Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:17]([Cl:18])=[C:16]([CH3:19])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:22][CH3:23])[C:12]([O:20][CH3:21])=[N:13]2.N1C=CC=CC=1>ClCCl>[Cl:18][C:17]1[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:19])[N:13]=[C:12]([O:20][CH3:21])[C:11]([O:22][CH3:23])=[N:10]2
Reactant: COc1nc2cc(C)c(Cl)c(N)c2nc1OC
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)Nc1c(Cl)c(C)cc2nc(OC)c(OC)nc12
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Methoxyacetylchloride (2.16 mL, 2.57 g, 23.66 mmol) was added to a solution of 5-amino-6-chloro-2,3-dimethoxy-7-methylquinoxaline (Preparation 113, 5 g, 19.72 mmol) and pyridine (1.91 mL, 1.89 g, 23.66 mmol) in dichloromethane (80 mL) at 0° C. After a further 1 hour at this temperature, the mixture was washed with 2M aqueous hydrochloric acid solution, brine, dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with diisopropyl ether and filtered to give 6-chloro-2,3-dimethoxy-5-methoxyacetamido-7-methylquinoxaline (6.06 g, 98%) as an off white solid, mp 170-171° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([Br:38])[CH:32]=2)=[CH:27][CH:26]=1)[C:9]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[CH2:20][CH2:21][CH2:22][CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:40][C:41]#[N:42].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:40][C:41]#[N:42])=[C:33]([Br:38])[CH:32]=2)=[CH:29][CH:30]=1)[C:9]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[CH2:20][CH2:21][CH2:22][CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 68.6 %

Procedure:
A mixture of N-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-1-benzofuran-3-carboxamide (1.5 g, 2.64 mmol), prepared in the previous step, bromoacetonitrile (220 μL, 3.16 mmol) and potassium carbonate (1.862 g, 13.5 mmol) in 75 mL of DMF was stirred under nitrogen at room temperature for 23 h. The reaction was partitioned between methylene chloride and water. If an emulsion forms saturated NaCl can be added to separate it. The organic layer was separated, extracted multiple times with water, dried (MgSO4), and the solvent removed under reduced pressure to give N-benzyl-N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-2-butyl-1-benzofuran-3-carboxamide (1.1 g, 69%) as a yellow oily solid, MS (ESI) m/z 607 [M+H]+. Elemental Analysis for C35H31BrN2O3: Calc'd: C, 69.19; H, 5.14; N, 4.61; Found: C, 67.76; H, 5.44; N, 4.29
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[CH:11][C:5]=2[CH:4]2[O:14][CH:3]12.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].[H-].[Na+].O>CS(C)=O>[CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[CH:11][C:5]=2[C@@H:4]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[C@@H:3]1[OH:14]
Reactant: CC1(C)Oc2ccc(C=O)cc2C2OC21
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2ccc(C=O)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-formyl-2H-benzo[b]pyran (0.48 g, prepared using the method described in U.K. Pat. No. 1.511.187) and 2-pyrrolidone (0.20 g) in dry dimethyl sulphoxide (30 ml) was added sodium hydride (0.07 g, 80% dispersion in oil). After stirring at room temperature for 4 hours, water was added and the aqueous phase immediately extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulphate. Filtration, evaporation and chromatography (chromatotron, pentane-ethyl acetate gradient elution, 2 mm silica gel) gave a fraction (150 mgs) which was recrystallised to give the title compound as crystals (80 mgs) of m.p. 196°-197.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:48][N:49]1[CH2:54][CH2:53][CH2:52][C:51]([NH2:61])([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:50]1>CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:61][C:51]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:52][CH2:53][CH2:54][N:49]([CH3:48])[CH2:50]1)=[O:6]
Reactant: CN1CCCC(N)(c2ccccc2)C1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCCC(NC(=O)c2cccc(C(F)(F)F)c2Cl)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.9 %

Procedure:
To a solution of 33 mg (0.144 mmol) 2-chloro-3-(trifluoromethyl)benzoic acid (commercial), 75 mg (0.197 mmol) HATU and 90 ul (0.524 mmol) N-ethyldiisopropylamine in DMF (1 ml) was added a solution of 25 mg (0.131 mmol) rac-1-methyl-3-phenyl-piperidin-3-ylamine (Example A.1) in DMF (0.25 ml). The mixture was stirred at room temperature for 22 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed once with water and twice with a saturated sodium carbonate solution. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 27 mg (52%) of the title compound as a light yellow oil. MS (m/e): MS (m/e): 397.2 (M+H)
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10](NC(CC3SC=CC=3)=O)[C:11](=O)[N:8]2[C:7]=1C([O-])=O)=O.[Na+].C(=O)(O)[O-:29].[Na+].[N-]=[N+]=[N-].[Na+]>O>[N:8]12[CH2:11][CH2:10][CH:9]1[S:22][CH2:23][C:6]([C:5]([OH:4])=[O:29])=[CH:7]2
Reactant: O=C([O-])O
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1=CN2CCC2SC1
Temperature: 50 °C

Procedure:
A solution of commercial cephalothin sodium salt (5.0 g), sodium bicarbonate (1.06 g), sodium azide (0.82 g) and water. (75 ml) is heated at approximately 50° C. (122° F.) until TLC (thin layer chromatography) shows the starting material is consumed. The reaction is cooled to approximately 3° C. (37° F.), covered with ethyl acetate and acidified with 1N HCl . The ethyl acetate extract is dried over Na2SO4, filtered and the filtrate is concentrated to dryness to give [6R[6a,7B]]-3-(azidomethyl)-8-oxo-7-](2-thienylacetyl) amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-carboxylic acid. A mixture of this azido intermediate (1.0 g), 10% Pd/C (1.0 g), NaHCO3 (1.54 g) and 75% methanol/H2O is subjected to hydrogenation at room temperature until TLC shows the disappearance of starting azide. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is dissolved in water, acidified with 1N HCl and the solution is washed with CHCl3. The aqueous phase is concentrated to dryness and the crude product is purified using 50W-X4 cation exchange resin to give product (II).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.CCOCC>CN1CCCC1=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C1CSCCN1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCSCC3)c(F)c21
Reaction time: 2 h

Procedure:
A 289 mg portion of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in 3 ml of 1-methyl-2-pyrrolidone. A 350 mg portion of thiomorpholine was added and the mixture was stirred for 2 hours. Ether was added, the solid collected and recrystallized from acetone, giving 250 mg of the desired product as a white solid, mp 308°-310° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-])=O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)([O-])=O.[Sn](Cl)Cl>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([NH2:17])=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)[nH]c1cc([N+](=O)[O-])ccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)[nH]c1cc(N)ccc12
Yield: 78.3 %

Procedure:
To a solution of compound 3 (6.00 g, 23.3 mmol) in a mixture of acetic acid (200 mL) and hydrochloric acid (35 mL) was added 44.3 g (0.024 mol, Aldrich Co.) of tin(II) chloride. The mixture was refluxed for 24 h under argon. After cooling, the precipitate was separated from the solvent by filtration and washed several times with cold acetic acid. The resulting diammonium salt was dissolved in water followed by addition of an aqueous solution of sodium hydroxide until the pH was around 10. The precipitate was collect by filtration and dried under vacuum. Recristallization in ethanol afforded 3.60 g of the title product as a shiny gray solid. M.P. 248° C. (dec.). (Yield: 78%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10]O)[CH2:4][CH2:3]1.[C:12]([NH:19][C:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:20]([NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[N:19][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:7]1
Reactant: CN1CCC(CCCO)CC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CN1CCC(CCCN(C(=O)OC(C)(C)C)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100 mL, 3-neck, round bottom flask were added 3-(1-methyl-piperidin-4-yl)-propan-1-ol (1.91 g, 0.012 mol), Polymer Labs (Varian) PL-TPP resin (9.83 g, 0.014 mol), N,N′,N″-tri-Boc-guanidine (4.36 g, 0.012 mol) and THF (anhydrous, 100 mL). The resultant mixture was stirred and cooled to 2° C., at which time DEAD (2.53 g, 0.014 mol) was added drop wise over 10 min. Upon completion of addition, the flask was warmed to room temperature, aged for 4 h and filtered to remove the resin bound oxide. The resultant cake was rinsed with THF (25 mL) and heptane (2×25 mL). The filtrates were combined, extracted with saturated aqueous NaHCO3 (2×25 mL), dried over anhydrous MgSO4, filtered and concentrated. The resultant residue was triturated in hot ethanol (25 mL), cooled to room temperature and filtered. The filtrate was concentrated to yield N-[3-(1-methylpiperidin-4-yl)-propyl]-N,N′,N″-tri-Boc-guanidine.
Reaction SMILES: [N:1]1[C:2]2[N:3]([C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH:4]=[CH:5][CH:6]=1.[ClH:14]>[Pd]>[ClH:14].[NH:1]1[CH2:6][CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=[C:2]12
Reactant: c1ccc2c(c1)nc1ncccn12
Agent: [Pd]
Agent: Cl
Product: c1ccc2c(c1)nc1n2CCCN1

Procedure:
0.602 g benzimidazo[1,2-a]pyrimidine hydroperchlorate was heated for 9 h in a hydrochloric acid solution (2 M HCl) with palladium on activated charcoal, with H2 fed in. Subsequent filtration, removal of the solvent and addition of diethyl ether yielded the 1,2,3,4-tetrahydro-benzimidazo[1,2-a]pyrimidine hydrochloride in the form of colorless crystals, which were recrystallized from ethanol.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]#[C:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1
Reactant: C#CCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(1-butyn-4-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[N:30]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:29]=[N:28][N:27]=1>>[CH:11]1[C:2]([O:1][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[N:29]=[N:28][N:27]=2)=[CH:3][C:4]2[CH2:5][CH2:6][C:7]([NH:8][C:9]=2[CH:10]=1)=[O:12]
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: ClCCCCc1nnnn1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Reaction time: 5 h
Yield: 84.8 %

Procedure:
A mixture of 10 grams of 6-hydroxy-3,4dihydroquinolin-2(1H)-one (Compound I, 0.0613 mole), 4.05 grams of flaked potassium hydroxide (0.0650 mole) and 1.5 grams of K2CO3 (0.011 mole), was stirred in 130 ml of 1-botanol in a flask equipped with a soxhlet extraction apparatus containing 28 grams of 3 Å molecular sieves. The mixture was heated to reflux while passing the solvent over the molecular sieves for 30 minutes. Thereafter 18 grams of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole (Compound II, 0.0742 moles, which are 1.2 equivalents with respect to Compound I) were added and the reflux was allowed to continue for about 5 hours. The reaction mixture was cooled thereafter to room temperature, and the solid product was collected by filtration, washed with 1-butanol and water and dried at 50° C. overnight to afford 19.2 grams of crude Cilostazol at 70.0% yield.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([Cl:34])[CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:29]([C:28]3[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:17]4[C:16]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:26][C:27]=3[Cl:34])=[O:30])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)c(Cl)c1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 66, reaction of 0.198 g of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine with 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in dichloromethane in the presence of N,N-diisopropylethylamine gives the product as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[O:32])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:12][CH:13]=2)[C:8](=[O:37])[C:7]([C:38](OCC)=[O:39])=[CH:6]1.[CH2:44]([CH2:46][NH2:47])[OH:45]>>[CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[O:32])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[N:25]=3)=[CH:12][CH:13]=2)[C:8](=[O:37])[C:7]([C:38]([NH:47][CH2:46][CH2:44][OH:45])=[O:39])=[CH:6]1
Reactant: NCCO
Reactant: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCN(C)C)cn1
Product: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NCCO)cn3CCN(C)C)cn1
Temperature: 87.5 °C

Procedure:
A suspension of ethyl 1-(2-(dimethylamino)ethyl)-4-oxo-6-(6-(3-propylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Example 174, 50 mg, 0.09 mmol) in ethanolamine (0.5 mL) was heated to 85-90° C. for 3 h. The reaction mixture was cooled to room temperature and the precipitate that formed was isolated by filtration and washed with acetonitrile and water then dried overnight under high vacuum.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[NH:11])[S:7][CH:8]=1.CN1CCOCC1.[CH3:31][O:32][C:33](Cl)=[O:34]>C1COCC1>[CH3:31][O:32][C:33](=[O:34])[NH:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[NH:11])[S:7][CH:8]=1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(CN)cs1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)NCc1csc(NC(=N)NCc2c(OC)cccc2OC)n1

Procedure:
To 360 mg (1.12 mmol) N-[4-(aminomethyl)-1,3-thiazole-2-yl]-N′-(2,6-dimethoxybenzyl)guanidine hydrochloride, Example 154 free base, in 13.5 ml THF were added 0.2 ml NMM, and 0.1 ml chloroformic acid methyl ester in 1.5 ml THF were added drop-wise with stirring. Following completion of the reaction, the mixture was concentrated, was diluted with dichloromethane, was washed with saturated NaCl solution, was dried and was concentrated. Chromatography of the crude product on silica gel (dichloromethane/methanol 0-1%) yielded 140 mg; ESI-MS [M+H+]=380.05.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].C[O-].[Na+].[C:12](O)(=[O:14])C>CO.CCOCC>[CH3:12][O:14][C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)=[NH:2]
Reactant: CC(=O)O
Reactant: N#Cc1cncnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=N)c1cncnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
To a stirred suspension of 5-cyanopyrimidine (5.0 g, 47 mmol) in methanol (50 mL) was added 25% by weight sodium methoxide in methanol (1.2 g, 23 mmol). The mixture was stirred at room temperature for 17 h under nitrogen atmosphere and then acetic acid (2.72 ml, 47 mmol) was added dropwise. The resulting mixture was stirred for 4 h and then evaporated under reduced pressure to remove methanol and yield a residue. The residue was dissolved in ether (150 mL) and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to yield methylpyrimidine-5-carbimidate (4.9 g, 75% yield). The crude product was used without further purification. 1H NMR (400 MHz, DMSO-d6, δ): 3.83 (s, 3H); 9.18 (s, 2H); 9.30 (s, 1H); 9.54 (s, 1H). ES-MS: [M++1]=138.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1>>[CH2:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[CH2:18][C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: BrCCc1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(CCc2ccccc2)c2ccccc12
Yield: 105.5 %

Procedure:
The same procedures used in Example 7 were repeated except for using 2.00 g of indole-3-carbaldehyde instead of the indole-4-carbaldehyde used in Example 7 and 2.35 g of 2-phenethyl bromide to give 3.34 g of 1-phenethylindole-3-carbaldehyde as a brown oily substance. The yield thereof was found to be 97%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14](=O)[CH3:15])[C:9]2=O)=[CH:5][CH:4]=1.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[CH:13]=[C:14]([CH3:15])[N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:9]=32)=[CH:5][CH:4]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC(C)=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(cc(C)n1C[C@@H](C)O)C2
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
A solution of 1.45 g of (RS)-6-methoxy-2-(2-oxopropyl)-1-indanone and 60 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 90 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.05 g (61%) of (R)-1-(7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow solid with m.p. 110°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.[O:17]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][CH2:32][CH3:33])[CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:31]([C:26]1[CH:25]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)[CH2:32][CH3:33]
Reactant: COC(=O)Cc1ccc(OCCCBr)cc1
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(CC(=O)OC)cc1

Procedure:
A solution of the product from Step A (11.0 g, 38.58 mmol), 4-phenoxy-2-propylphenol (PCT Application WO97/28115; 8.0 g, 35.07 mmol) and cesium carbonate (12.0 g, 36.82 mmol) in DMF (80 mL) was stirred at 40° C. overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with 10% of ethyl acetate in hexane to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12](/[C:11](/[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:14]\[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:20]=1)#[N:13]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 33.8 %

Procedure:
Compound 1 (281 mg) and ethyl chloroacetate (245 mg) were dissolved in acetone, and potassium carbonate was added to the resultant solution, followed by reflux for three hours. The resultant mixture was subjected to filtration, and insoluble matter was removed from the mixture. The resultant filtrate was concentrated to dryness under reduced pressure, followed by recrystallization, to thereby produce the target product (124 mg, yield: 34%).