Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:12]([CH2:15]C)CC)C.[OH2:17].N>O1CCCC1>[C:1]1([C@H:7]([NH:9][C:15]([NH2:12])=[O:17])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCN(CC)CC
Reactant: O
Agent: N
Solvent: C1CCOC1
Product: C[C@@H](NC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (1R)-1-phenylethylamine (1 g) and triethylamine (1.15 ml) in tetrahydrofuran (25 ml) solution, 4-nitrophenylchlorocarbonate (1.66 g) was added at −20° C. and the mixture was stirred at room temperature for 30 minutes. Further, 28% ammonia water (4 ml) was added to the reaction solution and the mixture was stirred at room temperature for 30 minutes. The tetrahydrofuran was distilled off in vacuo, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with 2N sodium hydroxide aqueous solution, distilled water, saturated potassium hydrogensulfate aqueous solution, and saturated saline and dried over with anhydrous sodium sulfate, then concentrated. The residue was recrystallized from ethyl acetate/hexane to obtain the title compound (860 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:18][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc(C)c(COc2cccnc2N)c(C)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(C)c1

Procedure:
A mixture of 2-amino-3-(2,4,6-trimethylbenzyloxy)pyridine (2.00 g, 0.0082 mol), 4chlorophenyl isothiocyanate (1.68 g, 0.0099 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.37 g (70%), m.p. 180°-182 ° C.
Reaction SMILES: Cl(O)(=O)(=O)=O.[C:6]1([CH3:24])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[S:14]([O:17][N:18]=C(OCC)C)(=[O:16])=[O:15].O>C1COCC1>[C:6]1([CH3:24])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[S:14]([O:17][NH2:18])(=[O:16])=[O:15]
Reactant: CCOC(C)=NOS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
70% aq. perchloric acid (4.34 g, 2.6 ml, 43.2 mmol, Eq: 4.12) was added to ethyl N-mesitylsulfonyloxyacetimidate (2.99 g, 10.5 mmol, Eq: 1.00) in THF (4 ml) at 0° C. The reaction mixture was stirred for 1 h at 0° C. The mixture was poured into water (60 ml) and extracted with CH2Cl2 (20 ml+2×10 ml). The combined organic layers were dried over Na2SO4. The solution was used without further purification in the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[O:12]>>[NH2:1][CH:2]([CH:11]([OH:12])[C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: O=Cc1ccco1
Reactant: NCC(=O)O
Product: NC(C(=O)O)C(O)c1ccco1

Procedure:
The substrate solution was prepared by dissolving glycine (14.0 mg, 0.186 mmol) and furaldehyde (15.5 μL, 0.187 mmol) in buffer (10.0 mL). When 360 μL of this was added to the enzyme solution (0.2 mg SHMT in 40 μL), the concentration of each substrate was 17 mM.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=N/S(C2SC=CC=2)(=O)=O)/[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:32]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:12])[C:2]([Cl:1])=[CH:3]2)(=[O:30])=[O:31])=[CH:27][CH:28]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Solvent: C1CCOC1
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2ccc(Cl)cc2)c2ccccc21

Procedure:
5.2.34 4-chloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)benzenesulfonamide (12e) was prepared according to the procedure for 12a except using 4-chlorobenzenesulfonamide, TiCL4.2THF and THF as solvent which afforded the title compound 452.2 mg (61.8%) as a yellow solid, m.p.: 138-140° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]6[CH:27]=[CH:26][N:25]([CH2:28][C:29]([O:31]C(C)(C)C)=O)[N:24]=6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:36][NH:37][CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:36][N:37]([CH3:38])[C:29](=[O:31])[CH2:28][N:25]1[CH:26]=[CH:27][C:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:13][CH2:12]4)=[CH:15][N:16]=3)[CH:19]=2)=[N:24]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Cn1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Cn1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-ylacetate (10 mg, 0.02 mmol) in trifluoroacetic acid (0.5 mL) and methylene chloride (0.5 mL) was stirred overnight at RT. The volatiles were removed under reduced pressure. The residue [LCMS: (M+H)=411.0] was dissolved in N,N-dimethylformamide (0.5 mL) and treated with dimethylamine (2M in THF, 0.016 mL, 0.032 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11 mg, 0.026 mmol), and N,N-diisopropylethylamine (11 μL, 0.064 mmol). The reaction mixture was stirred overnight at RT, and then purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=438.1.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.C(OP([CH:21]([CH3:27])[C:22]([CH:24]1[CH2:26][CH2:25]1)=O)(=O)OCC)C.O.[NH2:29][NH2:30]>>[CH:24]1([C:22]2[C:21]([CH3:27])=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:30][N:29]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: CCOP(=O)(OCC)C(C)C(=O)C1CC1
Reactant: NN
Solvent: O
Product: Cc1c(C2CC2)nnc2c1[C@@H]1CC[C@@]2(C)C1(C)C

Procedure:
light yellow solid. MS (EI): 242.2 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo [2.2.1]heptane-2,3-dione, (2-Cyclopropyl-1-methyl-2-oxo-ethyl)-phosphonic acid diethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]1([CH2:32][O:33][CH3:34])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2([CH2:32][O:33][CH3:34])[CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: COCC1(CBr)CC1
Product: COCC1(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 1-bromomethyl-1-methoxymethyl-cyclopropane (described in WO 2001032633) gave the title compound. ES-MS m/e (%): 465.5(M+H+).
Reaction SMILES: [C:1]([O:5][CH2:6]C)(=[O:4])[C:2]#[CH:3].C(N(CC)CC)C.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].CCOCC>C1COCC1>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Br:15]
Reactant: Oc1ccccc1Br
Reactant: C#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C=COc1ccccc1Br
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a stirring solution of 972 mg (11.56 mmol) of ethyl propiolate in 20 mL of THF at 0° C. is added a solution of 1.61 mL (11.56 mmol) of triethylamine in 5 mL of THF, followed by a solution of 2.0 g (11.56 mmol) of 2-Bromophenol in 5 mL of THF. The resulting clear orange-brown solution is stirred 5 h at 0° C., then poured into 100 mL of Et2O and extracted with H2O (1×100 mL). The organic layer is separated and washed with sat. Na2CO3 (1×100 mL), dried (MgSO4), and the solvent removed in vacuo to provide 2.97 g of the title compound as an orange oil which is used without any further purification: 1H NMR (CDCl3, 300 MHz) δ7.71 (d, 1H, J=12.3), 7.61 (d, 1H, J=7.4), 7.37-7.08 (m, 3H), 5.47 (d, 1H, J=12.3), 3.72 (s, 3H); Rf =0.40 in hexane/EtOAc 5/1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]C(C#N)[C:6]=2[CH:21]=1.[OH-:22].[K+].[CH2:24]([OH:27])[CH2:25]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C@H:25]([C:24]([OH:27])=[O:22])[C:6]=2[CH:21]=1
Reactant: N#CC1CC(CCc2ccccc2)Oc2ccc(F)cc21
Reactant: [OH-]
Reactant: OCCO
Agent: [K+]
Product: O=C(O)[C@H]1C[C@H](CCc2ccccc2)Oc2ccc(F)cc21

Procedure:
2,3-dihydro-6-fluoro-4-cyano-2-(2-phenylethyl)-4H-1-benzopyran (2.7 gm) and solid KOH (2.7 gm) were suspended in ethylene glycol (100 mL) and heated under reflux for 1.5 hours, then poured onto ice/H2O (300 mL), and extracted with diethyl ether, and the organic extracts discarded. The aqueous layer was acidified to pH 1 with 6N HCl, and extracted with ethyl acetate, and the extracts washed with H2O, brine, dried, filtered and evaporated to yield the title compound (2.9 gm, m.p. 105°-108° C.).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:10][C:11]([S:15][CH3:16])=[N:12][C:13]=1O)#[N:7].CN(C)C1C=CC=CC=1.O>O1CCOCC1>[Cl:3][C:13]1[N:12]=[C:11]([S:15][CH3:16])[N:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:8]=1[C:6]#[N:7]
Reactant: COc1cccc(-c2nc(SC)nc(O)c2C#N)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2nc(SC)nc(Cl)c2C#N)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (0.75 ml) was added to a stirred solution of 5-cyano-4-(3-methoxyphenyl)-2-methylthio-6-hydroxy-pyrimidine (example 1a, 305 mg) in dry 1,4-dioxane (1 ml). A drop of N,N-dimethylaniline was added. After 3 h at 80° C., the mixture was cooled to 0° C. in an ice bath and crushed ice was slowly added. After cessation of the exothermic reaction, H2O (3 ml) was added. The solids were collected by filtration and dried in vacuo.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:36])[CH2:29][CH2:30][C:31]([O:33]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][NH2:38].[C-]#N.[Na+]>CCO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:36])[CH2:29][CH2:30][C:31]([NH:38][CH3:37])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reactant: CN
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)CCC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Temperature: 50 °C
Yield: 83 %

Procedure:
A solution of (S)-ethyl 4-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-4-oxobutanoate (124 mg, 0.25 mmol) in a ˜33% methylamine solution in EtOH (5 mL) was treated with catalytic amount of sodium cyanide and allowed to heat at 50° C. for 3 days. The reaction mixture was then evaporated, washed with water and air dried to afford the title compound as a colorless foam (100 mg, 83%). LC/MS (Method B) 3.23 min, [M+1]+ 480.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[CH3:9][C:10]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:16][CH2:17][CH:18]=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O.C(O)C>[OH:8][N:7]=[CH:18][CH2:17][CH2:16][C:10]([CH3:9])([S:20]([CH3:23])(=[O:22])=[O:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: NO
Reactant: CCOC(=O)C(C)(CCC=O)S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(CCC=NO)S(C)(=O)=O
Reaction time: 15 h
Yield: 98 %

Procedure:
Sodium bicarbonate (2.29 g, 27.3 mmol, 1.05 equiv) was added to a solution of hydroxylamine hydrochloride (1.94 g, 27.3 mmol, 1.05 equiv) in water (100 mL) at room temperature. After the evolution of gas ceased (approx. 30 min), a solution of ethyl 2-methyl-2-(methylsulfonyl)-5-oxopentanoate (6.14 g, 26.0 mmol, 1.0 equiv) in ethanol (100 mL) was added dropwise over 30 min, and the reaction was allowed to stir overnight (approx. 15 h). The reaction mixture was concentrated under reduced pressure to half the volume (approx. 100 mL) and partitioned between dichloromethane (200 mL) and water (100 mL). The aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the title compound (6.4 g, 97%, approx. 1:1 mixture of E/Z isomers). MS (LCMS) m/z 252.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ1.34 (td, J=7.12, 1.17 Hz, 6H) 1.56-1.72 (m, 6H) 2.11-2.19 (m, 2H) 2.19-2.29 (m, 1H) 2.44 (d, J=3.71 Hz, 4H) 2.51-2.63 (m, 1H) 3.06 (d, J=2.93 Hz, 6H) 4.30 (qd, J=7.12, 3.22 Hz, 4H) 6.66-6.88 (m, 1H) 7.43 (d, J=5.07 Hz, 1H).
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[C:22]([NH:29]CCCN)(OC(C)(C)C)=O>>[NH2:29][CH2:22][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)NCCCN
Product: NCCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 3-(Boc-amino)-propylamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 316 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (1H, br. s.) 10.84 (1H, s) 8.66 (1H, t, J=5.56 Hz) 8.04 (1H, d, J=6.83 Hz) 7.87 (3H, d, J=5.27 Hz) 7.36-7.42 (1H, m) 7.30 (1H, d, J=5.27 Hz) 6.81 (1H, br. s.) 6.67 (1H, d, J=7.03 Hz) 3.23 (2H, q, J=6.44 Hz) 2.66-2.82 (2H, m) 1.67-1.81 (2H, m)
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2.C[C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=O.[CH2:38](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.CCCCCC>[CH3:24][O:23][C:14]1[CH:15]=[C:16]([O:19][CH2:20][O:21][CH3:22])[CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][O:1][C:31](=[O:33])[C:30]2[CH:29]=[CH:37][C:36]([CH3:38])=[CH:35][CH:34]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:26])([CH3:25])[CH:6]=[C:5]2[CH3:27]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCCP(CCCC)CCCC
Reactant: COCOc1ccc(-c2ccc3c(c2CO)C(C)=CC(C)(C)N3)c(OC)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)cc2)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
5-Hydroxymethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 1, 1.00 g, 2.71 mmol), 2-methylbenzoic acid (739 mg, 5.43 mmol), tri-n-butylphosphine (1.35 mL, 5.40 mmol), and 1,1′-(azodicarbonyl)dipiperidine (1.37 g, 5.43 mmol) were dissolved in anhydrous benzene (30 mL), and then the mixture was stirred under argon atmosphere at room temperature overnight. Hexane (30 mL) was added to the reaction mixture, and then the unsoluble materials were filtered out. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (967 mg) as a colorless amorphous product. (Yield 73%)
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([OH:18])=O)[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.C[O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25]>>[CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([C:24]([NH2:25])([CH3:26])[C:23]([OH:27])=[O:22])=[O:18])[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)C(C)(N)C(=O)O)nc(Cl)c2c1

Procedure:
Analogously to Example A-56, 0.040 g of 7-isopropoxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid were allowed to react with 0.020 g of L-Alanine methyl ester hydrochloride to give, after hydrolysis of the intermediate ester, 0.047 g of a white solid: MS-(−)-ion, M−1=353.1 amu.
Reaction SMILES: [CH3:1][C:2]([OH:12])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[CH3:3].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22].[CH2:25]1C[O:28][CH2:27][CH2:26]1>CN(C)C1C=CN=CC=1>[C:20]([O:12][C:2]([CH3:1])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:11])([O:10][C:27](=[O:28])[CH:26]=[CH2:25])[CH3:9])[CH3:3])(=[O:23])[CH:21]=[CH2:22]
Reactant: C=CC(=O)Cl
Reactant: C1CCOC1
Reactant: CC(C)(O)CCCCC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(C)(C)CCCCC(C)(C)OC(=O)C=C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 300-mL three-necked round-bottom flask fitted with nitrogen inlet, magnetic stirrer, and a dropping funnel, 8.7 g (0.05 mol) of 2,7-dimethyl-2,7-octanediol prepared as in Background Example 1, 16.7 mL (0.12 mol) of triethylamine (Fisher), 1.46 g (0.012 mol) of 4-(dimethylamino) pyridine (Aldrich), and 80 ml of dry THF were added under nitrogen atmosphere, and the solution was cooled to 0° C. The mixture of 10.8 g (0.12 mol) of distilled acryloyl chloride (Aldrich) and 20 mL of dry THF was added dropwise. After 2 hours of stirring, the reaction vessel was allowed to warm to room temperature and stirring was continued overnight. Precipitated salts were removed by filtration. A 150 mL volume of diethyl ether was added to the filtrate, and the resulting precipitate was also removed by filtration. The reaction mixture was washed with distilled water and dilute aqueous sodium bicarbonate and was dried with anhydrous magnesium sulfate. Evaporation of the solvents gave an oily residue, which was then purified by column chromatography (silica gel/hexanes). A colorless oily liquid was obtained, yield 3.2 g (23%). 1HNMR(CDCl3), δ from TMS: 1.29 [m, 4H —CH2CH2C(CH3)2O—], 1.42 [s, 12H, —C(CH3)2O—], 1.74 [m, 4H, —CH2CH2C(CH3)2O—], 5.66, 6.25 [m, 4H, CH2═CH—]. 5.98 [m, 2H, CH2═CH—]. IR (film): 2978, 2943, 2868 cm−1(C—H stretch); 1722 cm−1(C═O stretch); 1636, 1620 cm−1(C═C stretch); 1299, 1205 cm−1(C—O—C stretch); 985 cm−1(═CH wag); 964 cm−1(═CH2 wag); 812 c−1(═CH2 twist).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH:11]=[CH:10][C:6]=1[C:7]([O-:9])=O.[Li+].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[N:38][CH:39]=1>C(Cl)Cl.CN(C=O)C>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH:48][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]3([CH3:19])[O:18][CH2:17][CH2:16][O:15]3)=[CH:13][C:5]=2[O:4][CH2:3][O:2][CH3:1])=[N:38][CH:39]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: COCOc1cc(C2(C)OCCO2)ccc1C(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCOc1cc(C2(C)OCCO2)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a suspension of lithium 2-(methoxymethoxy)-4-(2-methyl-1,3-dioxolan-2-yl)-benzoate (0.08 g, 0.29 mmol) in CH2Cl2 (2 mL) at 0° C. was added DMF (2 drops) followed by oxalyl chloride (0.025 mL, 0.29 mmol). Vigorous bubbling occurred. The reaction was stirred at room temperature for 30 min and then the solvent was removed under reduced pressure. The residue was suspended in CH2Cl2 (10 mL) and cooled to 0° C. Pyridine (0.07 mL, 0.87 mmol) and N-(5-chloropyridiri-2-yl)-2-aminobenzamide (0.072 g, 0.29 mmol) were added and the reaction was stirred at room temperature for 6 h. The reaction was quenched with H2O:EtOAc (10 mL each) and extracted with EtOAc (3×30 mL). The organic solution was washed with 2 NHC (cold), H2O (10 mL), 2 N NaOH (cold) and H2O (10 mL), dried (Na2 SO4), and concentrated. The resulting residue was purified by silica gel flash chromatography (n-hexanes through 30% EtOAc/n-hexanes) to obtain the desired product (0.110 g, 76%); TLC Rf: 0.42 (40% EtOAc/n-hexanes).
Reaction SMILES: [CH2:1]([N:4]=[C:5]([NH2:15])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)[CH2:2][CH3:3].I([O-])(=O)(=O)=[O:17].[Na+].CCOC(C)=O.CO>CO.O>[CH2:1]([N:4]=[C:5]([NH2:15])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:14])=[O:17])[N:8]=1)[CH2:2][CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCN=C(N)Nc1ccnc(SC)n1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN=C(N)Nc1ccnc(S(C)=O)n1

Procedure:
A solution of 4-(2-propylguanidino)-2-methylthiopyrimidine (1.6 g.) in MeOH (25 ml.) was heated on a steam bath while a solution of sodium metaperiodate (1.6 g.) in water (15 ml.) was added dropwise over 15 minutes. Further sodium metaperiodate in water (10% w/v) was added until analysis by t.l.c. on silica using EtOAc/MeOH 4:1 v/v as eluant showed absence of starting material. The reaction mixture was evaporated in vacuo, and the residue partitioned between methylene chloride and water. The organic phase was worked up to give 4-(2-propylguanidino)-2-methylsulphinylpyrimidine, m.p. 179°-180°.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])(C)(C)C.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(CCCCCN)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@@H]1CCN(CCCCCNC(=O)Nc2ccccc2)C1

Procedure:
5-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-pentylamine (1.52 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isocyanate (0.58 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.75 g) to give 4-amino-5-chloro-2-methoxy-N-((3S)-1-(5-(3-phenylureido)pentyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[O:4]1.[C:21]1(C)[CH:26]=[CH:25][C:24]([S:27](O)(=O)=O)=[CH:23][CH:22]=1.C1(S)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:10]1[CH2:9][CH2:8][C:5]2([O:4][CH:3]([CH2:2][S:27][C:24]3[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=3)[CH2:7][O:6]2)[CH2:12][CH2:11]1)[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Sc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CCN2CCC3(CC2)OCC(CSc2ccccc2)O3)cc1

Procedure:
2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (Compound 1, 50 gm, 0.18 mole) and Para Toluenesulfonic Acid (PTSA, 2 gm) were dissolved in toluene (350 ml) at room temperature. 20 gm of thiophenol was added drop wise to the above solution. The reaction was refluxed for 13 hrs at reflux temperature. The solvent was distilled off to get the light brown solid product with a melting point of 58° C. The yield of the product was 95%.