Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33])(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](OCC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[BH4-].[Li+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:19][CH2:18][CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:33])([F:34])[F:35])(=[O:24])=[O:25])=[N:16][CH2:15]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4C(F)(F)F)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a mixture of ethyl {2-[7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (1.4 g), lithium borohydride (0.30 g) and tetrahydrofuran (20 mL) was added methanol (3 mL), and the mixture was stirred at room temperature for 3 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:5-7:3), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (0.79 g, yield: 61%) as colorless needle crystals. MS: 484 (MH+). melting point 153-154° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([O:38][Si](C(C)(C)C)(C)C)[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:26]=CN=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[OH:47]>ClCCl>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:38])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][O:47][CH:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccncc1)NC(=O)OCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccoc1)NC(=O)OCc1cccnc1
Yield: 60 %

Procedure:
Using the procedure of Example 4G but replacing (2S,3S,5S)-2-(Boc-amino)-5-(N-((3-pyridinyl)methoxy-carbonyl)amino)-1-phenyl-6-(4-pyridinyl)-3-(tert-butyl-dimethylsilyloxy)hexane with the resultant compound of Example 5D provided, after silica gel chromatography using 5% methanol in dichloromethane, 334.5 mg (60%) of the desired compound as a white solid. 1H NMR (CDCl3) δ 1.38 (s, 9H), 1.66 (t, 2H), 2.61 (d, 2H), 2.85 (t, 3H), 3.70 (m, 2H), 3.89 (m, 1H), 4.84 (br d, 1H), 5.07 (br, 1H), 5.12 (s, 2H), 7.14-7.31 (m, 7H), 7.40 (m, 1H), 7.76 (br d, 1H), 8.57 (dd, 1H), 8.64 (br s, 1H). Mass spectrum: (M+H)+ =510.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([C@H:8]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH3:9])[CH2:4][CH2:3]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@@H](O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cis-(R)-tert-butyl 1-(4-hydroxycyclohexyl)ethylcarbamate (575 mg, 2.363 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. under nitrogen. Triethylamine (478.2 mg, 658.7 μL, 4.726 mmol) followed by methanesulfonylchloride (284.2 mg, 192.0 μL, 2.481 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The crude mixture was washed with 1M HCl, water and a saturated aqueous solution of sodium bicarbonate. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the compound as a white solid (706 mg, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14]O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:16])[CH:8]=2)[N:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:11]2[CH2:14][CH2:13][N:12]=[C:10]2[C:9]2[CH:8]=[C:7]([F:16])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: OCCNc1nc(Cl)nc2ccc(F)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Fc1ccc2c(c1)C1=NCCN1C(Cl)=N2

Procedure:
A suspension of 2-chloro-6-fluoro-4-(2-hydroxyethylamino)quinazoline (7.0 g, 29 mmol) in dichloromethane (140 ml) was heated at reflux for 4 hours with thionyl chloride (4.2 ml, 58 mmol) and triethylamine (8 ml, 58 mmol). The cooled mixture was evaporated to dryness and extracted with water (80 ml). The acidic water solution was neutralized with 25% aqueous ammonia (approx. 7 ml) and the resulting precipitate was filtered off and dried to give the title compound as light yellow crystals, m.p. 209°-211° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][NH2:23]>O1CCOCC1>[NH:22]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:23]
Reactant: NN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Solvent: C1COCCO1
Product: COc1ccc(N(C)c2nc(NN)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (100 mg, 0.33 mmol) in 2 ml of 1,4-dioxane was added 0.4 ml of hydrazine. The reaction mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was diluted with EtOAc (20 ml), washed with saturated NaHCO3 aq., brine, dried over Na2SO4, filtered and concentrated by vacuum, yielding 20 mg (21%) of yellow solids. 1H NMR (CDCl3): 7.52-7.49 (m, 1H), 7.44-7.39 (m, 1H), 7.12-7.08 (m, 2H), 6.93-6.88 (m, 3H), 6.77-6.71 (m, 1H), 6.01 (brs, 1H), 4.11 (brs, 2H), 3.83 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][S:5][C:6]1[C:7]([CH3:16])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[Cl-].[NH4+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C:15]2[C:6](=[C:7]([CH3:16])[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)[S:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(SCC=C(C)C)c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1C)SCCC2(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
67.9 g (0.27 mol) of methyl 3-(3-methyl-2-butenylthio)-2-methylbenzoate were dissolved in 600 ml of methylene chloride and, at −5 to 0° C., 206.4 g (1.09 mol) of titanium tetrachloride in 600 ml of methylene chloride were added dropwise, and the mixture was stirred at 0° C. for three hours. The mixture was subsequently stirred into 1.5 kg of ice and 500 ml of saturated ammonium chloride solution, the organic phase was separated off and dried and the solvent was removed. This gave 62.9 g of an orange oil which was directly used further. To characterize the product, a sample was chromatographed over silica gel (mobile phase: cyclohexane/ethyl acetate=10/1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[C:11]([Si:15]([CH3:23])([CH3:22])[O:16][CH2:17][CH2:18][C@@H:19]1[CH2:21][O:20]1)([CH3:14])([CH3:13])[CH3:12]>CCO.O>[C:11]([Si:15]([CH3:23])([CH3:22])[O:16][CH2:17][CH2:18][C@@H:19]([OH:20])[CH2:21][NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CCOc1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(NC[C@H](O)CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 80 °C
Yield: 62 %

Procedure:
A solution of 4-ethoxy-aniline (commercial; 3.2 mL) in EtOH/water (9:1; 150 mL) was reacted with (2R)-2-[2-[[(tert-butyl)dimethylsilyl]oxy]ethyl]-oxirane (prepared according to WO 2007/144423) and further heated at 80° C. overnight. The solvents were removed under reduced pressure and the residue was purified by CC (EA/Hept 1:1), affording a brown oil (5.22 g; 62% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[C:25]=2[F:26])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1[N+](=O)[O-]
Yield: 91.9 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (3.64 g, 10 mmol) and 2,3-difluorobenzene boronic acid (2.35 g, 14.9 mmol) according to the general procedure B. Obtained as a yellow solid (3.22 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:64])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][CH2:52][CH2:53][O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:47]([O:62][CH3:63])[CH2:46]2)[CH:7]([CH3:65])[CH:6]([O:66][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:74])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:64])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][CH2:52][CH2:53][O:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH:47]([O:62][CH3:63])[CH2:46]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 17-ethyl-20-fluoro-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16tetraone (10 mg) in acetonitrile (500 μl) is added a solution of 2% HF in aqueous acetonitrile (200 μl), and the mixture is stirred at room temperature. After 2.5 hours, the solution is diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound.
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C:4]1[CH:24]=[C:23]([Cl:25])[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=1>O.CO>[Na+:2].[NH2:3][C:4]1[CH:24]=[C:23]([Cl:25])[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([O-:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:13])(=[O:14])[CH2:12][C:6]=2[CH:5]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)[O-])cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (0.018 g, 0.47 mmol) in water (0.2 mL) was added to a solution of Example 2 (0.167 g, 0.47 mmol) in methanol (5 mL) and stirred at 25° C. for 15 min. The solvent was removed under vacuum, and dried to obtain the title compound. Yield: 0.16 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.55 (s, 3H, CH3), 4.92 (s, 2H, CH2), 5.57 (s, 2H, NH2), 6.60 (m, 2H, Ar), 7.90 (s, 1H, Ar), 8.10 (s, 1H, Ar); MS: m/e (ES−) 352 (M-Na); analysis: C15H11ClNNaO5S.2H2O requires C, 43.75,H, 3.67, N, 3.40, Cl, 8.61, S, 7.79; found: C, 44.20,H, 3.34, N, 3.49, Cl, 9.25, S, 8.36%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: O=[N+]([O-])O
Product: O=C(O)C1(c2ccc(Cl)c([N+](=O)[O-])c2)CCCCC1

Procedure:
Prepared analogously to Example 1b from 1-(4-chlorophenyl)-cyclohexanecarboxylic acid and fuming nitric acid at −25° C.
Reaction SMILES: P([O-])([O-])(O)=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.P([O-])(O)(O)=O.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH2:45][OH:46].NC1C=CC=C2C(N(O)C(=O)C=12)=O.CCN1C2C=CC(S([O-])(=O)=O)=CC=2S/C/1=N\N=C1/SC2C=C(S([O-])(=O)=O)C=CC=2N/1CC.[NH4+].[NH4+]>C(O)C>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH:45]=[O:46]
Reactant: COc1ccc(CO)cc1OC
Agent: CCn1/c(=N/N=c2\sc3cc(S(=O)(=O)[O-])ccc3n2CC)sc2cc(S(=O)(=O)[O-])ccc21
Agent: Nc1cccc2c1C(=O)N(O)C2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Product: COc1ccc(C=O)cc1OC
Reaction time: 0.17 h
Yield: 92 %

Procedure:
22 ml of a dipotassium hydrogen phosphate/citric acid buffer solution of pH 4.5 (prepared by titrating a 0.2 M potassium dihydrogen phosphate solution with a 0.1 M citric acid solution and diluting to 1/4) were treated at 45° C. with 269 mg (1.60 mmol) of 3,4-dimethoxybenzyl alcohol in 1 ml of ethanol. 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide were added with stirring. After approx. 10 minutes, the mixture was treated with 5 ml of an aqueous solution of 2 mg/ml laccase from Trametes versicolor (specific activity approx. 18 IU/mg, defined with ABTS as substrate). After a reaction time of 22 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 92% of 3,4-dimethoxybenzaldehyde.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][N:3]1[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16].FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)CN1CCN(Cc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl 2-(2-oxo-3-benzylimidazolidinyl)acetate (2.51 g, 8.64 mmol) in dichloromethane (15 ml) was added trifluoroacetic acid (10 ml). After stirring the mixture at room temperature for 1 hour, the solvent was removed under reduced pressure. The oily residue was crystallized by treating with ethyl acetate and filtered off to give 2-(2-oxo-3-benzylimidazolidinyl)acetic acid (1.56 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:37]([NH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:39])[CH3:38]
Reactant: Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 25 °C

Procedure:
A chilled (0° C.) solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide (40.0 mg, 0.111 mmol) in DMF (1 mL) was treated with 4-dimethylaminopyridine (1 mg, 0.01 mmol), DIEA (0.39 mL, 2.2 mmol) and acetic anhydride (0.062 mL, 0.66 mmol). The mixture was allowed to gradually warm to room temperature. The solution was diluted with ethyl acetate (30 mL) and washed with saturated aqueous NH4Cl (3×10 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 70-100% ethyl acetate in hexanes to afford the title compound as a white solid.
Reaction SMILES: Cl.O[CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1.S(Cl)(Cl)=O.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CCOCC.CO.O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH:3]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:7]1
Reactant: c1c[nH]cn1
Reactant: COc1ccccc1N1CCN(CC(O)c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COc1ccccc1N1CCN(CC(c2ccccc2)n2ccnc2)CC1

Procedure:
A mixture of 1-(2-hydroxy-2-phenylethyl)-4-(2-methoxyphenyl) piperazine hydrochloride (1.6 g) and thionyl chloride (5 ml) was stirred at reflux for 5 min. The clear solution was then diluted with ether and the precipitated product collected by filtration and washed well with ether. The solid was added to a solution of imidazole (2.4 g, 40 mmol) in methanol (20 ml) and heated to reflux for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed several times with water, dried (Na2SO4), and concentrated in vacuo. The residue was dissolved in ethanol (10 ml) and acidified with ethereal-HC1. Further addition of ether precipitated the hydrochloride (1.07 g, 55%), which was recrystallised from methanol-ethanol (20 ml; 1:3) to afford the title compound as the trihydrochloride 1.25 hydrate (0.54 g), m.p. 203°-204° C. (Found: C,53.2; H,6.4; N,11.2. C22H26N4O.3HC1.1.25 H2O requires C,53.4; H,6.4; N,11.3%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[CH2:12][N:11]([CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C@@H:10]1[CH2:27][O:28]CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:36]>[Pd].C(O)C>[ClH:36].[OH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C@@H:10]1[CH2:27][OH:28]
Reactant: OCC(O)CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OCC(O)CN1C[C@@H](O)[C@H](O)[C@H]1CO

Procedure:
The title compound was synthesized as described for compound 9 using (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-(2,3-dihydroxyprop-1-yl)pyrrolidine (Compound 17) (0.424 g, 0.89 mmol), ethanol (80 ml), 10% Pd/C (0.1 g), and excess of 4 M hydrochloric acid to convert the amine to the hydrochloride salt. (2R,3R,4R)-3,4-Dihydroxy-2-hydroxymethyl-1-(2,3-dihydroxyprop-1-yl)pyrrolidine hydrochloride was obtained as white crystals (0.216 g, yield: 100%) with melting point above 230° C. (decomposition).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=3)[C:3]=2[O:15][CH2:16][O:17][CH3:18])=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(-c2ccc(F)cc2)c(C)cc2cc(OC)ccc12
Yield: 98.5 %

Procedure:
2-Bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14) (0.3 g, 0.964 mmol), 4-fluorobenzeneboronic acid (0.27 g, 1.93 mmol), tetrakis(triphenylphosphino)palladium (0) (0.11 g, 0.0964 mmol), 2 M sodium carbonate (5 mL) and ethylene glycol dimethyl ether (5 mL) were added in a sealed tube and reacted as described above to give 0.31 g (96%) of the title compound (203) as a white solid. 1H NMR (400 MHz, d-CDCl3): δ 2.21 (s, 3H), 3.12 (s, 3H), 3.93 (s, 3H), 4.75 (s, 2H), 7.08-7.08 (m, 1H), 7.11-7.17 (m, 3H), 7.30-7.33 (m, 2H), 7.44 (s, 1H), 8.01 (d, J=9.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[C:16]([CH3:32])=[C:17]([NH:21]C(=O)OCC5C=CC=CC=5)[CH:18]=[CH:19][CH:20]=4)=[C:13]([CH3:33])[N:12]=[C:11]([C:34](=[O:36])[NH2:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.I[Si](C)(C)C>C(#N)C>[NH2:21][C:17]1[C:16]([CH3:32])=[C:15]([C:14]2[C:6]3[C:5]4[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=4)[NH:8][C:7]=3[C:11]([C:34]([NH2:35])=[O:36])=[N:12][C:13]=2[CH3:33])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(C(N)=O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(NC(=O)OCc2ccccc2)c1C
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1nc(C(N)=O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(N)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
To a solution of benzyl (3-(7-bromo-1-carbamoyl-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenyl)carbamate (1.10 g, 2.02 mmol) in acetonitrile (100 mL) at 0° C. was added iodotrimethylsilane (1.10 mL, 8.10 mmol) dropwise. The mixture was stirred at room temperature for 1.5 h. After concentration, diethylamine (2 mL) and ethyl acetate (150 mL) were added to the residue. The mixture was washed with water (2×40 mL), washed with brine (40 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate in hexane (20%-35%-50%) afforded 4-(3-amino-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide (0.411 g, 1.00 mmol, 50% yield) as a tan solid. LC/MS M+1=409.1 and 411.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:8]=1.C(OCC)(=O)C>[Pt](=O)=O.O.O.O.C([O-])(=O)C.[Na+]>[O:10]1[CH2:11][CH2:12][O:13][CH:9]1[C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:14]
Reactant: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(C2OCCO2)c1
Yield: 100 %

Procedure:
2-(5-Methoxy-2-nitrophenyl)-1,3-dioxolane (15.00 g, 0.06661 mol), platinum dioxide (900 mg, 0.004 mol) and sodium acetate trihydrate (700 mg, 0.005 mol) were placed in a pressure flask, followed by ethyl acetate (400 mL, 4 mol). The reaction mixture was then purged under N2 for at least 3 times, and H2 was introduced (purged 3 times) and maintained at 52 psi for 3 hours. The reaction mixture was then filtered, and solvent was removed to give a pure product (13 g, 100%). 1H NMR (CHLOROFORM-d) δ: 6.96 (d, J=2.8 Hz, 1H), 6.76 (dd, J=8.5, 3.0 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 5.84 (s, 1H), 4.00-4.18 (m, 4H), 3.89 (br. s., 2H). MS (M+1): 196.10.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[C:3]=1[S:12][CH3:13].N1C=CC=NC=1.[CH3:20][SH:21].[Na]>O1CCCC1>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[C:3]([S:12][CH3:13])=[C:2]([S:21][CH3:20])[N:7]=1
Reactant: CS
Reactant: COc1nc(Cl)c(SC)c(OC)n1
Agent: [Na]
Solvent: c1cncnc1
Solvent: C1CCOC1
Product: COc1nc(OC)c(SC)c(SC)n1

Procedure:
Into a 100-milliliter, 4-necked flask equipped with a reflux condenser, thermometer and stirrer, were charged 5.51 g of 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine and 50 ml of tetrahydrofuran. After causing the pyrimidine derivative to dissolve completely in the solvent, a 15% aqueous solution of sodium methyl mercaptan (commercially available; product of Tokyo Kasei Kogyo K.K.) was added dropwise and the resultant mixture was refluxed for 5 hours.