Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]([F:46])([F:45])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[C:34]([F:33])([F:45])[F:46])(=[O:43])=[O:42])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3ccccc3C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (30.5 mg, 0.07mmol) in anhydrous CH2Cl2 (4 ml) was added 2-(Trifluoromethyl)benzene sulfonyl chloride (25.0 mg, 0.10 mmol) and diisopropylethylamine (24 μl, 0.14 mmol). The reaction stirred at room temperature 3 hours, was diluted with EtOAc and washed with sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (35.4 mg, 79% ). Calcd for C33H35F6NO4S (M+H) 655.69, Found 656.2.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([Cl:35])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:35][C:22]1[CH:21]=[C:20]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([F:8])[CH:10]=3)[CH2:15]2)[CH:25]=[C:24]([CH3:26])[C:23]=1[NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(F)ccc3C2)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (121 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (200 mg, 0.63 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([N+:13]([O-])=O)=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6]>CO.[Pd]>[NH2:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:2]([OH:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(C(=O)O)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
To a solution of 3-hydroxy-4-methoxy-6-nitrobenzoic acid (Journal of Natural Product, 1986, 49 (3), 445-448) (10.0 g, 46.9 mmol) in methanol (150 mL) was added 10% Pd/C (0.1 eq.). The reaction was stirred under a hydrogen atmosphere (1 atm.) at room temperature for 5 h. The solution was filtered and the filtrate was evaporated to afford 2-amino-5-hydroxy-4-methoxybenzoic acid (INTERMEDIATE V1.1) (7.0 g, 38.3 mmol, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]([OH:19])[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH:13]3[O:19][C:16](=[O:18])[CH2:15][CH2:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2)o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CCC(c2ccc(-c3ccc(F)cc3)o2)O1

Procedure:
A mixture of 3.8 g (0.014 mole) of 4-[5-(4-fluorophenyl)-2-furanyl]-4-hydroxybutanoic acid and 60 ml of 10% hydrochloric acid was warmed at 45° for 2 hrs and then cooled in an ice bath. The solid was filtered, washed with water and air-dried to yield 3.3 g (95%). An analytical sample was prepared by dissolving a sample in ethyl acetate (Darco), diluting with hexane and drying the resulting solid in a vacuum pistol at room temperature, m.p. 57°-59°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[CH:56]=[CH:55][N:54]=[C:53]([C:57]3[NH:61][CH:60]=[C:59]([C:62]([O:64][CH3:65])=[O:63])[CH:58]=3)[CH:52]=2)[CH:47]=[CH:48][CH:49]=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[CH:56]=[CH:55][N:54]=[C:53]([C:57]3[NH:61][CH:60]=[C:59]([C:62]([O:64][CH3:65])=[O:63])[CH:58]=3)[CH:52]=2)[CH:47]=[CH:48][CH:49]=1)=[O:9]
Reactant: COC(=O)c1c[nH]c(-c2cc(Nc3cccc(N)c3)ccn2)c1
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c(-c2cc(Nc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methyl-2-furoic acid (22 mg, 0.18 mmol), HATU (73 mg, 0.19 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of methyl 5-(4-((3-aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (50 mg, 0.16 mmol). The mixture was stirred at room temperature for 3 hours and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate as off-white solid.
Reaction SMILES: [C:1]1([SH:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl[CH2:10][C:11]([C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>>[S:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[S:8][CH:10]=[C:11]1[C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: Sc1ccccc1S
Product: CCOC(=O)C(=NOC)C1=CSc2ccccc2S1
Yield: 6.8 %

Procedure:
o-Benzenedithiol (7.1 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (11.4 g.) in a similar manner to that of Example A-(i) to give ethyl 2-(1,4-benzodithiin-2-yl)-2-methoxyiminoacetate (syn isomer, 1.0 g.), yellow crystals, mp. 78° to 81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:49]=[C:50]([CH:58]=[CH:59][CH:60]=1)[C:51]([O:53]C(C)(C)C)=[O:52]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:48]2[CH:49]=[C:50]([CH:58]=[CH:59][CH:60]=2)[C:51]([OH:53])=[O:52])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1cccc(C(=O)O)c1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, tert-butyl 3-aminobenzoate was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)=[C:4]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[OH:19])[CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.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>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]([C:4]2[CH:3]=[C:2]([C:32]3[CH:31]=[CH:30][N:29]=[C:28]([F:27])[CH:33]=3)[S:6][C:5]=2[C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)[OH:19])=[CH:21][CH:22]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: OC(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1cc(-c2ccnc(F)c2)sc1-c1ncn(C2CCCCO2)n1
Yield: 93.6 %

Procedure:
A mixture of {5-bromo-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}(4-chlorophenyl)methanol (734 mg, 1.61 mmol), 2-fluoro-4-pyridinylboronicacid (455 mg, 3.23 mmol), tetrakis(triphenylphosphine)palladium(0) (93.3 mg, 0.0807 mmol) and cesium carbonate (1.58 g, 4.84 mmol) in 1,4-dioxane (10.1 mL, 129 mmol) and water (1.45 mL, 80.7 mmol) was irradiated in a microwave oven at 140° C. under argon for 20 min. The reaction mixture was dry loaded onto silica gel and purified by column chromatography (SiO2, elution with EtOAc in hexanes, 0-80% gradient) to afford (4-chlorophenyl){5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanol as a white solid (0.71 g, 92.8%). LCMS: (AA) ES+ 471.1, 473.1
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].BrC1(Br)C2C(=NC(Cl)=C(Br)C=2)NC1=O>C1COCC1.[Cl-].[NH4+].[Zn]>[Cl:11][C:7]1[N:6]=[C:5]2[NH:4][C:3](=[O:12])[CH2:2][C:10]2=[CH:9][CH:8]=1
Reactant: O=C1Nc2nc(Cl)ccc2C1(Br)Br
Agent: O=C1Nc2nc(Cl)c(Br)cc2C1(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1Cc2ccc(Cl)nc2N1
Reaction time: 2 h

Procedure:
A solution of 2.36 g (7.26 mmol) of the mixture of 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and 3,3,5-tribromo-6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one in THF (70 mL) and saturated ammonium chloride solution (70 mL) was treated with 6 g (92 mmol) of powdered zinc. The mixture was stirred for 2 hours, and another 6 g (92 mmol) portion of zinc was added. Stirring was continued another 2 hours. The zinc was filtered off and washed with ether. The ether phase was separated, and the aqueous phase was extracted twice with a 1:1 mixture of THF/ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The crude residue was loaded onto 7.5 g of silica gel and chromatographed on silica gel, eluting with a 90% hexane/10% ethyl acetate to 66% hexane/33% ethyl acetate gradient to give 0.647 g of the title compound. 1H NMR (DMSO-d6): δ 3.57 (s, 2H), 7.04 (d, J=7.6 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 11.2 (bs, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH:19]1[C:24]([N:25]=[C:26]=[O:27])=[CH:23][C:22]2[C:28]([F:35])([F:34])[O:29][C:30]([F:33])([F:32])[O:31][C:21]=2[CH:20]=1>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH:16][C:26]([NH:25][C:24]3[CH:19]=[CH:20][C:21]4[O:31][C:30]([F:33])([F:32])[O:29][C:28]([F:34])([F:35])[C:22]=4[CH:23]=3)=[O:27])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)cc2)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a slurry of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (143 mg, 0.59 mmol) in DCM (1 mL) at 0° C. was added dropwise a solution of 2,2,4,4-tetrafluoro-6-isocyanato-1,3-benzodioxene (150 mg, 0.60 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 12 h. The resulting precipitate was filtered and washed with DCM to afford the desired product (125 mg, 41%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:29]1[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]1[N:38]1[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: c1ccc2[nH]c(N3CCOCC3)nc2c1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N4CCOCC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 4-(1H-benzo[d]imidazol-2-yl)morpholine were reacted to give 238. LCMS m/z: 576.4 (MH+)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].O[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:3][C:2](=[CH2:4])[C:1]([O:6][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: COC(=O)/C=C/c1ccc(OCCO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCOc1ccc(/C=C/C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.56 g (30 mmol) of methacrylic acid in 10 ml of THF were slowly added dropwise to a solution of 6 g (27 mmol) of methyl (E)-3-[4-[2-hydroxyethoxy]-phenyl]-acrylate, 5.85 g (28.3 mmol) of N,N′-dicyclohexylcarbodiimide (DCC) and 0.37 g (3 mmol) of 4-dimethylamino-pyridine in 80 ml of tetrahydrofuran (THF). The batch was stirred at room temperature overnight. In order to complete the reaction there were added firstly a further 1.46 g (7.1 mmol) of DCC and, after stirring for one hour, a further 0.5 g (5.9 mmol) of methacrylic acid. The batch was stirred for a further 24 hours, filtered and the filtrate was extracted 3 times each time with 200 ml of 5% acetic acid and 200 ml of water. The ether phase was dried over Na2SO4, evaporated and the residue was recrystallized from cyclohexane. Subsequently, the still slightly impure product was filtered over a thin silica gel layer (eluent: diethyl ether/hexane=1:1). This gave 8.3 g of 2-[4-[(E)-2-methoxycarbonyl-vinyl]-phenoxy]-ethyl 2-methyl-acrylate as a white powder with a melting point of 81-82° C. and an absorption maximum of λmax. (in CH2Cl2)=306.5 nm (ε=23675 l/mol cm).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:12](=S)=[S:13].C(N(CC)CC)C.C(N=C=NC(C)C)(C)C>C(#N)C.O>[CH:1]([C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[N:6]=[C:12]=[S:13])([CH3:3])[CH3:2]
Reactant: S=C=S
Reactant: Cc1ccc(C(C)C)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N=C=S)c1
Temperature: 40 °C
Yield: 48.4 %

Procedure:
To 2-isopropyl-5-methylaniline (1.0 g, 6.7 mmol) in a 25 mL vial equipped with a stir bar, Vigreux column, and nitrogen was added carbon disulfide (3.0 mL, 50 mmol). The reaction was heated to 40° C. and cooled immediately. To this solution was added triethylamine (0.93 mL, 6.7 mmol). The reaction was heated to 50° C. for 90 minutes and cooled to room temperature overnight. The reaction mixture was transferred to a 100 mL round-bottomed flask and concentrated. The residue was taken up in acetonitrile (33.5 mL) and treated with N,N′-diisopropycarbodiimide (1.04 mL, 6.70 mmol). The reaction was stopped after a few h and concentrated. Purification by flash column chromatography using 2.5-5% ethyl acetate/hexanes as eluent provided a mixture of products. Re-purification by reversed phase column chromatography using 5-100% acetonitrile/water as eluent provided the title compound (65% in dichloromethane, 0.62 g, 31%), which was used without further purification: IR (thin film) 2963 (m), 2924 (m), 2869 (w), 2089 (vs), 1611 (w), 1501 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.6 Hz, 1H), 7.09-7.03 (m, 2H), 3.19 (h, J=6.8 Hz, 1H), 2.30 (s, 3H), 1.24 (d, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 141.50, 136.70, 134.59, 128.84, 128.58, 127.12, 126.05, 29.20, 22.83, 20.62.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1)([O-:3])=[O:2].[O:21]1[CH2:24][C:23](=O)[CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:23]3[CH2:24][O:21][CH2:22]3)[CH2:11][CH2:10]2)=[C:6]([C:17]([F:20])([F:18])[F:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1COC1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(OC2CCN(C3COC3)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (1.0 g, 1.0 eq, 3.5 mmol) and oxetan-3-one (0.35 g, 1.4 eq, 4.8 mmol) in 1,2-dichloroethane (50 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.3 g, 1.8 eq, 6.2 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (50 mL) and pardoned with aqueous saturated NaHCO3 solution (100 mL). The layers were separated and the organic layer was washed with brine solution (2×50 mL). The combined organic layers were dried over Na2SO4. Removal of the solvents and purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 0:1 to 1:9) as eluent gave the product in 77% yield.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:26])([CH3:25])[C:17](=[O:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CS(C)=O.O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:17]1([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:2][O:24]1)([CH3:26])[CH3:25]
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Reaction time: 6 h
Yield: 73.6 %

Procedure:
15.7 g (71.2 millimoles) of trimethylsulphoxonium iodide are dissolved in 16 g of dimethylsulphoxide under a nitrogen atmosphere. 9.4 g (71.2 millimoles) of potassium tert.-butylate are added at room temperature, while cooling. The mixture is subsequently stirred for 6 hours and a solution of 20 g (64.1 millimoles) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanone in 30 ml of tetrahydrofuran is then added. The reaction mixture is stirred at room temperature for 15 hours and under reflux for 4 hours, cooled and poured onto water. The mixture is extracted with methylene chloride and the organic phase is dried over sodium sulphate and concentrated in vacuo. 15.4 g (73.7% of theory) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-yl-methyl)-oxirane of refractive index nD20 1.5539 are obtained. ##STR13##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.CN1CCCC1=O.C[O-].[Na+].[CH2:24](Cl)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CO.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: CC(C)CCCCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[O-]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: COC(=O)C=Cc1ccc(OCCCCCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol was removed by distillation from a mixture of 14.2 g (79.7 mmol) 4-hydroxycinnamic acid methyl ester, 150 ml N-methylpyrrolidone and 14.4 g (79.7 mmol) 30% sodium methylate solution in methanol, then 0.5 g tetrabutylammonium chloride and 15.5 g (95.6 mmol) isononyl chloride were added. The addition was followed by heating with stirring for 8 hours to 160 C. After cooling to room temperature, the solution was filtered off from the sodium chloride formed, concentrated to dryness under reduced pressure, the evaporation residue taken up in methylene chloride, washed with water, dried with sodium sulfate and, after concentration by evaporation, chromatographed on silica gel (Merck) (eluent: methylene chloride/toluene =8.2). 20.1 g (91% of the theoretical) 4isononyloxycinnamic acid methyl ester were obtained in the form of a colorless oil having a refractive index at 20 C of 1.5414.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[O:66]1[CH2:71][CH2:70][CH:69]([NH2:72])[CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3=[CH:17][NH:18][CH:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:72][CH:69]5[CH2:70][CH2:71][O:66][CH2:67][CH2:68]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])[N:20]=[C:7]23)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1NC1N=C2C(=CN1)N(C)C(=O)C(F)(F)CN2C1CCCC1
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.015 g (0.15 mmole) tetrahydro-pyran-4-ylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.04 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-3,5,6,7,8,9-hexahydro-2H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-124) as a white solid.