Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[O:12]([CH2:19]C=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[O:12]([CH2:19][CH:1]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3][O:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: O=CCOc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C=COC(COc2ccccc2)C1
Temperature: -5 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
1-Methoxy-3-(trimethylsilyloxy)-1,3-butadiene (4.95 ml; 26 mmol) was added to a solution of phenoxyacetaldehyde (3.56 g, 26 mmol) in DCM (40 ml). The solution was cooled to −5° C. A 2.3 M solution of zinc chloride in DCM (5.6 ml, 13 mmol) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane (1:1) as eluent, to give 2.36 g of 2-phenoxymethyl-2,3-dihydropyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:43][O:44][CH2:45][C:46]1[NH:47][CH:48]=[C:49]([OH:53])[C:50](=[O:52])[N:51]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH2:45][C:46]2[NH:47][CH:48]=[C:49]([OH:53])[C:50](=[O:52])[N:51]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(/C(=N/OCc2nc(=O)c(O)c[nH]2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 14 h
Yield: 104.6 %

Procedure:
(6R, 7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (125 mg) (0.2 mmol), 41 mg (0.26 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 50 mg (0.26 mmol) of p-toluenesulphonic acid hydrate are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 14 hours the mixture is concentrated in a high vacuum at room temperature and the residue is treated with water. The product is filtered off and washed in succession with water, ethanol and diethyl ether. There are obtained 160 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[C:3]([NH:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:22]1([N:25]2[CH2:30][C:29]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[O:28][CH2:27][C:26]2=[O:36])[CH2:24][CH2:23]1>CN(C)C=O.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:33]2[CH2:34][CH2:35][C:29]3([O:28][CH2:27][C:26](=[O:36])[N:25]([CH:22]4[CH2:23][CH2:24]4)[CH2:30]3)[CH2:31][CH2:32]2)[C:3]([NH:5][CH3:6])=[O:4])=[C:8]([F:14])[CH:9]=1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: CNC(=O)C(Br)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)-N-methylacetamide (0.579 mmol) in N,N-dimethylformamide (3 mL) was treated with potassium carbonate (1.715 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.632 mmol). The reaction was allowed to stir at room temperature overnight. The reaction solution was then diluted with water (50 mL) and was extracted three times with dichloromethane. The organic layers were combined and were washed with water three times, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-6% methanol/dichloromethane) afforded the title compound as a yellow oil (185 mg, 63% yield). MS(ES)+ m/e 454.0/455.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)c2ccc(C(F)(F)F)cc2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl- 6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Trifluoromethylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-trifluoromethylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Br)[CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:17]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: BrCC(CBr)OCc1ccccc1
Solvent: O
Product: CC(C)N1CC(OCc2ccccc2)C1
Temperature: 80 °C

Procedure:
11 Parts of 2-benzyloxy-1,3-dibromo-propane, 30 parts of iso-propylamine and 30 parts of water were added to a stainless autoclave, and the mixture was heated at 80° C. for 2 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result, 18 parts of 3-benzyloxy-1-(iso-propyl)azetidine boiling at 104°-107° C. under 2 mm Hg were obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:21]2[CH2:20][CH2:19][CH:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16]3)[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-methylthiophenylboronic acid (240 mg; 1.431 mmol) in dichloromethane (6 mL) was treated with activated powdered 4 Å molecular sieves (1.5 g), Cu(OAc)2 (87 mg; 0.477 mmol), tert-butyl 4,4′-bipiperidine-1-carboxylate (128 mg; 0.477 mmol) and triethylamine (134 μL; 0.954 mmol). The reaction vessel was purged with oxygen and the mixture stirred under an oxygen atmosphere at ambient temperature for 18 hr. The now brown mixture was filtered through Celite. The eluant was adsorbed onto silica gel. The silica gel was exhaustively eluted without fractionation (1:1 hex/MTBE). The eluant was evaporated to a yellow oil and chromatographed (PTLC; 2:1 hex/MTBE). The major band was collected affording the title compound. LRMS calc: 390.2. obs: 391.1 (M+H), 291.1 (M-BOC+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[NH:10][CH:9]=[CH:8]2.Br[CH2:16][CH2:17][CH2:18][Cl:19].O>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][O:14][C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: ClCCCBr
Reactant: COc1cc2cc[nH]c2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cc[nH]c2cc1OCCCCl
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 108.6 %

Procedure:
To a stirred suspension of sodium hydride (0.94 g, 19.6 mmol of a 50% oil dispersion) in dimethylformamide (20 ml) under nitrogen and cooled to -5° C. was added, dropwise, 5-methoxy-6-hydroxyindole (3.2 g, 19.6 mmol) dissolved in dimethylformamide (60 ml) so that the temperature did not exceed -2° C. After complete addition, the reaction was stirred for 45 minutes at 0° C. While maintaining the reaction temperature between -5° C. and 0° C., a solution of 1-bromo-3-chloropropane (3.1 g, 19.6 mmol) dissolved in dimethylformamide (15 ml) was slowly added. The mixture was stirred at ambient temperature under nitrogen for 21 hours. The reaction was cooled in an ice bath, and water was added to destroy the excess sodium hydride, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4 and concentrated to yield 5.3 g of a dark, oily liquid. This was combined with an additional sample, for a total of 10.0 g, and purification by preparative HPLC (Waters Associates prep LC/System 500) provided 5.1 g of a brown solid. A 2.5 g sample was recrystallized from isopropyl alcohol to yield 1.1 g (30%) of 6-(3-chloropropoxy)o5-methoxyindole as beige crystals, m.p.=73°-75° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:15][CH:16]=[CH2:17].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Si:18]([O:1][C:2]1[C:3]([CH2:15][CH:16]=[CH2:17])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[CH2:12][CH:13]=[CH2:14])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1O[Si](C)(C)C(C)(C)C
Yield: 97.2 %

Procedure:
The product of Step B (3.1 g, 13.36 mmol) was treated with tert-butyldimethylsilyl chloride (2.22 g, 1.1 equiv), triethylamine (3 mL) and DMAP (0.1 equiv) in dichloromethane overnight. The mixture was concentrated and flash chromatographed with 5% and then 10% ethyl acetate in hexane to furnish 4.5 g (97%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([O:49][CH3:50])[CH:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:8]=[CH:13][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[CH:48]=[CH:47][N:46]=[C:45]([O:49][CH3:50])[CH:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:7][CH2:6]1
Reactant: COc1cc(-c2cc(C)c(Br)c(C)c2)ccn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccnc(OC)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-2-methoxy-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.30 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.N12CCCN=C1CCCCC2.[CH3:36][CH:37]([CH3:40])[CH2:38][OH:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[O:39][CH2:38][CH:37]([CH3:40])[CH3:36]
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: CC(C)CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)COC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 80 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
A mixture of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.0075 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mol) in 2-methylpropanol (25 ml) was stirred for 72 hours at 80° C. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97.5/2.5). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.8 g (25%) of (±)-2-[3-chloro-4-[(4-chloro-phenyl)(2-methylpropoxy)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 133).
Reaction SMILES: F[B-](F)(F)F.[C:6]1([CH2:12][CH2:13][C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[FH:17].F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:6]1([CH2:12][CH2:13][C:14]([F:17])=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: F
Reactant: O=C(O)CCc1ccccc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(F)CCc1ccccc1
Reaction time: 24 h
Yield: 69 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (750 mg, 3.3 mmol) in dichloromethane (10 mL) at room temperature was added 3-phenylpropanoic acid (245 mg, 1.6 mmol) and triethylamine trihydrofluoride (266 μl, 1.6 mmol). The reaction mixture was stirred for 24 hours, then an aqueous solution of sodium bicarbonate (5%) was added and stirring was continued for 30 minutes. The organic phase was isolated and dried with magnesium sulphate. The solution was diluted with pentane (10 mL) and the solution was passed through a pad of silica gel with pentane elution. Solvent were evaporated in vacuum to provide 3-phenylpropanoyl fluoride (168 mg, 68%) as a clear liquid. 1H NMR (CDCl3, 300 MHz) δ 7.30-7.17 (m, 5H), 2.96 (t, J=7.6 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H); 19F NMR (CDCl3, 282 MHz) δ 44.8 (s, 1F); 13C NMR (CDCl3, 75 MHz) δ 163.0 (d, 1JC-F=180.2 Hz), 139.1, 128.9, 128.5, 127.0, 34.7 (d, =50.7 Hz), 30.2.
Reaction SMILES: [F:1][CH:2]([F:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.[NH:38]1[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:1][CH:2]([F:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:25]([N:38]3[CH2:43][CH2:42][S:41][CH2:40][CH2:39]3)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: C1CSCCN1
Reactant: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 150 °C

Procedure:
A solution of 56.0 mg (0.065 mmol, purity 60%) of the compound from Example 62A in 1-methyl-2-pyrrolidone (2.0 ml) was admixed with 37.0 μl (40.0 mg, 0.390 mmol) of thiomorpholine and 34.0 μl (25.0 mg, 0.195 mmol) of N,N-diisopropylethylamine and then heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 30 min. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 14.7 mg (47% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(Nc2ccc(Cl)nc2)c(C(=O)O)c1
Temperature: 130 °C
Yield: 46 %

Procedure:
A mixture of 6-chloropyridin-3-amine (11.67 mmol, 1.5 g) and 2-bromo-5-methylbenzoic acid (23.34 mmol, 5.02 g), Cu (1.17 mmol, 0.1 g), Cu2O (0.58 mmol, 0.1 g) and K2CO3 (23.34 mmol, 3.2 g) in 1,2-dimethoxyethane (15 ml) was heated at 130° C. for 16 hours, under argon atmosphere. Water was added and the mixture was filtered through celite. HCl 2N aqueous solution was added until pH 6 and the solid formed was filtered off. The crude was purified by chromatography eluting with DCM/MeOH mixtures affording 1.40 g (yield 46%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (60 mg, 0.21 mmol), 4-methoxyphenyl boronic acid (33 mg, 0.22 mmol), potassium carbonate (69 mg, 0.5 mmol), Pd(dppf)Cl2CH2Cl2 (13 mg, 0.016 mmol), 1.7 mL dioxane and 0.4 mL water was stirred at 150° C. in a microwave for 30 min. The resulting mixture was partitioned between ethyl acetate and water. The combined organic layers were dried over Na2SO4 and concentrated to give a dark brown solid. The crude product was purified by preparative thin layer chromatography using 90:9.5:0.5 CH2Cl2:MeOH:conc NH4OH as eluant. The resultant brown solid was washed with ethyl ether to provide 31 mg (50%) of 1-[2-(4-methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a brown solid. MP 207-208° C., M+H 310.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:74][C:73]2[CH:75]=[CH:76][C:70]([F:69])=[CH:71][CH:72]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:37]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccc(F)cc3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 4-fluoroaniline (8.64 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20 mg, 55.5%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])S(C)(=O)=O)(=[O:4])=[O:3].O.[OH-].[Li+]>CO>[CH3:1][S:2]([NH:5][C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate (22.9 g) and lithium hydroxide monohydrate (7.5 g) in aqueous methanol (50%) was stirred at room temperature for 18 hours. The resulting solution was acidified with concentrated hydrochloric add and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige solid, NMR (acetone d6); 3.1(2s,6H), 7.57(dd,1H), 8.15(d,1H), 8.23(d,1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)C>O>[CH:22]1([NH:27][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NC1CCCC1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC3CCCC3)cc2c1=O
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A mixture of 140 mg (0.44 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 0.17 ml (1.76 mmol) of cyclopentylamine and 3 ml of ethanol is heated at 150° C. in a closed vial in a microwave reactor for 5 minutes. After cooling to room temperature, water is added and the resulting suspension is filtered. Conc. aqueous hydrochloric acid is added to the filtrate until a pH value of 2-3 is reached and the formed suspension is filtered. The residue is crystallized from ether-hexane to yield 52 mg (31%) of the title compound as red crystals, m.p. 146-155° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)[N:10]=1.S(Cl)([Cl:24])=O>>[Cl:24][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH3:21])=[N:18][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cn1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethanol (1.87 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hr. After concentration under reduced pressure, ice water was added to the residue. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (1.41 g, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 95–96° C.