Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Sn](CCCC)(CCCC)CCCC)[CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:23]=[N:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:26][CH:27]=1>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.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:22]2[N:23]=[N:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:26][CH:27]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Reactant: Clc1ccc(-c2ccccn2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2ccc(-c3ccccn3)nn2)n1

Procedure:
The 3-(6-methylpyridin-2-yl)-6-(pyridin-2-yl)pyridazine 44 was prepared according to the general Stille coupling method, starting from a mixture of 2 g (5.23 mmol) of 6-methyl-2-tributylstannylpyridine 22, 666 mg (3.49 mmol) of 3-chloro-6-(pyridin-2-yl)pyridazine 8a, 208 mg (0.18 mmol) of tetrakis(triphenylphosphine)palladium(0) and 50 ml of freshly distilled toluene. The reaction medium is stirred at reflux for 18 h. The residue obtained is chromatographed on silica gel (eluent: ethyl acetate/petroleum ether=2/8). The coupling product 44 is isolated with a yield of 90%.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([C@H:19]2[O:12][CH2:11][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CCCC1CCC(C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(F)c(F)c3)OC2)CC1

Procedure:
In 40 cm3 of dichloromethane, 1.5 g (0.008 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol, 1.5 g (0.01 mol) of 3,4-difluorobenzaldehyde (manufactured by Aldrich), and 0.1 g of TsOH were refluxed for 3 hours over a hot water bath fitted with a Dean-Stark trap and the water formed was removed continuously from the reaction system. The reaction solution was washed with water and the dichloromethane was distilled off. The distillation residue was recrystallized from a solvent mixture of acetone and methanol to yield 1.6 g (0.005 mol) of trans-2-(3',4'-difluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition points, measured by DSC, were: ##STR31## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.C(Cl)Cl.CS(C)=O>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC(c1ccccc1)c1ccc2occc2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc2occc2c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of benzofuran-5-yl(phenyl)methanol (4.0 g, 18 mmol) and triethylamine (7.3 mL, 54 mmol) in 30 mL 1:1 DCM/DMSO under nitrogen at 0° C. was added a solution of SO3*py (8.5 g, 54 mmol) in 20 mL DMSO dropwise via addition funnel. The reaction was allowed to stir 5 h at 0° C. and was quenched by addition of water and 250 mL Et2O. The organic layer was washed with water, 1N HCl, 1N NaOH, brine, and was dried over sodium sulfate, filtered, and concentrated. The resulting solid benzofuran-5-yl(phenyl)methanone was used without further purification. MS (ESI) m/z: Calculated: 222.1; Observed: 223.0 (M++1).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH3:42])=[C:10]([CH:41]=2)[C@H:11]([C:29]2[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=2[CH3:40])[O:12]C(=O)[C@H](C2C=CC3C(=CC=C(OC)C=3)C=2)C)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[OH:12][C@@H:11]([C:29]1[C:30]([CH3:40])=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][C:38]=1[CH3:39])[C:10]1[CH:41]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=[CH:8][C:9]=1[CH3:42]
Reactant: COC(=O)c1cc(C)c([C@H](OC(=O)[C@@H](C)c2ccc3cc(OC)ccc3c2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2ccnc2)cc1[C@@H](O)c1c(C)cc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
Methyl (R)-4-[5-(1-imidazolyl)-α-{(S)-2-(6-methoxy-2-naphthyl)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate (35 g) obtained in Example 9 was suspended in methanol (280 ml) and an aqueous solution (70 ml) containing sodium hydroxide (6.2 g) was added, which was followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated and to the residue were added dimethylformamide (210 ml) and water (210 ml), which was followed by neutralization with glacial acetic acid (17.5 ml). The precipitated crystals were collected by filtration, washed with water and acetone, and recrystallized from dimethylformamide to give 17.8 g of (R)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, melting point 286-288° C. (decomposition), optical rotation [α]D21 +260.5° (c=1.0, dimethylformamide).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]3[C:23]4[C:22](=[O:24])[NH:21][C:20]([NH:25]C(=O)CCCCCCC)=[N:19][C:18]=4[NH:17][CH:16]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[K+]>>[NH2:25][C:20]1[NH:21][C:22](=[O:24])[C:23]2[C:15]([CH2:14][NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]4[CH:35]=[CH:36][C:2]([NH2:1])=[CH:3][CH:4]=4)=[CH:12][CH:11]=3)=[CH:16][NH:17][C:18]=2[N:19]=1
Reactant: CCCCCCCC(=O)Nc1nc2[nH]cc(CNc3ccc(Cc4ccc(N)cc4)cc3)c2c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(Cc2ccc(NCc3c[nH]c4nc(N)[nH]c(=O)c34)cc2)cc1

Procedure:
The synthesis of 2-amino-5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 24 follows the same steps as the synthesis of 4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoic acid 21, except that octanoic acid{5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide 18 is reacted with 4,4′-methylene dianiline 22 to form octanoic acid (5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 23. Octanoic acid (5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 23 is then reacted with 5M KOH to form 2-amino-5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 24.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Li]C(CC)C.CN(C)[CH:20]=[O:21]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:3]=1[CH:20]=[O:21]
Reactant: CC(C)COc1cccc(F)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)COc1cccc(F)c1C=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 1-fluoro-3-isobutoxybenzene (1.7 g, 10 mmol, EXAMPLE 16, Step 1) in tetrahydrofuran (15 mL) was added dropwise s-BuLi (0.99 M in cyclohexane, 12 mL, 12 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 1 h. N,N-dimethylformamide (1.2 mL, 15 mmol) was added to the mixture, and the mixture was warm to −20° C. After being stirred at −20° C. for 1 h, the mixture was quenched with aq. sodium hydrogencarbonate (30 mL). The mixture was extracted with ethyl acetate (60 mL) and washed with water (30 mL). The extract was dried over magnesium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 30:1) to give 1.2 g (61%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[O:24][C:25]=1[CH3:26].FC(F)(F)C1C=CC=CC=1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2ccccc2C(F)(F)F)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1C(F)(F)F
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3C(F)(F)F)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 4-chloromethyl-5-methyl-2-(2-trifluoromethyl-phenyl)-oxazole (prepared from 2-trifluoromethyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[C:17](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.ClCCl>O1CCOCC1>[CH3:17][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccn2c(C3CCOCC3)ncc12
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nccn2c(C3CCOCC3)ncc12
Yield: 77.2 %

Procedure:
Through a suspension of 8-chloro-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (2.23 mmol, 531 mg) and potassium carbonate (3.35 mmol, 463 mg) in dioxane (1.5 mL) was bubbled nitrogen for 5 minutes and then trimethylboroxine (4.47 mmol, 1.249 mL, 50 wt % solution in tetrahydrofuran) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.223 mmol, 181 mg) were added. After heating the reaction at 100° C. for one hour the reaction mixture was filtered and concentrated in vacuo. Dichloromethane and water were added, the organic layer separated, dried (sodium sulfate) and concentrated in vacuo to yield 374 mg 8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:24](=[O:26])=[O:25]>C1CCCCC1>[SH:10][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: CC(C)c1ccccc1S
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: CC(C)c1cccc(C(=O)O)c1S
Reaction time: 24 h

Procedure:
To a solution of 1.0 mmol 2-isopropylthiophenol and 2.2 mmol TMEDA in 2 mL cyclohexane was added 2.2 mmol n-BuLi. Then after stirring 24 h it was added to solid CO2 and stirred for 16 h when extraction and chromatography provided 2-mercapto-3-isopropylbenzoic acid. The methyl ester of this was treated as in example 3 to provide the title compound.
Reaction SMILES: ClC1C(CN2C(=O)N3C=CC(C4C=CC(Cl)=CC=4)=C(C4C=CN=CC=4)C3=N2)=CC=C(C(F)(F)F)N=1.[OH-].[NH4+].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][N:48]3[C:51](=[O:67])[N:52]([CH2:54][C:55]4[C:56]([NH:65]C)=[N:57][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:60]=4)[N:53]=[C:47]3[C:46]=2[C:68]2[CH:73]=[CH:72][N:71]=[CH:70][CH:69]=2)=[CH:41][CH:40]=1>>[NH2:65][C:56]1[C:55]([CH2:54][N:52]2[C:51](=[O:67])[N:48]3[CH:49]=[CH:50][C:45]([C:42]4[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=4)=[C:46]([C:68]4[CH:73]=[CH:72][N:71]=[CH:70][CH:69]=4)[C:47]3=[N:53]2)=[CH:60][CH:59]=[C:58]([C:61]([F:64])([F:63])[F:62])[N:57]=1
Reactant: CNc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: [NH4+]
Agent: [OH-]
Product: Nc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Yield: 33 %

Procedure:
The title compound (6 mg, 33% yield) as a yellow powder was prepared from 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (22 mg, 0.043 mmol), and 28% aqueous ammonium hydroxide solution (0.5 mL) according to the procedures described for 7-(4-chlorophenyl)-2-((2-(methylamino)-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. HPLC/MS: retention time=2.87 min, [M+H]+=497.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(OC)cc2)nc(N)n1
Yield: 61 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 4-methoxy-phenylamine provided the title compound (61% yield). 1H NMR (DMSO-d6) δ 1.34 (t, 3H, J=6.9 Hz, CH3), 3.74 (s, 3H, CH3), 4.10 (q, 2H, J=7.0 Hz, CH2), 6.18 (s, 2H, NH2), 6.71 (s, 1H, Ar), 6.89 (d, 2H, J=8.6 Hz, Ar), 7.12 (d, 1H, J=8.9 Hz, Ar), 7.39 (dd, 1H, J=8.8 Hz, 2.9 Hz, Ar), 7.53 (d, 2H, J=8.6 Hz, Ar), 7.94 (d, 1H, J=2.8 Hz, Ar), 8.93 (s, 1H, NH).
Reaction SMILES: FC1C=CC=C(F)C=1C(Cl)=O.C1(OC)C=CC=CC=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(O)C#C.C1C=CC2C(=CC=CC=2O)C=1.[OH-].[Na+].[F:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:53]=1[C:59]1([C:73]2[CH:78]=[CH:77][C:76]([O:79][CH3:80])=[CH:75][CH:74]=2)[O:64]C2C=CC3C(C=2C=C1)=CC=CC=3>C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:53]=1[C:59]([C:73]1[CH:74]=[CH:75][C:76]([O:79][CH3:80])=[CH:77][CH:78]=1)=[O:64]
Reactant: COc1ccc(C2(c3c(F)cccc3F)C=Cc3c(ccc4ccccc34)O2)cc1
Agent: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cl)c1c(F)cccc1F
Solvent: S=C=S
Solvent: COc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2c(F)cccc2F)cc1
Reaction time: 1 h

Procedure:
2,6-difluoro-4'-methoxybenzophenone was prepared by Friedel-Crafts reaction of 2,6-difluorobenzoyl chloride with anisole in carbon disulfide using aluminum chloride as catalyst. 4.8 grams (0.02 mole) of the benzophenone was converted to the propargyl alcohol using the conditions described in Example 1, Step 2. The crude propargyl alcohol was taken up in 200 milliliters of benzene and 3.0 grams (0.02 mole) of naphthol and 0.1 grams of p-toluene sulfonic acid catalyst was added to the benzene solution. After stirring for 1 hour, the reaction mixture was poured into an equal volume of 5 percent aqueous sodium hydroxide. The organic layer was separated and the benzene solvent removed on a rotary evaporator. The residue was chromatographed on silica using a 4:1 mixture of hexane:ethyl acetate as elutant. The photochromic fractions were collected and crystallized from n-propanol. 1.2 grams of product having a melting range of 122-124° C. was obtained. NMR analysis confirmed the product to be 3(2,6-difluorophenyl)-3(4-methoxyphenyl)-3H- naphtho[ 2,1-b]pyran.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[C:16]([OH:18])=[O:17].OS(O)(=O)=O.[CH3:24]O>>[OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[C:16]([O:18][CH3:24])=[O:17]
Reactant: CO
Reactant: NS(=O)(=O)c1ccc(SCCCO)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(S(N)(=O)=O)ccc1SCCCO

Procedure:
4-(3-hydroxypropylthio)-3-carboxybenzene-sulfonamide (15 g, 0.0515 mol) and concentrated H2SO4 (4 ml) were dissolved in methanol (150 ml) and refluxed on a steam bath for about 5 hours. The solvent was removed and the residue was treated with water. The mixture was extracted with ethylacetate, which was washed with water, saturated sodium bicarbonate, water and brine. After drying, removal of the solvent left a tannish solid. Recrystallization from 1,2-dichloroethane gave 13.5 g of a white solid. M.p.=123°-125°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.CC([O-])=O>C(O)C.[Pd]>[NH:1]1[CH2:2][CH2:3][CH:4]([CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=Cc1ccncc1)C(=O)OCC
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)C(=CC1CCNCC1)C(=O)OCC
Reaction time: 20 h

Procedure:
A solution of diethyl (4-pyridylmethylene)malonate [XXVIIIb] (97.6 g) in absolute ethanol (1 L) was hydrogenated in the presence of acetic acid glacial (35.5 g) and 10% Palladium on activated carbon catalyst (9.7 g) at 60° C. and 200 psi for 20 hours. The catalyst was filtered off and the resulting solution of the title compound in the form of acetic acid salt was used directly in the next step.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[C:2]=[O:3].[NH4+:24].[OH-]>C1COCC1>[O:23]=[C:15]1[C:14](=[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]([CH2:4][NH:1][C:2]([NH2:24])=[O:3])[O:6]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: [NH4+]
Reactant: O=C=NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of 3-(3-Isocyanatomethyl-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (65 mg, 0.21 mmol) in THF (4 ml) at room temperature was added concentrated NH4OH (2 ml). The reaction was stirred 5 minutes and then partitioned between EtOAc and water. The organic layer was washed with very dilute HCl, brine, dried with anhydrous Na2SO4 and rotary evaporated to obtain a solid. The solid was recrystallized from EtOAc/MeOH to give [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-ylmethyl]-urea as a yellow solid (46 mg, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[O:37](C1C=CC(C(=O)C)=CC=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:2][CH:7]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(Oc5ccccc5)cc4)ccc3c1)n2C1CCCCC1
Yield: 31 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-phenoxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (42 mg, 31% yield).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CN(CCN(CCN(C)C)C)C.[Li]CCCC.CN([CH:38]=[O:39])C>C1COCC1>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:38]=[O:39])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of Intermediate 188.2 (7.50 g, 29.5 mmol) and PMDTA (6.5 mL, 31.1 mmol) in 30 mL THF at −78° C., was added BuLi (1.4 M in hexanes, 23.2 mL, 44.3 mmol). The thick slurry was stirred at −40° C. for 30 min, was recooled to −70° C. DMF (4.57 mL, 59 mmol) was added. The yellow solution was removed from the cooling bath and allowed to warm to rt and stirred 1 h. The reaction was quenched with sat. NH4Cl, then was diluted with hexanes. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), filtered through 2″ silica gel (eluting with 5% EtOAc/hexanes), then concentrated to afford 8.03 g of Intermediate 188.3 as a pale yellow oil.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12](=O)([O-:14])[O-:13].[K+].[K+].C(OCC)C.CCCCCC>O.CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([C:12]([OH:14])=[O:13])=[C:3]([CH3:11])[CH:2]=1)([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc([N+](=O)[O-])c1I
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reaction time: 16 h
Yield: 31.2 %

Procedure:
A mixture of 1.0 g (3.8mmol) of 2-iodo-nitrotoluene, 2.1 g (15.2mmol) potassium carbonate and 27 mg (0.038 mmol) of palladium(II) dichloride bis(triphenylphosphine) in a mixture of 5 mL of water and 10 mL of N,N-dimethylformamide. This was placed in a Fisher/Porter bottle under 15 psig of carbon monoxideand heated at 70 C. for 16 hours. The solution became homogeneous when heated. The reaction was cooled, diethyl ether and water was added, the organic layer separated and discarded. The aqueous layer was acidified with 1N hydrohloric acid, extracted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to yield 0.5 g of crude material. This dissolved in ethyl acetate, hexane added and the resulting brown solid discarded. The filtrate was concentrated, and then recrystallized fom diethyl ether/hexane to afford 215 mg of 4-nitro-2-methylbenzoic acid, m/e=182(M+H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1>C(Cl)Cl>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N+:14]=1[O-:9]
Reactant: Cc1cnc(C)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)c(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
3-Chloro per benzoic acid (10 g, 164.2 mmol) was added to a solution of 2,3,5-trimethylpyridine (10 g, 82.1 mmol) in DCM at 0° C. and the mixture was stirred at RT for 8 h (the reaction was monitored by TLC). The reaction was quenched with sodium bicarbonate solution and stirred for 1 h at RT. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2,3,5-trimethylpyridine 1-oxide (6.5 g, 58.0%) as a brown solid. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.15 (s, 1H), 2.55 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H). MS: [M+H]+: m/z=311.2.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[I:23]>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]=2[CH3:1])=[O:19])=[CH:16][C:15]=1[I:23]
Reactant: Cc1c(N)cccc1C(F)(F)F
Reactant: O=C(Cl)c1ccc(Cl)c(I)c1
Product: Cc1c(NC(=O)c2ccc(Cl)c(I)c2)cccc1C(F)(F)F

Procedure:
4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide was synthesized from 2-methyl-3-(trifluromethyl)aniline and 4-chloro-3-iodobenzoyl chloride according to the procedure dscribed in Example 183. 4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide was obtained as a white solid. MS (M−H+) 437.8; Calculated for C15H10ClF3INO: 439.