Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](=[O:21])[CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Br:1][C:13]1[C:12](=[O:21])[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[O:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: BrBr
Reactant: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)cc(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (7.06 ml) in chloroform (70 ml) was added dropwise to a stirred solution of ethyl 6-(4-chlorophenyl)-2,4-dioxohex-5-enoate (19.2 g) in chloroform (300 ml) at 5° to 10° C. The solution was stirred for 30 minutes at room temperature then evaporated to a yellow oil. This crude tribromide was dissolved in dimethylsulphoxide (150 ml), and 1,5-diazabicyclo[4.3.0]non-5-ene (16.9 g) was added at 20° to 25° C. The mixture was stirred for 30 minutes at room temperature then diluted with ice-water (300 ml) to precipitate a sticky brown solid. A solution of this crude product in chloroform was passed down a short column of silica-gel (100 g) and then evaporated. The residual solid was washed ethyl acetate-petroleum ether 60°-80° C., then recrystallised from ethyl acetate-petroleum ether 60°-80° C. to give the title product as yellow needles (mp 146°-149° C.).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4]1.[C:10]([S:13][CH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:16](O)=[O:17])(=[O:12])[CH3:11].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:10]([S:13][CH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:16]([NH:2][C@H:3]1[CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4]1)=[O:17])(=[O:12])[CH3:11]
Reactant: N[C@H]1CCNC(=O)C1
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)N[C@H]1CCNC(=O)C1
Reaction time: 18 h

Procedure:
Prepare 3(S)-amino-δ-valerolactam hydrochloride according to the procedure of J. Chem. Soc. Dalton Trans., 1987, p. 1127. Combine this lactam (0.29 g,2.0 mmol), 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (0.50 g,2.0 mmol), triethylamine (0.03 g,3.0 mmol), and HOBT (0.30 g,2.0 mmol) in DMF (20 ml). Add DEC (0.38 g,2.0 mmol). Stir 18 hr, partition between EtOAc and H2O, dry and concentrate. Chromatograph on silica, eluting with 3% MeOH/CH2Cl2 to obtain the title compound as a foam, [α]D26 =-28.6° (EtOH)
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][NH:14][C:13]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1>C(O)(=O)C.[C].[Pd]>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][CH2:15][NH:14][C:13]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=c1[nH]ccn1-c1ccc(-n2cnnn2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1NCCN1c1ccc(-n2cnnn2)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
1-[4-(1H-1-Tetrazolyl)phenyl]-2(1H,3H)-imidazolone (5.0 g) was dissolved in acetic acid (500 ml) and 10% palladium-carbon (50% wet, 5.0 g) was added. The resulting mixture was stirred at 40° C. for 4 hours under a hydrogen atmosphere. The catalyst was filtered and washed with acetic acid. The filtrate and the washings were combined and distilled off under reduced pressure. The residue was crystallized from ethanol to give 1-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (4.1 g) as colorless crystals.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>O.CO>[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CCCCN(C(=O)OC(C)(C)C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCCC(=O)O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
NaOH (240 mg, 6 mmol) was dissolved in water (3 mL) and MeOH (10 mL). This solution was added to methyl 5-[(tert-butoxycarbonyl)(pyridin-2-yl)amino]pentanoate (200 mg, 0.64 mmol) dissolved in MeOH (15 mL). The mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 2N HCl to pH 7. The solvent was removed under reduced pressure. A citric acid solution (10 mL) was added and the mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated to give 128 mg (68%) of the product. 1H NMR (CDCl3) 8.36–8.34 (m, 1H), 7.65–7.52 (m, 2H), 7.02–6.98 (m, 1H), 3.97–3.91 (m, 2H), 2.38–2.32 (m, 2H), 1.69–1.62 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][CH:43]=2)O1>>[CH3:14][C:6]1[C:5]2[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])=[CH:3][C:2]([C:38]3[CH:43]=[N:42][C:41]([N:44]4[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]4)=[CH:40][CH:39]=3)=[CH:10][C:9]=2[N:8]([CH:11]([CH3:13])[CH3:12])[N:7]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (65 mg, 0.141 mmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (61 mg, 0.212 mmol). The product was collected as a white solid (54 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.49-8.63 (m, 2H) 8.43 (br. s., 1H) 7.97 (dd, J=8.84, 2.53 Hz, 1H) 7.89 (s, 1H) 7.32 (s, 1H) 6.87-6.96 (m, 1H) 5.91 (s, 1H) 5.03 (dt, J=13.07, 6.47 Hz, 1H) 4.38 (d, J=4.55 Hz, 2H) 3.40-3.61 (m, 5H) 2.77-2.82 (m, 3H) 2.53-2.57 (m, 2H) 2.43 (s, 3H) 2.13 (s, 3H) 1.53-1.60 (m, 2H) 1.46 (s, 3H) 1.44 (s, 3H) 0.93 (t, J=7.33 Hz, 3H); LC-MS (ES) m/z=542.2 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:23]([C:25]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)#[CH:24]>>[OH:31][C:25]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:22]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C#CC1(O)CCCCC1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#CC3(O)CCCCC3)cc1-2

Procedure:
Similar to as described in General Procedure E, reaction of 10-bromo-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide with 1-ethynylcyclohexanol gave the titled compound. M+H=409.2.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[O:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]2=[O:31])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:29][CH2:30][N:25]([CH:22]4[CH2:21][CH2:20][O:19][CH2:24][CH2:23]4)[C:26](=[O:31])[CH2:27]3)=[CH:4][C:5]=2[N:6]=1
Reactant: O=C1CNCCN1C1CCOCC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg, 0.57 mmol), in DMF (4 mL), was added 1-(tetrahydro-pyran-4-yl)-piperazin-2-one (116 mg, 0.63 mmol) and potassium carbonate (238 mg, 1.72 mmol). The mixture was stirred at RT for 4 h, then the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow solid (212 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].Cl.C=O.CO[CH2:20][Cl:21]>O.C(O)(=O)C>[F:14][C:11]([F:12])([F:13])[O:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([CH2:20][Cl:21])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: COCCl
Reactant: Cc1cc(C)c(C)c(OC(F)(F)F)c1
Agent: C=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OC(F)(F)F)c(C)c(C)c1CCl

Procedure:
A solution of 31.5 (0.15 mol) of 2,3,5-trimethyl-1-trifluoromethoxybenzene, 315 ml of acetic acid, 31.5 ml of concentrated hydrochloric acid, 31.5 ml of aqueous formaldehyde and 13 g (0.185 mol) of chloromethyl methyl ether was heated to 85° C. for 72 hours. (Small samples were worked up periodically after 48 hours to optimize the ratio of monochloromethyl product:dichloromethyl product:starting material). The solution was then cooled, poured into 1.5 liters of water and extracted with 3×500 ml of hexane. The hexane extracts were washed with 1 liter of water and 500 ml of saturated NaHCO3 solution, dried (MgSO4), filtered, and concentrated to give 30 g of crude (4-trifluoromethoxy 2,3,6-trimethylphenyl)methyl chloride containing some starting material, 2,3,5-trimethyl-1-trifluoromethoxybenzene, which was removed by distillation at 24°-30° C./0.05 mm. The residue (22 g), crude (4-trifluoromethoxy-2,3,6-trimethylphenyl)methyl chloride, was used directly in the next step.
Reaction SMILES: Cl[C:2]([C:5]1[CH:6]=[C:7]([CH:29]=[C:30]([OH:32])[CH:31]=1)[CH2:8][NH:9][CH2:10][C@@H:11]([OH:28])[C@@H:12]([NH:20]C(=O)OC(C)(C)C)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:20][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:11]([OH:28])[CH2:10][NH:9][CH2:8][C:7]1[CH:29]=[C:30]([OH:32])[CH:31]=[C:5]([C:2]([CH3:4])=[CH2:3])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cc(O)cc(C(C)(C)Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1cc(O)cc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1

Procedure:
A solution of 27.5 mg of tert-butyl (2S,3R)-4-(3-(2-chloropropan-2-yl)-5-hydroxybenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate and 0.8 mL of trifluoroacetic acid in 2 mL of CH2Cl2 was stirred at r.t. for 1 h and then concentrated. The 3-(((2R,3S)-3-amino-2-hydroxy-4-phenylbutylamino)methyl)-5-(prop-1-en-2-yl)phenol amine salt was used in the next reaction without further purification.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:34])([F:33])[C@@H:28]([OH:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[C@H:28]([OH:32])[C:27]([F:34])([F:33])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)[C@H](O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)[C@H](O)C(F)(F)F

Procedure:
The title compound, white solid (14.7 mg, 47.3%), MS (ISP) m/z=457.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and (S)-3,3,3-trifluoro-2-hydroxypropanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: CCOC(=O)C(Br)CC
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC)Oc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1b), the alkylation of 4-benzyloxy-phenol [Example 2a)] with ethyl (RS)-2-bromobutyrate in acetone using cesium carbonate as the base yielded the (RS)-2-(4-benzyloxy-phenoxy)-butyric acid ethyl ester as a brown oil; MS: m/e=314 (M)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:15]=1)=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]=2[CH3:10].[H-].[Na+].[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29]Br.C(OC(C)C)(C)C>CN(C)C=O>[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][N:15]1[C:5]2=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: COC(=O)c1cc(C)c2[nH]c(C)nc2n1
Reactant: BrCc1ccc2ccccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc4ccccc4c3Br)c2n1
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
To a suspension of methyl 2,7-dimethyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (625 mg) in N,N-dimethylformamide (6 ml) was added sodium hydride (70% in mineral oil, 125 mg) under ice-cooling, and the mixture was stirred for 30 min. 1-Bromonaphthalen-2-ylmethyl bromide (1.05 g) was added to the reaction mixture, and the mixture was stirred under ice-cooling for 3 hr. Diisopropyl ether (12 ml) was added to the reaction mixture and the precipitate was collected by filtration to give the objective compound (1.35 g) as a white powder.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[NH2:9][C:10]([NH2:12])=[S:11]>ClCCl.CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:12][C:10]1[S:11][CH:2]=[C:1]([C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)[N:9]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
2-Acetylfuran (5.1 g, 46.0 mmol) was dissolved in a mixed solvent of dichloromethane (50 mL) and methanol (50 mL), and tetra(n-butyl)ammonium bromide (22.3 g, 46.0 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was dissolved in acetonitrile (60 mL), thiourea (3.5 g, 46.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, and the resulting solid was dissolved in a mixed solvent of a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate, and subjected to liquid-liquid separation. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford 2-amino-4-(2-furyl)thiazole (1.53 g, 20%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C[O:9][C:10](=O)[CH2:11][C:12](=[O:15])[CH2:13][CH3:14]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:10](=[O:9])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:4][CH2:3]1
Reactant: CCC(=O)CC(=O)OC
Reactant: OC1CCNCC1
Product: CCC(=O)CC(=O)N1CCC(O)CC1

Procedure:
59.0 g (583 mmol) of 4-hydroxypiperidine and 79.7 g (612 mmol) of 3-oxovaleric acid methyl ester were heated for 9 h at 110° C., and the resulting methanol was removed via a distillation bridge. The reaction residue was freed from volatiles on a rotary evaporator, taken up in ethanol, and filtered through 600 ml of strongly acidic ion exchanger (Dowex® HCR-W2), concentrated again and purified by column chromatography (silica gel, eluent's gradient from ethyl acetate to ethanol). The pure product fractions were freed from solvent on a rotary evaporator and yielded 63.6 g (55%) of a viscous, clear, colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([OH:14])[C:7]([CH3:13])([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([O:14][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[C:7]([CH3:12])([CH3:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)COc2cc(Br)ccc2C1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COc2cc(Br)ccc2C1O[Si](C)(C)C(C)(C)C
Yield: 54226.5 %

Procedure:
To a solution of 7-bromo-3,3-dimethyl-chroman-4-ol (300 mg, 1.44 mmol) in DMF (3.33 mL) was added imidazole (119 mg, 1.75 mmol) followed by TBDMS-Cl (263 mg, 1.75 mmol). The next day, the reaction was diluted with ethyl acetate and washed with water (3×) and saturated sodium bicarbonate (1×). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified using silica gel chromatography (100% pentane to 50% pentane in ethyl acetate) to yield the desired product (290 g, 65% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].Cl>C(OCCO)C.[Cl-].[Na+].O.O>[CH3:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[CH:5]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: Cc1cc(Nc2cccc([N+](=O)[O-])c2)nc(N)n1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-4-chloro-6-methyl-pyrimidine (A8) [10.04 g, 69.93 mmol] and 3-nitroaniline 99.95 g, 72.02 mmol) in 2-ethoxyethanol (300 mL) was added c.HCl (30 mL), and the resulting solution was refluxed for ˜16 h. After this time, the reaction mixture was allowed to cool to room temperature, and then diluted with brine and H2O. The resulting suspension was filtered through a Celite pad, and the solid material thus collected re-dissolved in MeOH, and filtered through a pad of Celite. Solvent was removed under reduced pressure to give diamine E1 as an amorphous beige solid, which was used without further purification: 1H NMR (400 MHz, DMSO): δ 12.97 (br s, 1H, pyrimidinyl-N+—H), 11.03 (s, 1H, ArNHAr), 8.52 (s, 1H, ArH), 8.31 (d, J=7.83 Hz, 1H, ArH), 7.97 (ddd, J=8.20, 2.19, 0.72 Hz, 1H, ArH), 7.83 (v br s, 2H, ArNH2), 7.66 (t, J=8.21 Hz, 1H, ArH), 6.25 (s, 1H, ArH), 2.31 (s, 3H, ArCH3); LCMS (APCI+): 246 (100%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18](COCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl(O)(=O)(=O)=O>C(O)(=O)C.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(C)c(N)c(C(=O)O)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(C)c(N)c(C(=O)O)c3)cc12
Reaction time: 3 h
Yield: 57.8 %

Procedure:
551 mg (1.09 mmol) of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methyl-benzoic acid was dissolved in 10 mL of glacial acetic acid. 500 μL of 70% perchloric acid was added and the mixture left at ambient temperature for 3 h. The resulting solution was diluted with 100 mL of water and the resulting precipitate filtered off and dried by suction to afford 234 mg (0.63 mmol, 57%) of 2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methyl-benzoic acid as an orange-red solid. MS: m/z 375.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:22](/[CH:23]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)[CH:21]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1cccc(Cl)c1
Product: O=[N+]([O-])c1ccc(/C=C/c2cccc(Cl)c2)cc1

Procedure:
In an analogous manner to that described in Example 36a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 3-chlorobenzaldehyde yields the (E)-1-chloro-3-[2-(4-nitrophenyl)ethenyl]-benzene as an orange crystalline solid; MS: m/e=259 (M)+.
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:5]=1.[Cl:24]C(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:24][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CN(C)C)c2cccnc21
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 110 (1.25 g, 3.77 mmol) was added to toluene (20.0 mL) under an atmosphere of nitrogen at room temperature. Isopropyl chloroformate in toluene (1.0 M, 4.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours to provide a solution of 3-chloromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH3:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:14][O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:21]3[CH:22]=[CH:23][C:18]([CH2:17][C:16]([O:15][CH3:14])=[O:25])=[CH:19][CH:20]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OC)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 120.0 mg, 0.56 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 154.0 mg, 0.56 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (35.0 mg, 0.19 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-8% EtOAc-hexanes) afforded 140.0 mg (78%) of the title compound as an orange solid.