Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[C:9](=O)[NH:8][C:7]1=[O:18])([CH3:5])[CH3:4].[H][H].[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[CH:3]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:8][C:7]1=[O:18])([CH3:5])[CH3:4]
Reactant: Cc1ccc2c(=O)[nH]c(=O)n(C(C)C)c2c1
Reactant: [H][H]
Reactant: Br[Mg]c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(-c3ccccc3)nc(=O)n(C(C)C)c2c1
Reaction time: 15 h

Procedure:
To a suspension of 1.8 g sodium hydride in 25 ml tetrahydrofurane are added portionwise 13.08 g 1-isopropyl-7-methyl-quinazolin-2,4(1H,3H)-dione under constant release of hydrogen. 40 ml of a 2N solution of phenylmagnesiumbromide in tetrahydrofurane are added dropwise at 40° C. to the clear solution and the resulting suspension stirred at 40° for 15 hours. Water is added and the solvent is evaporated in vacuo. The residue is taken up with methylene chloride and 30 ml 12% hydrochloric acid. The organic layer is concentrated to give the title compound (recrystallized from toluene), m.p. 140°-143°.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C@H:16]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[OH-].[Li+]>C(O)C>[C:32]([O:31][C:29]([NH:28][C@@H:16]([C:7]1[S:8][C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1nc([C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)sc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(=O)O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
2-((1R)-1-(tert-Butoxycarbonylamino)-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid methylester (0.35 g; 0.716 mmol) was dissolved in ethanol (99%; 40 ml) and lithium hydroxide (0.112 g; 4.654 mmol) was added. The reaction mixture was stirred 12 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in water (50 ml) and diethyl ether (50 ml). The solution was made acidic with sodium hydrogensulfate (10%), and the organic phase was dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.185 g of 2-((1R)-1-(tert-butoxycarbonylamino)-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH2:7][CH3:8])[C:4]([OH:6])=[O:5].[CH3:10]O>O1CCOCC1>[NH2:2][C:3]([CH3:9])([CH2:7][CH3:8])[C:4]([O:6][CH3:10])=[O:5]
Reactant: CCC(C)(N)C(=O)O
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: CCC(C)(N)C(=O)OC
Temperature: 50 °C

Procedure:
2-amino-2-methylbutanoic acid HCl salt (20 g, 130.2 mmol) was suspended in 150 mL methanol. A solution of HCL (4M in dioxane was added and the mixture heated to 50° C. overnight. The mixture was cooled to room temperature and evaporated to dryness under vacuum. The resulting isovaline methyl ester (20 g) was used without further purification. 1H NMR (300 MHz, DMSO) δ 3.78-3.64 (m, 1H), 3.61 (s, 3H), 3.54-3.41 (m, 1H), 2.50 (d, J=1.6 Hz, 1H), 1.76 (s, 2H), 1.66-1.35 (m, 2H), 1.17 (s, 3H), 0.77 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH2:34][O:35][CH3:36]>CN(C=O)C>[CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:33][CH2:34][O:35][CH3:36])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20])[CH3:2]
Reactant: COCCBr
Reactant: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(O)c(OC)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OCCOC)c(OC)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-ethylanilino)-7-hydroxy-6-methoxy-3-quinolinecarboxamide (0.22 g, 0.65 mmol), DMF (15 ml), Cs2CO3 (0.64 g, 1.98 mmol), and 2-bromoethylmethylether was stirred at 100° C. for 2 h. The reactionmixture was evaporated and chromatographed on furnishing the title compound (0.045 g, 18%.
Reaction SMILES: C([CH:3]1[C:11]2[C:10]3[C:12](O)=[CH:13][C:14](C(C(C)CCCCC)C)=[CH:15][C:9]=3[O:8][C:7](C)(C)[C:6]=2[CH2:5][CH2:4]1)C.[ClH:28].O1CCN(CCCC(O)=O)CC1>>[ClH:28].[CH2:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][CH2:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(CC)CC1
Agent: Cl
Agent: O=C(O)CCCN1CCOCC1
Product: c1ccc2c(c1)OCC1=C2CCC1

Procedure:
1-Ethyl-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran from Example 30 is reacted with γ-morpholinobutyric acid hydrochloride following the procedure of Example 5 to produce 1-ethyl-4,4-dimethyl-7-(3-methyl-2-octyl)-9-[4-morpholino)butyryloxy]-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](C1C=C2C(=CC=1)NC=C2)=[O:4].[C:14]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](OC(F)(F)F)[CH:24]=2)[N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH:18]=1)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH:18]=[C:17]2[C:14](=[O:16])[CH3:15])=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: COC(=O)c1ccc2c(c1)c(C(C)=O)cn2CC(=O)O

Procedure:
was prepared from 1H-indole-5-carboxylic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS: 276 [M+H]+; tR (HPLC conditions k): 2.84 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][C:34]3([C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37]3)[CH2:33][CH2:32]2)=[CH:28][CH:27]=1>C(#N)C>[N:31]1([CH2:30][C:29]2[CH:45]=[CH:46][C:26]([CH2:25][O:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[CH:27][CH:28]=2)[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37]2)[CH2:33][CH2:32]1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1
Reactant: BrCc1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(CN3CCC4(C=Cc5ccccc54)CC3)cc2)cc1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
To a solution of ethyl(3S)-3-(4-hydroxyphenyl)hex-4-ynate (0.350 g, 1.5 mmol) in acetonitrile (25 mL) is added potassium carbonate (0.621 g, 4.5 mmol) and 1′-[4-(bromomethyl)benzyl]spiro[indene-1,4′-piperidine] (0.77 g, 2.1 mmol). The reaction mixture is heated for 16 hours at 90° C. The mixture is concentrated, diluted with water, and extracted with EtOAc (2×200 mL). The combined extracts are washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated to dryness to give the title compound (0.3 g, 38%). ESI/MS m/z 520 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:39]4[CH2:40][CH2:41][N:36]([C:33](=[O:35])[CH3:34])[CH2:37][CH2:38]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:31])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(=O)N1CCNCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CC(F)(F)C4)C3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and 1-acetylpiperazine. White solid (12%). MS (EI): 598.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].[C:23](OC)(=[O:27])[C:24]([CH3:26])=O>C1(C)C=CC=CC=1>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[N:1]=[C:24]([CH3:26])[C:23]1=[O:27]
Reactant: COC(=O)C(C)=O
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2nc(C)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1

Procedure:
A mixture of ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoate (1.90 g) and methyl pyruvate (0.55 ml) in toluene (15 ml) was heated under reflux for 1 hr. The reaction mixture was concentrated. The residue was washed with methanol and dried to give the object compound (0.50 g) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[O:37]1C2C=CC(C(=O)C)=CC=2[CH2:39][CH2:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]4[O:37][CH2:38][CH2:39][C:2]=4[CH:7]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc5c(c4)CCO5)ccc3c1)n2C1CCCCC1
Yield: 28 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2,3-dihydro-benzofuran-5-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (34 mg, 28% yield). MS: 490.19 (M+H+); HPLC Procedure A, retention time=11.50 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:14][CH2:15][CH2:16][CH:17]=[O:18])[CH2:12][CH3:13]>C1C=CC=CC=1>[CH2:11]([N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:9]([NH:8][C:6]1[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH3:13]
Reactant: CCCNCCC=O
Reactant: CSc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCCN(CCC=O)C(=O)Nc1nnc(SC)s1

Procedure:
A mixture of 5-methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-propylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-propyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.C(N(CC)CC)C.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25]>CC#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:15]([O:14][C:12]([C:4]1[CH:3]=[C:2]([C:25]#[C:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(Br)c2ccccc2n1
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#Cc2ccccn2)c2ccccc2n1
Temperature: 77.5 °C
Yield: 50.3 %

Procedure:
A mixture of ethyl 4-bromoquinoline-2-carboxylate (2.80 g, 10.0 mmol, J. Org. Chem. 1947, 12, 456), triethylamine (1.7 mL, 12 mmol), bis(triphenylphosphine)-palladium(II)chloride (0.561 g, 0.80 mmol), CuI (0.114 g, 0.60 mmol), and 2-ethynylpyridine (1.11 g, 10.8 mmol) in CH3CN (80 mL) is heated at 75-80° C. for 18 h in a sealed tube. Additional triethylamine (0.85 ml, 6.1 mmol), bis(triphenylphosphine)palladium (II) chloride (0.23 g, 0.40 mmol), and CuI (0.055 g, 0.29 mmol) is added and the mixture heated for an additional 18 h. The mixture is concentrated in vacuo and partitioned between water and chloroform. The chloroform extracts are washed with brine and evaporated. The residue is chromatographed on SiO2 (50% ethyl acetate/hexanes) to yield 1.52 g (50%) of a yellow solid. Precipitation from ethyl acetate gave the title compound as yellow crystals: mp 129-131° C.; MS ES+ m/e 303 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([C:7]1[N:15]2[C:10]([C:11]([O:16][CH2:17][C:18](=O)[CH2:19][CH3:20])=[CH:12][CH:13]=[CH:14]2)=[C:9]([CH2:22][C:23]([NH2:25])=[O:24])[C:8]=1[CH2:26][CH3:27])=[O:6].CCOC(C)=O.[CH:37]1[CH:42]=CC=C[CH:38]=1>>[CH2:17]([O:16][C:11]1[C:10]2[N:15]([C:7]([C:5](=[O:6])[C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([Cl:1])[CH:3]=3)=[C:8]([CH2:26][CH3:27])[C:9]=2[CH2:22][C:23]([NH2:25])=[O:24])[CH:14]=[CH:13][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:42]=[CH:37][CH:38]=1
Reactant: c1ccccc1
Reactant: CCC(=O)COc1cccn2c(C(=O)c3cccc(Cl)c3)c(CC)c(CC(N)=O)c12
Solvent: CCOC(C)=O
Product: CCc1c(CC(N)=O)c2c(OCc3ccccc3)cccn2c1C(=O)c1cccc(Cl)c1

Procedure:
2-(3-(m-Chlorobenzoyl)-2-ethyl-8-(2-oxobutyloxy)-indolizin-1-yl)acetamide 18d Mp, 191-192° C. (AcOEt-benzene). 68.4% Yield.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:40](O)(=O)C>CO>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:40])[CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Agent: C=O
Solvent: CO
Product: CN1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 18 h
Yield: 73 %

Procedure:
The 2-[4-tert-butyl-2-(piperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (450 mg, 0.86 mmol) was placed in a dry flask and diluted with dry MeOH (0.95 mL). Paraformaldehyde (54.0 mg, 1.8 mmol) and NaCNBH4 (167.0 mg, 2.7 mmol) were added, followed by acetic acid (0.5 mL). The reaction was allowed to stir for 18 h. More paraformaldehyde (54.0 mg), NaCNBH4 (107.0 mg) and acetic acid (1.0 mL) were added, and the reaction was stirred another 18 hrs under N2 at room temperature. The solvents were removed in vacuo, and the residue was diluted with H2O (5.0 mL). The flask was cooled in an ice bath while the pH was adjusted to 8 using saturated sodium bicarbonate. This solution was extracted with EtOAc (5×90 mL). The organics were combined and washed with a saturated solution of sodium bicarbonate and then brine. The organic layer was dried over MgSO4 and the solvents were removed in vacuo to obtain the desired product as a white solid (338.2 mg, 0.63 mmol, 73%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]2[N:21]3[C:22]4[C:17]([CH:18]([OH:23])[CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:24]I.O>O1CCCC1>[CH3:24][O:23][CH:18]1[C:17]2[C:22]3=[C:13]([N:12]=[C:11]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:21]3[CH2:20][CH2:19]1)[CH:14]=[CH:15][CH:16]=2
Reactant: CI
Reactant: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 49 %

Procedure:
A portion (115 mg) of 60% sodium hydride was added to anhydrous tetrahydrofuran (15 mL) under an argon atmosphere; 0.2 g of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol obtained in Example 4 was dissolved in anhydrous tetrahydrofuran (4 mL) and the solution was added dropwise to the first mentioned solution at room temperature. After stirring for 35 min at room temperature, methyl iodide (1.02 g) was added dropwise and the mixture was stirred for 4 hrs. Water was added to the reaction solution and the mixture was stirred; thereafter, the reaction solution was extracted with dichloromethane, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as a yellow oil (103 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.C[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCOCC1>[O:19]1[CH2:20][CH2:21][N:16]([C:2]2[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=2)[CH2:17][CH2:18]1
Reactant: CCCc1nc(Cl)nc(NCCO)n1
Reactant: CN1CCOCC1
Solvent: C1COCCO1
Product: CCCc1nc(NCCO)nc(N2CCOCC2)n1
Yield: 69.1 %

Procedure:
10.83 g (0.05 mole) of 2-[(4-chloro-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol and 15.15 g (0.15 mole) of N-methylmorpholine are mixed in 100 ml of dioxane. The mixture is heated under reflux for 20 hours; it is then cooled and the dioxane is removed under reduced pressure. The residue is dissolved in 200 ml of ethyl acetate. The solution is washed twice with 50 ml of water, dried over sodium sulfate and concentrated. The product crystallizes during the evaporation. 9.23 g of 2-[(4-morpholino-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol identical to the product obtained above are obtained.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C1(C#C)CCCCC1.[C:29]([C:31]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)#[CH:30]>>[OH:37][C:31]1([C:29]#[C:30][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C#CC1(O)CCCCC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C#CC1CCCCC1
Product: Nc1nc(C#CC2(O)CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 79 %

Procedure:
The procedure of Example 1 was repeated except that 1.14 g (2.9 mmol) of 2-iodoadenosine was used as the starting compound, that the cyclohexylacetylene was replaced by 1-ethynyl-1-cyclohexanol, and that the reaction was carried out at a temperature of 100° C. for one hour, respectively, whereby 0.91 g (2.3 mmol) of crystalline 2-[(1-hydroxycyclohexane-1-yl)ethynyl]adenosine was obtained (yield: 79%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:17]=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].Cl>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:17]=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[C:15]=2[OH:16])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(-c2scc(C=O)c2O)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2scc(C=NNC(=S)Nc3ccc(C(=O)O)cc3)c2O)cc1
Yield: 23.2 %

Procedure:
2-(4-t-Butylphenyl)-3-hydroxy-4-formylthiophene (50 mg, 0.19 mmol) synthesized in Reference Synthetic Example 25 and 4-hydrazinocarbonothioylaminobenzoic acid (40 mg, 0.19 mmol) were stirred with dimethylformamide (1.9 mL) and concentrated hydrochloric acid (0.1 mL) at room temperature for 12 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and purified by silica gel column chromatography (chloroform). Methanol/chloroform was added to the resulting crude product, and the precipitated yellow solid was recovered by filtration to give the desired product as a pale yellow solid (20 mg, yield 23%).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:17]=[C:16]([CH3:18])[C:15](I)=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH2:32]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[CH2:32]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]([C:15]2[C:16]([CH3:18])=[CH:17][C:9]([N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:10]3[C:14]=2[CH2:13][CH2:12][CH2:11]3)[OH:45])=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1I)CCC2
Reactant: CC(C)c1cc(C=O)ccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1C(O)c1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a solution of dibenzyl(7-iodo-6-methylindan-4-yl) amine (583 mg) in dry tetrahydrofuran (10 mL) was added a 1.48 mol/L solution of tert-butyllithium in n-pentane (1.30 mL) at −100° C. The mixture was stirred for 15 min. Adding dropwise 4-benzyloxy-3-isopropylbenzaldehyde (320 mg) in tetrahydrofuran (5 mL), the reaction mixture turned orange solution. The reaction mixture was stirred at ambient temperature for 15 min, and then warmed to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride to quench the reaction. Adding brine, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethyl acetate=3/1−1/1) to give the title compound (497 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:12]([NH2:14])=O>O>[CH3:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][NH:14][C:7]2=[O:8]
Reactant: NC=O
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: O
Product: Cc1ccc2nc[nH]c(=O)c2c1

Procedure:
8 g of 5-methyl 2-aminobenzoic acid and 15 ml formamide was heated at −170° C. 1.5 hour. Water was added and the solid filtered to give 7.3 g of 6-methyl 4-quinazolinone as a light brown-white solid, mp—268° C.