Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[F:3][N:4]([F:19])[C:5]([N:16]([F:18])[F:17])([CH2:11][NH:12][N+:13]([O-:15])=[O:14])[CH2:6][NH:7][N+:8]([O-:10])=[O:9]>[N+]([O-])(O)=O>[F:3][N:4]([F:19])[C:5]1([N:16]([F:17])[F:18])[CH2:11][N:12]([N+:13]([O-:15])=[O:14])[CH2:1][N:7]([N+:8]([O-:10])=[O:9])[CH2:6]1
Reactant: O=[N+]([O-])NCC(CN[N+](=O)[O-])(N(F)F)N(F)F
Reactant: C=O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])N1CN([N+](=O)[O-])CC(N(F)F)(N(F)F)C1

Procedure:
Under the conditions of nitrolysis of 2,2-bis(difluoramino)-N-(nitratomethyl)-N-nitro-N,N′-bis(4-nitrobenzenesulfonyl)-1,3-propanediamine in ca. 98% nitric acid, the liberated formaldehyde equivalent becomes available for cyclization of the N-desulfonated bis(primary nitramine), 2,2-bis(difluoramino)-N,N′-dinitro-1,3-propanediamine. The cyclization occurred spontaneously at room temperature, consuming the 2,2-bis(difluoramino)-N,N′-dinitro-1,3-propanediamine intermediate and forming 5,5-bis(difluoramino)hexahydro-1,3-dinitropyrimidine (RNFX) [1H NMR (CD3CN): δ 4.85 (s, 4 H), 6.06 (s, 2 H); 1H NMR (acetone-d6): δ 5.07 (s, 4 H), 6.31 (s, 2 H); 13C NMR (CD3CN): δ 45.3 (m, J=6 Hz), 60.6 (s) (not all carbons detected due to low S/N); 19F NMR (CD3CN): δ 29.67; 19F NMR (acetone-d6): δ 29.31)].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([NH2:19])=[CH:4][CH:3]=1.[Cu](C#N)[C:21]#[N:22].C(OCC)(=O)C>[C-]#N.C([N+](CC)(CC)CC)C.O1CCOCC1.CCCCCCC.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:21]([C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([NH2:19])=[CH:4][CH:3]=1)#[N:22]
Reactant: CC(C)(C)c1ccccc1Oc1nc(Br)ccc1N
Reactant: N#C[Cu]C#N
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCCCCCC
Product: CC(C)(C)c1ccccc1Oc1nc(C#N)ccc1N
Temperature: 105 °C
Yield: 162.6 %

Procedure:
A mixture of 123a (1000 mg, 3.1 mmol), copper cyanide (1120 mg, 12.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (114 mg, 0.12 mmol), 1,1′-Bis (diphenylphosphino) ferrocene (276 mg, 0.5 mmol) and tetraethylammonium cyanide (486 mg, 3.1 mmol) in dioxane (16 ml) was heated at 105° C. for 4.5 h. The reaction was completed as determined by TLC (30% ethyl acetate in heptane). The mixture was cooled to rt, diluted with ether (50 ml) filtered over Celite® and concentrated to give 1.3476 g of yellow foam. The foam was recrystallized from 30% ethyl acetate in heptane to give 123b (753.6 mg, 91% yield) as a brown powder. [M+H]+=268.13. 1H NMR (500 MHz, CDCl3) δ ppm 1.36 (s, 9H), 4.53 (s, 2H), 6.96 (dd, J=7.97, 4.12 Hz, 2H), 7.17 (t, J=7.42 Hz, 1H), 7.24 (m, 2H),7.44 (d, J=7.70 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[C:9]2[C:10](=[O:15])[CH2:11][CH2:12][C:13]=2[CH3:14])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1=C(c2cc(F)ccc2N)C(=O)CC1
Solvent: c1ccncc1
Product: CC1=C(c2cc(F)ccc2NS(=O)(=O)c2ccc(C)cc2)C(=O)CC1

Procedure:
0.700 g (3.14 mmol) of 2-(2-amino-5-fluorophenyl)-3-methyl-2-cyclopenten-1-one, 0.298 g (3.76 mmol) of pyridine, 0.598 g (3.76 mmol) of p-toluenesulfonyl chloride, and 3 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (1.000 g, 85%).
Reaction SMILES: [CH3:1][CH:2]([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][CH:18]([CH3:22])[C:19](O)=[O:20])[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>O1CCCC1>[CH3:22][CH:18]([S:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][S:6][CH:2]([CH3:1])[CH2:3][OH:4])[CH2:19][OH:20]
Reactant: CC(SCCCCCCCCCCSC(C)C(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CO)SCCCCCCCCCCSC(C)CO
Yield: 83.7 %

Procedure:
A solution in tetrahydrofuran of 7 g (0.0200 mole) of (±)-2,15-dimethyl-3,14-dithia-1,16-hexadecanedioic acid was slowly poured under a current of nitrogen into an agitated suspension of 2.3 g (0.0605 mole) of LiAlH4 in tetrahydrofuran. The reaction medium was then heated under reflux for 3 hours 15 mins. After neutralisation of the excess reducing agent with ethyl acetate and aqueous alkali, the reaction mixture was filtered and then the solvents were eliminated from the filtrate. The residue was separated between water and methylene chloride. The organic phase was recovered and then washed to neutrality and dried. The solvent was evaporated under reduced pressure and the residue was washed by trituration with petroleum ether. After filtration, 5.4 g of a white crystalline powder was obtained which was insoluble in water. (H is understood that the (+) and (-) isomers can be separated from the racemic form by known methods).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:27][CH2:26][C@:12]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])[N:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:15][CH2:16][C@@H:11]3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:27][CH2:26][C@:12]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])[N:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:15][CH2:16][C@@H:11]3[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2=C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: N#Cc1ccc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
N-[(4aR,8aS)-6-(4-Cyanophenyl)-8a-(2,4-difluorophenyl)-4,4a,8,8a-tetrahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C25) (64 mg, 0.13 mmol, 1 equiv) was dissolved in 1,2-dichloroethane (2.0 mL) and cooled to 0° C. Triethylsilane (0.32 mL, 2.0 mmol, 15 equiv) and trifluoroacetic acid (0.5 mL) were added and reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized by addition of a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as a white solid. Yield: 37 mg, 58%. LCMS m/z 490.3 [M+H+]. 1H NMR (400 mhz, CDCL3) δ 8.24 (d, J=7.0 Hz, 2H), 7.63-7.66 (m, 2H), 7.41-7.56 (m, 5H), 6.90-7.01 (m, 2H), 4.78 (dd, J=11.5, 2.3 Hz, 1H), 4.33 (dd, J=12.3, 1.6 Hz, 1H), 3.99 (d, J=12.3 Hz, 1H), 3.32-3.36 (m, 1H), 3.07 (dd, J=12.9, 4.1 Hz, 1H), 2.68 (dd, J=12.9, 2.7 Hz, 1H), 2.12-2.22 (m, 1H), 1.91-1.96 (m, 1H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:38][CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42])[CH:36]=O>>[CH3:42][CH:41]([CH2:40][CH2:39][CH:38]=[C:35]([CH3:36])[CH3:34])[CH:43]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)=CCCC(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)=CCCC(C)C=CCc1ccccc1
Yield: 74.1 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.20 g, 7.15 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.5 mL, 7.15 mmol, 1.0 equiv.) and 2,6-dimethylhept-5-enal (1.51 g, 10.7 mmol, 1.5 equiv.), 1.21 g (74%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-])=O)[CH:4]=1>CO>[NH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OC)cc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1ccc(OC)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A solution of methyl 4-methoxy-2-nitrobenzoate (9.0 g, 43 mmol) in MeOH (100 mL) was degassed and purged with nitrogen. To this solution was added 10% palladium hydroxide on carbon (1.2 g). The reaction mixture was degassed, purged with hydrogen and allowed to stir at rt overnight. The reaction mixture was filtered through Celite®, the Celite was washed with MeOH and the filtrate was concentrated to give methyl 2-amino-4-methoxybenzoate (7.80 g, 76%) as a brown solid. LCMS (FA): m/z=182.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[C:14]([F:18])=[CH:13][C:3]=1[C:4](C1C=CC(F)=CC=1)=[O:5].[OH:19]O>OS(O)(=O)=O.O=S(=O)=O>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[C:14]([F:18])=[CH:13][C:3]=1[C:4]([OH:5])=[O:19]
Reactant: OO
Reactant: O=C(c1ccc(F)cc1)c1cc(F)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(F)c(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
28.7 g (0.1 mol) of 2,4-dichloro-4',5-difluorobenzophenone are dissolved in 250 g of 10% oleum, and 25 g of 50% hydrogen peroxide solution are added at temperatures up to 30° C. When the metered addition has ended (30 min), the mixture is heated for 8 h at 50° C. and, after cooling, is poured on to 250 g of ice. This mixture is kept for 8 h at 140° C. and 4-fluorophenol is then recovered by steam distillation (7.5 g, 0.0673 mol, 67%, m.p. (DSC) 42.6° C.). 2,4-dichloro-5-fluorobenzoic acid is isolated as described in Example 1 (17.0 g, 0.0813 mol, 81%, m.p. 143°-145° C.). (DSC =differential scanning calorimetry)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][N:20](C)C(=O)C>O.O.O.[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[C:19]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:20]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: CC(=O)N(C)C
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: O
Product: COC(=O)c1ccc(O)c(C#N)c1
Reaction time: 21.5 h

Procedure:
A mixture of methyl 3-bromo-4-hydroxybenzoate (Journal of Organic Chemistry (1997), 62(13), 4504-4506; 3.47 g, 15.0 mmol), potassium ferrocyanide trihydrate (1.394 g, 3.30 mmol), palladium acetate (0.034 g, 0.150 mmol), 1,1-bis(diphenylphosphino)ferrocene (0.166 g, 0.300 mmol), and sodium carbonate (1.590 g, 15.00 mmol) in dry N,N-dimethylacetamide (DMA) (30 ml) was degassed by evacuation and refilling with nitrogen, and the mixture was heated under nitrogen at 125° for 18 h. More potassium ferrocyanide trihydrate (700 mg), palladium acetate (34 mg) and 1,1′-bis(diphenylphosphino)ferrocene (166 mg) were added, and stirring was continued under nitrogen at 130° for 21.5 h. More sodium carbonate (1.59 g), palladium acetate (0.034 g, 0.150 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.166 g, 0.300 mmol) was added, and heating was continued at 130° with stirring under nitrogen for 4 h. The solvent was evaporated in vacuo and the residue treated with glacial acetic acid (3 ml) and partitioned between water (100 ml) and ethyl acetate (100 ml). The layers separated poorly, hence the mixture was filtered through Celite filter aid, and the aqueous layer was further extracted with ethyl acetate (70 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried (MgSO4) and evaporated in vacuo to give a black solid which was purified by flash chromatography on silica, eluting with 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (1.01 g)
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[C:39]([C:44]([O:46]C)=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].O.Cl>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[C:39]([C:44]([OH:46])=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccccc1-c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccccc2C(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-carboxylate (50 mg, 0.07 mmol), aqueous potassium hydroxide (1.1 mL, 3M, 3.3 mmol), water (1.5 mL) and ethanol (3.6 mL) were stirred at 20° C. for 23 hours. The reaction mixture was acidified by HCl (aq., 1N). Volatiles were removed under reduced pressure. The resulting mixture was worked up with ethyl acetate, washed with brine. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to an oil. This oil was purified by a reverse-phase preparative HPLC (column: Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% v/v TFA buffered)/H2O (0.1% v/v TFA buffered) gradient mixture to afford 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-carboxylic acid. LCMS calc.=697.15; found=698.16 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 7.94 (t, J=7.0 Hz, 1H), 7.85 (d, J=7.0 Hz, 1H), 7.68-7.63 (m, 2.5H), 7.63-7.59 (m, 1.5H), 7.59-7.54 (m, 1H), 7.47-7.35 (m, 4H), 7.14 (dd, J=8.0, 2.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 5.53 (d, J=8.0 Hz, 0.4H), 5.42 (d, J=8.0 Hz, 0.6H), 5.02 (d, J=15.5 Hz, 0.6H), 4.85 (d, J=15.5 Hz, 0.4H), 4.11-4.02 (m, 0.4H), 3.87-3.77 (m, 3.6H), 0.99 (d, J=6.5 Hz, 0.6H), 0.93 (d, J=7.0 Hz, 0.4H), 0.58 (d, J=7.0 Hz, 1.2H), 0.54 (d, J=6.5 Hz, 1.8H).
Reaction SMILES: [OH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[OH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2[nH]c(O)nc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
According to the procedure of A. T. James, et al., J. Chem. Soc., 1515, (1950), to cooled (0° C.), stirred nitric acid (300 mL) was added all at once 2-hydroxy-1H-benzimidazole. After 1 minute a yellow precipitate had formed. The cooling bath was removed and stirring was continued for 10 minutes. The mixture was poured onto ice, and the off-white solid was collected by filtration and dried under vacuum at 60° C. to give 25.1 g (94%) of product m.p. >300° C.
Reaction SMILES: BrC1C=CC2OCCC=2C=1.C([Li])CCC.CCCCCC.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:28](N(OC)C)=[O:29])[CH3:23]>C1COCC1.O.C(O)(C)C>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:28]=[O:29])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH3:23]
Reactant: CCOc1cc(C(=O)N(C)OC)ccc1OC
Agent: Brc1ccc2c(c1)CCO2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 148.4 %

Procedure:
To a solution of 5-bromo-2,3-dihydro-benzofuran (1.0 g, 5.0 mmol) in THF (10 mL) was added a solution of n-butyllitium in hexane (1.8 mL, 2.5 N, 4.5 mmol) at −78° C. and kept for 20 min. To the mixture was added a solution of 3-ethoxy-4,N-dimethoxy-N-methyl-benzamide (1.1 g, 4.6 mmol) in THF (10 mL) at −78° C. After 30 min, isopropanol (1 mL) and water (10 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with HCl (1N, 50 mL), water (50 mL), brine (50 mL) and dried over MgSO4. Removal of solvent and gave 2,3-dihydro-benzofuran-5-yl)-(3-ethoxy-4-methoxy-phenyl)-methanone as an oil (1.23 g, 92% yield). The oil was used in the next step without further purification.
Reaction SMILES: [OH-].[K+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:9][CH:8]=1)([CH3:5])[CH3:4].OC[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.[N+](C1C=CC(OC(=O)NC2C=CC(OC(C)C)=CC=2)=CC=1)([O-])=O>O>[CH:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH2:33][CH2:36][CH2:37][N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:20][CH2:21]2)=[O:15])=[CH:11][CH:12]=1)([CH3:5])[CH3:4]
Reactant: OCCCN1CCCCC1
Reactant: COc1ccc2c(C3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)ncnc2c1
Agent: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(OCCCN5CCCCC5)ccc34)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
Solid KOH (112 mg, 2 mmol) was added to a mixture of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 82 mg, 0.2 mmol), prepared as described in Example 29, and 3-hydroxypropylpiperidine (0.25 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and diluted with water. The mixture was extracted with DCM and the organic layer was drawn off and washed with water thrice, with brine once, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3 mL of 3M HCl/MeOH and the mixture was stirred at rt for 2 h and then concentrated in vacuo. This was suspended in anhydrous MeOH (3 mL), and to it DIEA (1.75 mL, 0.6 mmol) was added followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (96 mg, 0.3 mmol), as prepared in Example 1a, and the mixture was stirred at rt overnight. It was then concentrated in vacuo and the residue was dissolved in DCM and washed extensively with water thrice and brine once and then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 1% MeOH/DCM followed by 90:9:1 DCM:MeOH:NH4OH) to obtain 14 mg (13% overall yield from 29a) of pure 4-(7-(3-piperidin-1-yl-propoxy)-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.13 (s, 1H), 8.05 (d, 1H), 7.35-7.21 (m, 4H), 6.84 (d, 2H), 6.33 (s, 1H), 4.48 (m, 1H), 4.32-4.15 (m, 4H), 3.68 (m, 1H), 3.13 (m, 2H), 2.7-2.45 (m, 6H), 2.20-1.90 (m, 8H), 1.75-1.58 (m, 4H), 1.31 (d, 6H). LC/MS (ESI): calcd mass 531.3, found 532.6 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][CH:17](OS(C)(=O)=O)[C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)([CH3:20])[CH3:19])=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)([CH3:20])[CH3:19])=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(Cc1ccc(OCc2ccccc2)c[n+]1[O-])OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C=Cc1ccc(OCc2ccccc2)c[n+]1[O-])Oc1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 121.2 %

Procedure:
1.69 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2-(methylsulphonyloxy)butyl]pyridine N-oxide were added to a solution of 0.14 g of 80% sodium hydride in 15 ml of isopropanol and the solution was stirred at 20° C. for 16 hours. The solvent was then removed by evaporation and the residue was partitioned between ethyl acetate and sodium chloride solution The organic phase was washed with sodium chloride solution and then evaporated to give 1.64 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-1-butenyl]pyridine N-oxide in the form of a pale cream solid of melting point 125° C. after recrystallization from ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: COCC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: COCC(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
70 mg of crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methoxyacetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 28.1 mg of 119. MS (Q1) 425 (M)+
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44]>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: NCCCCCc1ccccn1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCCc2ccccn2)c2ccc(OC)cc2)cc1
Yield: 252.7 %

Procedure:
As in Example 134, a solution of (E)-5.5-bis(4-methoxyphenyl) -2,4-pentadienoic acid 4-nitrophenyl ester (1.72 g) and 2-Pyridinepentanamine (0.657 g) in tetrahydrofuran (25 mL) was stirred for 17 hours at room temperature and was worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate) and then was crystallized from ethyl acetate to provide 4.6 g of (E)-5,5-bis(4-methoxyphenyl)-N-[5-(2-Pyridinyl) pentyl]-2,4-pentadienamide, mp 99°-100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:20](N)([NH2:23])(=[O:22])=[O:21]>O1CCOCC1>[N:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:20]([NH2:23])(=[O:22])=[O:21])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 16.8 %

Procedure:
A solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.50 g) and sulphamide (1.90 g) in dioxan (30 ml) was heated under reflux for 1 hour and then evaporated. The residue was triturated with water and the mixture was filtered. The solid was crystallised from a mixture of N,N-dimethylformamide and water to give the title compound (0.11 g), m.p. 216°-219° C. Found: C,54.03; H,5.59; N,20.68. C15H19N5O2S requires: C,54.05; H,5.75; N,21.01%.