Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:9]([C:10]#[N:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.N(OC(C)(C)C)=O>C1COCC1>[S:3]1[C:4]2[CH:9]([C:10]#[N:11])[CH2:8][CH2:7][C:5]=2[N:6]=[CH:2]1
Reactant: N#CC1CCc2nc(N)sc21
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#CC1CCc2ncsc21
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a soln. of 2-amino-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carbonitrile (1.00 g, 6.05 mmol) in THF (54 mL) was added tert-butyl nitrite (1.04 g, 9.08 mmol) and the mixture was stirred at 65° C. for 3 h. Subsequently, the mixture was quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (10-80% EtOAc/Hept) provided a yellow oil.
Reaction SMILES: C[S-].[Na+].[CH3:4][C:5]([C:8]1[CH:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[S:17][C:18]([S:21]C)=[N:19][N:20]=2)[CH:11]=[C:10]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:9]=1[OH:27])([CH3:7])[CH3:6].[OH-].[Na+]>CN(C)C=O.O>[CH3:26][C:23]([C:10]1[CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]2[S:17][C:18](=[S:21])[NH:19][N:20]=2)[CH:13]=[C:8]([C:5]([CH3:4])([CH3:6])[CH3:7])[C:9]=1[OH:27])([CH3:24])[CH3:25]
Reactant: CSc1nnc(/C=C/c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Agent: C[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(/C=C/c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Temperature: 75 °C
Yield: 56.4 %

Procedure:
Sodium thiomethoxide (0.5 9, 0.007 mole) is added to a solution of (E)-2,6-bis(1,1-dimethyl ethyl)-4-[2-[5-(methylthio)-1,3,4-thiadiazol-2-yl]ethenyl]-phenol (1.0 g, 0.0028 mole) in dimethylformamide (10 ml). The resulting mixture is heated to 75° C. for two hours. The solution is cooled and diluted with water (20 ml). The mixture is treated with 1M NaOH (6 ml) and the aqueous solution is washed with ether (2×). The aqueous layer is made acidic by the addition of cold 6M HCl (3 ml) and the product is then extracted with a 1:1 ethyl acetate/diethyl ether mixture (2×). The combined organic layers are washed with brine and dried over MgSO4. Filtration and concentration in vacuo, followed by recrystallization from ethyl acetate/hexane gives 0.55 g of (E)-5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-thiadiazol-2(3H)-thione. (0.98 g theor., 57%), mp 248°-249° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Si:24]([O:31][C:32]([CH3:45])([CH3:44])[CH2:33][N:34]1[CH:38]=[C:37]([Sn](C)(C)C)[N:36]=[C:35]1[CH3:43])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O1CCOCC1.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>[Si:24]([O:31][C:32]([CH3:45])([CH3:44])[CH2:33][N:34]1[CH:38]=[C:37]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[N:36]=[C:35]1[CH3:43])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: Cc1nc([Sn](C)(C)C)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 35.6 %

Procedure:
To a mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-4-(trimethylstannyl)-1H-imidazole (690 mg, 1.6 mmol) in dioxane (2 mL) was bubbled with N2 for about 2 min and then stirred at 120° C. for 35 min under the irradition of microwave. Filtered, concentrated and purified by pre-TLC (pure EtOAc) to give 160 mg of 9-(1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. Yield=46%. LC-MS: m/z=548 [M+H+]
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1)=[O:5].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:12][C:11]1[C:6]([C:4](=[O:5])[CH2:3][NH:2][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:14])([F:25])[F:26])=[N:7][CH:8]=[C:9]([Cl:13])[CH:10]=1
Reactant: NCC(=O)c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 65.8 %

Procedure:
To a suspension of 3.7 g of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone hydrochloride in 50 ml of ethyl acetate, 30 ml of water and 3.5 g of 2-(trifluoromethyl)benzoyl chloride were added, and 6.1 g of potassium carbonate in 30 ml of water was added dropwise with stirring under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was mixed with 20 ml of ethyl acetate, the resulting organic layer was collected, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 6:4) as the eluent to obtain 3.8 g of the desired product as pale yellow crystals.
Reaction SMILES: C([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([Br:15])[C:6]=1[CH:7]=[O:8])(=O)C.C(=O)(O)[O-].[Na+]>CO>[OH:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([Br:15])[C:6]=1[CH:7]=[O:8]
Reactant: COc1ccc(Br)c(C=O)c1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Br)c(C=O)c1O
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To the aldehyde 11 (17.7 g) in aqueous methanol (125 mL) was added sodium bicarbonate (7.6 g, 1.1 eq.) and the turbid bright yellow solution stirred for 2 hours. The solution was acidified, extracted with dichloromethane and the solvent removed in vacuo to afford a yellow solid. The product was recrystallized from ethyl acetate/hexane to afford yellow crystals (14.7 g, 98%): m.p. 105.6-106.4° C., lit19 m.p. 102-103° C.; EIMS m/z 232 (M+, 81Br), 230 (M+, 79Br), 186, 107, 79, 54, 32; Anal. Calcd. For C8H7O3Br: C, 41.59; H, 3.05. Found: C, 41.83; H, 3.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[O:22]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[O:22])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)COC(=O)Cc2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a stirred solution of 4.45 g (28.9 mmol) of 4-fluorophenylacetic acid in 3.26 g (31.8 mmol) of triethylamine and 275 mL of acetonitrile was added 8.9 g (28.9 mmol) of 2-bromo-4'-(methylsulfonyl)acetophenone (prepared in Step 3) at ambient temperature. The reaction mixture was stirred for 30 minutes, concentrated in vacuo, and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography with ethyl acetate/hexane (1:1) gave 6.87 g (68%) of 2-(4-fluorophenyl)-1-[2-[4-(methylsulfonyl)phenyl]-2-oxoethoxy]ethanone as a colorless solid: NMR (CDCl3) δ 3.08 (s, 3H), 3.79 (s, 2H), 5.35 (s, 2H), 7.06 (s, t, J=9 Hz, 2H), 7.32 (dd, J=6 and 9 Hz, 2H), 8.06 (s, 4H).
Reaction SMILES: [CH3:1][CH:2](C)[C:3]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)([CH3:7])[C:4]([O-:6])=[O:5].[CH3:24]O>[Pd]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]([CH3:7])([CH2:2][CH3:1])[C:4]([O:6][CH3:24])=[O:5])=[CH:10][CH:11]=1
Reactant: CO
Reactant: CC(C)C(C)(Oc1ccc(OCc2ccccc2)cc1)C(=O)[O-]
Agent: [Pd]
Product: CCC(C)(Oc1ccc(O)cc1)C(=O)OC

Procedure:
A solution of methyl-(4-(benzyloxy)phenoxy)-2-methylbutanoate (32 g) in 100 mL MeOH was hydrogenated using 10% Pd/C at 40 psi. The mixture was filtered through a pad of celite to remove the catalyst. The filtrate was concentrated to afford thick oily residue (21 g, quantitative).
Reaction SMILES: N[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][C:10]([C:13]#[N:14])=[CH:11][N:12]=2)=[CH:6][N:7]=1.N(OCCC(C)C)=O.C(Br)(Br)[Br:24]>>[Br:24][C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][C:10]([C:13]#[N:14])=[CH:11][N:12]=2)=[CH:6][N:7]=1
Reactant: BrC(Br)Br
Reactant: N#Cc1cnc(-c2cnc(N)nn2)s1
Agent: CC(C)CCON=O
Product: N#Cc1cnc(-c2cnc(Br)nn2)s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2-(3-Amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (30 mg, 0.15 mmol) was dissolved in 1 mL of bromoform and heated to 90° C. Isoamyl nitrite (88 mg, 0.75 mmol) was added and stirred at 90° C. for 2 h. The reaction mixture was then concentrated and used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[C@H:3]1[C:14]([O:16]C(C)(C)C)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(F)F)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(F)F
Yield: 96.8 %

Procedure:
A mixture of 5.2 g of the product of Step B and 500 mg of p-toluene sulfonic acid in 40 ml of toluene was refluxed for 25 mintues and after cooling, 400 ml of ether were added thereto. The mixture was washed with water and the organic phase was dried and evaporated to dryness to obtain 4.1 g of (1R,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2-difluoroethoxy)-1-propynyl]-cyclopropane-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:14]2=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CCN(C(C)C)C(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>ClCCCl>[CH3:19][C:16]1([CH3:20])[C:17](=[O:18])[N:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[C:2]([NH:1][C:40](=[O:41])[CH2:39][Cl:38])[CH:3]=2)[C:14](=[O:28])[N:15]1[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CCl)c2)C(=O)N1Cc1ccncc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
500 mg (1.27 mmol) 3-(3-amino-4-trifluormethoxy-phenyl)-5,5-dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione and 172 mg (1.33 mmol) Hünig's base were dissolved in 20 ml 1,2-dichloroethane. The mixture was cooled to −20° C. and treated with a solution of 143 mg (1.27 mmol) chloroacetylchlorid in 15 ml 1,2-dichloroethane. After stirring 1 h at 0° C., 5 ml ethanolic hydrochlric acid were added and the mixture evaporated to dryness. The raw material, containing huening's base hydrochloride was used without further purification.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17]C)=[O:16])=[CH:12][CH:13]=2)[N:8]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:21][N:20]=2)[CH:7]=1>O.C1COCC1>[CH3:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[N:8]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:21][N:20]=2)[CH:7]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4ccccn4)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.837 g, 19.94 mmol, 3 eq) was added to a solution of 244a) (2.5 g, 6.64 mmol, 1 eq) in water/THF (1:1, 40 mL) and the reaction mixture was stirred for 16 h at room temperature. The solvents were removed under reduced pressure and the residue was dissolved in water (100 mL), washed with ether (50 mL) and acidified with 2N hydrogen chloride solution. The aqueous phase was then extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with water and brine (50 mL), dried over sodium sulfate, and evaporated. White solid. Yield: 1.5 g (63% of theory)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:15]([Cl:16])=[CH:14][C:7]2[O:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1.Cl.[CH3:18][O:19][C:20](=O)[O:21]C>>[CH3:18][O:19][C:20]([CH:11]1[CH2:10][CH2:9][O:8][C:7]2[CH:14]=[C:15]([Cl:16])[C:4]([Cl:3])=[CH:5][C:6]=2[C:12]1=[O:13])=[O:21]
Reactant: COC(=O)OC
Reactant: O=C1CCCOc2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCOc2cc(Cl)c(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A suspension of sodiumhydride in parrafin (0.35 g, 60%) was added to 5 ml dimethylcarbonate. To this suspension 7,8-Dichloro-3,4-dihydro-2H-benzo[b]oxepin-5-one (4.3 mmol) dissolved in 2 ml dimethylcarbonate was added dropwise at room temperature. The mixture was refluxed for two hours, cooled to room temperature and stirred overnight. 25 ml of 2 mol/l hydrochloric acid were added to the mixture. The resulting solution was extracted by ethyl acetate. The organic phase was dried over sodiumsulfate and the solvent removed in vacuo. The residue was dissolved in diethyl ether. 7,8-Dichloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester was obtained by crystallization from this solution in a yield of 40%. LC-MS 2.3 min, 289.0 (MH+), 2.8 min, 289.0 (MH+)
Reaction SMILES: 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.[CH3:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][C:36]=1[N:42]1[C:49]2[N:45]([N:46]=[C:47]([C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)[CH:48]=2)[CH:44]=[CH:43]1.[C:56]([C:60]1[CH:61]=[C:62]([CH:66]=[C:67]([C:69]#[N:70])[CH:68]=1)[C:63](O)=[O:64])([CH3:59])([CH3:58])[CH3:57]>CS(C)=O.C(OCC)(=O)C>[C:56]([C:60]1[CH:61]=[C:62]([CH:66]=[C:67]([C:69]#[N:70])[CH:68]=1)[C:63]([NH:39][C:38]1[CH:40]=[CH:41][C:35]([CH3:34])=[C:36]([N:42]2[C:49]3[N:45]([N:46]=[C:47]([C:50]4[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=4)[CH:48]=3)[CH:44]=[CH:43]2)[CH:37]=1)=[O:64])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)c1cc(C#N)cc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
144 mg (0.38 mmol) of HATU and 81 mg (0.63 mmol) of N,N-diisopropylethylamine were added to a solution of 91 mg (0.31 mmol) of the compound of Example 6A and 173 mg (purity 37%, 0.31 mmol) of 3-tert-butyl-5-cyanobenzoic acid [lit.: WO 2008/021388 A1, intermediate E, page 164] in 2.0 ml of DMSO. The reaction was stirred at 25° C. for 16 h. The reaction mixture was then diluted with ethyl acetate and the phases were separated. The organic phase was washed twice with in each case 50 ml of saturated sodium bicarbonate solution and then dried over sodium sulphate. After filtration, the mixture was concentrated under reduced pressure and the residue obtained in this manner was purified by double chromatography on a Biotage system (first run: 25 g Snap column, mobile phase gradient ethyl acetate/hexane, starting with 20% ethyl acetate, then increasing rapidly to 100% ethyl acetate, then ethyl acetate/methanol, from 0% methanol increasing steadily to 50% methanol; second run: 10 g Snap column, mobile phase gradient ethyl acetate/hexane, starting with 20% ethyl acetate, then increasing rapidly to 100% ethyl acetate, then ethyl acetate/methanol, from 0% methanol increasing steadily to 50% methanol). This gave 17.8 mg (11% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1B1OC(C)(C)C(C)(C)O1)[NH2:14].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>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>[NH2:14][C:13]1[CH:15]=[CH:16][C:17]([C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[C:11]([F:10])[CH:12]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
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: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cc(Br)cnc2N)c(F)c1
Temperature: 80 °C
Yield: 87.6 %

Procedure:
5-Bromo-3-iodopyridin-2-amine (300 mg), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (238 mg), tetrakis(triphenylphosphine)palladium (58 mg) and potassium carbonate (416 mg) were suspended in dioxane (5 ml) and water (0.5 ml), and the suspension was heated under reflux at 80° C. for two days. After leaving to cool, a saturated aqueous sodium bicarbonate solution was added, and the organic layer was extracted with ethyl acetate and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane:ethyl acetate=1:2 (v/v)] to give 248 mg of the title compound as a solid.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Cl.[O-]CC.[Na+].[Na].[O:19]1[CH2:23][CH2:22][O:21][CH:20]1[C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([NH:29][NH2:30])=O>C(O)C.CCOCC>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[NH:30][N:29]=[C:27]([C:26]3[CH:31]=[CH:32][CH:33]=[C:24]([CH:20]4[O:19][CH2:23][CH2:22][O:21]4)[CH:25]=3)[N:9]=2)=[CH:10][CH:11]=1
Reactant: NNC(=O)c1cccc(C2OCCO2)c1
Reactant: N#Cc1ccc(OC(F)F)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: FC(F)Oc1ccc(-c2nc(-c3cccc(C4OCCO4)c3)n[nH]2)cc1
Reaction time: 65 h
Yield: 62 %

Procedure:
To a solution of 4-(difluoromethoxy)benzonitrile (5 g, 30 mmol) in ethanol at 4° C. was bubbled dry HCl(g) for 3 h. The resulting mixture was stoppered and kept at 4° C. for 65 h. Ether (40 ml) was then added with ultrasonication to precipitate the imidate hydrochloride salt, which was washed twice with dry ether (40 ml) and then dried under vacuum (0.05 mmHg) at 20° C. To a solution of imidate hydrochloride salt (1 g, 4 mmol) in ethanol (15 ml) was added sodium ethoxide solution dropwise (sodium: 98 mg, 4 mmol in 5 ml of dry ethanol) at room temperature. The reaction was allowed to stir for a further 30 min then 3-[1,3]Dioxolan-2-yl-benzoic acid hydrazide was added (824 mg, 4 mmol) and the mixture was heated to reflux for 22 h until the starting materials were consumed. The reaction mixture was evaporated to dryness and chromatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc/nHexane (3:7), the product fractions were combined and evaporated to afford the title compound as a white solid (885 mg, 62% yield), MS: m/e=359.1 (M+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[O:56][N:55]=[CH:54][C:53]=2[C:57](O)=[O:58])=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[O:56][N:55]=[CH:54][C:53]=2[C:57]([N:10]2[CH2:11][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]([CH2:12][OH:13])[CH2:9]2)=[O:58])=[CH:50][CH:51]=1
Reactant: OCC1CNCC1c1ccccc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CC(CO)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-(4-methylphenyl)isoxazole-4-carboxylic acid (7 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (4 mg). MS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1629.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:16]1[C:25]2[C:24](=[O:26])[N:23]([CH3:27])[CH:22]=[N:21][C:20]=2[CH:19]=[C:18]([Cl:28])[N:17]=1>O1CCOCC1>[Cl:28][C:18]1[N:17]=[C:16]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=2)[C:25]2[C:24](=[O:26])[N:23]([CH3:27])[CH:22]=[N:21][C:20]=2[CH:19]=1
Reactant: Nc1nc(CO)cs1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cnc2cc(Cl)nc(Nc3nc(CO)cs3)c2c1=O
Temperature: 80 °C

Procedure:
(2-aminothiazol-4-yl)methanol (70.0 mg, 0.54 mmol) and K2CO3 (148.6 mg, 1.08 mmol) were added to a solution of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (123.7 mg, 0.54 mmol) in 1,4-dioxane (2.7 mL). The reaction mixture was heated at 80° C. overnight, cooled down, quenched with H2O (20 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (10% methanol/dichloromethane) to give 7-chloro-5-(4-(hydroxymethyl)thiazol-2-ylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one as a white solid product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][NH2:13])=[C:4]([F:14])[CH:3]=1.[C:15]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)(=O)[CH3:16].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:16][C:15]1[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:10])[CH3:11])[C:2]([Cl:1])=[CH:3][C:4]=2[F:14])[N:13]=[C:19]2[C:18]=1[CH2:23][CH2:22][CH2:21][CH2:20]2
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Reactant: CC(=O)C1CCCCC1=O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: Cc1c2c(nn1-c1cc(OC(C)C)c(Cl)cc1F)CCCC2
Yield: 39.1 %

Procedure:
4-Chloro-2-fluoro-5-isopropoxyphenylhydrazine (1.8 g), 2-acetylcyclohexanone (1.0 g) and a catalytic amount of acetic acid were dissolved in xylene (5 ml). The resultant mixture was heated under reflux for 8 hours while removing water. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.9 g of 3-methyl-2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (Compound No. 5). nD14.5 1.5607.