Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:36])=[C:20]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:21]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].C(N(CC)CC)C.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>O1CCCC1.C(OCC)(=O)C>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:20]1[CH:21]=[C:16]([O:15][C:13]2[CH:12]=[CH:11][C:9]3[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[S:7][C:8]=3[CH:14]=2)[CH:17]=[CH:18][C:19]=1[CH3:36])=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CN4CCN(C)CC4)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
N-[5-({2-[(Chloroacetyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (8.0 mL), triethylamine (155 μL, 1.13 mmol) and 1-methylpiperazine (100 μL, 0.902 mmol) were added, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (50 mL×2) and saturated brine (50 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (106 mg, 40%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35]([N:4]3[C:5](=[O:27])[C:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]3[CH2:1][CH3:2])[CH:36]=[CH:37][C:31]=2[O:30]1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 76.7 %

Procedure:
A mixture of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.50 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.52 g), copper(II) acetate (0.49 g), pyridine (0.55 mL), triethylamine (0.94 mL), molecular sieves 4 A (1.0 g) and dichloromethane (5 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.54 g, 80%) as a pale-yellow liquid.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([C:30](OC)=[O:31])[N:23]=[C:22]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:34]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH2:30][OH:31])[N:23]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(CO)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 4 h
Yield: 116.6 %

Procedure:
A solution of 0.36 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate (prepared as described in Example 1) in 4 ml of a 4N solution of hydrogen chloride in dioxane was allowed to stand at room temperature for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with ethyl acetate, to give crystals, which were collected by filtration to give 0.35 g of the title compound in the form of its hydrochloride, melting at 192°-195° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Ca+2:27]>[OH-].[Na+].O>[Ca+2:27].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C@H:9]([C:20]([O-:22])=[O:21])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C@H:9]([C:20]([O-:22])=[O:21])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-])c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A solution of 34.2 g (0.1 moles) of N-p-chlorobenzoyl-L-tryptophane in 1,000 ml of 0.1 N NaOH, kept at room temperature, was quickly admixed while stirring with 6.05 g (0.11 equiv.) of CaCl2 previously dissolved in 100 ml H2O. The N-p-chlorobenzoyl-L-triptophane starts precipitating forthwith in the form of calcium salt. The reaction mass is stirred during two hours at least to allow the precipitate of conveniently enlarging in volume. The resulting precipitate is filtered and washed with water till chlorine ions disappear. The product is dried in a circulating air oven at 90° C during 12 hours. 34.4 g product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH2:15][C:16]3[N:20]4[C:21](=[O:33])[C:22]5[NH:23][CH:24]=[N:25][C:26]=5[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:19]4=[N:18][N:17]=3)[N:10]=2)=[CH:5][CH:4]=1.[Br:34]N1C(=O)CCC1=O>CN(C=O)C>[Br:34][C:24]1[NH:23][C:22]2[C:21](=[O:33])[N:20]3[C:16]([CH2:15][CH2:14][C:11]4[N:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[O:13][N:12]=4)=[N:17][N:18]=[C:19]3[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:26]=2[N:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCc3noc(-c4ccc(OC)cc4)n3)nnc12
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCc3noc(-c4ccc(OC)cc4)n3)nnc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 3-2-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (160 mg, 0.36 mmol) in DMF (15 mL) at room temperature was added N-bromosuccinimide (110 mg, 0.61 mmol). After stirring at 70° C. for 1 hour, the reaction mixture was concentrated and purified by preparative LCMS to provide the desired product. LCMS calculated for C22H24BrN8O3 (M+H): 527.1, 529.0; found: 527.0, 529.0.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([Cl:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-bromoaniline (2.58 g 14.99 mmol) in dry CH2Cl2 (100 mL) was treated with 4-chloro-3-nitrobenzoyl chloride (3.60 g, 17.99 mmol) and N,N-diisopropyl-ethylamine (3.14 mL, 17.99 mmol), and the resulting mixture stirred at room temperature for 17 hours. The solvent was concentrated under vacuum giving the title compound and the residue taken up in ethyl acetate (100 mL) and washed with water and brine. The organic extract was dried over Na2SO4, filtered and concentrated under vacuum giving the title compound as a tan solid (5.132 g, 14.45 mmol, 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH3:28]>CC(C)=O>[CH2:27]([O:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH2:13][CH2:14]1)[CH3:28]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)(C)OC(=O)NCCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCN1CCN(CCCCNC(=O)OC(C)(C)C)CC1
Yield: 55.7 %

Procedure:
A mixture of (4-piperazin-1-yl-butyl)carbamic acid tert-butyl ester (17) (1.94 g, 7.54 mmol), sodium iodide (1.13 g, 7.54 mmol), potassium carbonate (3.13 g, 22.61 mmol), and 5-bromopentanoic acid ethyl ester (1.55 mL, 9.80 mmol) in acetone (60 mL) was stirred at reflux for 24 h. After removal of solvent by rotary evaporation, the resulting residue was diluted with dichloromethane and insoluble inorganics were filtered off. The liquid filtrate was concentrated in vacuo and the resulting residue was purified by Biotage silica gel column chromatography using methanol/dichloromethane (gradient 0% to 5%) to give a yellow oil, which was further purified by Biotage chromatography using ethyl acetate/dichloromethane (gradient 30% to 99%) to afford 18 as a yellow oil (1.62 g, 56%): 1H NMR (500 MHz, CDCl3) δ 1.27 (t, 3H), 1.43 (s, 9H), 1.52 (m, 6H), 1.65 (m, 2H), 2.34 (m, 6H), 2.48 (m, 6H), 3.11 (m, 2H), 4.12 (q, 2H), 5.21 (br, 1H); ESI MS m/z 386 [C20H39N3O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:13](I)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCI
Reactant: COC(=O)c1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)O)c(Cl)c1
Reaction time: 8 h
Yield: 632.5 %

Procedure:
0.25 g of methyl 2-chloro-4-hydroxybenzoate was dissolved in 10 ml dimethylformamide, and 0.23 g of ethyl iodide and 0.21 g of potassium carbonate were added, and the mixture was stirred for 8 hours. After diluting the reaction mixture, it was extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was dissolved in 6 ml methanol, and 3 ml of 1 N sodium hydroxide was added, and the solution was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 1.7 g of 2-chloro-4-ethoxybenzoic acid.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH:25]([C:29](O)=[O:30])[C:26](O)=[O:27])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][C:25]2[C:26](=[O:27])[O:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:29]=2[OH:30])[CH2:15][CH2:16]1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(O)C(Sc1ccccc1CC1CC1)C(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1ccccc1CC1CC1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.990 mL, 4.83 mmol), and diethyl ester of [[2-(cyclopropylmethyl)phenyl]thio] propanedioic acid (1.00 g, 3.10 mmol) m.p. 165-167° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.25 (dd, 2H), 0.52 (dd, 2H), 1.21 (m, 1H), 2.50 (d, 2H), 6.87 (s, 1H), 6.92 (m, 1H), 7.05 (m, 2H), 7.32 (m, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4]Cl.[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][O:24][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[O:6][CH2:4][CH2:3][S:2][CH3:1])[N:14]=[CH:13][N:12]=[C:11]2[O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CSCCCl
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCSC
Temperature: 110 °C
Yield: 53.9 %

Procedure:
2-Chloroethyl methyl sulphide (1.2 g, 10.9 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (2.25 g, 8.4 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (6.0 g, 43.4 mmol) in DMF (70 ml). The mixture was heated at 110° C. for 4 hours and allowed to cool. The mixture was filtered, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4) to give 6-methoxy-7-(2-methylthioethoxy)4-phenoxyquinazoline (1.55 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40]>CC(CC)=O.O>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[C:31](=[O:40])[C:32]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]4[C:34]3=[O:35])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCN1C(=O)c2ccccc2C1=O
Yield: 94.1 %

Procedure:
A solution of 1.00 g (0.005 mol) of rac-cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-1H-benzo[e]indole in 60 ml of ethyl methyl ketone was treated with 0.86 g (0.006 mol) of potassium carbonate, 0.29 g (0.002 mol) of sodium iodide and 1.50 g (0.005 mol) of N-(5-bromopentyl)phthalimide. The mixture was heated under reflux for 24 hours and, after cooling, treated with water. The mixture was extracted with ethyl acetate, the extracts were dried with sodium sulphate and the solvent was distilled off in a vacuum. Chromatography over silica gel with methylene chloride/methanol 20:1 gave 1.97 g (95%) of rac-N-[5-(cis-1,2,3a,4,5,9b-hexahydro-6-methoxy-3H-benzo[e]indol-3-yl)pentyl]phthalimide.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:43]=[C:42]([OH:44])[C:36]2[CH2:37][CH:38]([CH2:40][OH:41])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[N:45]1([C:49]([C:51]2[CH:56]=[CH:55][C:54](F)=[CH:53][C:52]=2[F:58])=[O:50])[CH2:48][CH2:47][CH2:46]1>>[C:26]([O:30][C:31]([C:33]1[CH:43]=[C:42]([O:44][C:54]2[CH:55]=[CH:56][C:51]([C:49]([N:45]3[CH2:48][CH2:47][CH2:46]3)=[O:50])=[C:52]([F:58])[CH:53]=2)[C:36]2[CH2:37][CH:38]([CH2:40][OH:41])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(c1ccc(F)cc1F)N1CCC1
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 1.57 (s, 9 H) 2.26-2.38 (m, 2 H) 3.06-3.17 (m, 1 H) 3.67-3.78 (m, 1 H) 3.81-3.90 (m, 1 H) 4.09-4.18 (m, 3 H) 4.18-4.25 (m, 2 H) 4.92-5.02 (m, 1 H) 6.63-6.68 (m, 1 H) 6.78 (dd, J=8.59, 2.27 Hz, 1 H) 7.21 (d, J=1.26 Hz, 1 H) 7.49-7.56 (m, 1 H) 8.02 (s, 1 H); LCMS for C24H24FNO6 m/z 444.00 (M+H)+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].C([CH2:19][CH2:20][NH:21][C:22]1C=CC(C=O)=C[CH:23]=1)C1C=CC=CC=1>>[CH2:22]([N:21]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:10]=[C:20]1[CH3:19])[CH3:23]
Reactant: O=Cc1ccc(NCCCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21
Yield: 86.1 %

Procedure:
Following a procedure similar to that described in Example 3A but employing 6.5 g. of 81.9% sodium p-toluenesulfinate, 6.3 g. of 95% 4-(benzylethylamino)benzaldehyde and 3.8 g. of 86.1% 1-ethyl-2-methyl-1H-indole, there was obtained 15.3 g. of 3-{[4-(benzylethylamino)phenyl](4-methylphenylsulfonyl)methyl}-1-ethyl-2-methyl-1H-indole as a gray tar-like product.
Reaction SMILES: C[C@H:2]1[CH2:30][O:29][C@@:5]2(O[C@H:8]3[CH2:10][C@H:11]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@:12]4(C)[C@H:7]3[C@@H:6]2C)[CH2:4][CH2:3]1.[OH-].[K+].C(OCC(CC)CCCC)C1[O:36]C1>C1(C)C=CC=CC=1>[CH2:6]([CH:5]([O:29][CH2:30][CH3:2])[CH:4]1[O:36][CH2:3]1)[CH2:7][CH2:8][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(CC)COCC1CO1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCC(OCC)C1CO1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a 250 mL, round bottom 3-neck flask equipped with a condenser, a nitrogen in/out let, a mechanical stirrer, a thermo-watch, and a heating mantle, a mixture of 30 g of 35,000 Mw PEG and toluene (80 mL) was heated to 60° C. At this temperature, KOH (0.77 g, 0.02 mol, in 1 g of water) was added and the reaction mixture was stirred for 1 hour. 2-Ethyl hexyl glycidyl ether (1.91 g, 0.02 mole) was added and the reaction temperature was kept at 110° C. for 5 hours. After the reaction mass was cooled to 60° C., toluene (80 mL) was further added. The solution was precipitated into 300 mL of hexane. After filtration and washing with ethyl acetate (100 mL×3×) and drying in vacuum, a white polymer (31 g) was obtained. 1H NMR showed 5.2% hydrophobe incorporation. The Brookfield viscosity of a 5% aqueous solution of this oligomer was >200,000 cps (BF LV, S-63, 0.3 rpm at 25° C.). Paint performance: SG10 M (standard formulation). TE %=0.11, Viscosity Loss upon Tinting (VLT)=−24 KU. For UCAR 379 G, TE %=0.28, VLT=−30 KU.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:28])=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>C[O-].[Na+].CO>[OH:28][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:20]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(Oc4ccccc4)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(Oc4ccccc4)cc3)sc2c1O
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A mixture of 7-hydroxy-2-(4-phenoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (75 mg, 0.19 mmole) and glycine (286 mg, 3.81 mmole) in 0.5 M sodium methoxide/methanol (7.2 ml) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. Water (75 ml) was added and pH was adjusted to 10 with 1N HCl (2 ml). The mixture was extracted with methyl tert-butyl ether (2×30 ml) and dichloromethane (30 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl (3 ml). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (55 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.45 (br s, 1H), 8.87 (s, 1H), 8.17 (m, 2H), 7.47 (m, 2H), 7.17 (m, 5H), 4.03 (d, J=6.3 Hz, 2H); MS: (+) m/z 421.07 (M+1). (−) m/z 419.87 (M−1).
Reaction SMILES: [CH:1]1([CH:4]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[O:5][C:6]2[CH:28]=[CH:27][C:9]([CH2:10][NH:11][C:12]3[C:17]([N+:18]([O-])=O)=[CH:16][C:15]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:29][CH3:30])[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH:1]1([CH:4]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[O:5][C:6]2[CH:28]=[CH:27][C:9]([CH2:10][NH:11][C:12]3[C:17]([NH2:18])=[CH:16][C:15]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:29][CH3:30])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(Oc2ccc(CNc3ncc(-c4cnn(C)c4)cc3[N+](=O)[O-])cc2OC)C2CC2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(Oc2ccc(CNc3ncc(-c4cnn(C)c4)cc3N)cc2OC)C2CC2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a stirred solution of N-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (1.10 g, 2.13 mmol) and ammonium chloride (0.564 g, 10.54 mmol) in ethanol (8 mL) and water (2 mL) was added iron powder (0.596 g, 10.67 mmol). The mixture was heated to 80° C. After 2 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated. Chromatographic purification of the residue (neutral alumina, 2% methanol in dichloromethane elute) afforded 0.984 g (95%) of N2-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2,3-diamine as a brown solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][C@@H:25]([CH:41]([CH3:43])[CH3:42])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C@H:22]([CH2:44][C@H:45]([C:49](=[O:57])[NH:50][C:51]([C:54](=[O:56])[NH2:55])([CH3:53])[CH3:52])[CH:46]([CH3:48])[CH3:47])[O:21]C1(C)C)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO>[C:54]([C:51]([NH:50][C:49](=[O:57])[C@H:45]([CH:46]([CH3:48])[CH3:47])[CH2:44][C@H:22]([OH:21])[C@@H:23]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][C@@H:25]([CH:41]([CH3:43])[CH3:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=1)([CH3:52])[CH3:53])(=[O:56])[NH2:55]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5 mg of p-toluenesulfonic acid (monohydrate) are added to 82 mg of 3-tert-butoxycarbonyl-5(S)-{2-[N-(1-carbamoyl-1-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-di-methyl-1,3-oxazolidine in 5 ml of methanol at 0° C. The reaction solution is stirred for a further 18 hours at room temperature. After evaporation of the solvent, 20 ml of saturated sodium hydrogen carbonate solution are added to the residue and extraction is carried out repeatedly with ethyl acetate. The organic extracts are concentrated by evaporation and purified by means of FC (35 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.47.