Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCOc1ccc(Cl)cc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(COc2ccc(Cl)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 55 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with α,4-dichloroanisole was carried out as described in Example 3, Step A, except that only 5 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (25 mL for 0.162 mmole, gradient elution using 0.25-1.0% MeOH/CH2Cl2) to give the desired material as a colorless oil in 55% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) 758 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[S:9][C:8]([C:10](O)=[O:11])=[CH:7][C:6]=2[CH:13]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[S:9][C:8]([C:10]([N:17]([O:18][CH3:19])[CH3:16])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2s1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2cc(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-difluoro-1-benzothiophene-2-carboxylic acid (synthesized by the method of WO2003/055878, 1.95 g, 9.10 mmol), N,O-dimethylhydroxyamine hydrochloride (977 mg, 10.0 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g, 10.0 mmol) and N-hydroxybenzotriazole (1.35 g, 10.0 mmol) in dichloromethane (20 mL) was added triethylamine (1.90 mL, 13.7 mmol) at room temperature. The mixture was stirred at room temperature overnight, and then to the reaction solution was added 10% hydrochloric acid solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a crude 5,7-difluoro-N-methoxy-N-methyl-1-benzothiophene-2-carboxamide (2.48 g) as a colorless solid. The resultant was used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([F:18])[CH2:12][CH2:11][CH:10]([C:13](OCC)=[O:14])[CH2:9]1>C1COCC1.C(OCC)C>[F:7][C:8]1([F:18])[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1
Reactant: CCOC(=O)C1CCC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
6.4 ml of a 1M solution of lithium aluminum hydride in THF are initially charged in 40 ml of diethyl ether. With ice cooling, 1.12 g of ethyl 3,3-difluoro-cyclopentanecarboxylate dissolved in 10 ml of diethyl ether are added dropwise under argon. After one hour, the cooling bath is removed, and the reaction mixture is stirred for another three hours. The reaction mixture is then poured onto ice-cold saturated ammonium chloride solution and filtered off over a filtration aid. The filtrate is washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. This gives 625 mg of (3,3-difluorocyclopentyl)methanol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])[N:3]=1
Reactant: NCc1ccccc1F
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Fc1ccccc1CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(2-fluorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-fluorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]([CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])(=[S:11])[NH2:10]>O1CCOCC1>[S:11]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:10]=[C:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cccc(OCC(N)=S)c1
Reactant: O=C1CCCCC1Br
Solvent: C1COCCO1
Product: COC(=O)c1cccc(OCc2nc3c(s2)CCCC3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.3 %

Procedure:
After a mixture of 2-bromocyclohexanone (865 mg, 4.9 mmol), methyl 3-(thiocarbamoylmethoxy)benzoate (1.00 g, 4.4 mmol) and 1,4-dioxane (10 ml) was stirred at room temperature for 5 hours and then at 80° C. for 12 hours, it was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the resulting residue and the product formed was extracted with ethyl acetate. The extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=hexane:ethyl acetate=4:1) to give methyl 3-(4,5,6,7-tetrahydrobenzothiazol-2-ylmethoxy)benzoate (369 mg, 1.2 mmol, 27%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[NH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])CCC.Cl[P:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.P>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[N:17][P:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(C)c1NC(=N)c1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: P
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=NP(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
N1-(2,6-dimethylphenyl)benzamidine (3.36 g, 15.0 mmol) was dissolved in 50 mL of diethylether and cooled to 0° C. Butyllithium (7.50 mL of 2.0 M solution in diethylether, 15.0 mmol) was added dropwise, producing a fluffy white suspended solid. The slurry was warmed to room temperature and stirred for 2 hours. Chlorodiphenylphosphine (2.69 mL, 15.0 mmol) was added slowly at room temperature. The suspended solid became finer and denser and the solution became slightly yellow upon complete addition of the phosphine. Stirring was continued for 1 hour. The solution was filtered to remove a small amount of white solid, presumably lithium chloride, and the solvent was removed in vacuo. The yellow foamy residue was suspended in 50 mL of pentane and stirred for 3 hours. Filtration and drying afforded 3.46 g (56%) of off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+].CO>N1C=CC=CC=1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:24](=[O:26])(=[O:25])[N:23]1[CH3:22]
Reactant: CNS(=O)(=O)Cl
Reactant: COc1ccccc1C(=O)c1ccc2cccnc2c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccccc1C1c2ccc3cccnc3c2NS(=O)(=O)N1C
Yield: 43.5 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(2-methoxy-phenyl)-methanone (Intermediate 369) (152 mg, 0.55 mmol), N-methylsulamoyl chloride (Intermediate 213) (212 mg, 1.64 mmol) and NaBH4 (21 mg, 0.55 mmol) in pyridine (10 ml) gave the title compound (85 mg, 44%) after trituration from MeOH.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][CH:13]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC2CC2)C(C)C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopropylamine (10 g, 169.5 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (7.0 g, 37.83 mmol) obtained as described in Preparation 1, in methanol (50 ml) and stirring was continued for 12 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.0 g, 46.0 mmol) was added to it. Cooling was removed after 10 min. and stirring was continued for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH ˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford 1-carbethoxy-4-cyclopropylamino-3-methylpiperidine. Yield 6.0 g (70%), C12H22N2O2, m/z 227 (M+1), PMR (CDCl3): 0.38 (m, 4H), 0.88 (dd, 3H), 1.28 (t, 3H), 1.54 (m, 1H), 2.06 (m, 2H), 2.32 (m, 1H), 2.48 (m, 1H), 2.84 (m, 1H), 3.06 (m, 1H), 3.72 (m, 1H), 3.88-4.24 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].[C:30](O)(=[O:33])[CH2:31][OH:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(Cl)CCl>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:31](=[O:32])[CH2:30][OH:33])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(O)CO
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(-c2ccc(NC(=O)CO)cc2)n1-c1ccc(C(N)=O)cc1C
Reaction time: 24 h
Yield: 56.5 %

Procedure:
Under a nitrogen atmosphere, 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11A, see scheme 11) (102 mg, 0.26 mmol), glycolic acid (40 mg, 0.52 mmol), TBTU (167 mg, 0.52 mmol), and EDC (101 mg, 0.65 mmol) were dissolved in 1 mL N, N-dimethylformamide. After 24 hrs, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (1500 microns, 10% IPA/CH2Cl2). The desired band (rf=0.25) was isolated and dried under high vacuum to yield 3-{1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-hydroxyacetylamino)-phenyl]-1H-pyrrol-2-yl]-propionic acid ethyl ester (18B) (66 mg, 60%, yellow powder).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:6]([CH:8]=1)[NH2:7].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:6]([NH:7][S:29]([C:21]2[O:20][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH:22]=2)(=[O:30])=[O:31])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1SCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cc1
Yield: 71.4 %

Procedure:
Following General Procedure B, the title compound (475 mg, 72%) was prepared from 5-chloro-2-((4-nitrobenzyl)thio)aniline (411 mg, 1.40 mmol) and benzofuran-2-sulfonyl chloride (303 mg, 1.40 mmol) in pyridine (5 ml).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].[H-].[Na+].[C:16]([O:19][C@H:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][Br:25])(=[O:18])[CH3:17].O>CS(C)=O>[C:16]([O:19][C@H:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][Br:25])(=[O:18])[CH3:17].[C:16]([O:19][C@H:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][N:5]1[C:6]2[N:7]=[CH:8][N:9]([CH3:13])[C:10]=2[C:11](=[O:12])[N:2]([CH3:1])[C:3]1=[O:4])(=[O:18])[CH3:17]
Reactant: Cn1c(=O)[nH]c2ncn(C)c2c1=O
Agent: CC(=O)O[C@H](C)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)n(C)c(=O)c2c1ncn2C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 120.5 %

Procedure:
To a stirring solution of 1,7-dimethylxanthine (0.30 g, 1.67 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (42 mmg, 1.75 mmol) in one portion. After stirring for 30 minutes, (R)-5-acetoxy-1-bromohexane (0.31 g, 1.75 mmol) was added next. (R)-5-Acetoxy-1-bromohexane was prepared according to methods described in U.S. patent application Ser. No. 09/002,345, which is incorporated herein by reference. After heating at 80° C. for 18 hours, water (25 ml) was added and the aqueous solution was extracted with dichloromethane (3×20 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate to give (R)-3-(5-acetoxyhexyl)-1,7-dimethylxanthine (0.34 g, 64%, yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=[O:32])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:30]([OH:32])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:29])[CH2:12][CH2:13]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(C)O)cc2F)CC1
Temperature: 25 °C

Procedure:
0.086 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml ethanol and 0.26 mmol sodium borohydride was added. The mixture was refluxed for 40 min., cooled to room temperature, quenched with water, acidified with HCl 1N and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified on silica eluting with heptane/ethylacetate to yield after evaporation the title compound. MS (m/e): 465.4 (M+H+, 100%)
Reaction SMILES: [Cl:1][N:2]1[C:6]2[C:7]([CH3:14])=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][CH2:3]1.[CH3:15][N:16]1[C:20](O)=[CH:19][CH:18]=[N:17]1.C(#N)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.O.C(N(CC)CC)C>[Cl:1][N:2]1[C:6]2[C:7]([CH3:14])=[C:8]([C:11]([O:13][C:20]3[N:16]([CH3:15])[N:17]=[CH:18][CH:19]=3)=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][CH2:3]1
Reactant: Cn1nccc1O
Reactant: Cc1c(C(=O)O)ccc2c1N(Cl)CS2
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CC#N
Product: Cc1c(C(=O)Oc2ccnn2C)ccc2c1N(Cl)CS2

Procedure:
1 g of 3-chloro-4-methylbenzothiazol-5-carboxylic acid (4.4 mol) and 0.46 g of 1-methyl-5-hydroxypyrazole (4.7 mol) were dissolved in 50 ml of abs. acetonitrile and admixed with 1 g of EDC, 0.7 ml of triethylamine and a catalytic amount of DMAP. After the reaction had ended, the solution was poured into water and the product was extracted with ethyl acetate. The organic phase was washed and dried and the product was purified by crystallization/column chromatography. Yield: 0.22 g (16%).
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:13]([CH3:14])[C:12](=[O:15])[CH:11]=[CH:10][N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][N:13]1[C:12](=[O:15])[CH:11]=[CH:10][N:9]2[C:8]1=[N:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]12
Reactant: Cn1c(N[C@@H]2CCC[C@H]2O)nccc1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1C(=O)C=CN2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of 2-((1R,2R)-2-hydroxycyclopentylamino)-3-methylpyrimidin-4(3H)-one (130 mg, 0.62 mmol) in anhydrous THF (2 mL) is added triphenylphosphine (163 mg, 0.62 mmol). Five minutes later, diethyl azodicarboxylate (DEAD, 0.45 mL, 0.93 mmol) in toluene is added dropwise. The mixture is stirred at room temperature for 2 hours. Solvent is removed under vacuum, the residue is treated with 0.02 N HCl (40 mL). The precipitate is filtered off, and the filtrate is washed with CH2Cl2. The aqueous phase is evaporated to dryness under high vacuum to give product as solids (108 mg, yield 92%), which is used for the next reaction without further purification. MS (ESI) m/z 192.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)[CH3:18]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: CCOC(=O)CCNc1ccc2c(c1)CCC2
Temperature: 100 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
Tetrabutylammonium bromide (200 mg) was added to a mixture of 5-aminoindan (5 g, 37.6 mmol), ethyl 3-chloropropionate (4.7 mL, 37.6 mmol) and potassium carbonate (5.2 g, 37.6 mmol). The mixture was stirred at 100° C. for 16 hours. After cooling to room temperature (rt), the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:20-1:10, v/v), gave 6.2 g (71%) of the title compound. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.03 (d, J=7.6 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J=7.6 Hz, 1H), 4.15 (q, 2H), 3.86 (br, 1H), 3.43 (t, 2H), 2.82 (m, 4H), 2.60 (t, 2H), 2.06 (m, 2H), 1.27 (t, 3H).
Reaction SMILES: [C:1]([CH:4]([C:9](=[O:31])[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:29]=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=3)[N:21]=2)=[CH:15][CH:14]=1)[CH3:11])C(OC)=O)(=[O:3])[CH3:2].[H][H].ClC1C=C2C(=CC=1)N=C(OC1C=CC(OC(C)C(Cl)=O)=CC=1)C=N2.[Na].COC(=O)CC(C)=O.C([O-])(=O)CCCC.[Cl-].[Na+]>CS(C)=O>[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:10]([CH3:11])[C:9](=[O:31])[CH2:4][C:1](=[O:3])[CH3:2])=[CH:18][CH:17]=1)[CH:29]=[N:28]2
Reactant: COC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Reactant: [H][H]
Agent: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Agent: CCCCC(=O)[O-]
Agent: COC(=O)CC(C)=O
Solvent: CS(C)=O
Product: CC(=O)CC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1

Procedure:
In the same manner, methyl 2-acetyl-4-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]-3-oxopentanoate (XIV; X' is chloro and X" is hydrogen) is prepared from 2-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]propionic acid chloride and the sodium salt of methylacetoacetate. This pentanoate is then heated with sodium chloride and DMSO to yield 5-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]-2,4-hexanedione (XV; X' is chloro and X" is hydrogen).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[C:22](=O)([O:24]CC)[NH2:23]>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[C:5]2[C:6](=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:23][C:22]1=[O:24]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NCC(F)(F)F
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 190 °C
Yield: 73.1 %

Procedure:
A mixture of 62.7 g of 2-(2,2,2-trifluoroethylamino)-5-chlorobenzophenone, 107 g of ethyl carbamate and 10 g of zinc chloride was heated at 190° C. (oil bath temperature) for 3 hours. After cooling, the reaction mixture was dissolved in chloroform and the insoluble material was filtered off. The chloroform solution was washed successively with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure and the residual solid was washed 3 times with 100 ml of isopropyl ether and dried to give 49.5 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone as a pale gray powder. Recrystallization from ethanol gave pale yellow needles, m.p. 186.5°-187.5° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2([OH:10])[CH2:9][O:8][CH2:7]2)[CH2:5][CH2:4]1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:10][C:6]1([CH:3]2[CH2:5][CH2:4]2)[CH2:9][O:8][CH2:7]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: OC1(C2CC2)COC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Oc1ccccn1)OC1(C2CC2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (315 mg, 7.88 mmol) in THF (20 mL) was added 3-cyclopropyloxetan-3-ol (750 mg, 6.57 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (1421 mg, 6.57 mmol) in THF (20 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified via biotage (40 g column, 5-40% EtOAc:Hex) to give the expected product 3-cyclopropyloxetan-3-yl pyridin-2-yl carbonate (290 mg, 18.76% yield) as a clear thick oil. 1H NMR (400 MHz, CHLOROFORM-d) d 8.54-8.36 (m, 1H), 7.89-7.77 (m, 1H), 7.34-7.25 (m, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.84 (d, J=8.5 Hz, 2H), 4.42 (d, J=8.3 Hz, 2H), 1.67-1.56 (m, 1H), 0.81-0.72 (m, 2H), 0.72-0.63 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Cc1ccc(F)cc1
Yield: 73 %

Procedure:
A solution of 4-fluorobenzyl sulfonylacetic acid (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 73% yield.