Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+].I[CH2:32][CH:33]([OH:36])[CH2:34][OH:35].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])=[O:23])=[CH:25][CH:26]=1
Reactant: OCC(O)CI
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 7.17 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([O:28][CH2:29][CH2:30][OH:31])[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:28][CH2:29][CH2:30][OH:31])[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: OCCOc1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(OCCO)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 205, Step 2 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.20 mmol) and 2-[(6-bromopyridin-2-yl)oxy]ethanol (48.8 mg, 0.22 mmol) as starting materials.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12][C:13]1[S:14][C:15](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:18])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[CH3:12][C:13]1[S:14][C:15]([C:2]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=2[CH:4]=[O:5])=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: COc1ccc(Br)c(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc(C)nc2C)c(C=O)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To a solution of 2-bromo-5-methoxybenzaldehyde (200 mg, 0.93 mmol) in DMF (10 mL) and H2O (2 mL) are added 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (333 mg, 1.4 mmol), Pd(PPh3)4 (107 mg, 0.09 mmol) and K2CO3 (257 mg, 1.9 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×10 mL). The combined organic layer is dried, (MgSO4), filtered and is concentrated and the residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 2-(2,4-Dimethyl-thiazol-5-yl)-5-methoxy-benzaldehyde (150 mg, 65%) as a white foam.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11](O)=[O:12])[CH:9]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH:1]1([C:4]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11]([Cl:19])=[O:12])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)c(C2CC2)cc1CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C2CC2)cc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid in 20 ml of dichloromethane were treated with 2.1 g of oxalyl chloride and a catalytic amount of dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the crude residue of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetyl chloride (2.5 g) was used for the next step.
Reaction SMILES: C1(C[O:8][C:9](=[O:89])[CH2:10][N:11]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([N:26]([CH2:47][CH2:48][O:49][C:50](=[O:66])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:27][CH2:28][O:29][C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:25])[CH2:19][CH2:18][N:17]([CH2:67][C:68]([O:70]CC3C=CC=CC=3)=[O:69])[CH2:16][CH2:15][N:14]([CH2:78][C:79]([O:81]CC3C=CC=CC=3)=[O:80])[CH2:13][CH2:12]2)C=CC=CC=1>CCO.[Pd]>[O:66]=[C:50]([O:49][CH2:48][CH2:47][N:26]([CH2:27][CH2:28][O:29][C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:24](=[O:25])[CH2:23][N:20]1[CH2:21][CH2:22][N:11]([CH2:10][C:9]([OH:89])=[O:8])[CH2:12][CH2:13][N:14]([CH2:78][C:79]([OH:81])=[O:80])[CH2:15][CH2:16][N:17]([CH2:67][C:68]([OH:70])=[O:69])[CH2:18][CH2:19]1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCCCCCC)C(=O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCCCCCC)C(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
10% Pd/C (1.6 g) was added to a solution of 10-[2-[bis[2-[(1-oxohexadecyl)oxy]ethyl]amino]-2-oxoethyl]-1,4,7,10-tetraazacyclo-dodecane-1,4,7-triacetic acid tris(phenylmethyl)ester (16 g; 12.9 mmol) in EtOH (500 mL) and the suspension was stirred for 12 h under hydrogen atmosphere at room temperature. After filtration through a Millipore® filter FT 0.45 μm the solution was evaporated under reduced pressure to give the desired compound. Yield 93%. HPLC: 98% (area %). The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:25][CH2:26][CH2:27][CH2:28][S:29](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:31])=[O:30]>>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([NH:21][CH2:20][CH:19]([CH2:22][O:23][CH3:24])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)COC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)COC

Procedure:
3-Hexadecylthio-2-methoxymethylpropylamine IVk3 is allowed to react and worked up by the same procedure as described in (4). m.p. 41.5°-43° C. The summary of the experimental and the physical data of the product are listed in Table 7.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:16])[CH2:14][NH2:15].C(O)C>O>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:15][CH2:14][CH2:13][NH2:16])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: NCCN
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Solvent: CCO
Solvent: O
Product: NCCNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]

Procedure:
0.13 mole (30.6 g) of 2,4,5-trichloronitrobenzene is added to a solution of 78 g of ethylenediamine in 100 ml of 96° ethanol and 117 ml of water. After heating under reflux for 1 h 30 min, the reaction mixture is cooled. After dilution with iced water, the expected product precipitates. It melts as 84° C.-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:12][NH2:13])=[O:11].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].Cl>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([NH:13][NH:12][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])=[O:28]
Reactant: NNC(=O)Cc1ccc(F)cc1Cl
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCl)NNC(=O)Cc1ccc(F)cc1Cl
Reaction time: 1.5 h

Procedure:
A mixture of 2-(2-chloro-4-fluorophenyl)acetohydrazide (909 mg, 4.5 mmol) and DIPEA (0.817 ml, 4.7 mmol) in dry DCM (65 ml) was added over 20 min to 4-chlorobutyryl chloride (0.505 ml, 4.5 mmol) in dry DCM (5 ml). After 1.5 h, 2M HCl was added and the precipitated 4-chloro-N-[(2-chloro-4-fluorophenyl)acetyl]butanohydrazide was filtered off, washed with water and dried (1.24 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:26]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (0.150 g; 0.580 mmol) in N,N-dimethylformamide (2 mL) is added 4-chlorophenylsulfonyl chloride (0.122 g; 0.580 mmol) and triethylamine (0.243 mL; 1.740 mmol). The mixture is stirred at room temperature overnight. After this time, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are washed with aqueous saturated sodium bicarbonate solution, 1N hydrochloric acid, and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material is purified by preparative HPLC to afford title compound. ESI m/z 412 [M+NH4]+
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].C(=O)(OO)N.S(=O)(=O)(O)O.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([NH2:29])[CH:26](O)[CH3:27])[CH:21]=[CH:22][C:23]=1[F:24]>O>[F:17][C:18]1[CH:19]=[C:20]([C@H:25]2[C@H:26]([CH3:27])[O:2][C:1](=[O:4])[NH:29]2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CC(O)C(N)c1ccc(F)c(F)c1
Reactant: O=C([O-])[O-]
Agent: NC(=O)OO
Agent: O=S(=O)(O)O
Agent: [Cs+]
Solvent: O
Product: C[C@@H]1OC(=O)N[C@H]1c1ccc(F)c(F)c1

Procedure:
Recovery Procedure B. Cesium carbonate (2 g) was added to another portion of the hydroxy carbamate mixture, and after about thirty minutes at room temperature the reaction mixture was diluted with water (50 ml). Sulfuric acid (10 eq.) was then added, and the mixture was refluxed for 30 minutes to obtain a mixture of the title compound plus 1-(3,4-difluorophenyl)-2-hydroxy-propylamine. Isolation by neutralization with NaOH to a pH=8-9, and extraction with MTBE afforded the title compound, which was obtained in 90% ee by evaporative removal of the MTBE.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[C:21]4=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]4[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1.O>CS(C)=O.CCOC(C)=O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]4[C:21]5=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]5[CH2:19][CH2:18][CH2:17]4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:32][CH:33]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc4[nH]ccc4c3)C2=N1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=S1(=O)CCN2CCCC(c3ccc4c(ccn4CCc4ccc(F)cc4)c3)C2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 2 %

Procedure:
To a mixture of cesium carbonate (435 mg) and 9-(1H-indol-5-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (200 mg) in DMSO (5 mL) was added 1-(2-bromoethyl)-4-fluorobenzene (136 mg). The mixture was stirred at room temperature for 1 day. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous sodium sulfate. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc), concentrated and dissolved in THF (dry) (25 mL) and MeOH (25 mL). Then platinum(IV) oxide (46 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was purified by column chromatography (1st: NH silica gel, eluted with MeOH in EtOAc, 2nd: silica gel, eluted with EtOAc) to give the title compound (5.7 mg) as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[Cl:9][CH2:10][C:11](Cl)=[O:12].O>ClCCl.N1C=CC=CC=1>[Cl:9][CH2:10][C:11]([C:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: O=C1NC2C=CC1C2
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1NC2(C(=O)CCl)C=CC1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
10.1 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in a mixture of dichloromethane (10 ml), pyridine (8.4 ml) and 0.22 g of 4-N,N-dimethylaminopyridine at 10° C. under nitrogen. 13.5 g of chloroacetyl chloride were added dropwise over the course of 1 h. The temperature rose to 44° C. The mixture was stirred for a further 2 h at room temperature. 100 ml of water were added to the solution. After phase separation, the aqueous phase was extracted with 100 ml of dichloromethane. The combined organic phases were dried with sodium sulphate and completely evaporated. The residue was boiled in 100 ml of diisopropyl ether under reflux in the presence of 1 g of active charcoal for 10 minutes. After hot filtration, the filtrate was cooled to room temperature, and the solid was filtered and dried. 10.35 g of title compound were obtained. The yield was 60%.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]([OH:28])[CH2:25][O:26][CH3:27])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:41].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:41][C:17]([C:19]4[S:20][C:21]([CH:24]([OH:28])[CH2:25][O:26][CH3:27])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: COCC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1-hydroxy-2-methoxyethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.36 g), ammonium acetate (1.33 g) and acetic acid (15 mL) was stirred at 100° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, 2M aqueous sodium hydroxide solution (1.3 mL), tetrahydrofuran (6 mL) and methanol (6 mL) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (1.27 g, yield 90%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 517 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#N.[CH3:10][NH:11][CH2:12][CH2:13][NH2:14].CO>>[OH2:9].[CH3:10][N:11]1[CH2:12][CH2:13][N:14]=[C:1]1[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][N:11]1[CH2:12][CH2:13][N:14]=[C:1]1[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CNCCN
Solvent: CO
Product: CN1CCN=C1c1ccc(O)cc1
Product: O
Reaction time: 8 h

Procedure:
Anhydrous hydrogen chloride gas was bubbled into a cold (0° C.) stirred solution of p-cyanophenol (30 g, 0.25 mole) in 120 ml methanol for 70 min. The resultant heavy suspension was stopped and stirred overnight. After cooling in an ice bath, the solid was collected by filtration and rinsed twice with cold methanol. The solid was then dried under nitrogen to a weight of 46.56 g. The solid was resuspended in 150 ml methanol, chilled in an ice bath, and N-methylethylenediamine (22 g, 0.25 mole) was added. The reaction became a clear solution and it was heated at reflux temperature for one hour. The solvent was then evaporated and the residual oil was dissolved in water. It was basified first using 50% sodium hydroxide solution and then using sodium bicarbonate solution. The solid was collected by filtration and rinsed with water, 2-propanol, and isopropyl ether. The slightly wet solid weighed 20.71 g. The mother liquor and rinsings were combined and concentrated to yield a second crop which weighed 22.55 g. A portion of the first crop was recrystallized from acetonitrile/methanol, filtered and dried, mp 122°-125° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH:23]([N:19]1[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:5][N:2]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:3]5)[CH:27]=[CH:26][C:9]=4[C:10]=3[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(C)(=O)=O)C3)ccc1-2

Procedure:
Following the procedure for 395, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene hydrochloride salt and methanesulfonyl chloride were reacted. The reaction mixture was loaded directly onto a silica column with no aqueous work-up to give 259 isolated as a white solid (67 mg, 84%). LCMS: RT=10.97 min, [M+H]+=446. 1H NMR δ (ppm) (CDCl3): 8.36 (1H, d, J=8.20 Hz), 7.90 (1H, d, J=0.68 Hz), 7.16 (1H, dd, J=8.24, 1.88 Hz), 7.02 (1H, d, J=1.85 Hz), 5.93-5.83 (1H, m), 4.42-4.36 (2H, m), 4.30-4.22 (2H, m), 4.10-4.03 (2H, m), 3.83-3.73 (1H, m), 3.43-3.37 (2H, m), 2.90 (3H, s), 1.61 (6H, d, J=6.63 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH3:17])[N:9]=[CH:8][N:7]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]2=[O:26].ClC1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=1.[CH:35](N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH3:35])[C:17]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=1)[N:9]=[CH:8][N:7]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])[C:6]2=[O:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(Cl)ncn1
Reactant: CNCCOc1cc2ncn(COC(=O)C(C)(C)C)c(=O)c2cc1OC
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN(C)c1cc(C)ncn1
Yield: 80 %

Procedure:
A solution of 6-methoxy-7-(2-(methylamino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (363 mg, 1 mmol) and 4-chloro-6-methylpyrimidine (257 mg, 2 mmol), (J. Het. Chem., 1969, 6, 879), in N,N-diisopropylethylamine (2 ml) was heated at reflux for 30 minutes. The volatiles were removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (365 mg, 80%).
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:27][C@@H:28]([CH2:41][NH2:42])[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[OH:27][C@@H:28]([CH2:41][NH:42][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 28) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a yellowish solid; mp>150° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1-40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.55-2.95 (m, 4 H), 3.60-4.10 (m, 14 H), 4.90 (br s, 1 H), 6.56 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.0 Hz, 1 H), 6.87 (dd, J=7.9, 7.9 Hz, 1 H), 7.02 (d, J=8.9 Hz, 2 H), 7.45 (d, J=8.9 Hz, 2 H), 7.54 (s, 1 H), 10.65(s, 1 H), 10.75 (brs, 1 H); MS (ES) m/z: 290.0 ((M+2H)2+, 100%); 579.1 (MH+, 80%); HRMS Calcd. for C29H36N6O5S (MH+): 579.2390. Found: 579.2392.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21]N(S(CC5CCCC5)(=O)=O)C4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.N1C[CH:35]([NH:37][C:38]2C(F)=CN=C(C3C4C(=NC=C(Cl)C=4)N(S(C4C=CC(C)=CC=4)(=O)=O)C=3)[N:39]=2)C1.N([Si](C)(C)C)=C=[O:67]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21][CH2:35][N:37]4[C:38]([NH2:39])=[O:67])[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=S(=O)(CC1CCCC1)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: Cl
Product: NC(=O)N1CCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Yield: 79 %

Procedure:
According to the procedure for compound 469 using 61 mg (0.11 mmol) of 6c and isocyanatotrimethylsilane (15.14 μL, 0.11 mmol) afforded 87 mg (79% yield) of 512, as a white solid: