Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:26])[CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: FC1(F)CNC1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CC(F)(F)C2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 13A, 52 mg (0.4 mmol) of 3,3-difluoroazetidine hydrochloride and 175 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 3 h. The precipitated solid is filtered off and the filtrate is concentrated under reduced pressure. The residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 36 mg (32% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(C)(=O)=O)cc3CO1)CC2
Yield: 43.4 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (155 mg, 0.50 mmol, HPLC 0.776 min) and methanesulfonyl chloride (43 ul, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as a light brown solid (84 mg, 43%, HPLC 1.178 min), MS (ISP) m/e=388.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:6]=[N:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)=[N:3][CH:2]=1)#[N:9]
Reactant: CCCCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCOc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
6.0 G. of 4-chloro-5-cyano-2-(4-n-pentyloxyphenyl)-pyrimidine are reacted in 260 ml. of 50% dioxane with 23.0 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-pentyloxyphenyl)-pyrimidine as colorless crystals having a melting point of 98.0°-98.1° C. (smectic); nematic at 102.1° C; clearing point 133.2° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[O:25])[NH:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:33]([F:38])([F:37])C(O)=O.[Na].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([O:25][CH:33]([F:38])[F:37])=[N:14][N:15]2[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(OCc3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(OC(F)F)c2ccc(OCc3ccccc3)cc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
Tert-butyl 6-(benzyloxy)-3-oxo-2,3-dihydroindazole-1-carboxylate (342 mg) which can be prepared according to the method described in Reference example 32, etc. and potassium carbonate (2.0887 g; manufactured by Sigma-Aldrich Co.) were suspended in dehydrated DMF (10 mL; manufactured by Kanto Chemical Co., Inc.), added with sodium chlorodifluoroacetic acid (853 mg; manufactured by Tokyo Chemical Industry, Co., Ltd.), and stirred at 80° C. for 12 hours. The reaction solution was added to water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=100:0→87:13) to obtain the title compound (264.7 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([O:26]C)=[O:25])(=[O:18])=[O:17])=[O:4].O.O.[OH-].[Li+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([OH:26])=[O:25])(=[O:18])=[O:17])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(NS(=O)(=O)c2ccsc2C(=O)O)ccc2c1CCCC2
Temperature: 60 °C

Procedure:
A solution of Example 463A (1.37 g, 3.36 mmol) in methanol (31 mL) and distilled water (3.5 mL) was treated with lithium hydroxide monohydrate (0.704 g, 16.78 mmol), heated to 60° C. for 30 minutes, cooled to room temperature, treated with 1N HCl, and concentrated. The aqueous layer was extracted with dichloromethane twice and the combined organic fractions were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 396 (M+H)+; (ESI(−)) m/e 394 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.98 (br s, 1H), 7.89 (d, 1H), 7.33 (d, 1H), 7.12 (s, 2H), 3.77 (s, 3H), 2.67 (br s, 2H), 2.53 (br s, 2H), 1.65 (quint, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methylacetophenone (0.712 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]-propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 205° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.37 (s, 3 H), 3.99 (s, 2 H), 6.69 (s, 1 H), 7.26 (m, 7 H), 7.68 (m, 2 H), 11.83 (bs, 1 H).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].O>CC(N(C)C)=O>[CH2:12]([C:11]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC=O
Reactant: NC(=O)c1ccccc1N
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
Anthranilamide (300 mg, 2.20 mmol) was dissolved under argon in dimethylacetamide (5 ml), valeraldehyde (199 mg, 2.31 mmol) and Na2S2O5 (628 mg, 3.31 mmol) were added, and the mixture was stirred under reflux conditions for 4 h. After cooling to room temperature, water was added to the reaction mixture. By suction-filtering and thoroughly drying the solid formed, 2-butylquinazolin-4(3H)-one (254 mg, 54% of theory) was obtained as a colorless solid. 1H NMR (400 MHz, CDCl3 δ, ppm) 8.26 (d, 1H), 7.74 (dd, 1H), 7.69 (d, 1H), 7.46 (dd, 1H), 7.30 (br. s, 1H, NH), 2.75 (t, 2H), 1.82 (quint, 2H), 1.49 (sext, 2H), 1.00 (t, 3H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>C(Cl)Cl>[C:18]([Si:15]([CH3:17])([CH3:16])[O:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a mixture of 2-methyl-2-(4-nitro-phenyl)-propan-1-ol (as prepared in the previous step, 1.50 g, 7.68 mmol) and t-butyl-dimethylsilyl chloride (1.51 g, 9.99 mmol) in 60 mL of DCM was slowly added imidazole (3.09 g, 45.4 mmol). After stirring at RT for 16 h, the mixture was treated with 40 mL of DCM and washed with H2O (30 mL), 15% aqueous citric acid (30 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-5% EtOAc/hexane) to give 1.82 g (65%) of the title compound as a light brown oil. 1H-NMR (CDCl3; 400 MHz): δ 7.85 (d, 2H, J=8.8 Hz), 7.52 (d, 2H, J=8.8 Hz), 3.59 (s, 2H), 1.35 (s, 6H), 0.86 (s, 9H), −0.04 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([NH2:22])[C@H:17]1[O:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[CH2:16]([NH:22][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[C@H:17]1[O:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC[C@@H]1CCCO1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@@H]2CCCO2)c1Cl
Yield: 98.5 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.01 g, 3.44 mmol), (2S)-tetrahydrofurfurylamine (0.33 mL, 3.20 mmol) and triethylamine (0.72 mL, 5.17 mmol) were reacted to form the desired product (1.12 g, 99%). EI-MS m/z 353(M-H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8](O)=[O:9])[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.CC(C)CC(Cl)=O.[BH4-].[Na+].Cl>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1([CH2:8][OH:9])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: CC(C)CC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1(CO)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of cyclopropane-1,1-dicarboxylic acid methyl ester (9 g, 62.4 mmol) in THF (180 mL), is cooled to 0° C. and triethylamine (9.7 mL, 69.6 mmol) and 3-methyl-butyryl chloride (9.1 mL, 9.6 mmol) are added and the reaction stirred for 1 h. In a separate flask, sodium borohydride (7.1 g, 188 mmol) is dissolved in THF (100 mL)/H2O (25 mL) and cooled to 0° C. The mixed anhydride is filtered through a sintered funnel to remove salts from previous reaction and added to the flask containing sodium borohydride and the reaction stirred for 1 h at 0° C. 1 N HCl is added and the product is extracted with EtOAc and then with CCl3H/iPrOH. It is then purified via FCC eluting with Heptane/EtOAc (100:0 to 20:80) to give 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.61 (t, J=5.81 Hz, 1H) 3.59 (s, 3H) 3.55 (d, J=6.06 Hz, 2H) 1.01 (d, J=3.03 Hz, 2H) 1.01 (d, J=10.36 Hz, 1H) 0.87 (d, J=3.03 Hz, 1H) 0.85-0.88 (m, 1H).
Reaction SMILES: [C@@H]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.Cl>>[NH:16]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:19]=2[N:18]=[CH:17]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl
Product: O=c1[nH]cnc2nc[nH]c12

Procedure:
The activity of the UdP enzyme was determined in a phosphorolysis test by incubating for 5 minutes at 30° C. the soluble fraction (cell extract) obtained by sonication of a known amount of a suspension of the cell paste and by centrifugation of the homogenate in 100 mM-pH 7 phosphate buffer containing 60 mM of the uridine substrate. The enzyme reaction was blocked by acidification with 0.1N HCl; the suspension was filtered and analysed by RP-HPLC on a C18 column (Hypersyl 100; 4.6×250 mm), eluting under isocratic conditions with a mobile phase constituted by 0.02 M K2HPO4 in methanol-H2O (4:96 v/v) and adjusted to pH 4.5 with NH4OH. The amount of uracil formed in the reaction was determined by reference to a standard curve and the enzyme activity of the cell preparation was calculated in μmol uracil/min/g wet cell paste (units/g). The activity of the PNP enzyme was determined in a phosphorolysis test by incubating for 10 minutes at 30° C. the soluble fraction (cell extract) obtained by sonication of a known amount of a suspension of the cell paste and by centrifugation of the homogenate in 100 mM-pH 7 phosphate buffer containing 50 mM of the inosine substrate. The enzyme reaction was blocked by acidification with 0.1N HCl; the suspension was filtered and analysed by RP-HPLC on a C18 column (Hypersyl 100; 4.6×250 mm), eluting under isocratic conditions with a mobile phase constituted by 0.02 M K2HPO4 in methanol-H2O (4:96 v/v) and adjusted to pH 4.5 with NH4OH. The amount of hypoxanthine formed in the reaction was determined by reference to a standard curve and the enzyme activity of the cell preparation was calculated in μmol hypoxanthine/min/g wet cell paste (units/g).
Reaction SMILES: C1C2NC3C(=CC=CC=3)SC=2C=CC=1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H]1CCOC1O)=O)CC(C)C)=O)CC(C)C)=O)CC(C)C)=O.[CH3:48][C:49]([O:73][C:74]1[CH:87]=[CH:86][C:85]2[S:84][C:83]3[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=3)[NH:77][C:76]=2[CH:75]=1)([CH3:72])[C:50]([NH:52][CH2:53][C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]1[CH2:69][CH2:68][O:67][CH:66]1[O:70]C)=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])=[O:51]>>[CH3:72][C:49]([O:73][C:74]1[CH:87]=[CH:86][C:85]2[S:84][C:83]3[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=3)[NH:77][C:76]=2[CH:75]=1)([CH3:48])[C:50]([NH:52][CH2:53][C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]1[CH2:69][CH2:68][O:67][CH:66]1[OH:70])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])=[O:51]
Reactant: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)C(C)(C)Oc1ccc2c(c1)Nc1ccccc1S2
Agent: CC(C)C[C@H](NC(=O)c1ccc2c(c1)Nc1ccccc1S2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CCOC1O
Product: CC(C)C[C@H](NC(=O)CNC(=O)C(C)(C)Oc1ccc2c(c1)Nc1ccccc1S2)C(=O)N[C@H]1CCOC1O

Procedure:
The experimental protocol is the same as that described for the compound of Example 2, starting with the compound of Example 59 instead of the compound of Example 1. A beige solid is obtained. Melting point: 127-128° C.
Reaction SMILES: [CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>CCOCC>[CH2:10]=[CH:11][CH2:12][CH:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CC[Mg]Br
Reactant: CCCCCCCC=O
Solvent: CCOCC
Product: C=CCC(O)CCCCCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of 1.2 mL (7.8 mmol) of octanal in 30 mL of ether was added 15.6 mL of a 1.0 M solution of allylmagnesium bromide in ether. The reaction was allowed to stir at room temperature for 18 h and then quenched with saturated NH4Cl. The product was extracted with ether (2×20 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography to give 0.79 g (60%) of the allylic alcohol. 1H NMR (400 MHz, CDCl3) δ 5.80-5.70 (m, 1H), 5.04-4.99 (m, 2H), 3.53 (m, 1H), 2.52 (br s, 1H), 2.20-2.05 (m, 2H), 1.381-34 (m, 2H), 1.25-1.15 (m, 10H), 0.80 (t, J=7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 133.6, 116.3, 70.6, 42.5, 37.5, 32.7, 30.6, 30.2, 26.7, 23.7, 15.2.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Br.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>O>[CH2:13]([NH:20][C:3]1[CH:4]=[CH:5][C:9]2[CH2:10][C@H:11]3[C@@H:6]([CH2:5][CH2:4][CH2:3][N:2]3[CH2:7][CH2:6][CH3:11])[CH2:7][C:8]=2[N:2]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: c1ccc2ncccc2c1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(NCc4ccccc4)ccc3C[C@@H]21
Temperature: 240 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido2,3-g]quinoline hydrochloride (2.27 g, 7.50 mmol) and benzylamine hydrobromide (15.0 g) was heated to 240° C. to form a brown, molten semi-solid. After 15 minutes, the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give a brown oil. Purification by flash chromatography (6% methanol in methylene chloride, NH4OH) provided (±)-trans-2-benzylamino-6-propyl-5,5a, 6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline (Rf=0.35, 561 mg, 22% yield) as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:11][NH:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:11][N:12]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: CNC
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)CCc1ccccc1

Procedure:
2-Phenylethyl bromide [0.01 mol.] and dimethylamine hydrochloride [0.02 mol.] are stirred at room temperature [24 hrs] and then refluxed [1 hr.] with potassium carbonate [0.06 in methanol. The insoluble materials are filtered and the solution evaporated and distilled to form N,N-dimethyl-2-phenylethylamine. The hydrochloride salt [m.p. 163-4° C.] is formed and recrystallized from ethanol. The structure was confirmed by its proton nmr spectrum, by its chemical ionization mass spectrum, and its correct elemental analyses.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCC[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-bromo-3-phenylpropane and 2-(2-amino -thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[CH:55](=[O:64])/[CH:56]=[CH:57]/[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[C@H:15]([CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:34])([CH3:36])[CH3:35])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:55]([OH:64])[CH:56]=[CH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: CC(C)(C)[Si](OCCCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@H](O)C=Cc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
To a stirring solution of (R)-4-benzyl-3-[5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-oxazolidin-2-one (1.64 g, 3.19 mmol) in dry methylene chloride (15.9 mL) in a flame dried round bottom flask under N2 at 0° C. was added titanium(IV) chloride (386 μL, 3.51 mmol). After 5 min, (−)-sparteine (1.83 mL, 7.97 mmol) was added. After 20 min, trans-cinnamaldehyde (442 μL, 3.51 mmol) was added dropwise to the purple suspension, and the resulting pale green-yellow solution was stirred for 1 h. The reaction was quenched by the addition of 50% saturated ammonium chloride (50 mL), diluted with water (100 mL), and then extracted with methylene chloride (3×30 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, 15-30% ethyl acetate in hexanes) to yield 1.72 g (83.1%) of the desired product as a white solid. MS (APCI), m+/z: (M+H)+=648.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:22](F)=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]>O>[F:12][C:13]1[C:14]([C:22]([O:4][CH:2]([CH3:3])[CH3:1])=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]
Reactant: O=C(F)c1nc(F)c(F)c(F)c1F
Reactant: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1nc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added drop-wise at room temperature to the 3,4,5,6-tetrafluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight, poured into a reparatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.454 g (48% yield, 96% GC purity, 93% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,4,5,6-tetrafluoropicolinate: 70 eV EIMS (GC) m/z=196 (31%), 178 (100%), 150 (45%), 100 (26%), 43 (34%). 1H NMR (400 MHz, CDCl3) δ 5.32 (hept, J=6.3 Hz, 1H), 1.42 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 159.81 to 159.74 (m), 149.22 to 148.78 (m), 148.04 to 147.86 (m), 146.49 to 146.10 (m), 145.65 to 145.47 (m), 138.53 (dd, J=34.3, 11.2 Hz), 135.79 (dd, J=34.4, 11.2 Hz), 129.02 to 128.74 (m), 70.97 (s), 21.60 (s). 19F NMR (376 MHz, CDCl3) δ −80.31 to −80.49 (m), −136.04 to −136.18 (m), −137.10 to −137.25 (m), −149.81 to −149.95 (m).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.6 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 1.00 g (7.40 mmol) of 6-fluoroindole in 10 mL of dry dimethylformamide is reacted with 0.335 g (8.88 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.553 mL (8.88 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature 15 h. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 0.525 g of the title compound, 48% yield. MS, ES=; 1H NMR (DMSO-d6) δ 7.523-7.488 (m, 1H); 7.300-7.292 (m, 2H); 6.852-6.825 (m, 1H); 6.411-6.409 (m, 1H); 3.767 (s, 3H) ppm.