Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH3:10].I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:23])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:10]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (430.55 mL of a 0.3M stock solution, 129.16 mmol) was cooled to −78° C. and then treated with a solution of (4-nitro-phenyl)-acetic acid ethyl ester (26.32 g, 125.83 mmol) in tetrahydrofuran/hexamethylphosphoramide (312.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction mixture was treated with a solution of iodomethylcyclopentane (27.75 g, 132.1 mmol) in hexamethylphosphoramide (27.75 mL). The mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction mixture was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (250 mL). This mixture was concentrated in vacuo, diluted with water (250 mL), and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with a saturated aqueous lithium chloride solution (2×250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (28.30 g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for C16H21NO4 (M+) 291.1470, found 291.1470.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)C.FC(F)(F)C(O)=O>C(#N)C>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:34][CH:35]=2)=[CH:9][CH:10]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(C=O)cc2)cc1
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 4-(8-(4-(diethoxymethyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide (180 mg, 0.35 mmol) in acetonitrile (10 mL) was added trifluoroacetic acid (5 mL), stirred for 30 min, Then the mixture was evaporated under reduced pressure to get the title compound (140 mg, yield 91%). LC-MS (ESI) m/z: 439(M+1)+.
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][C@H:8]([C:13](=[O:34])[NH:14][CH:15]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:26])=[O:25])[CH2:17][CH:16]1[OH:33])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Cl.O1CCOCC1.Cl.[O:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[CH:46]=[C:45]1C(O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[OH:33][CH:16]1[CH:15]([NH:14][C:13]([C@@H:8]([NH:7][C:6]([C:45]2[O:44][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[CH:46]=2)=[O:35])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:34])[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:26])[CH2:17]1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To {(S)-1-[3-Hydroxy-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester of Example 92h (0.22 g, 0.43 mmol) was added HCl/dioxane (4M, 20 ml, 80 mmol). The mixture was stirred at r.t. for 2 h before solvents and excess amount of HCl was removed on rotavapor. The resulting white solid was dissolved in 5 ml DMF. To the solution was added 2-benzofurancarboxylic acid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol). The mixture was stirred at r.t. overnight. DMF was then removed and the residue was redissolved in EtOAc (50 ml), washed with 10% NaHCO3 (50 ml×2) and brine (50 ml). Evaporation of the solvent gave crude product 0.26 g. Purification by column chromatograghy gave the title compound 0.15 g in 63% total yield; MS (M+H+): 556.8; 1H-NMR (400 MHz, CDCl3): •8.66-8.63(m, 1H), 7.94-7.11(m, 10H), 4.72(m, 1H), 4.01-2.98(m, 7H), 1.78-1.39(m, 5H), 1.02-0.85(m, 12H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[C:15][C:16]2[N:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:17]=2)[CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:18]1[CH:17]=[C:16]([C:15]#[C:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[N:20]2[C:19]=1[CH:24]=[CH:23][CH:22]=[N:21]2
Reactant: CC(C)(C)OC(=O)N1CCCC(C#Cc2cnc3cccnn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(#CC1CCCNC1)c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
To a solution of 1-BOC-3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl)piperidine (0.39 g, 1.2 mmol) in CH2Cl2 (10 mL) was added TFA (1.23 g, 10.8 mmol), the mixture was stirred at rt overnight and evaporated in vacuo. To the residue was added 10 mL 10% K2CO3 solution, extracted with EtOAc (20 mL×3), dried with Na2SO4, after filtration, and the filtrate was evaporated under reduced pressure to give 0.33 g product as yellow oil (107.0%). 1H NMR (300 MHz, CDCl3) δ: 8.43 (1H, d, J=4.5 Hz), 7.93-7.97 (1H, dd, J=1.8 and 9.0 Hz), 7.91 (1H, s), 7.05-7.09 (1H, dd, J=4.5 and 9.0 Hz), 2.82-2.98 (4H, m), 2.08-2.11 (1H, m), 1.75-1.84 (2H, m), 1.53-1.58 (2H, m).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1)#[N:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1)#[N:2]
Reactant: Oc1ccccc1
Reactant: CCCc1nc(C#N)c(C#N)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1nc(C#N)c(C#N)nc1Oc1ccccc1
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
2,3-Dicyano-5-chloro-6-n-propylpyrazine (0.207 g; 0.001 mole) was dissolved in 15 ml of acetone, and a solution prepared from 0.094 g (0.001 mole) of phenol, 0.040 g (0.001 mole) of sodium hydroxide, 0.7 ml of water and 5 ml of acetone was added dropwise over the period of 5 minutes. Then, the mixture was stirred at 5° to 10° C. for 10 minutes. The reaction mixture was worked up in the same way as in Example 9, and recrystallized from benzene to afford 0.150 g (yield 57%) of 2,3-dicyano-5-phenoxy-6-propylpyrazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]=1[F:31])[CH3:2].Cl.CO.N#N>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][CH2:14][C:15]([F:22])([F:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]=1[F:31])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2ccccn2)C(=O)OC(C)(C)C)c1F
Agent: Cl
Agent: N#N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Through a 0° C. solution of 0.6 g (1.6 mmol) ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro4-pyridinyl)acetate 1-4 in 12 mL EtOAc was passed a steady stream of HCl gas for 20 min, then the reaction mixture was allowed to stir at 0° C. for 20 min. A precipitate formed so 1 mL MeOH was added to make the reaction homogeneous and HCl gas was passed through the mixture for another 15 min., then a stream of N2 gas for 5 min, then the mixture poured into 300 mL EtOAc/100 mL 2M NaOH/15 mL conc NaOH and the layers mixed and separated. The aqueous, layer was back extracted with 50 mL EtOAc and the combined organic layers washed with 150 mL water, and brine, then dried over Na2SO4, filtered, concentrated, to give ethyl(5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetate 1-5 which was used without further purification. 1H NMR (400 mHz, CDCl3) δ8.66 (br d, 1H, J=4.76 Hz); 7.88 (s, 1H); 7.82 (ddd, 1H, J=7.7, 7.7, and 1.64 Hz); 7.69 (d, 1H, J=7.87 Hz); 7.39 (dd, 1H, J=4.76 and 7.33 Hz); 5.21 (br m, 1H); 4.43 (dt, 2H, J=13.9 and 6.05 Hz); 4.18 (q, 2H, J=7.14 Hz); 3.75 (d, 2H, J=1.65 Hz); 1.26 (t, 3H, J=7.14 Hz). Mass spectrum (electrospray) M+H=374.1
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:22][CH2:23][CH:24]([OH:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCC(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCO
Product: OC(CNC[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1)c1ccccc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-amino-1-phenylethanol in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=423.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[CH:25]=2)[CH2:18][CH2:17]1)=[O:15].[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[N:8]1([C:6]2[CH:5]=[CH:4][C:3]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]5[C:28](=[O:31])[O:29][CH2:30][C:26]=5[CH:25]=4)[CH2:18][CH2:17]3)=[O:15])=[C:2]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:7]=2)[CH:12]=[N:11][N:10]=[N:9]1
Reactant: OB(O)c1ccccc1
Reactant: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4Br)CC3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4-c4ccccc4)CC3)ccc21
Temperature: 80 °C

Procedure:
A mixture of 5-[2-(4-{[2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (40 mg, 0.08 mmol), PhB(OH)2(24 mg, 0.2 mmol), Na2CO3 (42 mg, 0.4 mmol) and Pd(PPh)4(10 mg) in 3 mL of toluene and 3 mL of ethanol was heated to 80° C. under N2 overnight. The solution was concentrated to get the crude product, which was purified via prep-TLC to afford 5-[2-(4-{[5-(1H-tetrazol-1-yl)biphenyl-2-yl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one. 1H-NMR (300 MHz, CDCl3) δ ppm 9.0 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.67˜7.70 (m, 1H), 7.53˜7.63 (m, 2H), 7.44˜7.49 (m, 3H), 7.30˜7.37 (m, 4H), 5.28 (s, 2H), 3.58˜3.74 (m, 4H), 3.17˜3.30 (m, 2H), 2.87˜2.98 (m, 2H), 2.39˜2.69 (m, 4H), 2.22˜2.36 (m, 2H).
Reaction SMILES: C(C1C=CC(OCC2ON=C(CC3C=C(C=CC=3)[C:19]([OH:21])=[O:20])N=2)=C(C)C=1O)(=O)C.[Cl:29][C:30]1[C:31]([OH:54])=[C:32]([C:51](=[O:53])[CH3:52])[CH:33]=[CH:34][C:35]=1[O:36][CH2:37][C:38]1[O:42][N:41]=[C:40]([CH2:43][C:44]2[CH:49]=[CH:48][C:47](I)=[CH:46][CH:45]=2)[N:39]=1>>[C:51]([C:32]1[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]2[O:42][N:41]=[C:40]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:19]([OH:21])=[O:20])=[CH:46][CH:45]=3)[N:39]=2)=[C:30]([Cl:29])[C:31]=1[OH:54])(=[O:53])[CH3:52]
Reactant: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(Cl)c1O
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(C(=O)O)c3)no2)c(C)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(C(=O)O)cc3)no2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoic acid of Example 140, employing 1-{3-chloro-2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone. 1H NMR (DMSO-d6) δ 13.05 (s, 1H), 12.86 (s, 1H), 7.92 (d, 1H), 7.85 (m, 2H), 7.38 (d, 2H), 6.84 (d, 1H), 5.72 (s, 2H), 4.18 (s, 2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[C:5]([O:8][CH3:9])(=[O:7])[CH3:6]>>[CH3:1][O:4][CH2:2][CH2:3][CH2:9][O:8][C:5](=[O:7])[CH3:6]
Reactant: CC1CO1
Reactant: COC(C)=O
Product: COCCCOC(C)=O

Procedure:
A process according to claim 1 wherein propylene oxide is reacted with either methyl acetate to produce methoxypropylacetate or with ethyl acetate to produce ethoxypropylacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].S(OC)([O:22][CH3:23])(=O)=O.CO.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[CH3:1][C:2]1[C:3]([CH2:23][OH:22])=[N:4][CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: Cc1c[n+]([O-])cc(C)c1OCC(F)(F)C(F)(F)F
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1cnc(CO)c(C)c1OCC(F)(F)C(F)(F)F
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,5-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide (2.5 g) and dimethyl sulfate (1 ml) was heated at 120° C. for 30 minutes and methanol (12.5 ml) was added, after which a solution of ammonium persulfate (4.3 g) in water (20 ml)-methanol (10 ml) was added dropwise at 80° C. over a period of 30 minutes and the mixture was stirred for 30 minutes. After concentration, ice was added and the mixture was neutralized with sodium carbonate, and then was extracted with chloroform. After drying the extract over sodium sulfate, the solvent was evaporated to give 2.2 g of 3,5-dimethyl-2-hydroxymethyl-4-(2,2,3,3,3pentafluoropropoxy)pyridine as oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[CH:17][C:18]([CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31])=O.[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].C([NH+]1C2=NC3C(N=C2N(CC)C1C#CC=C1N(CC)C2=NC4C(N=C2N1CC)=CC=CC=4)=CC=CC=3)C>N1C=CC=CC=1>[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[CH3:6][N+:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]#[C:18][CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31]
Reactant: CN1C(=CC(=O)C=C2C=Cc3ccccc3N2C)C=Cc2ccccc21
Agent: CCN1C(=CC#CC2N(CC)c3nc4ccccc4nc3[NH+]2CC)N(CC)c2nc3ccccc3nc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1C(=CC#Cc2ccc3ccccc3[n+]2C)C=Cc2ccccc21
Reaction time: 0.08 h
Yield: 35 %

Procedure:
Phosphoryl chloride (1.0 ml) is added to a stirred suspension of 1,3-Bis(1-methyl-2-(1H)-quinolylidene)acetone (0.68 g, 0.002 mol) in pyridine (10 ml). The mixture is stirred for 5 min., then the solid is collected and washed with a little pyridine, then with ether. The dye is converted to its perchlorate salt by solution in methanol, followed by addition of aqueous sodium perchlorate solution. After recrystallization from acetonitrile, the yield of purified dye is 0.30 g (36%) with the melting point indistinct. The following two dyes were prepared by procedures similar to that described above: 1,3-Diethyl-2-[(1,3-diethyl-1H-imidazo[4,5-b]quinoxalin-2-(3H)-ylidene)-1-propynyl]-1H-imidazo[4,5-b]quinoxalinium perchlorate. ##STR20## Recrystallized from acetonitrile. Purified yield 35% mp >300°. 1,3,3-Trimethyl-2-[(1,3,3-trimethyl-2-indolinylidene)-1-propynyl]-3H-indolium perchlorate. ##STR21## Recrystallized from methanol. Purified yield 43% mp. 194°-7° dec.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)[N:4]=1>O1CCCC1>[NH2:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)[N:4]=1
Reactant: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(Cl)c2cc1OC
Reactant: N
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of anhydrous ammonia and 4-chloro-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline in 100 ml. of tetrahydrofuran is heated at 100° C. for a period of 16 to 24 hours and the product isolated according to the procedure of Example 127(a) to provide 4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl)-6,7-dimethoxyquinazoline.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl-].[Cl:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1.[CH3:35][N:36]([CH2:38][CH:39]1[CH2:44][CH2:43][C:42](=O)[CH:41]=[C:40]1[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=1)[CH3:37]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:13]=[C:42]2/[CH:41]=[C:40]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH:39]([CH2:38][N:36]([CH3:37])[CH3:35])[CH2:44][CH2:43]/2)=[CH:33][CH:34]=1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cccc(C2=CC(=O)CCC2CN(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cccc(C2=C/C(=C/c3ccc(Cl)cc3)CCC2CN(C)C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
21.6 g potassium tert-butylate and 65 g 4-chlorobenzyltriphenylphosphonium chloride were suspended in 800 ml analytical grade toluene under a nitrogen atmosphere at room temperature and the suspension was then stirred at 70° C. for one hour. 11.5 g 4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enone in 100 ml analytical grade toluene were added at this temperature and the mixture was stirred at 70° C. for 3 days. The mixture was quenched with 500 ml water. The phases were separated and the aqueous phase was washed 3 times with 200 ml ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and then freed from the solvent in vacuo. The solid which had precipitated out was filtered off and washed with diiso-ether. The combined organic phases were freed from the solvent in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate/methanol=9/1. 5.2 g E-[4-(4-chloro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine base were obtained as the first product fraction. To prepare the hydrochloride, the base was dissolved in 50 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 4.7 g (27.6% of theory) of the title compound 46 were obtained in this way in the form of white crystals. 3.5 g Z-[4-(4-chloro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine base were obtained as the second product fraction. To liberate the hydrochloride, the base was dissolved in 50 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 3 g (17.6% of theory) of the title compound 41 were obtained in this way in the form of white crystals.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1.[NH3:18]>ClCCl>[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:18])=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1
Reactant: N
Reactant: O=C(O)c1ccc(SC2CC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionylchloride (342 μL, 4.7 mmol) is added to a solution of 4-cyclopropylsulfanyl-benzoic acid (prepared as described in WO07003960, 190 mg, 0.98 mmol) in dichloro-methane (1.9 mL). The mixture is heated at reflux for 30 min and concentrated under reduced pressure. The residue is treated with toluene, and all volatiles are evaporated. The residue is dissolved in chloroform (1.9 mL) and treated with concentrated aqueous ammonia (770 μL, 9.8 mmol). The mixture is stirred at room temperature for 1 h and then extracted with water. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 137 mg (72% of theory); ESI mass spectrum: [M+H]+=194; Retention time HPLC: 0.45 min (X011_S03).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH3:22]
Reactant: COc1ccccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.5 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.6 mmol of 2-methoxybenzenethiol, and 1.6 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 170-172° C. dec.). 1H NMR (DMSO-d6) δ 3.76 (bs, 5 H), 5.44 (dd, 1 H), 6.26 (t, 1 H), 6.85 (m, 1 H), 6.91 (t, 1 H), 7.34-7.50 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[C:20]([CH:23]=3)[CH:21]=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[C:20]([C:21]#[CH:32])[CH:23]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
152 mg (0.79 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphate in 2 mL MeOH are added to a solution of 300 mg (0.66 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (Example 3.55b) and 183 mg (1.32 mmol) K2CO3 in 9 mL MeOH. The reaction solution is stirred for for 3 h at RT and diluted with 20 mL DCM. The organic phase is extracted twice with saturated NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by HPLC-MS.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>ClCCl>[Cl:3][C:14]1[CH:15]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=[C:12]([CH3:17])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C(C)(C)C)cc[n+]1[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C)cc(Cl)n1
Temperature: 100 °C

Procedure:
Add phosphorus oxychloride (15 mL) to 4-tert-butyl-2-methyl-pyridine 1-oxide (2.00 g, 12.10 mmol) and heat to 100° C. for 36 hours. Evaporate off the excess phosphorus oxychloride. Treat the oil cautiously with ice and water with stirring and make basic by treatment with aqueous bicarbonate solution. Extract with dichloromethane (3×75 mL) and pool, desiccate, filter, and concentrated. Chromatograph the crude product on silica using a gradient of (0→5→8%) ethyl acetate in dichloromethane to afford the title compound (0.82 g, 4.46 mmol). MS (ESI), m/z 184 (M+1).