous saturated ammonium chloride solution and extracted twice with diethyl ether. The combined organic layers were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was dissolved in DCM and purified by column chromatography (100 g silica gel; heptane/EtOAc 9:1) to yield 501 mg (47%) 7-bromo-4-fluoro-1H-indole as an orange oil. MS (EI) 213.0 (100), 215.0 (100) (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH2:21])[CH3:14].N>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH2:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH:21][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:12])=[N:11][C:3]=1[O:2][CH3:1])[CH3:14]
Reactant: CCN1CCCC1CN
Reactant: COc1nc(Cl)ccc1C(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCN1CCCC1CNC(=O)c1ccc(Cl)nc1OC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
5.02 g (0.025 mole) of crude 2-methoxy-6-chloronicotinoyl chloride are dissolved in 75 ml of absolute chloroform and the solution is added dropwise in the course of 30 minutes at 25°-30° C to a solution of 7.7 g (0.06 mole) of 1-ethyl-2-(aminomethyl)-pyrrolidine in 75 ml of absolute benzene. The reaction mixture is stirred for 3 hours at 50° C, cooled, and 10 ml of a 5 N ethanolic ammonia solution are added thereto. The organic solvents are evaporated in vacuo and the residual crude base is chromatographed through a column of basic silica gel with benzene which contains 0.5% of methanol. Pure N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxy-6-chloronicotinamide is obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][N:9]=[C:2]([NH:1][S:11]([CH3:10])(=[O:13])=[O:12])[CH:3]=1)#[N:6]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccnc(N)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C#N)ccn1
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
A solution of 2-amino-isonicotinonitrile (1 g, 8.4 mmol) and methanesulfonyl chloride (0.716 mL, 9.2 mmol) in pyridine (10 mL) is stirred at room temperature for 12 hours. The mixture is poured onto ice and stirred for 20 min. The mixture is filtered and washed with water (100 mL), followed by diethyl ether (100 mL). The solid is dried in vacuo to afford N-(4-cyanopyridin-2-yl)-methanesulfonamide (1.1 g, 66%). MS: 198 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 3.32 (s, 3H), 7.27 (s, 1H), 7.48 (d, J=5.1 Hz, 1H), 8.53 (d, J=5.3 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[NH:9][CH2:8][C@H:7]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:6]1)=[N+:2]=[N-:3].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CO>[N:1]([CH2:4][C@@H:5]1[CH2:6][C@@H:7]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:18][CH2:19]3)=[CH:13][N:12]=2)[CH2:8][N:9]1[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1
Reactant: COC(=O)CBr
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CN1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Temperature: 65 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a solution of the product from Example 201A (290 mg, 1.114 mmol) in triethylamine (388 μl, 2.79 mmol) and methanol (0.3 mL) was added methyl bromoacetate (175 μL, 1.894 mmol), and the resulting mixture was stirred at 65° C. for 18 hours. The cooled mixture was concentrated in vacuo and partitioned between 1 N sodium bicarbonate and ethyl acetate. The organic extract was dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to give the title compound as an oil (203 mg, 54.8%). 1H NMR (500 MHz, pyridine-d5) δ ppm 6.74 (s, 1H), 4.63 (s, 1H), 4.36 (d, J=61.9 Hz, 1H), 4.08 (dt, J=14.2, 6.0 Hz, 1H), 3.81 (dd, J=42.1, 9.2 Hz, 1H), 3.62 (dd, J=11.3, 4.3 Hz, 1H), 3.46-3.27 (m, 1H), 2.23 (dd, J=21.4, 10.3 Hz, 1H), 2.17-2.04 (m, 1H), 1.49 (d, J=8.4 Hz, 11H); MS (ESI) m/z 333 (M+H)+.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:16][C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH:2]([CH3:4])[CH3:3])=[CH:21][N:22]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)nc1
Reaction time: 2 h

Procedure:
2-Bromopropane (1.13 mL, 12 mmol) and potassium carbonate (1.43 g, 10.4 mmol) were successively added to a DMF (10 mL) solution of 6-bromopyridin-3-ol (1 g, 5.75 mmol), and the mixture was stirred at 80 degrees for 2 hours. The solution was brought back to room temperature, diluted with ethyl acetate, and washed twice with distilled water, and once with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain the target (1.28 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].CN(C=O)C.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:8]=1
Reactant: CCOC(=O)c1c(O)nc(-c2ccc(O)cc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)nc(-c2ccc(O)cc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: 100 °C

Procedure:
In 2.5 ml of phosphorus oxychloride was suspended 130 mg of 3,4-diethoxycarbonyl-2-hydroxy-6-(4-hydroxyphenyl)-5-nitropyridine, whereto 0.4 ml of DMF was added. The mixture was heated at 100° C. for 30 minutes. Then, 0.4 ml of DMF was added and the mixture was heated for further 30 minutes. After the solvent was distilled off, ice-water was added, followed by neutralization with sodium hydrogencarbonate and extraction with ethyl acetate. After the organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried, the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent:ethyl acetate).
Reaction SMILES: C[O-].[Na+].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1.[C:12]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:14])[CH3:13]>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5](/[CH:4]=[CH:13]/[C:12]([C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)=[O:14])[CH:6]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/c1cccnc1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
A 28% solution of sodium methoxide in MeOH (0.9 g) was added to a mixture of nicotinaldehyde (6.71 g) and 6-acetyltetraline (10.83 g) in MeOH (50 ml) and the mixture was stirred at room temperature for 12 hours. After removal of the solvent, the residue was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate =1:1) followed by recrystallization from hexane-ethyl acetate to give the titled compound (9.30 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+]([O-])=O)[CH:3]=1.[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18]>CCO>[N+:12]([O-:15])([OH:14])=[O:13].[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17]([NH2:18])=[NH:16])=[C:3]([N+:12]([O-:15])=[O:13])[CH:4]=1
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc(O)cc1[N+](=O)[O-]
Yield: 54 %

Procedure:
A mixture of 4-amino-2-nitrophenol (25 mmol, 3.85 g) in EtOH (6 mL) on an ice bath was treated with nitric acid (69% aq soln.; 1.8 mL). To this of cyanamide (50% aq. soln.; 4 mL) was added. The reaction mixture was refluxed under N2 for 22 h. The solvent was evaporated. The dark brown solid residue was washed with EtOH and was dried under high vacuum to afford the title compound as a grey solid (3.53 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]2[N:9]=[C:25]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:28][CH:27]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1c(Cl)cnc(N)c1N
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Product: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCCCC4)cc3)nc12

Procedure:
By a procedure similar to Example 269 but using 5-chloro-4-methoxypyridin-2,3-diamine and 4-(2-piperidin-1-ylethoxy)benzaldehyde, the title compound was obtained as the bis(trifluoroacetate).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6](=[S:12])[NH:5][C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: COCCn1c(N)cc(=O)[nH]c1=S
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Yield: 36.5 %

Procedure:
6-Amino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.0 g, 5.0 mmol) was suspended in 10% acetic acid (20 mL). Sodium nitrite (0.38 g, 5.5 mmol) was added and the resulting mixture was heated at 75° C. for 1 h. The reaction mixture became first pink and then purple. Water (20 mL) was added and the reaction mixture was put in the fridge overnight. The purple solid was collected by filtration and washed with water to give the title compound (0.42 g, 37%). A second crop of product (0.22 g, 19%) was obtained by reducing the volume of the purple filtrate. The crude product was used in the following step without further purification.
Reaction SMILES: [N:1]1([C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:25])[C:17]=3[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=O)=[C:9](Cl)[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:27][NH:28][NH2:29]>N1C=CC=CC=1>[N:1]1([C:5]2[N:6]=[CH:7][N:8]=[C:9]3[N:28]([CH3:27])[N:29]=[C:11]([C:13]4[CH:14]=[N:15][N:16]([CH3:25])[C:17]=4[C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[C:10]=23)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3N3CCC3)cnn2C)cc1
Reactant: CNN
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(-c3nn(C)c4ncnc(N5CCC5)c34)cnn2C)cc1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of [4-(azetidin-1-yl)-6-chloropyrimidin-5-yl][1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C6) (from Step 6, ≦0.576 mmol) in pyridine (5.0 mL) was added methylhydrazine (0.302 mL, 5.74 mmol), and the reaction was stirred at 85° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified via silica gel chromatography (Gradient: 0 to 30% methanol in dichloromethane) to provide the title product as a colorless oil. Yield: 200 mg, 0.556 mmol, 97% over two steps. LCMS m/z 360.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.21-2.30 (m, 2H), 2.34 (br s, 3H), 3.75-4.04 (br m, 4H), 3.91 (s, 3H), 3.99 (s, 3H), 7.20 (br AB quartet, JAB=8.1 Hz, ΔνAB=33 Hz, 4H), 7.67 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:11])[C:8]([OH:13])=[O:12])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)C(=O)O
Product: CC(C(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
reacting phenol with pyruvic acid in an acidic medium to obtain 2,2-bis-(4-hydroxyphenyl) propionic acid;
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]([F:20])[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[N:21]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]([F:20])[CH2:7]1)=[N+:22]=[N-:23]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(OS(C)(=O)=O)CC1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(N=[N+]=[N-])CC1F
Temperature: 100 °C

Procedure:
To a stirred solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorocyclohexyl methanesulfonate (570 mg, 1.75 mmol) in DMF (10 mL) was added sodium azide (340 mg, 5.24 mmol). The reaction mixture was heated to 100° C. overnight, diluted with EtOAc, and washed with water. The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][N:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([N:20]([CH2:19][CH2:18][OH:17])[CH3:21])=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N:20]([CH2:19][CH2:18][OH:17])[CH3:21])=[CH:30][CH:29]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: CN(CCO)c1ccc(C(=O)[O-])cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc(NC(=O)c4ccc(N(C)CCO)cc4)cc3)cc2)cc1

Procedure:
Compound 330 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(N-2-hydroxylethyl-N-methylamino)benzoate. [M+H]+ calcd for C33H35N4O5: 567.26; found: 567.04.