Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(C(F)(F)F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 4-(trifluoromethyl)benzoyl chloride (0.67 g, 3.20 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.90 mL, 6.40 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (50 mL), ethyl acetate (50 mL) and dried overnight in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-trifluoromethyl-benzamide as a white solid (0.70 g, 49% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.75 min (95.6%); mp: 241-243° C.; 1H NMR (DMSO-d6) δ 1.92-2.14 (m, 1H), 2.29-2.48 (m, 1H), 2.54-2.67 (m, 1H), 2.80-3.04 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.6 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 5.11 (dd, J=5.1, 13.2 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.56 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 8.11 (d, J=8.1 Hz, 2H), 9.39 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.87, 47.13, 51.59, 122.15, 122.97, 123.90 (q, J=270 Hz), 125.38 (q, J=3.5 Hz), 127.13, 128.21, 130.47, 131.23 (q, J=31.6), 137.92, 142.42, 143.53, 165.14, 167.91, 170.98, 172.85; LCMS: MH=446; Anal Calcd for C22H18N3O4F3+0.35H2O: C, 58.50; H, 4.17; N, 9.30. Found: C, 58.55; H, 3.81; N, 9.18.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].C([Li])CCC.[CH3:20][N:21]=[CH:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1>[CH3:20][NH:21][CH:22]([C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1]
Reactant: CN=Cc1ccsc1
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccsc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
To a chilled, solution (-50° C.) of 19.13 g of 2,2-dimethyl-N-[(2-methyl)phenyl]propanamide in 200 ml of tetrahydrofuran was added, dropwise over 1.5 hours, 88 ml of a 2.5M solution of n-butyllithium in hexane. Upon completion of the addition, the resultant solution was stirred for 2 hours with cooling. A solution of 15.0 g of 3-thiophene-carboxaldehyde methylimine in 30 ml of toluene, was then added, dropwise over 15 minutes, to the cooled solution. Upon completion of the 3-thiophenecarboxaldehyde methylimine addition, the reaction mixture was stirred for 20 minutes at 0° C., quenched by the addition of 300 ml of water, concentrated, and extracted with dichloromethane. The combined extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. HPLC of the oil (Water's Associates Prep LC/System 500; silica gel; methanol as the eluent) afforded a semipurified product which was subsequently chromatographed under otherwise identical conditions utilizing ethyl acetate, followed by methanol as eluents. Concentration of the appropriate fractions and trituration with hexane yielded 18.0 g of N-[2-[2-(methylamino)-2-(3-thienyl)ethyl]phenyl]-2,2-dimethylpropanamide. mp 81°-84° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[N:23]=[CH:22][C:21]2[NH:20][CH2:19][C@@H:18]3[CH2:24][O:25][CH2:26][CH2:27][N:17]3[C:16]=2[N:15]=1.CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O.O>[Cl:13][C:14]1[N:23]=[CH:22][C:21]2[N:20]([CH2:9][C:8]3[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH2:19][C@@H:18]3[CH2:24][O:25][CH2:26][CH2:27][N:17]3[C:16]=2[N:15]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cc1
Yield: 32.1 %

Procedure:
4-Methylsulphonylbenzyl bromide (121 mg, 0.485 mmol) was added to a mixture of (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 100 mg, 0.441 mmol) and potassium tert-butoxide (59.4 mg, 0.529 mmol) in DMSO (2206 μL) at room temperature. The resultant mixture was stirred overnight at room temperature and subsequently diluted with EtOAc and water. The mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, eluting with 0-10% MeOH/CHCl3 gradient) to afford the title compound as an off-white solid (55.9 mg, 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1OC)[CH:5]=[O:6].[H-].[CH2:13]1COCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[CH3:13]
Reactant: COc1ccc(C=O)cc1F
Reactant: C1CCOC1
Agent: [H-]
Product: Cc1ccc(CO)cc1F
Reaction time: 0.5 h

Procedure:
3-fluoro-p-anisaldehyde (12.5 g, 81.1 mmol) was dissolved in 100 ml THF. Under N2 a solution of diisobutylalumium hydride (100 ml, 1M in THF) was added at 0° C. over 30 min. The reaction was stirred for 30 min and quenched with 250 ml 1 N HCl solution. The mixture was stirred for 15 min and filtered through a short column of Celite®. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried with MgSO4, and concentrated to give an oil in 11.6 g. This product was used without further purification. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Br:7].S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:13])=[O:10])[S:5][C:6]=1[Br:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)c(Br)s1
Product: O=C(Cl)c1cc(Br)c(Br)s1

Procedure:
Using the procedure of Preparation A, 2.86 g (10.0 mmoles) of commercially available 4,5-dibromo-2-thiophenecarboxylic acid was added to 10 ml of thionyl chloride to give a heterogeneous mixture. Heating the reaction mixture helped the solution become homogenous. Concentration of the reaction solution gave 3.15 g of crude 4,5-dibromo-2-thiophenecarbonyl chloride as a brown oil. The crude acid chloride, dissolved in 10 ml of N,N-dimethylformamide was slowly added to 1.76 g (8.33 mmoles) of 5-chloro-2,3-dihydro-2-oxo-1H-indole-1-carboxamide and 3.05 g (25.0 mmoles) of 4-(N,N-diemthylamino)pyridine in 40 ml of N,N-dimethylformamide. Workup gave 2.82 g of orange solid which was recrystallized from 2-butanone to give 1.61 g (3.37 mmoles, 40% yield) of pure title compound as a yellow solid, m.p. 229°-231° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]>C1(C)C=CC=CC=1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[OH:13][C:5]1[C:4](/[CH:1]=[CH:2]/[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[C:10](=[O:12])[CH3:11]
Reactant: C=CCc1cccc(C(C)=O)c1O
Agent: Cl[Pd]Cl
Solvent: Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: C/C=C/c1cccc(C(C)=O)c1O
Temperature: 120 °C

Procedure:
40 g (227 mmol) of 1-(3-allyl-2-hydroxyphenyl)ethanone are dissolved in 120 ml of toluene, and 2.17 g (5.6 mmol) of bis(benzonitrile)dichloropalladium(II) are added. The reaction mixture is heated at 120° C. overnight. Cooling to room temperature is followed by filtration through kieselguhr and removal of the solvent in vacuo. 20.9 g (95% of theory) of the title compound are obtained and are reacted without further purification in the next stage.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.ClS(O)(=O)=[O:21]>ClCCl>[C:7]1([C:5]2[NH:6][C:2](=[O:21])[O:3][C:4]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Yield: 75 %

Procedure:
2-Chloro-4,5-diphenyl-oxazole from Step 2 (1.53 g, 6 mmol) was added to chlorosulfonic acid cooled to 0° C. (20 mL), and the stirred solution was warmed to room temperature for 1.0 hour. The mixture was added dropwise to ice and dichloromethane (50 mL) with stirring. The resultant layers were separated, and the organic layer was washed once with water and added to a 0° C. stirred solution of ammonium hydroxide (10 mL). The mixture was stirred for 1.0 hour and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with 1 N HCl followed by brine and water, dried over MgSO4 and concentrated. Recrystallization from ethyl acetate/hexanes gave a white solid (1.5 g, 75%): mp 158-159° C. 1H NMR (acetone-d6) 300 MHz δ 7.98 (d, J=8.7 Hz, 2H) 7.78 (d, J=8.7 Hz, 2H) 7.64-7.70 (m, 2H) 7.42-7.5 (m, 3H) 6.72 (bs, 2H). Anal. Calc'd. for C15H11N2O3SCl: C, 53.82; H, 3.31; N, 8.37. Found: C, 53.92; H, 3.32; N, 8.33.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][C:4](=O)[CH2:5]Cl.ClC=CC(=O)C(C)C.[NH2:16][C:17]1[N:21]=[CH:20][NH:19][N:18]=1>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[N:18]2[N:19]=[CH:20][N:21]=[C:17]2[N:16]=[CH:5][CH:4]=1
Reactant: Nc1nc[nH]n1
Reactant: O=C(C=CCl)CCl
Agent: CC(C)C(=O)C=CCl
Solvent: CC(=O)O
Product: ClCc1ccnc2ncnn12

Procedure:
1,4-Dichloro-1-buten-3-one (10.9 g) (prepared in a manner analogous to the preparation of 1-chloro-4-methyl-1-penten-3-one described in Example 20 below), 3-amino-1,2,4-triazole (6.5 g) and glacial acetic acid were heated under reflux for 1 hour and 30 minutes. The reaction mixture was poured onto ice and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and the solvent was evaporated to give a solid. The crude product was purified by flash chromatography using as eluent a mixture of dichloromethane and ethanol (in the ratio 97:3 respectively), followed by recrystallisation from tetrachloromethane, to give 7-chloromethyl-1,2,4-triazolo[1,5-a]pyrimidine. Yield 10.15 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][N:14]([CH3:20])[CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:17]2[CH2:18][CH2:19][CH:15]([N:14]([CH3:20])[CH3:13])[CH2:16]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Reactant: CN(C)C1CCNC1
Solvent: C1CCOC1
Product: CN(C)C1CCN(S(=O)(=O)c2ccc(F)c(Br)c2)C1
Yield: 68.8 %

Procedure:
A solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (Combi-blocks) (250 mg, 0.91 mmol), N,N-dimethylpyrrolidin-3-amine (218 mg, 1.9 mmol) in tetrahydrofuran (5.7 mL) was stirred at ambient temperature for 16 hours. The solvent was evaporated and residue was purified by flash chromatography (silica gel, dichloromethane/gradient with MeOH) to afford the title compound (220 mg, 69% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.CS(O)(=O)=O>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NC1CCc2ccccc21
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NC3CCc4ccccc43)c3ccccc3nc21
Temperature: 110 °C
Yield: 50.8 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mol), DMSO (3 mL) and 1-aminoindane (1 g) was heated at 110° C. for 16 hours. The reaction mixture was cooled and then was poured into water (100 mL). The solid which formed was collected by filtration and dried to afford the product as the free base. The free base was dissolved in methanol and then was treated with methanesulfonic acid. The methanol was evaporated and the residue was crystallized from hot methanol/2-propanol and then was recrystallized from hot methanol/2-propanol to afford 717 mg of 1-ethyl-N-(1-indanyl)-1H-pyrazolo[3,4-b]quinolin-4amine.CH3 SO3H, m.p. 233°-235° C.
Reaction SMILES: [ClH:1].C([CH:9]([C:27](=[O:29])[OH:28])[C@H:10]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)=[O:13])[NH2:11])C1C=CC=CC=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=2)[CH:32]=[CH:31]1.[Li+].[OH-].Cl>>[ClH:1].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([NH:11][C@@H:10]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:13])[CH2:9][C:27](=[O:29])[OH:28])=[O:40])[CH:37]=2)[CH:32]=[CH:31]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)C(Cc3ccccc3)C(=O)O)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CN1CCC(C2CCN(C(=O)[C@@H](CC(=O)O)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Prepared from 1-[(β-benzyl)-D-aspartyl]-4-(1-methylpiperidin-4-yl)piperidine Hydrochloride and indole-6-carboxylic acid using methods substantially equivalent to General Coupling Method 1. Ester deprotection with 2 eq LiOH and final purification and HCl salt formation via prep HPLC.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCC(O)N1
Reactant: CCCCCCCCCCO
Product: CCCCCCCCCCOC1CCC(=O)N1
Reaction time: 24 h

Procedure:
3 g of 5-hydroxy-pyrrolidin-2-one and 1.5 g of Amberlite resin IR 120H in 60 cm3 of n-decanol are agitated at 60° C. for 3 hours. The resin is filtered off and the solvent is eliminated by distilling at 60° C. under 0.4 mm of Hg. The residue is taken up in 50 cm3 of n-hexane, kept for 24 hours at -5° C./-10° C., separated, and 3.5 g of the expected product is obtained, m.p. 44°-46° C. After re-crystallizing from n-hexane, m.p. 48°-49° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:24][C:25]1(OCC)[CH:32]2[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:34][CH:26]1[CH2:27]3)[CH2:31]2)[CH3:23]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:25]3([O:24][CH2:22][CH3:23])[CH:32]4[CH2:33][CH:28]5[CH2:29][CH:30]([CH2:34][CH:26]3[CH2:27]5)[CH2:31]4)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC1(OCC)C2CC3CC(C2)CC1C3
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)C2CC3CC(C2)CC1C3
Yield: 47.6 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 2,2-diethoxyadamantane (2.28 g, 10 mmol) in the same manner as the example 20 to give the compound 24 (249 mg, 47.5%) as oil.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:5][C:4]=1[CH3:21])=O.[CH3:22][C:23]1([CH2:29][OH:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:30][CH2:29][C:23]1([CH3:22])[CH2:28][CH2:27][N:26]([CH2:1][C:3]2[CH:20]=[CH:19][C:6]([O:7][CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]3)=[CH:5][C:4]=2[CH3:21])[CH2:25][CH2:24]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1C=O
Reactant: CC1(CO)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCC(C)(CO)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a solution of 69A (3.00 g, 10.3 mmol) in DCM (50 mL) was added (4-methylpiperidin-4-yl)methanol (2.56 g, 15.5 mmol) followed by DIPEA (3.60 mL, 20.6 mmol). The reaction mixture was stirred at RT for 20 min and then sodium triacetoxyborohydride (6.55 g, 30.9 mmol) was added. The mixture was stirred at RT overnight and then washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted several times with DCM. The organic layers were filtered through a phase separator and then evaporated. There was obtained 3.1 g (74%) of the product as an oil. 1H NMR (500 MHz, CDCl3): δ 0.95 (s, 3H), 1.33 (m, 2H), 1.45 (s, 9H), 1.51 (m, 2H), 2.26 (m, 2H), 2.30 (s, 3H), 2.51 (m, 2H), 3.38 (s, 2H), 3.39 (s, 2H), 3.99 (m, 2H), 4.27 (m, 2H), 4.84 (m, 1H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.16 (d, 1H), MS (APCI+) m/z 405 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:16]=2[O:15][CH2:14]1>C(O)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:35][N:36]=[C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=5)[NH:7][C:6]4=[O:11])=[O:34])=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: O=C(CCc1ccc2c(c1)OCO2)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3dione in acetic acid was added 3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 151 mg of the title compound (89%) as a yellow solid in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C([O-])C.[Na+].C(O)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[C:15]([NH2:17])=[NH:16].C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25]CC)=O)C>O>[CH2:31]([O:30][C:28]([C:22]1[C:23]([OH:25])=[N:16][C:15]([C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[N:17][CH:21]=1)=[O:29])[CH3:32]
Reactant: N=C(N)c1ncccn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ncccn2)nc1O
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a fresh prepared solution of sodiumethanolate in ethanol (prepared from 0.44 g (18.92 mmol) Na in 20 ml Ethanol) 1.50 g (9.46 mmol) pyrimidine-2-carboxamidine hydrochloride was added. After 10 min. 1.89 ml (9.46 mmol) diethyl ethoxymethylenemalonate was added at 0° and the resulting suspension was stirred for 12 hrs. After addition of 20 ml H2O, the pH was adjusted to 5 and the aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was triturated with 5 ml diisopropylether, filtered off and dried to give 1.62 g (70%) 4-hydroxy-[2,2′]bipyrimidinyl-5-carboxylic acid ethyl ester as a light yellow powder, MS (EI): 246.1 (M+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([CH2:14][CH2:15]O)[CH2:13][CH2:12]1.C(N(CC)CC)C.Cl.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=2)=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.O>[CH:11]1([CH2:14][CH2:15][NH:39][C:35]2[CH:34]=[C:33]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:25])([F:40])[F:41])=[CH:28][CH:29]=3)[CH:38]=[CH:37][CH:36]=2)[CH2:13][CH2:12]1
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OCCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(-c2cccc(NCCC3CC3)c2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64.2 %

Procedure:
To a solution of oxalyl chloride (0.17 mL, 1.95 mmol) in anhydrous CH2Cl2 (5 mL) under nitrogen at −78° C. was added dropwise a solution of anhydrous DMSO (0.18 mL, 2.6 mmol) in anhydrous CH2Cl2 (2.5 mL), ensuring the temperature remained below −60° C. To this was added a solution of 2-cyclopropyl ethanol (0.132 g, 1.3 mmol) in anhydrous CH2Cl2 (2.5 mL), again ensuring temperature remained below −60° C. The reaction mixture was stirred at −78° C. for 20 mins, then treated with triethylamine (0.543 mL, 3.9 mmol) in anhydrous CH2Cl2 (3 mL). The resultant mixture was allowed to gradually warm to room temperature and stirred for 16 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and water (5 mL) prior to the addition of 2M HCl (0.5 mL). The mixture was stirred vigorously for 20 mins, then passed through a hydrophobic frit. The organic solution was stood over molecular sieves for 2 h, then decanted into a clean flask. To this solution was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.31 g, 1.3 mmol), followed by sodium triacetoxyborohydride (0.386 g, 1.82 mmol) and acetic acid (74.3 μL, 1.3 mmol). The resultant mixture was stirred at room temperature under nitrogen for 20 h. The reaction mixture was quenched with sat. NaHCO3 aq. (15 mL) and extracted with CH2Cl2 (2×20 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (20 g Silica column) eluted with 1:200 EtOAc:cyclohexane afforded the title compound as a colourless oil (255 mg).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1)[CH3:10]>CC(O)=O>[CH2:9]([C:11]1[C:16]([I:1])=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1)[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1ccnc(N)c1
Solvent: CC(=O)O
Product: CCc1cc(N)ncc1I
Temperature: 65 °C

Procedure:
1-Iodopyrrolidine-2,5-dione (NIS, 3.87 g, 17.2 mmol) was added in portions to 4-ethylpyridin-2-amine (2.00 g, 16.4 mmol) in AcOH (60 m) during 30 min at 65° C. The mixture was heated at 65° C. for 36 hours, was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane 25 to 40%) to provide 4-ethyl-5-iodopyridin-2-amine: LC-MS: [(M+1)]+=249.00
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5]1[CH:14]=[C:13]([CH2:15][O:16][C:17]2[CH:32]=[CH:31][C:20]([C:21]([O:23]CC3C=CC=CC=3)=[O:22])=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1>O1CCCC1.CO>[CH3:4][C:5]1[CH:14]=[C:13]([CH2:15][O:16][C:17]2[CH:32]=[CH:31][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Cc1cc(COc2ccc(C(=O)OCc3ccccc3)cc2)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(COc2ccc(C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.6 %

Procedure:
2.3 ml (18.6 mmol) of an 8N aqueous solution of sodium hydroxide and 5 ml of water are added to a solution of 3.6 g (9.3 mmol) of benzyl 4-(2-methylquinolin-4-ylmethoxy)benzoate diluted in 20 ml of tetrahydrofuran and 30 ml of methanol. The reaction medium is stirred at ambient temperature for 48 h then 1 ml of an 8N aqueous solution of sodium hydroxide is added and the mixture is heated at 70° C. for 5 h. After evaporation of the tetrahydrofuran, water and a 1N aqueous solution of acetic acid are added. The suspension is stirred overnight at ambient temperature then filtered. The solid obtained is dried under vacuum at 40° C. for 6 h. 2.2 g (81%) of 4-(2-methylquinolin-4-ylmethoxy)benzoic acid are obtained in the form of a white solid.