Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[CH3:22][O:23][C:24](=[O:28])[C@@H:25]([CH3:27])[NH2:26].C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:28])[CH3:27])=[O:16])=[C:5]2[OH:20]
Reactant: COC(=O)[C@@H](C)N
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 80 °C
Yield: 65.4 %

Procedure:
To ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (100 mg, 339 μmol, see Example 2) and D-alanine methyl ester hydrochloride (71 mg, 509 mmol) was added 1,4-dioxane (339 μL) and N-ethyl-N-isopropylpropan-2-amine (177 μL, 1018 μmol). The reaction was then heated at 80° C. for 16 hours. The resulting reaction mixture was evaporated to give the title compound (78 mg) as an amorphous solid after purification via preparatory LC. MS m/e=352 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[F:22].C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:19]2[CH:18]=[CH:17][C:16]([F:22])=[C:15]([Cl:14])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(I)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a 50 ml of isopropyl alcohol solution containing 15.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and 24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96.7 mmol) were added 1.54 g of copper (I) iodide (8.1 mmol), 9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol), and heated under reflux under a nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and filtered using Celite. The substance remained in the filter was washed with ethyl acetate and the filtrate was concentrated under reduced pressure together with the washings, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 15.9 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18](Cl)[N:17]=[N:16][C:15]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH3:30])[CH:24]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N#N>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[N:16][C:15]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH3:30])[CH:24]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CNc2nnc(Cl)cc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COc1cc(CNc2nnccc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1
Reaction time: 3 h

Procedure:
6-Chloro-3-[(2-methoxy-pyridin-4-ylmethyl)-amino]-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide (150 mg, 0.35 mmol) was dissolved in MeOH (5 mL). 10% Pd/C (50 mg) was added to above under N2 atmosphere. The system was charged with H2 balloon, and the reaction was stirred under H2 gas for 3 h. The crude was subjected to Flash chromatography (5% MeOH/DCM) for further purification, affording desired product as yellow solid. MS (ES+): 392 (M+H). Calc'd. for C22H25N5O2—391.20.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:25])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(OC)(C)C.C(O)(C)C>[CH3:24][O:23][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[C:9](=[O:25])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c(CCOS(C)(=O)=O)c(C)c2c(OC)c1OC
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4)CC3)c(C)c2c(OC)c1OC
Yield: 49 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,6,7-trimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 34) and 1-phenylpiperazine; yield 49%; m.p. 136°-137° C. (from TBME/isopropanol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:29](Cl)[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>>[N:24]1([CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]5[CH:38]=[CH:37][C:36]6[O:35][CH2:34][O:33][C:32]=6[CH:31]=5)=[CH:7][CH:6]=4)[O:9][CH:10]=3)=[CH:16][CH:17]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: Oc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Product: c1cn(CCCc2ccc(OCc3coc(-c4ccc(OCc5ccc6c(c5)OCO6)cc4)n3)cc2)cn1
Yield: 43 %

Procedure:
In substantially the same manner as in Working Example 131, 2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole was allowed to react with piperonylchloride to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[4-(3,4-methylenedioxyphenylmethoxy)phenyl]oxazole. The yield was 43%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 124-125° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2.C([BH3-])#N.[Na+].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2
Reactant: CN(C)C=Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)CCc1ccc([N+](=O)[O-])c2[nH]ncc12
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
16.2 g of N,N-dimethyl-N-[2-(7-nitro-1H-indazol-4-yl)ethenyl]amine is dissolved in 200 ml of acetic acid and combined under ice cooling in incremental portions with 6.3 g of sodium cyanoborohydride within 30 minutes. After another 30 minutes, the mixture is combined with ice and ethyl acetate, adjusted to 8-9 with concentrated sodium hydroxide solution, and extracted with ethyl acetate. The solution is dried, concentrated, and the residue recrystallized from ethyl acetate/diisopropyl ether, thus obtaining 13.8 g of N,N-dimethyl-N-[2-(7-nitro-1H-indazol-4-yl)ethyl]amine, mp 145°-146° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:13]=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:27])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>CO>[C:15]([O:19][C:20](=[O:27])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:13][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=Cc1ncccc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNCc1ncccc1-c1ccccc1
Yield: 81 %

Procedure:
An anhydrous MeOH solution (2.0 mL) of 3-phenyl-pyridine-2-carbaldehyde (38 mg, 0.21 mmol) (Iqbal, N. et al. J. Med. Chem. 1998, 41, 1827-1837) and (4-Amino-butyl)-carbamic acid tert-butyl ester (40 mg, 0.21 mmol) was stirred overnight at room temperature, after which NaBH4 (16 mg, 0.41 mmol) was added and the reaction mixture stirred for an additional hour. The solvent was removed in vacuo and the residue dissolved in CH2Cl2 (15 mL) and treated with saturated aqueous NaHCO3 (25 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford {4-[(3-Phenyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (59 mg, 0.17 mmol) as a yellow oil. The yellow oil was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)ccc1O
Product: CCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Yield: 51 %

Procedure:
The reaction of 2,5-dihydroxybenzoic acid methyl ester with 1-bromodecane under conditions described in Example 58 gave 5-(decyloxy)-2-hydroxybenzoic acid methyl ester (51% yield, mp 40°-43°).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=N)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=C(c2ccccc2)c2ccccc2)[C@H](O)C1
Yield: 87.9 %

Procedure:
tert-butyl-4-amino-3-hydroxypiperidine-1-carboxylate (11.9 g; 55 mmol) and benzophenone imine (10 g; 59 mmol; 1.05 eq.) were dissolved in anhydrous toluene and heated to reflux for 18 hrs. Monitored the reaction by TLC (30% EtOAc/hexanes with 0.1% triethylamine). The crude reaction was concentrated and purified by flash column chromatography. Isolation gave 18.4 g of the title compound in an 86% yield. LC/MS (ES+)[(M+H)+]: 381 for C23H28N2O3.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[O:18]1CC[CH2:20][CH2:19]1.[BH4-].[Na+]>CO>[OH:18][CH:19]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)[CH3:20]
Reactant: C1CCOC1
Reactant: CC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution containing 4-acetoxy-4'-hydroxy-1,1'-biphenyl from part A (5.0 g, 23.6 mmol) in methanol (500 mL) and tetrahydrofuran (30 mL) is treated with sodium borohydride (0.9 g, 23.8 mmol) in portions over 30 minutes at room temperature. After 2 hours, the reaction mixture is concentrated under reduced pressure, diluted with water (400 mL), acidified with 2N HCl and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over MgSO4 and concentrated to a solid residue. Crystallization of the solid from ethyl acetate gives 4.7 g (92.9%) of the title compound, m.p. 159°-160° C.; MS (El m/z): 214 (M)+ and 199 (b.p. M-CH3)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:16]([C:3]1[CH:4]=[C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(COc2ccccc2)ccc1Br
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(COc2ccccc2)ccc1Sc1ccc(O)cc1
Yield: 84.3 %

Procedure:
The product from Example 221b (0.16 g, 0.52 mmol) was reacted with 90% 4-mercapto-phenol (0.073 g, 0.52 mmol) in DMF at 80° C. under nitrogen in the presence of potassium carbonate (0.126 g, 0.91 mmol). The reaction was quenched after 18 h by pouring into dilute HCl and extraction with ether. The combined extracts were dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexanes to give the title compound (0.155 g, 84%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([NH:14][C:12]1[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-isobutylamino-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M59) (0.56 g, 0.98 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (299 mg, 67%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([S:13]([OH:16])(=[O:14])=[O:15])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)O)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)N1CCc2cc([N+](=O)[O-])c(S(=O)(=O)O)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
16.0 g (66 mmol) of 1-acetylindoline-6-sulfonic acid (Compound 2-2 in Scheme II) was dissolved in 160 mL of cone, sulfuric acid. The solution was cooled to 0° C. using ice/water bath. Nitric acid (90%, fuming) (3.0 mL, 1.1 eqv.) was added dropwise over 10 min. The resulting pale yellow solution was stirred at 0° C. for 2 h and then slowly poured onto 200 g of ice. The crystals formed were collected by filtration and washed successively with cold water acetone and ether. Drying under vacuum over P2O5 afforded 18.2 g of the title compound. 1H MNR (d6-DMSO) δ: 8.47 (s, 1H), 7.40 (s, 1H), 5.54 (OH+H2O), 4.12 (t, J=8.5 Hz, 2H), 3.13 (t, J=8.5 HZ, 2H) and 2.17 (s, 3H). 13C NMR (d6-DMSO) δ: 169.19, 144.18, 143.17, 139.54, 133.54, 119.10, 115.23, 48,67, 26.75 and 24.01.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)nc1
Product: N#Cc1ccc(-c2ccc(O)cn2)cc1
Yield: 26 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 2-bromo-5-hydroxypyridine and 4-cyanophenylboronic acid to afford the title compound as a yellow solid (300 mg, 26%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Mg+2].[Cl-].[Cl-].[I:13]I>C1COCC1>[I:13][C:5]1[C:4]([Cl:9])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8]
Reactant: II
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Clc1nc(Cl)c(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A dry, argon-filled Schlenk tube with a magnetic stirrer bar and septum is initially charged with 2,4,6-trichloropyrimidine (184 mg, 1 mmol) in anhydrous THF (1 ml). After adding (TMP)2Zn.MgCl2 (3.16 ml, 1.2 mmol) at 25° C., the mixture is stirred for 1 h. Then a solution of iodine (355 mg, 1.4 mmol), dissolved in anhydrous THF (2 ml), is added dropwise and the reaction mixture is stirred at 25° C. for 1 h. After dilution with aqueous sat. NH4Cl solution (30 ml) and extraction with ethyl acetate (3×30 ml), the combined organic phases are dried over Na2SO4, and distillative removal of the solvent and purification by column chromatography on silica gel (heptane:ethyl acetate) afforded the desired compound (240 mg, 78% of theory) as a colourless crystalline product.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[NH:5].[OH:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@H:15]([CH2:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@:19]3([OH:34])[CH2:20][CH2:21][C@@H:22]2[CH:32]=O)[CH2:14]1>Cl.O1CCOCC1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][NH:6][C:4](=[NH:5])[NH:3]/[N:2]=[CH:32]/[C@H:22]1[CH2:21][CH2:20][C@:19]2([OH:34])[C@H:18]3[C@H:27]([CH2:26][CH2:25][C@:23]12[CH3:24])[C@:28]1([CH3:31])[C@@H:15]([CH2:14][C@@H:13]([OH:12])[CH2:30][CH2:29]1)[CH2:16][CH2:17]3
Reactant: CN(C)CCNC(=N)NN
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: Cl
Agent: I
Solvent: C1COCCO1
Product: CN(C)CCNC(=N)N/N=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 14.3 %

Procedure:
To a solution of 0.64 g of 1-amino-3-(2-dimethylaminoethyl)guanidine hydroiodide (prepared following the procedure described in Houben-Weil, Metoden der Organischen Chemie, Band VIII, page 183) in 20 ml of 10-4M hydrochloric acid a solution of 1.10 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 25 ml of dioxane was added dropwise at room temperature. After 3 hrs, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether to give 0.15 g of the title compound (I-ag) as hydroiodide, white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[N:14]=2)[C:9](F)=[N:10][CH:11]=1)=[CH2:5])C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[O:29][CH3:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CN(C=O)C>[NH2:20][C:15]1[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]2[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[N:10][C:9]=2[NH:28][C:25]2[CH:26]=[N:27][C:22]([Cl:21])=[C:23]([O:29][CH3:30])[CH:24]=2)[N:14]=1
Reactant: C=C(OCC)c1cnc(F)c(-c2nc(C)nc(N)n2)c1
Reactant: COc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a mixture of 4-(5-(1-ethoxyvinyl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (100 mg, 0.363 mmol) and 6-chloro-5-methoxypyridin-3-amine (Small Molecules, Inc) (86 mg, 0.545 mmol) in 1 mL of THF and 0.3 mL of DMF at 0° C. was added sodium bis(trimethylsilyl)amide (1.09 mL of 1.0 M solution in THF, 1.09 mmol) dropwise and the dark red solution was stirred at this temperature for 30 min. It was quenched with 4 mL of 0.5 N HCl and stirred at RT for 10 min. The mixture was treated with 1 N NaOH to pH of about 8. It was extracted twice with EtOAc (30 mL). The combined organic phases were washed with brine and dried over Na2SO4. It was concentrated to half of its volume, the precipitated tan solid was filtered through a fritted funnel, rinsed with 2 mL of ether, collected and dried to give 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-chloro-5-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (90 mg, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.63 (s, 1H), 9.29 (s, 1H), 9.03 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.06 (br., 1H), 7.90 (br., 1H), 3.96 (s, 3H), 2.60 (s, 3H), 2.47 (s, 3H). m/z (ESI, positive ion) 386.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[N:13]=2.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:38][CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)(=O)=O>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:38][CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[N:13]=2
Reactant: COc1nc2c(N)nc(OCC3CCCO3)nc2[nH]1
Reactant: CS(=O)(=O)OCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCC3CCCO3)nc2n1CC1CCOCC1
Temperature: 60 °C
Yield: 54.3 %

Procedure:
8-(Methoxy)-2-[(tetrahydro-2-furanylmethyl)oxy]-9H-purin-6-amine trifluoroacetate salt (0.30 g) was dissolved in dry DMF (5 mL). To this solution was added anhydrous potassium carbonate (0.4376 g) and then the reaction mixture was heated to 60° C. under nitrogen for 1 hour. The reaction mixture was then cooled to room temperature before adding tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.1690 g) and then the resultant reaction mixture was heated to 90° C. for 2.5 hours. The reaction mixture was cooled and then quenched with water (50 mL), followed by extraction into ethyl acetate (50 mL, 3 times). After separating, the organic layers were combined and dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave mobile oil which was then purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (10-45%). This gave the title compound as a white solid (0.1560 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24].[CH2:26](I)[CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([C:23](=[O:25])[CH3:24])[CH:18]=1)[CH2:27][CH2:28][CH3:29]
Reactant: COc1cc2nccc(Oc3ccc(O)cc3C(C)=O)c2cc1OC
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone (compound 176) (54 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Butyl iodide (88 mg) and potassium carbonate (110 mg) were added to the solution, and the mixture was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (41 mg, yield 65%).