Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2)[CH3:5].[Se](=O)=[O:19]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH:17]=[O:19])[CH:13]=[CH:12]2)[CH3:5]
Reactant: O=[Se]=O
Reactant: COC[C@@H](C)Oc1cccc2ccc(C)nc12
Solvent: O
Solvent: C1COCCO1
Product: COC[C@@H](C)Oc1cccc2ccc(C=O)nc12
Yield: 90.1 %

Procedure:
To a solution of (R)-8-(1-methoxypropan-2-yloxy)-2-methylquinoline (0.45 g, 1.9 mmol) in dioxane (35 mL) and water (0.35 mL) was added selenium dioxide (0.26 g, 2.3 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.42 g, 88%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:4]=1
Reactant: OCc1cccnc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.4 g) in DMF (8 ml) was added dropwise a solution of 3-pyridinemethanol (1.09 g) in DMF (5 ml), and the mixture was stirred at room temperature for 30 minutes. Then a solution of tert-butyl bromoacetate (1.62 ml) in DMF (5 ml) was added to the mixture. After stirring for one hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOEt (20 ml), washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified with SiO2 column chromatography (eluted with 1% MeOH in CHCl3) to give tert-butyl (3-pyridylmethoxy)acetate (435 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[CH3:2].CI.[CH2:36](I)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH3:36])[CH2:15][C:16]2[O:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCOC(=O)COc1c(C)cc(NCc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reactant: CCI
Solvent: CI
Product: CCOC(=O)COc1c(C)cc(N(C)Cc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
The title compound was prepared in analogy to example 15.4 from the above prepared (2,6-dimethyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester, but using methyl iodide as electrophile instead of ethyl iodide, as off-white solid, MS: 477.5 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1>[CH3:18][C@H:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:24]1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc(Br)cc1
Reactant: C[C@@H]1CNCCN1
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CCN1
Yield: 100 %

Procedure:
Synthesized according to general procedure 8. The reaction was set up with 4-bromo-N-(pyrimidin-4-yl)benzenesulfonamide (2.4 mmol), (R)-2-methylpiperazine (4.7 mmol), Pd(dba)3 (0.12 mmol) 2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), and toluene (12 mL). For the purification, 10% MeOH in CH2Cl2 with the addition of 1% triethylamine was used as a solvent system to obtain the desired amine as a white solid. (900 mg, 100% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=334.3; tR=0.4 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9]Br>OS(O)(=O)=O.O=S(=O)=O>[Br:9][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cccnc1C
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1cc(Br)cnc1C

Procedure:
2,3-Dimethylpyridine is treated with bromine in oleum to give 3-bromo-5,6-dimethylpyridine which is converted into a Grignard reagent, and this is treated with ethyl orthoformate and the product hydrolysed to give 5,6-dimethylpyridine-3-carboxaldehyde. This aldehyde is condensed with malonic acid and the product is hydrogenated and esterified to give ethyl β-(5,6-dimethyl-3-pyridyl)propionate. Substitution of this ester for ethyl β-(3-pyridyl)propionate in the procedure of Example 6 and fusion of the product with 2-(5-methyl-4-imidazolylmethylthio)ethylamine gives 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([OH:13])[CH:11]2[CH2:12][N:8]([CH2:9][CH2:10]2)[CH2:7]1)C.[NH2:15][NH2:16]>CO>[OH:13][C:6]1([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH:11]2[CH2:12][N:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: NN
Reactant: CCOC(=O)CC1(O)CN2CCC1C2
Solvent: CO
Product: NNC(=O)CC1(O)CN2CCC1C2
Reaction time: 8 h
Yield: 107 %

Procedure:
To a solution of the product of step (a) (1.12 g, 0.0056 moles) in methanol (20 ml) at room temperature was added anhydrous hydrazine (1.76 ml, 0.056 moles) and the mixture was stirred overnight. The mixture was concentrated in vacuo and azeotroped twice with toluene (100 ml) by heating to reflux in an apparatus fitted with a Dean-Stark trap to give the subtitle compound (1.11 g).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH2:18]([O:20][CH:21]([O:29][CH2:30][CH3:31])[C:22]1[S:26][CH:25]=[C:24]([CH:27]=O)[CH:23]=1)[CH3:19]>C1COCC1>[CH2:18]([O:20][CH:21]([O:29][CH2:30][CH3:31])[C:22]1[S:26][CH:25]=[C:24](/[CH:27]=[CH:3]/[C:1]#[N:2])[CH:23]=1)[CH3:19]
Reactant: CCOC(OCC)c1cc(C=O)cs1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(/C=C/C#N)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (100 mg, 0.0008 mol) in THF (2 mL, 0.02 mol) cooled at 0° C. and 1.0 M potassium tert-butoxide in THF (0.8 mL) was added dropwise. The bath was removed and the reaction was warmed to room temperature for 30 minutes. The reaction was cooled to 0° C. and a solution of 5-(diethoxymethyl)thiophene-3-carbaldehyde (170 mg, 0.00079 mol) in THF (2 mL, 0.02 mol) was added drop wise. The reaction was stirred overnight at room temperature. The reaction was partitioned between water and ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (ethyl acetate:hexane, 1:5) to give (2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile as an oil (160 mg, 84.9%). 1H NMR (300 MHz, CDCl3): δ 7.4-7.0 (m, 3H), 5.65 (m, 1H), 4.2 (m, 1H), 3.65 (m, 4H), 1.25 (m, 6H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=[O:5])C.[OH-].[Li+]>>[C:30]([C:26]1[CH:25]=[C:24]([N:7]2[CH2:8][CH:9]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])(=[O:12])=[O:13])[CH2:10][CH:6]2[C:4]([OH:5])=[O:3])[CH:29]=[CH:28][CH:27]=1)#[N:31]
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Product: N#Cc1cccc(N2CC(S(=O)(=O)c3ccccc3C(F)(F)F)CC2C(=O)O)c1

Procedure:
In analogy to the procedure described in example 253e, 1-(3-cyano-phenyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=425.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[Li].BrBr.[CH3:33][S:34]SC>C1(C)C=CC=CC=1.CCOCC>[Cl:19][C:14]1[CH:13]=[C:12]([CH:9]2[O:8][C:5]3=[N:6][CH:7]=[C:2]([S:34][CH3:33])[CH:3]=[C:4]3[CH2:11][CH2:10]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CSSC
Reactant: Clc1ccc(C2CCc3cc(Br)cnc3O2)cc1Cl
Agent: BrBr
Agent: [Li]
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCC
Solvent: CCOCC
Product: CSc1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: -100 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.6 g of 6-bromo-2-(3,4-dichlorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine in a mixture of 50 ml of toluene and 25 ml of anhydrous ether was cooled to -100° C. under nitrogen and 3.8 ml of 2.9M tert-butyllithium/pentane was added dropwise over about 5 minutes while keeping the temperature below -100° C. This gave a deep blue-green mixture containing the lithio intermediate (i.e., lithium replacing the bromine in the starting material). After 20 minutes, 1.8 ml of dimethyldisulfide was added. The mixture was then allowed to warm to 0° C. and it was partitioned between ether and water. The ether layer was washed with aqueous saturated sodium chloride solution, dried over potassium carbonate and concentrated to a yellow oil which solidified on cooling. Column chromatography on silica gel (20% ethyl acetate/hexane) gave pure product which was further recrystallized from hexane/ethyl acetate to give 2-(3,4-dichlorophenyl)-3,4-dihydro-6-(methylthio)-2H-pyrano[2,3-b]pyridine as colorless needles melting at about 109°-111° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2].CI.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:13]1[C:7]2[CH:6]=[C:5]([O:22][CH2:23][CH3:24])[C:4]([O:3][CH2:1][CH3:2])=[CH:21][C:8]=2[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][CH2:11][C:12]1=[O:14])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NCC(=O)N2
Solvent: CI
Product: CCOc1cc2c(cc1OCC)N(Cc1ccccc1)C(=O)CN=C2c1ccccc1
Yield: 32 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIag), and MeI by benzyl bromide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 32%. M: 158–160° C. 1H-NMR (CDCl3, 300 MHz): d 1.33 (t, 3H, CH3), 1.40 (t, 3H, CH3), 3.84–3.95 (m, 3H, OCH2+1H CH2) 4.04 (q, 2H OCH2), 4.87 (m, 1H CH2), 5.15 (AB system, ? d=0.74, JAB=15.4, 2H, —NCH2), 6.58 (s, 1H Ar), 6.81 (s, 1H Ar), 7.07–7.46 (m, 10H Ar).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30].CS(Cl)(=O)=O>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:31])[CH3:30])[CH2:22][CH2:23]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Reactant: CC(=O)Cl
Agent: CS(=O)(=O)Cl
Product: CC(=O)N1CCC(CS(=O)(=O)c2ccc3c(c2)nc(CC(C)(C)C)n3CC2CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-5-[(piperidin-4-ylmethane)sulfonyl]-1,3-benzodiazole (STEP D of Example 5) and acetyl chloride instead of 5-(azetidin-3-ylmethylsulfonyl)-1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazole and methanesulfonyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:41])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([CH3:40])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][C:35]1[CH:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:41])[NH:22][C:9]4[CH:10]=[C:11]([C:18]([F:21])([F:19])[F:20])[C:12]([O:14][CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:38]=[C:37]([CH3:39])[N:36]=1
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M199) (319 mg, 0.545 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (172 mg, 68%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1

Procedure:
4-(6-Chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-yl amine hydrochloride (0.155 g, 0.465 mmol) was reacted with methanesulfonyl chloride (0.0531, 0.465 mmol) and triethylamine (0.290 g, 2.87 mmol) in 5 mL of chloroform at 0° C. for one hour and 16 hours at room temperature. The reaction mixture was poured into 50 mL of water and extracted with 3×50 mL of ethyl acetate. The pooled organic layers were washed with 50 mL of brine, dried with magnesium sulfate, filtered and vacuum evaporated to a yellow residue, 0.121 g. This was purified by chromatography using a Chromatotron mounted with a 2 mm silica gel plate and eluted with 5% methanol in chloroform. Pure product was isolated by vacuum evaporation of the appropriate fractions; 0.015 g (8.7%) M.P. 240°-245° C. (dec).
Reaction SMILES: [C:1]([C:3]1([CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[OH-].[Na+]>CO.O>[C:1]([C:3]1([CH:9]([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)C(C(=O)OCC)C1(C#N)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CC1(C(C(=O)O)C(=O)O)CCCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
50 g Diethyl (1-cyanocyclohexyl)-malonate are dissolved in 175 mL methanol at 40° C. At this temperature, a solution of 29.9 g sodium hydroxide in 150 mL water is added dropwise. The reaction mixture is stirred for 30 minutes at 40° C. After cooling to 20° C., the precipitated product (sodium salt) is filtered off with suction, the filter cake is washed with 50 mL methanol and the product is dried at 60° C. to constant weight. The product is dissolved in 500 mL of water at 10° C., and adjusted to a pH of one to two at 10-15° C. with concentrated hydrochloric acid. The substance which precipitates out is extracted three times with, in each case, 300 mL ethyl acetate. The combined ethyl acetate phases are dried and evaporated on a rotary evaporator at 35° C. The white residue obtained is dried to constant weight at 35° C. in a vacuum drying cabinet. 35.5 g of the title compound are obtained (89.8% of theory); m.p. 99.9° C.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:4]1=2.[OH:21]O>C(O)(=O)C>[CH3:1][S:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:4]1=2)=[O:21]
Reactant: CSC1c2ccccc2COc2ccc(C(=O)O)cc21
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)C1c2ccccc2COc2ccc(C(=O)O)cc21
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Dissolve with warming 380 mg. of 6,11-dihydro-11-methylthiodibenz[b,e]oxepin-2-carboxylic acid in 38 ml. of glacial acetic acid. Place the reaction mixture in an oil bath at 40° C. and add 1.5 ml. of 30% hydrogen peroxide. Stir the mixture at 40° C. for 3 1/2 hours until the solution clears. Dilute with 300 ml. of water and separate the precipitate by filtration to obtain the title product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH-].[K+].C(O/[CH:14]=[CH:15]/[C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=1)CCC.[I-].[NH2:25][N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.O>[Cl:23][C:18]1[N:17]=[C:16]([C:15]2[CH:14]=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[C:21]([Cl:22])=[CH:20][N:19]=1
Reactant: N[n+]1ccccc1
Reactant: CCCCO/C=C/c1nc(Cl)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.3 %

Procedure:
K2CO3 (20.82 g, 150.65 mmol) and KOH (16.91 g, 301.31 mmol) were added in one portion to a mixture of (E)-4-(2-butoxyvinyl)-2,5-dichloropyrimidine (Intermediate 22, 74.46 g, 301.31 mmol) and 1-aminopyridinium iodide (66.9 g, 301.31 mmol) in DMSO (1.415 L) at r.t. The mixture was stirred at r.t. for 1.5 h and then at 90° C. for 4 h. After cooling, the mixture was diluted with water (5 L) and stirred for 0.5 h. The resulting solid was collected by filtration and washed with water (5 L). Purification by FCC, eluting with 0-20% EtOAc in CH2Cl2 gave the title compound (16.2 g, 20%) as a cream solid after trituration with diethyl ether; 1H NMR: 7.29 (1H, td), 7.74 (1H, ddd), 8.58 (1H, dt), 8.82 (1H, s), 8.98 (1H, dt), 9.10 (1H, s). m/z: ES+, MH+ 264.89.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:5]=2[N:6]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:5]=2[N:6]=1
Reactant: CCOC(=O)C1CCc2sc(Br)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCc2sc(Br)nc21
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of the product from step A (4.92 g, 17.82 mmol) was dissolved in methanol (20 mL) and added dropwise to a mixture of 5 N NaOH (4.25 mL, 21.25 mmol), water (16 mL) and methanol (30 mL). After addition was complete the mixture was stirred for 2 h. The methanol was removed by evaporation and the pH of the remaining aqueous was adjusted to ˜2.5 with conc. HCl. The mixture was saturated with solid NaCl and extracted with EtOAc (×3); combined EtOAc layers washed with sat. NaCl, dried over Na2SO4 and treated with activated charcoal overnight. The filtered mixture was evaporated. The residue was triturated with EtOAc, and the solid filtered to give 1.94 g of the desired product. The mother liquors were evaporated and purified by MPLC using a gradient rising from 100% Hexanes to 100% EtOAc in Hexanes to give a further 0.82 g of the title product (2.76 g in total, 62%) as an off white solid. 1H NMR (500 MHz CDCl3) δ: 4.04 (m, 1H), 3.02-3.08 (m, 1H), 2.88-2.94 (m, 1H), 2.78-2.83 (m, 2H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].CC(C)([O-])C.[K+].[CH3:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:23])[C:21]=1[CH3:22])=[CH:18][C:17]([S:24]([O-])(=[O:26])=[O:25])=[CH:16][CH:15]=2.[Na+].II.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.O.C1(C)C=CC=CC=1>[CH3:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:23])[C:21]=1[CH3:22])=[CH:18][C:17]([S:24]([CH2:4][N+:1]([O-:3])=[O:2])(=[O:25])=[O:26])=[CH:16][CH:15]=2
Reactant: C[N+](=O)[O-]
Reactant: Cc1oc2ccc(S(=O)(=O)[O-])cc2c(=O)c1C
Agent: CC(C)(C)[O-]
Agent: II
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc2ccc(S(=O)(=O)C[N+](=O)[O-])cc2c(=O)c1C
Reaction time: 0.5 h
Yield: 7.5 %

Procedure:
Nitromethane (0.92 ml, 17 mmol) was added dropwise to a stirred solution of potassium t-butoxide (0.84 g, 8.4 mM) in N,N-dimethylformamide (DMF; 40 ml) at -5° C. When the addition was complete, stirring was continued for 30 minutes at -5° C. Sodium 2,3-dimethyl-4-oxo-4H-chromene-6-sulphonate (2.2 g, 8.5 mM) was then added, followed immediately by iodine (1.07 g, 4.2 mM). The mixture was allowed to attain ambient temperature and stirred overnight. The reaction mixture was then added to a solution of citric acid (15 g) and sodium metabisulphite (3 g) in water (150 ml). The aqueous mixture was extracted with dichloromethane (3×50 ml) and the combined organic extracts were washed with sodium chloride solution. The solvent was removed by evaporation and the residual semi-solid purified by flash vacuum chromatography on silica, eluting with ethyl acetate/hexane (1:1 v/v), to give 2,3-dimethyl-6-(nitromethyl-sulphonyl)-4H-chromen-4-one as a solid (178 mg, 7.1% yield), m.p. 206°-209° C. [after recrystallisation from toluene]; NMR (d6DMSO): 2.0(3H,s), 2.45(3H,s), 7.5(2H,s), 7.75(1H,d), 8.1(1H,dd), 8.45(1H,d); microanalysis, found: C,49.0; H,3.6; N,4.7%; C12H11NO6S requires: C,48.5; H,3.6; N,4.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43]C)[N:38]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Li+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]3[NH:38][C:39](=[O:43])[CH:40]=[CH:41][CH:42]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1cccc(-c2cc3nc(N4CCOC[C@H]4c4ccccc4)n(C[C@H]4CC[C@H](C)CC4)c3c(-c3cncc(Cl)c3)n2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(-c4cccc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-(5-chloropyridin-3-yl)-6-(6-methoxypyridin-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine (63.0 mg, 0.104 mmol), p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol), and lithium chloride (44.1 mg, 1.04 mmol) in DMA (1.0 mL) was heated at 100° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (2×10 mL), and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 10% CH2Cl2/MeOH) afforded 6-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}pyridin-2(1H)-one. 1H NMR (400 MHz, CDCl3) δ 10.69 (br s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.50 (m, 1H), 8.02 (s, 1H), 7.86 (m, 1H), 7.50 (dd, J=9.0, 6.8 Hz, 1H), 7.32-7.41 (m, 2H), 7.23-7.31 (m, 3H), 6.79-6.86 (m, 1H), 6.58 (d, J=9.0 Hz, 1H), 4.66 (m, 1H), 4.08-4.14 (m, 2H), 3.92-4.07 (m, 2H), 3.62-3.74 (m, 1H), 3.36-3.54 (m, 3H), 1.39-1.51 (m, 2H), 1.02-1.18 (m, 1H), 0.80-0.94 (m, 1H), 0.75 (d, J=6.4 Hz, 3H), 0.55-0.71 (m, 4H), 0.36-0.52 (m, 2H). MS ES calc'd. for C34H35ClN6O2 [M+H]+ 595. found 595.