Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.O[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C:55]1=[O:60]>C(Cl)Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:52][CH2:53][N:54]5[CH2:59][CH2:58][CH2:57][CH2:56][C:55]5=[O:60])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: O=C1CCCCN1CCO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCCCC4=O)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 3c from 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 33 mg (0.23 mmol) 1-(2-hydroxyethyl)-piperidin-2-one. After the elimination of the desiccant and solvent the residue was taken up in DCM and again purified by chromatography (silica gel, DCM/EtOH/NH3 95:5:0.5). The fractions containing the product were combined, concentrated by evaporation i.vac., triturated with DIPE, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[CH:8][C:7]=2[CH:14]=1.CN1C=CN=C1.I(C1C=CC=CC=1)=[O:25].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:25]1[C@H:8]2[C@@H:9]1[C:10]([CH3:13])([CH3:12])[O:11][C:6]1[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[C:3]([O:2][CH3:1])=[CH:14][C:7]=12
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C=C2
Reactant: O=Ic1ccccc1
Agent: Cn1ccnc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@H]21
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution (300 mL) of acetonitrile containing 6-methoxy-2,2-dimethyl-7-nitro-2H-1-benzopyran (10.0 g, 42.5 mmol), N-methyl imidazole (0.678 mL, 8.50 mmol), Ph,Ph salen manganese complex (XX) (880 mg, 0.850 mmol) and iodosobenzene (18.7 mg, 85.0 mmol) were added at room temperature and the mixture was stirred for 2 hours. Upon the completion of the reaction, aqueous sodium thiosulfate solution was added to the reaction solution, the resulting solution was filtered through celite. The resulting filtrate extracted with ethyl acetate. The organic phase was washed with water and sodium chloride solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=4/1) and the aimed product was obtained as yellow crystal (yield: 75%, optical purity: 99.7% ee).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[CH:32]=[CH:31][CH:30]=[CH:29][C:17]=1[CH2:18][N:19]1[C:23]([CH3:24])=[C:22]([CH2:25][NH:26][CH3:27])[C:21]([CH3:28])=[N:20]1.O1CC1>CO>[Cl:15][C:16]1[CH:32]=[CH:31][CH:30]=[CH:29][C:17]=1[CH2:18][N:19]1[C:23]([CH3:24])=[C:22]([CH2:25][N:26]([CH3:27])[CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]2[CH:13]=[CH:14][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:21]([CH3:28])=[N:20]1
Reactant: CNCc1c(C)nn(Cc2ccccc2Cl)c1C
Reactant: CCOc1ccc(OCC2CO2)cc1
Solvent: C1CO1
Solvent: CO
Product: CCOc1ccc(OCC(O)CN(C)Cc2c(C)nn(Cc3ccccc3Cl)c2C)cc1
Temperature: 68 °C
Yield: 61.4 %

Procedure:
2-((4-Ethoxyphenoxy)methyl)oxirane (0.06 g, 0.32 mmol) and 1-(1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (0.10 g, 0.38 mmol) were dissolved in methanol (0.32 ml), warmed to 68° C. and stirred until the oxirane was consumed as observed by TLC. The solution was cooled to room temperature and the solvent removed under reduced pressure. The resulting oil was purified using flash column chromatography with 1:2:0.01 ethyl acetate:hexanes:triethylamine as the eluting solvent to yield 0.09 g (63%) of 1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-(4-ethoxyphenoxy)propan-2-ol as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.35 (dd, J=7.8, 1.2, 1H), 7.17 (td, J=7.7, 1.3, 1H), 7.12 (td, J=7.5, 1.2, 1H), 6.85-6.79 (m, 4H), 6.48 (dd, J=7.6, 0.9, 1H), 5.28 (s, 2H), 4.12-4.04 (m, 1H), 3.97 (q, J=7.0, 2H), 3.90 (d, J=4.9, 2H), 3.47 (d, J=13.2, 1H), 3.34-3.29 (m, 1H), 2.60 (dd, J=12.2, 9.7, 1H), 2.48 (dq, J=12.2, 3.9, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.11 (s, 3H), 1.38 (t, J=9.1, 3H). 13C NMR (75 MHz, CDCl3) δ 153.47, 153.04, 148.04, 138.67, 135.31, 131.92, 129.43, 128.79, 127.58, 127.50, 115.63, 115.63, 115.53, 115.53, 113.71, 71.25, 66.37, 64.14, 59.51, 51.70, 50.28, 42.09, 15.13, 12.36, 9.82. HRMS (m/z): [MNa]+ calc for C25H32ClN3O3Na+, 480.20. found 480.2030.
Reaction SMILES: [C:1](=[S:3])=[S:2].OS(O[CH2:9][C@@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1)(=O)=O>[OH-].[Na+]>[CH2:9]1[C@H:10]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19]2)[C:1](=[S:3])[S:2]1
Reactant: S=C=S
Reactant: O=S(=O)(O)OC[C@@H]1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Product: S=C1SC[C@@H]2Cc3ccccc3CN12
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Carbon disulphide (40 g.) is added dropwise at 20° C., with vigorous stirring, to a solution of (S)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (100 g) in 0.25N sodium hydroxide solution (4,000 cc.). The reaction is exothermic. A solid precipitates and the reaction mixture then sets solid. Stirring is continued for 3 hours. The reaction mixture is neutralised by adding 4N hydrochloride acid. The crystals formed are filtered off, washed copiously with water and then recrystallised from ethanol (3,000 cc.) to give (S)-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline-3-thione (77 g. ) in the form of fine white needles melting at 150° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.OCCN1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[NH:33]1[C:32]2[C:31](=[C:4]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:5]=[CH:6][CH:8]=2)[CH:35]=[CH:34]1
Reactant: OCCN1CCNCC1
Reactant: OCCN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: OCCN1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Via 2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-ethanol, prepared from N-(2-hydroxyethyl)piperazine (commercially available).
Reaction SMILES: CN(N=O)C([O:5][CH2:6][CH3:7])=O.[CH2:10]([N:17]1[CH2:22][CH2:21]C(=O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-2].[Ba+2]>CO>[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:7][C:6](=[O:5])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)N(C)N=O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Ba+2]
Agent: [O-2]
Solvent: CO
Product: O=C1CCCN(Cc2ccccc2)CC1
Temperature: -5 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
N-methyl-N-nitrosourethane (1.39 ml, 10.8 mmol) was added dropwise to a solution of 1-benzyl-4-piperidone (2.0 g, 10.6 mmol) in methanol (4 ml) at −15° C. over a period of 30 minutes while maintaining the temperature at −5° C. or lower. During the addition, barium oxide (65 mg, 0.423 mmol) was added thereto in small portions. The resulting mixture was stirred overnight at −15° C. and then filtered, and the filtrate was distilled under reduced pressure to remove the solvent and diethyl ether was added to the residue. The insoluble material was filtered off and a saturated aqueous sodium hydrogencarbonate solution was added to the filtrate, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain 1-benzyl-4-azepanone (662 mg, 31%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccc5ccccc5n4)cc3)cc2)CC1
Temperature: 60 °C

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.181 g, 0.5 mmol) was dissolved in DMF and then sodium hydride (60% in mineral oil, 0.028 g, 0.7 mmol) was added. After 20 minutes 2-chloroquinoline (0.1145 g, 0.7 mmol) was added and the reaction was heated to 60° C. for 3 hours. No product was observed by analytical LCMS so the reaction was heated to 100° C. overnight. After cooling the reaction was submitted to standard aqueous workup to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[NH3:21]>>[OH:17][CH2:18][CH2:19][CH:15]([C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]([NH2:21])=[O:20]
Reactant: N
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Product: CC1(C(CCO)C(N)=O)OCCc2c1[nH]c1ccccc21
Temperature: 90 °C

Procedure:
A suspension of 4,5-dihydro-3-(1,3,4,9-tetrahydro-1-methyl pyrano[3,4-b]indol-1-yl)-2(3H)-furanone (described in Example 1, 20 g, 0.073 mole) in liquid ammonia is heated at 90° C. in a pressure apparatus for three hours. The apparatus is rinsed with ethanol and the yellow solution is evaporated. The residue is crystallized from methanol to afford α-(2-hydroxyethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetamide (16.15 g), mp 159°-161° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([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)=CC=1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccccc2)c2onc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of 7-bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (125.4 mg, 0.35 mmol), phenylboronic acid (85 mg, 0.69 mmol), cesium carbonate (339 mg, 1.04 mmol), tetrakis(triphenylphosphine)palladium (40 mg, 0.03 mmol), and dioxane (1.5 ml) was refluxed for 18 h before it was cooled to room temperature and quenched with water. It was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (63 mg): MS: (+) m/z 361.07 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][CH:25]1[NH:29][C:28](=[O:30])[CH2:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:29]4[CH:25]([CH3:24])[CH2:26][CH2:27][C:28]4=[O:30])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4C(=O)CCC4C)cn3)CC2)c(C)c1
Yield: 32.1 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (113 mg) described in Preparation Example 232 and 5-methylpyrrolidin-2-one (36 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (38 mg) was obtained.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N12CCCN=C1CCC[CH2:27][CH2:26]2.C(Br)C>C1C=CC=CC=1>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([N:7]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:26][CH3:27])=[O:13])=[CH:15][CH:16]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C(=O)O)cc2)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: CCBr
Product: CCOC(=O)c1ccc(N(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Yield: 75.5 %

Procedure:
4-(Di-p-tolylamino)benzoic acid (69.7 g, 0.22 mol) dissolved in benzene (500 mL), was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (38 mL, 0.25 mol), followed by the addition of ethyl bromide (33 mL, 0.44 mol). The reaction was filtered to remove salts, washed with saturated ammonium chloride until neutral (1.5 L), washed with water, washed with brine, and dried over magnesium sulfate. The solvent was removed at 40° C. and the residual crystalline solid was washed with cold ethanol to give ethyl 4-(di-p-tolylamino)benzoate (57.4 g, 76% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].[C:19](O)(C)(C)C.CCOC(C)=O>O.Cl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:2]1[C:3]2[C:10]3[CH2:19][CH2:11][CH2:12][CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:15]
Reactant: Clc1ncnc2sc3c(c12)CCC3
Reactant: CC(C)(C)O
Reactant: CCNCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)c1ncnc2sc3c(c12)CCCC3

Procedure:
To a slurry of 0.044 g 4-chloro-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine (0.196 mmol) in 1 mL of 100:1 H2O/HCl was added 0.014 g (0.02 mL, 0.106 mmol) diethylamine. The mixture was heated to reflux, and an additional 0.2 mL diethylamine and 1 mL of t-butanol were added and heated continued at reflux for an additional 1 h. TLC (20% EtOAc/80% pet ether) showed complete reaction and the 1H NMR of the isolated material was consistent with the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7](Br)[N:6]=1)=[O:4].[CH3:17][NH:18][S:19]([C:22]1[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=1)(=[O:21])=[O:20]>N1C=CC=CC=1>[OH:15][C:14]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([N:18]([CH3:17])[S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:20])=[O:21])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: CNS(=O)(=O)c1cn(C)cn1
Solvent: c1ccncc1
Product: COC(=O)c1nc(N(C)S(=O)(=O)c2cn(C)cn2)c2cccnc2c1O
Reaction time: 1 h

Procedure:
A solution of methyl-5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (0.969 g, 3.42 mmol), N,1-dimethyl-1H-imidazole-4-sulfonamide (0.60 g, 3.42 mmol) and Cu2O (0.49 g, 3.42 mmol) in pyridine (15 mL) was heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (1.0 g) in water (20 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (1.0 g in water 20 mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was suspended in acetonitrile (10 mL) and the resulting solid collected by filtration. The solids were washed with diethyl ether (5 mL) and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:27])=[CH:20][CH:19]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: COC1=C(c2ccc(CCC(=O)O)cc2)C(=O)N(c2ccc(C(=N)N)cc2)C1
Reactant: OC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(c2ccc(CCC(=O)OC3CCCCC3)cc2)C(=O)N(c2ccc(C(=N)N)cc2)C1
Temperature: 40 °C

Procedure:
Prepared by passing dry hydrogen chloride through a solution of 1-(4-amidinophenyl)-3-[4-(2-carboxy-ethyl)phenyl]-4-methoxy-3-pyrrolin-2-one and an excess of cyclohexanol in methylene chloride for one hour and subsequently heating to 40° C. for one hour.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:34][O:35][C:36]1[CH:37]=[N:38][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[N:40][CH:41]=1.C(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:45]3[CH2:46][CH2:47][N:42]([C:39]4[N:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:41][N:40]=4)[CH2:43][CH2:44]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: COc1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cnc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 20.5 %

Procedure:
100 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 163 mg PFTU and 0.5 mL DIPEA were added to this solution and the mixture was stirred for 7 min at RT. Then, 88 mg 5-Methoxy-2-piperazin-1-yl-pyrimidine hydrochloride and 0.11 mL DIPEA dissolved in 1.5 mL DMF were added and the reaction was stirred 3 h at RT. Then, a saturated sodiumhydrogencarbonate solution and CH2Cl2 were added, the organic phase was separated and the solvent was removed. The residue was purified by HPLC and crystallized with diethylether to give 32 mg of the desired compound. Rt: 0.82 min (method E), (M+H)+: 492
Reaction SMILES: CC(CCCC[N:13]=[C:14]=[O:15])C(N=C=O)(C)C.[CH3:16][CH2:17]C[CH2:19][CH:20]([C:23]([O-:25])=[O:24])[CH2:21]C.CCC[CH2:29][CH:30]([C:33]([O-:35])=[O:34])[CH2:31]C.[Sn+2]>>[C:23]([OH:25])(=[O:24])[C:20]([CH3:21])=[CH2:19].[C:33]([OH:35])(=[O:34])[C:30]([CH3:31])=[CH2:29].[NH2:13][C:14]([O:15][CH2:16][CH3:17])=[O:34]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: CC(CCCCN=C=O)C(C)(C)N=C=O
Agent: [Sn+2]
Product: C=C(C)C(=O)O
Product: CCOC(N)=O
Reaction time: 3 h

Procedure:
To a mechanically-stirred mixture of 28.59 weight parts of trimethylhexamethylene diisocyanate and 0.04 weight part of stannous octoate in a reactor and purged with dry air, there is added 44.80 weight parts of polytetramethylene ether glycol, while maintaining the reaction temperature at 50° to 60° C. After the addition is complete, the mixture is heated to 70° to 80° C. and held for 3 hours. A 26.58 weight parts of hydroxyethyl methacrylate (HEMA) was added and the mixture was stirred at 70° to 80° C. until the percent NCO assay was below 0.01%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH3:12].C([Li])CCC.[C:18](=[O:20])=[O:19].O>O1CCCC1>[CH3:12][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=[CH:11][C:2]=1[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: Cc1c(Br)ccc2c1OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In 300 ml of dry tetrahydrofuran, was dissolved 32.0 g of 6-bromo-5-methyl-1,4-benzodioxane and after cooling the solution to -78° C., 96.7 ml of n-butyl lithium (n-hexane solution) was added dropwise over 20 minutes or more. After stirring at the same temperature for 1.5 hours, the reaction mixture was poured onto crushed dry ice and dry ice was sublimated while stirring. Water was added to the mixture and the tetrahydrofuran was removed under reduced pressure. The resulting alkaline aqueous solution was washed with methylene chloride and adjusted to pH 3 with a 5% hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain 20.9 g of 5-methyl-1, 4-benzodioxan-6-carboxylic acid (yield: 77%).
Reaction SMILES: [F:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>CCCCCC.C1(C)C=CC=CC=1>[OH2:4].[F:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]=[O:4]
Reactant: CCCCC(F)C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCC(F)C=O
Product: O
Reaction time: 5 h

Procedure:
A solution of ethyl 2-fluorocaproate (AX, R=n-pentyl) prepared in accordance with the method of Elkik and Assadi-Far, Compt. Rend. Series C, 262 (9) 763 (1966), (9.50 g, 58.6 mmol) in 45 ml of dry hexane was cooled under N2 to -75° in a 300 ml round bottom flask equipped with a 50 ml pressure-equalized addition funnel. Into the funnel was injected through a rubber septum, a solution of diisobutyl aluminum hydride in 30 ml of hexane, prepared from 15 ml of 1.2 molar diisobutyl aluminum hydride in toluene by evaporating the toluene in vacuo and replacing it by hexane. After addition of the diisobutyl aluminum hydride solution over a 35 min period the mixture was stirred magnetically for 5 hr at -70°±3°. At the same temperature 75 ml of 10% HCl was then added dropwise, the dry ice-acetone bath removed and stirring continued until a homogeneous solution resulted. After saturation with NaCl the aqueous solution was extracted with 3 100 ml portions of CH2Cl2. The combined extracts were washed with saturated sodium chloride (3×25 ml) and dried over anhydrous MgSO4. The solvent was removed in vacuo leaving a liquid residue which after distillation gave 6.04 g of 2-fluorohexanal hydrate (AXI, R=n-pentyl), bp 70°-80° at 167 mm. Various other side chains, i.e. Compounds AIII, wherein R=alkyl or alkenyl, may be prepared by variation of the Elkik and Assadi-Far procedure as is well recognized to the skilled worker.