Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C1C(=O)N([Br:22])C(=O)C1>C(O)(=O)C>[Br:22][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([N+:12]([O-:14])=[O:13])[C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
(I4A): Methyl 4-hydroxy-3-nitrobenzoate (15 g, 76 mmol) was suspended in acetic acid (152 ml) and then treated with NBS (20.31 g, 114 mmol). The mixture became a homogeneous yellow solution which was stirred for 2 h. The mixture was quenched with water and the suspension was filtered. Methyl 3-bromo-4-hydroxy-5-nitrobenzoate (20 g) was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=O)=[CH:4][CH:3]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:13])=[CH:6][CH:7]=1
Reactant: NC(=O)CCCc1ccc(F)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCCCc1ccc(F)cc1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
4(4-Fluorophenyl)-butyramide (Int. A4) (2.63 g) was dissolved in trifluoroacetic anhydride (10 ml) and stirred for 2 h. The solution was concentrated and then dissolved in dichloromethane and washed with 2N sodium hydroxide solution. The organics extracts were isolated, dried (MgSO4) and concentrated to yield the product (2.3 g, 100%) which contained ˜5% starting amide as an impurity. 1H-NMR (CDCl3) δ 1.96 (2H, app q), 2.31 (2H, t), 2.75 (2H, t), 6.98 (2H, m), 7.14 (2H, m). MS (APCI+)M+1=164, C10H10FN requires 163.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([OH:30])[CH2:26][CH:27]([CH3:29])[CH3:28].[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)([CH3:33])[CH3:32].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:30][CH:25]([C:3]1[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]=2[N:23]=[CH:24][C:2]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH:31]([CH3:33])[CH3:32])[CH2:26][CH:27]([CH3:28])[CH3:29]
Reactant: CC(C)c1ccccc1B(O)O
Reactant: CC(C)CC(O)c1c(Br)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)CC(O)c1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 100 °C
Yield: 42.8 %

Procedure:
To a solution of 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (65 mg, 0.134 mmol) in dioxane (1 mL) was added (2-isopropylphenyl)boronic acid (88 mg, 0.536 mmol), Pd(dppf)Cl2 (10 mg) and aq. 2N K3PO4 (0.2 mL). The mixture was heated at 100° C. for 5 h, cooled to RT and filtered. The filtrate was concentrated and dried to a residue which was purified by chromatography eluted with PE/EA (10:1 to 6:1) to give 5-(1-hydroxy-3-methylbutyl)-6-(2-isopropylphenyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 42.7% yield) as a solid. LCMS: [M+-THP-OH] 423 and TR=2.047 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:31](I)[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:31]([N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)CI
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with isobutyl iodide and cesium carbonate in N,N-dimethylacetamide to give N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a colorless solid. MS: 548.8 ([M+NH4]+)
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C1(C2CCNCC=2)C=CC=CC=1.C(O)(=[O:31])CS>C(O)C>[SH:1][CH2:2][C:3]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)=[O:31]
Reactant: O=C(O)CS
Reactant: SCCN1CC=C(c2ccccc2)CC1
Agent: C1=C(c2ccccc2)CCNC1
Solvent: CCO
Product: O=C(CS)N1CC=C(c2ccccc2)CC1

Procedure:
2.76 g of Na are dissolved in 180 ml of ethanol, 21.9 g of 1-(2-mercaptoethyl)-4-phenyl-1,2,3,6-tetrahydropyridine [obtainable by reacting 4-phenyl-1,2,3,6-tetrahydropyridine with thioglycolic acid to give 1-(2-mercaptoacetyl)-4-phenyl-1,2,3,6-tetrahydropyridine and reducing the latter with LiAlH4 and 23.2 g of methyl gramine-5-carboxylate are added, the mixture is boiled for 16 hours and evaporated, and the residue is worked up in the customary manner to give "P", hydrochloride, m.p. 202°-203°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:9][C:10]1[C:15]2[O:16][C:17]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]([OH:30])=[O:29])=[CH:23][C:18]=3[S:19](=[O:22])(=[O:21])[CH2:20][C:14]=2[CH:13]=[C:12]([S:31](Cl)(=[O:33])=[O:32])[CH:11]=1.O>C(OCC)(=O)C>[Cl:9][C:10]1[C:15]2[O:16][C:17]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]([OH:30])=[O:29])=[CH:23][C:18]=3[S:19](=[O:22])(=[O:21])[CH2:20][C:14]=2[CH:13]=[C:12]([S:31](=[O:32])(=[O:33])[NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)NCc3cccnc3)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(Aminomethyl)pyridine (0.22 mL, 2.1 mmol) was added to a suspension of Example 49j (0.8 g, 1.8 mmol) in ethyl acetate (40 mL). The reaction mixture was stirred at room temperature for 15 h, treated with water and extracted with butanol. The organic layer was washed with water, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.2 g, (20%); 1H NMR (DMSO-d6): δ 2.69 (s, 3H, CH3), 4.18 (d, 2H, CH2), 5.45 (s, 2H, CH2), 7.26 (d, 1H, Ar), 7.6 (d, 1H, Ar), 7.9 (s, 1H, Ar), 8.09 (s, 1H, Ar), 8.18 (s, 1H, Ar), 8.24 (s, 1H, Ar), 8.41 (d, 1H, Ar), 8.47 (s, 1H, Ar), 8.6 (s, 1H, OH).
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH3+:14])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([OH:4])=[O:3].Cl.[CH3:16]O>>[Cl-:1].[CH3:16][O:3][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([NH3+:14])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: [NH3+]C1(c2ccc(C(=O)O)cc2)CC1
Reactant: CO
Agent: Cl
Agent: [Cl-]
Product: COC(=O)c1ccc(C2([NH3+])CC2)cc1
Temperature: 25 °C

Procedure:
1-(4-Carboxyphenyl)cyclopropanaminium chloride from Example 16, Step 1 (4.17 mmol) in MeOH (10 mL) was heated to the reflux temperature, in the presence of HCl (4M in dioxane, 104 μL, 0.417 mmol), for 16 h and cooled to r.t. The mixture was concentrated to dryness and the residue was partitioned between EtOAc and a phosphate buffer (pH 10). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was dissolved in dioxane (10 mL) and excess HCl (4M in dioxane) was added. The mixture was then concentrated to dryness affording the desired product as a brown solid. The crude was used without further purification.
Reaction SMILES: [CH2:1]([Br:3])[Br:2].[OH-].[Na+].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[C:8]=1[OH:14]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([Br:3])[Br:2].[CH3:6][C:7]1[C:8]2[O:14][CH2:1][O:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: BrCBr
Solvent: O
Product: Cc1cccc2c1OCO2
Reaction time: 2 h
Yield: 111.7 %

Procedure:
400 g of methylene bromide and 50 g of tetrabutylammonium bromide are taken under reflux in a stirred apparatus and a solution of 400 ml of water, 130 g of sodium hydroxide and 200 g of 3-methylpyrocatechol are added dropwise in the course of 5 hours. At the end of the addition, the mixture is subsequently stirred for a further 2 hours, cooled and extracted with methylene chloride. The organic phase is dried and distilled on a column. After first runnings of unreacted methylene bromide, 175 g of 4-methyl-1,3-benzodioxole are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OC)(OC)OC.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20].[BH4-]>CO.C(Cl)Cl.C(O)(=O)C>[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:20]
Reactant: CCOCCCN
Reactant: CC(C)c1ccc(C=O)cc1
Agent: [BH4-]
Solvent: ClCCl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CCOCCCNCc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
p-iso-Propylbenzaldehyde (1.007 g, 6.798 mmol) was dissolved in methanol (5 ml). Trimethyl orthoformate (5 ml) was added. 3-Ethoxypropylamine (681 mg, 6.6 mmol) was then added and followed by acetic acid (0.2 ml). After standing at room temperature overnight, DCM (5 ml) was added and followed by borohydride on polymer support (5.28 g, 13.2 mmol). The mixture was shaken at room temperature for 4 days and then filtered. The filtrate was evaporated. The residue was dissolved in acetonitrile, then divided into two portions and loaded on 2 columns (ISOLUTE® PRS, 10 g/70 ml, wetted with acetonitrile). It was eluted with acetonitrile, then methanol and then methanol (NH3 sat.). The product fractions were combined and evaporated. Oil product 1.283 g was obtained, yield 83%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](Cl)=[N:6][CH:7]=1.[C:10](#[N:12])[CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([CH2:11][C:10]#[N:12])=[N:6][CH:7]=1
Reactant: CC#N
Reactant: Clc1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
27.0 g of 5-bromo-2,3-dichloropyridine was dissolved in 450 ml of anhydrous tetrahydrofuran and 7.33 g of acetonitrile was added at ambient temperature under argon. 262 ml of lithium hexamethyldisilazide (1N solution in tetrahydrofuran) was added dropwise over a period of 45 min, during which the temperature rose to 35° C. Subsequently, the reaction mixture was stirred at ambient temperature for 1 h, then the reaction mixture was poured into 800 ml of cold water and was extracted with two 1 L portions of diethyl ether. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. 29.4 g of crude material was obtained as a brown oil. It was purified by chromatography on silica gel, using heptane/ethyl acetate (9:1) as a eluent. Thus, 23.4 g of (5-bromo-3-chloro-pyridin-2-yl)-acetonitrile was obtained as a orange oil. 1H-NMR (CDCl3): 8.60 ppm (s, 1H), 7.92 ppm (s, 1H), 4.00 ppm (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Reactant: ClCCN1CCCC1
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCN2CCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 3A]) and 1-(2-chloro-ethyl)-pyrrolidine gave the title compound as off-white powder. MS: 376.5 (MH+, Cl).
Reaction SMILES: [C:1](OC)(=O)[CH2:2][C:3]([CH3:5])=O.[Li+].CC([N-]C(C)C)C.[CH:17]1([C:22](=[O:36])[CH2:23][CH2:24][C:25]2[C:30]([O:31][CH2:32][CH3:33])=[CH:29][N:28]=[C:27]([CH2:34][CH3:35])[CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:17]1([C:22]2([CH2:23][CH2:24][C:25]3[C:30]([O:31][CH2:32][CH3:33])=[CH:29][N:28]=[C:27]([CH2:34][CH3:35])[CH:26]=3)[O:36][CH2:5][CH2:3][CH2:2][CH2:1]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cnc(CC)cc1CCC(=O)C1CCCC1
Reactant: COC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cnc(CC)cc1CCC1(C2CCCC2)CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
Methyl acetoacetate (1.2 mL, 10.9 mmol) was added to a cooled −50° C. suspension of LDA [prepared from diisopropylamine (3.0 mL, 21.8 mmol), and n-BuLi (8.7 mL, 21.8 mmol) dissolved in THF (30 mL)]. The reaction was stirred for 30 mins and then a solution of 1-cyclopentyl-3-(5-ethoxy-2-ethyl-pyridin-4-yl)-propan-1-one (1.0 g, 3.6 mmol) dissolved in THF (30 mL) was added. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was poured into 1 N NaOH and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. The residue was dissolved in methanol (100 mL), treated with potassium carbonate (1.5 g, 10.9 mmol), and refluxed under N2 for 120 mins. The reaction mixture was partitioned between H2O and IPE. The aqueous layer was made neutral with 1N HCl and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated to give the product (1.3 g, 99% yield). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3H), 1.43 (t, J=6.8 Hz, 3H), 1.50-2.05 (br m, 9H), 2.34 (m, 2H), 2.62-2.77 (m, 6H), 3.44 (m, 2H), 4.11 (q, J=6.8 Hz, 2H), 6.90 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[CH:8]=[CH:9][CH:10]=1)(=O)C.[ClH:17]>C(O)C>[ClH:17].[NH2:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(-n2nnnc2S)c1
Agent: Cl
Solvent: CCO
Product: Nc1cccc(-n2nnnc2S)c1
Temperature: 25 °C

Procedure:
1-(3-Acetamidophenyl)-5-mercaptotetrazole (0.51 mol) (120 g) was dispersed in 450 ml of ethanol. While stirring the dispersion at room temperature, 300 ml of concentrated hydrochloric acid was added. They were further reacted at room temperature for 3 hours. At the end of the time, the reaction mixture was cooled with ice. Crystals thus precipitated were collected and washed with acetone to obtain 110 g of 1-(3-aminophenyl)-5-mercaptotetrazole hydrochloride. This amine hydrochloride was dispersed in 750 ml of acetonitrile, and 123 ml of triethylamine was added thereto. Then, 41.5 g of methyl chlorocarbonate was further added thereto at room temperature.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[O:19].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH:18]([C:14]1[N:13]([C:2]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: O=Cc1ncc[nH]1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc([N+](=O)[O-])cc1-n1ccnc1C=O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
Into a Round bottom flask, 2-fluoro-4-nitro-benzonitrile (10.4 g, 0.0624 mol), imidazole-2-carboxaldehyde (5.00 g, 0.0520 mol) and dimethyl sulfoxide (200 mL, 3 mol) were added at room temperature. potassium carbonate (7.19 g, 0.0520 mol) was added portion wise to the reaction mixture and heated at 55° C. for 60 minutes. The reaction was cooled at −20° C. overnight. The content was poured over ice and stirred for 30 minutes. The solid was filtered and washed with water. The resulting solid was dissolved with DCM and washed with Brine. The organic was separated, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-(2-formyl-imidazol-1-yl)-4-nitro-benzonitrile as a yellow solid (10.48 g, 83%). 1H-NMR (DMSO-D6, 400 MHz): δ9.75 (s, 1H), 8.68 (s, 1H), 8.55 (d, 1H), 8.40 (d, 1H), 7.99 (s, 1H), 7.57 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
4-Dimethylaminopyridine (2.55 g, 21.3 mmol) and triethylamine (46.9 ml, 340.8 mmol) in dichloromethane (100 ml) are added to a solution of (S)-(−)-4-benzyl-2-oxazolidinone (37.7 g, 213 mmol) in dichloromethane (300 ml). Next, isovaleroyl chloride (33.75 ml, 207 mmol) in dichloromethane (50 ml) is added to the previously prepared mixture and cooled to 0° C. keeping the internal temperature below 10° C. The reaction mixture is stirred for 30 minutes at 10° C., then the formed salts are filtered. Water (100 ml) is added and the phases are separated. The organic phase is washed with water (100 ml) and brine (100 ml), dried over sodium sulphate and evaporated to dryness obtaining 53 g of a yellow oil, which solidifies over time (yield 95%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[S:4]([C:7]1[C:15]2[O:14]C(C(C)(C)C)=[N:12][C:11]=2[CH:10]=[CH:9][C:8]=1[Cl:20])(=[O:6])=[O:5].S(=O)(=O)(O)O>O1CCOCC1.O>[NH2:12][C:11]1[C:15]([OH:14])=[C:7]([S:4]([N:3]([O:2][CH3:1])[CH3:21])(=[O:6])=[O:5])[C:8]([Cl:20])=[CH:9][CH:10]=1
Reactant: CON(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CON(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 25 °C

Procedure:
2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acid methoxy-methyl-amide (4.8 g, 14.42 mmol) in dioxane (55 ml) and water (20 ml) was treated with concentrated sulphuric acid (20 ml) added dropwise over 30 minutes maintaining the temperature <30° C. The reaction mixture was heated at reflux for 2.5 h and then allowed to cool to RT. Dioxane was removed in vacuo and the resulting aqueous residue was basified with sat. NaHCO3 solution (250 ml) to pH12. The reaction mixture was extracted with EtOAc (3×200 ml) and the combined organic extracts were washed with water (3×100 ml) sat. brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid; [M+H]+ 266.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]([OH:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the product from Example 170a (1.8 g, 6.2 mmol) in ethanol (50 mL) was added sodium borohydride (0.32 g, 8.64 mmol) portion wise. The reaction was stirred at room temperature for 16 h. The excess sodium borohydride was destroyed by addition of acetic acid. The reaction was poured onto ice/water and extracted with ethyl acetate. The organic phase washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The crude residue was purified by silica gel chromatography eluting with (hexanes/ethyl acetate/methanol (75:15:5) to give the desired product (0.98 g, 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cn1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.2) (1.50 g, 4.38 mmol) and commercially available 3-bromo-benzene-boronic acid (1.01 g, 5.03 mmol) according to the general procedure IIb. Obtained as a white solid (1.15 g, 56%). MS (EI) 448.0, 450.0 [(M)+]; mp 160° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH3:26])[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:59][CH2:58][N:57]3[C:50](=[CH:51][C:52]4[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55][C:56]=43)[C:49]2=[O:62])=[N:35][CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1)(=[O:30])[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:59][CH2:58][N:57]3[C:50](=[CH:51][C:52]4[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55][C:56]=43)[C:49]2=[O:62])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH3:26])[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COCCN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCCN1CCN(c2ccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)[C@@H](C)C1
Temperature: 100 °C
Yield: 65.1 %

Procedure:
A 50-mL round bottomed flask equipped with a reflux condenser was charged with 340e (180 mg, 0.412 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (327.3 mg, 0.824 mmol), Pd(dppf)Cl2 (16.8 mg, 0.0206 mmol), K3PO4 (174.7 mg, 0.824 mmol), sodium acetate (67.6 mg, 0.824 mmol), acetonitrile (10 mL), and water (3 drops). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 340f as a yellow oil (190 mg, 65%). MS-ESI: [M+H]+ 709.4