Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=[O:20])=[N+:2]=[N-:3].[CH2:28](O)[CH2:29][OH:30].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]2[O:30][CH2:29][CH2:28][O:20]2)[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])=[N+:2]=[N-:3]
Reactant: COc1cc(C=O)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C2OCCO2)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A mixture of 4.95 g (12.91 mmol) 3-{2-[2-(2-{2-azidoethoxy}ethoxy)ethoxy]ethoxy}-4,5-dimethoxybenzaidehyde 8, 5 ml (5.57 g, 90 mmol) ethylene glycol and 200 mg (1.0 mmol) p-toluene sulfonic acid monohydrate was refluxed in 120 ml of toluene for 8 hrs using a Dean-Stark trap. After cooling to room temperature the rection mixture was poured into 200 ml of diluted sodium bicarbonate solution, washed with water and brine and dried over magnesium sulfate. After removal of the solvent the residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate 1/1), giving 4.43 g (10.8 mmol, 80%) of the product as a clear oil. 1H-NMR (CDCl3) δ=6.73 (dd, 2H, J=5.0 Hz, J=1.8 Hz), 5.72 (s, 1H), 4.19 (m, 2H), 4.11 (m, 2H), 4.03 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.76-3.71 (m, 4H), 3.70-3.64 (m, 8H), 3.37 (m, 2H) ppm. 13C-NMR δ=153.3, 152.4, 139.2, 133.1, 105.4, 103.6, 103.4, 70.7, 70.6, 70.5 (2 peaks), 69.9, 69.6, 68.7, 65.1, 60.6, 56.0, 50.6 ppm. MS: m/z=427 [M]+. Anal. calcd for C19H29N3O8: C, 53.39, H, 6.84, N, 9.83. Found C, 52.30, H, 6.89, N, 9.72.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:29][C:28]1[CH:27]=[CH:26][C:25]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])=[CH:24][C:23]=1[C:22]([F:21])([F:33])[F:34]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Yield: 88 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-trifluoromethyl-4-chloro-phenylisocyanate to afford the title compound, yield: 88%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH:22]2[O:24][CH2:23]2)=[CH:17][CH:16]=1>C1COCC1.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])([CH:22]2[CH2:23][O:24]2)[OH:25])=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CO1
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccccc1F)C1CO1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 0.9 g of 2-bromofluorobenzene in 10 mL of THF and 20 mL of diethyl ether was added 3.2 mL of a 1.6M solution of n-butyllithium in hexanes at -78°. After the addition was complete, a solution of 0.9 g of 4'-chloro-2,3-epoxypropiophenone (J.T. Lumb, Tetrahedron Lett., 1970, 579) in 5 mL of ether was added, and the reaction mixture was allowed to warm to room temperature. After being quenched with 10 mL of saturated NH4Cl (aqueous), the mixture was separated, the organic phase was washed with brine, dried (MgSO4), filtered, concentrated, and triturated with hexanes to afford 1.0 g of the title compound, m.p. 120°-122°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.Cl.[NH:18]1[CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N:18]1([C:14]([C:11]2[N:12]=[CH:13][C:8]([Br:7])=[CH:9][N:10]=2)=[O:16])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ncc(Br)cn1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
Oxalyl chloride (1.50 mL, 16.79 mmol), followed by DMF (2 drops), were added to a mixture of 5-bromopyrimidine-2-carboxylic acid (2.86 g, 14.0 mmol) in DCM (40 mL). The reaction was stirred at RT for 2 hours, the volatiles removed in vacuo and the residue dissolved in DCM (40 mL). Azetidine hydrochloride (1.44 g, 15.39 mmol), followed by triethylamine (4.29 mL, 30.78 mmol), were added and the mixture stirred at RT for 72 hours. The mixture was concentrated in vacuo and ethyl acetate (100 mL) added to the residue. The organics were washed with water (100 mL), citric acid (50 mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow solid. The solid was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound as a yellow solid (0.86 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[N:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:17]1([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:4]3[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:26]4[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:28][CH:27]=4)[N:3]=3)[CH2:11][CH2:12]2)[CH2:19][CH2:18]1
Reactant: N#Cc1cc(Cl)nc(N2CCN(CC3CC3)CC2)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCN(CC3CC3)CC2)c1
Temperature: 100 °C

Procedure:
The nitrile 25D (2.4 g, 8.67 mmol), 4-trifluoromethoxyphenylboronic acid (2.15 g, 1.1 mol eq), palladium acetate (45 mg), cesium carbonate (4.5 g, 2 mol eq), and XPhos (190 mg) were mixed, placed under a nitrogen atmosphere and dioxane (10 mL) was added. The mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through a celite pad, washed with dioxane (2×20 mL) and concentrated under reduced pressure. The residue was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]([NH:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=3)[N:11]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1([NH:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])[N:13]=[C:12]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:34][CH:35]=3)[N:11]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a suspension of tert-butyl 4-(4-(1-(ethoxycarbonyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.6 g) in dichloromethane (15 mL) was added TFA (4.96 mL). The mixture was stirred at r.t. for 16 hours. All solvents were removed under vacuum to give product 4-(4-(1-(ethoxycarbonyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (1.35 g).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:11]Br>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CC1CCCCC1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CC1CCCCC1Br
Yield: 1055.4 %

Procedure:
To a solution of cyclohexylacetic acid (10 g, 70 mmol), in 100 ml of CCl4 was added red phosphorus (6.32 g, 204 mmol). The mixture was heated to reflux and bromine (70.7 ml, 1.38 mmol) was added over 3 hours dropwise through the condenser via addition funnel. The reaction was heated at reflux for 5 hours before it was quenched slowly with water then washed with 10% Na2SO4, water, then into NaHCO3. The sodium bicarbonate solution was brought to acidic pH using 1 N HCl. The solid was collected and the aqueous filtrate was extracted into CHCl3, washed with saturated Na2HSO4 solution then with water. The organic layer was dried over Na2SO4, filtered and concentrated and combined with solid collected earlier to provide 3.22 g 2-bromo cyclohexyl acetic acid as a white solid. Yield 21%; MS: 219.1 (M−H)−
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:18])(=[N:11]C(=O)C(F)(F)F)=[O:10])=[CH:5][CH:4]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@H:27]([CH3:31])[C@H:28]([OH:30])[CH3:29])[C:23]([C:32]([F:35])([F:34])[F:33])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C.[Cl-].[Na+].CO>[OH:30][C@H:28]([CH3:29])[C@H:27]([NH:26][C:24]1[C:23]([C:32]([F:35])([F:34])[F:33])=[CH:22][N:21]=[C:20]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([S:9]([CH3:18])(=[NH:11])=[O:10])=[CH:7][CH:8]=2)[N:25]=1)[CH3:31]
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc(N)cc1
Reactant: C[C@@H](O)[C@@H](C)Nc1nc(Cl)ncc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: CC#N
Solvent: C1COCCO1
Product: C[C@@H](O)[C@@H](C)Nc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1C(F)(F)F
Temperature: 60 °C
Reaction time: 9 h
Yield: 93.3 %

Procedure:
0.38 ml of 4N solution of hydrogen chloride in dioxane was added to 399 mg (1.50 mmol) of (RS)-S-(4-aminophenyl)-S-methyl-N-(trifluoroacetyl)sulfoximide and 404 mg (1.50 mmol) of (2R,3R)-3-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-butan-2-ol in 7.3 ml acetonitrile and stirred for 9 hours at 60° C. The mixture was evaporated to dryness. 32.2 ml methanol and 1040 mg (7.50 mmol) of potassium carbonate were added and it was stirred for 1.5 hours at room temperature. It was diluted with saturated sodium chloride solution and was extracted with ethyl acetate (3×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. 565 mg (1.40 mmol) of the raw product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:20][C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[N:18][N:17]=1.C[N:27](C=O)C.C1N=CN(C(N2C=NC=C2)=O)C=1.C([O-])(=O)C.[NH4+]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:20][C:19]([NH:21][CH2:22][C:23]([NH2:27])=[O:24])=[N:18][N:17]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Agent: CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Product: NC(=O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of {5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-acetic acid (75 mg, 0.16 mmol, 1 eq) in DMF CDI (35 mg, 0.21 mmol, 1.3 eq) was added. The reaction mixture was stirred at RT under argon for 3 hrs and then amoniumacetate (30 mg, 0.41 mmol, 2.5 eq) was added. The mixture was stirred for another 2 hrs. The resulting mixture was directly purified by preparative HPLC to afford the desired product (35 mg). LC/MS (Method A) [4.57 min; 455(M+1)]
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH:30]([CH:33]([CH3:36])[CH2:34]O)([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:31][CH:30]([CH:33]([CH3:36])[CH3:34])[CH3:32])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: CC(C)C(C)CO
Solvent: ClCCl
Product: CC(C)C(C)COC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropane-carboxylate in 30 ml of methylene chloride was added to a mixture of 3 ml of 1-dimethylamino-1-chloro-2-methyl-propen-1-yl [J. Org. Chem., Vol. 35 (1970), p. 3970] in 3 ml of methylene chloride and the mixture was stirred at room temperature for 15 minutes. After cooling the mixture to 5° C., 5 ml of 2-isopropyl-propanol were added thereto and the mixture was stirred at room temperature for 16 hours, was washed with water, with aqueous sodium chloride solution, was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 2.25 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(2-isopropyl-propyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+61.5°±2.5° (c=0.5% in benzene).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:15]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:22](=[O:23])[CH2:21][CH2:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)CCC2CCCC2)c[nH]1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
Ethylpyrrole-2-carboxylate (1.8593 g, 13.36 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (3.5756 g, 26.82 mmol) and 3-cyclopentylpropionyl chloride (4.1 mL, 26.59 mmol) in dichloroethane (20 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 4 h. 18.18 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for ˜60 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered and concentrated. The crude product was recrystallized from Hexanes/Ethyl acetate. The crude was dissolved in a minimal amount of hot EtOAc, then allowed to slowly cool to room temperature. When no product crystallized, a small amount of hexanes was pipetted down the sides of the flask. Pure crystals of desired product (2.3068 g, 65.6%) were obtained after sitting overnight. 1H (CDCl3, 400 MHz): δ 10.04 (1H, broad s), 7.55 (1H, s), 7.29 (1H, s), 4.34 (2H, q, J=7.1 Hz), 2.77 (2H, t, J=7.6 Hz), 1.85-1.67 (5H, m), 1.64-1.46 (4H, m), 1.36 (3H, t, J=7.1 Hz), 1.78-1.06 (2H, m) ppm. 13C (CDCl3, 100 MHz): δ 196.38, 161.09, 127.03, 126.14, 124.05, 114.76, 60.91, 39.82, 39.06, 32.53, 30.82, 25.11, 14.31 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.31; CH2 carbons: 60.91, 39.06, 32.53, 30.82, 25.11; CH carbons: 126.14, 114.76, 39.82 ppm. HPLC: 10.800 min.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([NH:17][CH:18]2[CH:23]3[CH:19]2[CH2:20][N:21]([S:24]([C:27]2[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=2)(=[O:26])=[O:25])[CH2:22]3)=[N:15][CH:16]=1)=[O:10].C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[OH:7][NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([NH:17][CH:18]2[CH:23]3[CH:19]2[CH2:20][N:21]([S:24]([C:27]2[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=2)(=[O:26])=[O:25])[CH2:22]3)=[N:13][CH:12]=1)=[O:10]
Reactant: O=C(NOC1CCCCO1)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NO)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a solution of N-(tetrahydro-2H-pyran-2-yloxy) 2-{[3-(2-napthylsulphonyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}pyrimidine-5-carboxamide (110 mg, 0.21 mmol) in MeOH (15 ml) and DCM (15 ml), was added TFA (1.5 ml) at r.t. The mixture was stirred for 8 h before removal of solvent in vacuo. Excess TFA was removed by re-dissolving in DCM (5 ml×2) and concentration to dryness under reduced pressure. Purification by preparative HPLC gave the title compound as a white solid (25.1 mg, 21%). LCMS purity 100%, m/z 426 [M+H]+, 1H NMR (400 MHz, d6-DMSO) δ: 1.15 (2H, s), 2.55 (1H, s), 3.20 (2H, d), 3.65 (2H, d), 7.65 (2H, m), 7.75 (1H, d), 7.90 (1H, m), 8.15-8.30 (3H, m), 8.50 (1H, s), 8.65 (2H, s).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2.[C:17](=[O:19])=[O:18].O>CCCCCC.C1COCC1>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([C:17]([OH:19])=[O:18])[C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2
Reactant: O=C=O
Reactant: Fc1cc2cc[nH]c2cc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Temperature: -75 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
1.25 ml (2 mmol) of a 1.6 M butyl lithium solution in hexane were diluted with 4 ml THF at −78° C. under nitrogen. 224 mg (2 mmol) of potassium-tert-butylate and then 156 mg (1 mmol) of 5,6-difluoro-1H-indol were added. The reaction was exothermal and an orange solution was obtained, which was stirred for 2 h at −75° C. Solid carbon dioxide was added at that temperature and the reaction mixture was allowed to warm to rt within 30 min. Water was added and the reaction mixture was extracted three times with diethyl ether. The aqueous layer was acidified with 1N aqueous HCl solution and extracted three times with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was stirred with n-hexane and a trace of diethyl ether for 15 min and filtered to yield 100 mg (51%) product as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): 13.6 (br, 1H), 11.2 (br, 1H), 7.85 (dd, 1H), 7.42 (s, 1H), 6.53 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.[CH3:10][N:11]1[C:15](B(O)O)=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[N:12]1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][N:11]1[C:15]([C:2]2[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=2)=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[N:12]1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1-c1ncc([N+](=O)[O-])s1
Temperature: 110 °C
Yield: 13.5 %

Procedure:
A mixture of 2-bromo-5-nitrothiazole (209 mg, 1 mmol), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (194 mg, 1 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 57 mg) and sodium carbonate (212 mg) in 3 ml DME, 0.5 ml EtOH and 0.5 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to silica gel flash chromatography (0-30% B; A: hexane; B: 50% EA in hexane) to furnish 37.5 mg of 2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-5-nitro-1,3-thiazole (65) as light yellow solid (yield: 13.5%; purity>90%).
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15](Cl)(=[O:17])=[O:16])=[O:5]>O1CCCC1>[CH3:2][N:3]([CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([NH2:1])(=[O:17])=[O:16])=[O:5]
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O

Procedure:
37 ml of concentrated ammonia solution (33% strength) are added dropwise at 5° C. and with stirring to a mixture of 77.8 g of 2-dimethylaminocarbonyl-5-nitrobenzenesulfonyl chloride and 780 ml of tetrahydrofuran. The mixture is subsequently stirred until the end of the reaction. The reaction mixture is concentrated under reduced pressure and the residue is stirred with a little water. Drying gives 66.9 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].Cl.CN(C)CCCN=C=NCC.O>O1CCCC1>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][N:16]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])=[O:6])=[CH:3][C:2]=1[Br:1]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Br
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A solution of 3-bromo-4-(methoxycarbonyl)benzoic acid (Example 76; 1.60 g, 6.2 mmol) in tetrahydrofuran (30 mL) was cooled to 10° C. and N-hydroxysuccinimide (781 mg, 6.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20 g, 6.5 mmol) were added. The solution was allowed to stir at room temperature overnight, then water was added and the solution was concentrated in vacuo to remove tetrahydrofuran. The mixture was extracted with ethyl acetate and the extracts were dried (MgSO4), filtered and evaporated under reduced pressure to furnish 2-bromo-4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzoic acid methyl ester (2.20 g, quantitative yield).