Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(O)=O.Cl.[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:7]1=[N:15][NH2:16].OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N>>[CH3:5][N:6]1[C:10]2[C:9]([S:8]/[C:7]/1=[N:15]\[NH2:16])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: Cn1c(=NN)sc2ccccc21
Agent: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=NO
Product: Cn1/c(=N/N)sc2ccccc21

Procedure:
Nitrous acid oxidation followed by reaction with 3-methyl-2-benzothiazolone hydrazone hydrochloride (MBTH) and then FeCl3 was used to measure the number of free amino groups (equivalent to the number of glucosamines) in the glycolchitosan and derived products (Davies et al., Meth. Enzymol. 161:442-446 (1988)). The assay was standardized with glucosamine on a weight basis. Also the MBTH/Fe3+ stage of this procedure was used to measure the number of aldehyde groups, similarly relying on standardization with glucosamine treated with nitrous acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.Br[CH2:11][C:12](=O)[CH2:13][CH3:14].[OH-:16].[Na+].Cl>>[CH2:13]([C:12]1[C:11]([OH:16])=[CH:8][C:3]2[C:2](=[CH:7][CH:6]=[N:5][CH:4]=2)[N:1]=1)[CH3:14]
Reactant: CCC(=O)CBr
Reactant: [OH-]
Reactant: Nc1ccncc1C=O
Agent: Cl
Agent: [Na+]
Product: CCc1nc2ccncc2cc1O
Reaction time: 72 h
Yield: 48 %

Procedure:
4-Amino-pyridine-3-carbaldehyde (100 mg) and 1-bromo-butan-2-one (124 mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6 ml), and the suspension was hermetically sealed and, in this state, was allowed to stand for 3 days. The reaction solution was neutralized with 10% hydrochloric acid, the precipitate was then filtered, and the residue was washed with water and chloroform. The powder as the residue was dried under the reduced pressure to give 2-ethyl-[1,6]naphthyridin-3-ol (69 mg, yield 48%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[OH-].[K+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].ICCCCCCCCCC>C(#N)C>[CH2:26]([N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: c1ccc(-c2ncc[nH]2)nc1
Reactant: CCCCCCCCCCCCI
Agent: CCCCCCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCCCCn1ccnc1-c1ccccn1
Yield: 103.7 %

Procedure:
A mixture of 14.5 g (0.1 mole) 2-(2-pyridyl)imidazole, 6 g (0.11 mole) ground KOH, 30 g (0.1 mole) iodododecane in about 150 ml of acetonitrile was stirred and refluxed for about 2 hours. The iododecane gradually went into solution as the reaction proceeded. After the 2 hours the reaction mixture was cooled and filtered. The resulting residue was extracted with hexane to give 32.5 g of crude product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:20][CH:21]([CH3:34])[CH2:22][CH2:23][NH:24][C:25](=O)[O:26]C1C=CC=CC=1>CN(C)C=O>[CH3:20][CH:21]([CH3:34])[CH2:22][CH2:23][NH:24][C:25]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:26]
Reactant: CC(C)CCNC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 25 °C
Yield: 48.3 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (2.0 g, 8.9 mmol, CAS No. 417722-11-3) which was described in WO 02/32872 was dissolved in N,N-dimethylformamide (20 ml); and sodium hydride (426 mg, 10.7 mmol) was added thereto at room temperature while stirring. The reaction mixture was cooled with ice bath after 30 minutes; phenyl N-(3-methylbutyl)carbamate (2.02 g, 9.75 mmol) was added thereto; and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated; and the residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=3:1) to yield the title compound as crystals (1.45 g, 4.3 mmol, 48%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([C:16]([OH:18])=O)[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:42][C:43]1[CH:44]=[C:45]([C:49]2[CH:54]=[CH:53][C:52]([CH2:55][C@@H:56]([C:58]3[NH:62][N:61]=[N:60][N:59]=3)[NH2:57])=[CH:51][CH:50]=2)[CH:46]=[CH:47][CH:48]=1>C1COCC1>[Cl:42][C:43]1[CH:44]=[C:45]([C:49]2[CH:50]=[CH:51][C:52]([CH2:55][C@H:56]([NH:57][C:16]([C:11]3([CH2:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]3)=[O:18])[C:58]3[NH:62][N:61]=[N:60][N:59]=3)=[CH:53][CH:54]=2)[CH:46]=[CH:47][CH:48]=1
Reactant: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnn[nH]1
Reactant: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(CC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(Cl)c3)cc2)c2nnn[nH]2)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a suspension of 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (197 mg, 0.750 mmol) in THF (8 ml) at room temperature was added EDC.HCl (192 mg, 1.000 mmol) and HOBT (134 mg, 0.875 mmol). The mixture was stirred at room temperature for 10 minutes and was added a solution of (S)-2-(3′-chlorobiphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethanamine (187 mg, 0.625 mmol) in THF and TEA (0.174 ml, 1.250 mmol). The mixture was stirred overnight at room temperature. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 1 to 3% EtOH/DCM) and gave the title compound: 134 mg (yield: 39%). LCMS (condition B): 544.3 (M+1); retention time=1.44 min.
Reaction SMILES: [F:1][C:2]1([F:12])[C:7]([F:9])([F:8])[O:6]C(Cl)=C(Cl)[O:3]1.[Cl:13]Cl.[C:15]([C:19]([Cl:22])(F)F)([Cl:18])([Cl:17])F>>[Cl:17][C:15]1([Cl:18])[C:19]([Cl:22])([Cl:13])[O:3][C:2]([F:12])([F:1])[C:7]([F:9])([F:8])[O:6]1
Reactant: ClCl
Reactant: FC1(F)OC(Cl)=C(Cl)OC1(F)F
Reactant: FC(F)(Cl)C(F)(Cl)Cl
Product: FC1(F)OC(Cl)(Cl)C(Cl)(Cl)OC1(F)F
Yield: 82 %

Procedure:
A solution of 118 g (0.52 mol) of 3 in 200 mL of CFCl2CF2Cl was stirred under a -80° condenser and irradiated with a sunlamp while chlorine was passed in until reaction ceased. Distillation gave 127.4 g (82%) of 2,2,3,3-tetrachloro-5,5,6,6-tetrafluoro-1,4-dioxane (4), bp 65° C. (40 mm).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ccnc2ccccc12
Reactant: c1ccc(CN2CCNCC2)cc1
Product: c1ccc(CN2CCN(c3ccnc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
To a solution of 4-chloroquinoline (3 g) in mixed xylenes (b.p. 137°-144° C.) (25 ml) was added 1 -benzylpiperazine (6.46 g). The mixture was heated to reflux with stirring for 20 hours then cooled to room temperature. The precipitate that formed was filtered and washed with xylene. To the combined filtrate and washings was added decolourising charcoal and the mixture was heated to reflux for 20 minutes, cooled and filtered through kieselguhr. The filtrate was evaporated to dryness to yield 1-benzyl-4-(4-quinolinyl)piperazine (4.55 g) as a yellow solid: m.p. 105°-106° C.; NMR (CDCl3) δ 2.75(4H,m), 3.26(4H,m), 3.66(2H,s) 6.84(1H,d), 7.35(5H,m), 7.45(1H,m), 7.65(1H,m), 8.03(2H,m), 8.73(1H,m); m/Z 304 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[C:8][Si](C)(C)C)=[CH:5][N:4]=[CH:3]1.[Li]CCCC.C[Si]([N:22]=[C:23]=[O:24])(C)C.O>C1COCC1.CCOC(C)=O>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:23]([NH2:22])=[O:24])=[N:4][CH:5]=1)#[CH:8]
Reactant: C[Si](C)(C)N=C=O
Reactant: Cn1cncc1C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cnc(C(N)=O)n1C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 1-methyl-5-trimethylsilanylethynyl-1H-imidazole (1.78 g, 10 mmol) in THF (30 mL) was slowly added a solution of nBuLi in hexanes (2.5M, 4.4 mL) at −78° C. and the resulting suspension was stirred at the same temperature for 1 h. Trimethylsilyl isocyanate (from Aldrich, 85% pure. 11.76 mmol, 1.6 mL) was slowly added to this suspension at −78° C. After stirring at −78° C. for another 30 minutes the reaction mixture was allowed to warm up slowly by removing the cooling bath. Water (2 mL) and MeOH (1 mL) was added to quench the reaction and the mixture was stirred overnight. More water and EtOAc was added to facilitate the extraction. The combined organic layers were dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue was purified on a silica gel column (eluent: 40-60% EtOAc in hexanes) to give the desired product as a white solid in 26% yield (387 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[C:14]([Cl:22])=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[ClH:23].C1(C2N=CNC=2)C=CC=CC=1>O1CCCC1>[Cl:23][C:19]1[CH:20]=[CH:21][CH:13]=[C:14]([Cl:22])[C:15]=1[C:16]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)=[O:17]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Cl
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: O=C(c1c(Cl)cccc1Cl)n1cnc(-c2ccccc2)c1

Procedure:
2.88 g of 4-phenylimidazole are dissolved in 7 ml of tetrahydrofuran; a solution of 2.12 g of dichlorobenzoyl chloride in 5 ml of tetrahydrofuran is then added, and the mixture is heated, in the course of which 4-phenylimidazole hydrochloride precipitates. The mixture is diluted with 15 ml of tetrahydrofuran, and is filtered at room temperature in vacuo. The filtrate is subsequently evaporated to dryness in a rotary evaporator, and the residue is recrystallised from 15 ml of ethyl acetate. The yield is 1.55 g (48.9% of theory) of the desired product, m.p. 135°-136° C. By concentration of the mother liquor by evaporation and recrystallisation from 8 ml of benzene, there are obtained a further two fractions (0.76 g, m.p. 135°-136° C.; and 0.41 g, m.p. 134°-135° C.). The total yield is hence 2.72 g (85.8% of theory).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28].[CH2:31]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:32]>>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:36]3[CH:38]=[CH:39][C:33]([CH2:31][CH3:32])=[CH:34][CH:35]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 501.12 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chloro-4-trifluoromethyl-benzenesulfonyl chloride and 4-ethyl-aniline.
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][C:7]1[CH:34]=[CH:33][C:10]2[C:11]3[C:20](=[O:21])[O:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:17]=4)[C:12]=3[CH2:30][CH2:31][O:32][C:9]=2[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C.CO>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([Si:5]([CH3:35])([CH3:36])[O:6][C:7]1[CH:34]=[CH:33][C:10]2[C:11]3[CH:20]([OH:21])[O:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[CH:17]=4)[C:12]=3[CH2:30][CH2:31][O:32][C:9]=2[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCc1c-2c(=O)oc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(O)C1=C2CCOc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 3 h

Procedure:
2,8-Bis-(tert-butyl-dimethyl-silyloxy)-11,12-dihydro-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-one (35 mg, 0.066 mmol) was dissolved in toluene (5 mL) and the resulting solution was cooled to −78° C. A solution of Dibal-H solution (70 μL, 1.5 M solution in toluene) was then added to above reaction mix at −78° C. The reaction mixture was stirred at −78° C. for 3 h. To the reaction mixture was then added methanol (0.5 mL), and then Rochelle solution (2 ml, 1M solution). The reaction mixture was gradually warmed to room temperature. The reaction mix was diluted with CH2Cl2 (30 mL), the organic layer was separated and dried over Na2SO4. The solution was filtered and evaporated to yield a crude product that was purified on SiO2 to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]([OH:19])=[O:18])[N:3]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:18][C:17]([C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:19])[CH3:26]
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C(=O)O)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from the compound of Example 73 by refluxing in ethanol in the presence of concentrated sulphuric acid, mp. 177.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:16]([O:17][CH3:18])[C:14]=1[OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:17][C:16]1[C:14]([O:15][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[C:13]([CH:21]=[CH:20][CH:19]=1)[CH:12]=[O:11]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 71 %

Procedure:
A mixture of 14.10 g (0.10 mole) of 4-fluoronitrobenzene, 16.40 g (0.10 mole) of o-vanillin, 30 g of powdered potassium carbonate, and 40 mL of DMF is heated with stirring to the boiling point. After 10 minutes the mixture is cooled to 100° C. and 300 mL of ice water is added. Petroleum ether (200 mL) is added and the entire mixture filtered and the cake is washed with 200 mL of water and then 200 mL of petroleum ether. The damp cake slurried in 100 mL of methanol and filtered; wt 19.50 g (71% yield); mp 130°-131° C.; mass spectrum (DEI), 273 (M+).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC=[C:37]([O:41]C)C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:37][O:41][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: COc1cccc(CCBr)c1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1cccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-bromo-ethyl)-3-methoxy-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([I:11])[N:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[I:11])[CH3:18]
Reactant: Nc1nc(I)c2[nH]cnc2n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(I)nc(N)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a solution of 2-amino-6-iodo-purine (78.3 g, 0.3 mol) in DMF (1960 mL) was added ethyl bromoacetate (55.1 g, 0.33 mol) and potassium carbonate (82.9 g, 0.6 mol). The resulting reaction mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated to small volume (about 150 mL) in vacuo and the residue was dissolved in water. The solid was filtered off, washed with water and ethyl ether, and dried in vacuo to give the titled compound (98.4 g, 95%). 1H-NMR (500 MHz; DMSO-d6) δ 8.06 (s, 1H), 6.90 (br.s, 2H), 4.94 (s, 2H), 4.17 (q, 2H), 1.22 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccccc1)(C(=O)OCC)C(=O)c1ccc[nH]1
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
2-(1H-Pyrrole-2-carbonyl)-malonic acid diethyl ester (0.79 mmol, 0.21 g) in DME (3 ml) was treated with lithium bis-trimethylsilylamide (0.79 mmol, 133 mg). The resulting solution was held at room temperature for 30 minutes, then treated with benzyl bromide (0.79 mmol, 0.10 ml). The resulting solution was held at room temperature overnight, then diluted with ethyl acetate (30 ml), and washed with saturated ammonium chloride (10 ml), followed by brine (20 ml). The organics were concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 0.23 g (84%) of 2-benzyl-2-(1H-pyrrole-2-carbonyl)-malonic acid diethyl ester. 1H NMR (CDCl3) δ 10.01 (1H, s), 7.25-7.17 (4H, m), 7.14 (1H, dt, J=2.7, 1.3), 7.03-6.98 (1H, m), 6.86 (1H, ddd, J=3.8, 2.4, 1.3), 6.29-6.25 (1H, m), 4.22 (4H, q, J=7.1), 3.47 (2H, s), 3.39 (2H, s), 1.25 (6H, t, J=1.7).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:12]3[CH:13]=[CH:14][S:15][C:11]=3[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][C:26](O)=[O:27])=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)[Cl:45]>>[ClH:45].[N:1]1([CH2:6][CH:7]2[C:12]3[CH:13]=[CH:14][S:15][C:11]=3[CH2:10][CH2:9][N:8]2[C:26](=[O:27])[CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[CH2:16][CH2:17][CH2:18]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2c(c1)CCC2
Reactant: ClC(Cl)Cl
Reactant: c1cc2c(s1)CCNC2CN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cl
Product: O=C(Cc1ccc2c(c1)CCC2)N1CCc2sccc2C1CN1CCCC1

Procedure:
Prepared as Example No. 3, from 1.5 g (6.76 mmoles) of 4-(pyrrolidin-1-yl)methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1.4 g (7.95 mmoles) of indan-5-yl acetic acid and 2.4 g (11.76 mmoles) of dicyclohexylcarbodiimide in 50 ml of dry chloroform.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cccc(C)c3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cccc(C)c3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 77.7 %

Procedure:
A mixture of 2.81 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-6-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.35 g of 2-(dimethylamino)ethyl chloride hydrochloride, 2.7 g of potassium carbonate and 40 ml of acetone is refluxed for 16 hours. After the reaction is completed, the inorganic materials are removed by filtration and then washed with chloroform. The filtrate and the washing are combined and then evaporated to remove solvent. The residue is converted into its hydrochloride and then recrystallized from a mixture of ethanol and ether. 2.93 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-6-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 3/4 hydrate are obtained. Yield: 77%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[C@@H:23]([OH:38])[C@@H:24]([NH:34][C:35](=[O:37])[CH3:36])[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]([CH3:42])=O.COC(C)=C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C@@H:9]1[C@H:23]1[O:38][C:40]([CH3:42])([CH3:39])[N:34]([C:35](=[O:37])[CH3:36])[C@H:24]1[CH2:25][C:26]1[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: COc1ccc(CO[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)N(C(=O)OC(C)(C)C)C2)cc1
Agent: C=C(C)OC
Solvent: ClCCl
Product: COc1ccc(CO[C@@H]2C[C@H]([C@H]3OC(C)(C)N(C(C)=O)[C@H]3Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 1 h
Yield: 607.3 %

Procedure:
Add to a solution of (2R,4R)-2-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-4-(4-methoxy-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.64 g, 10.55 mmol) in dichloromethane (25 mL) and acetone (25 mL) p-toluene sulfonic acid pyridine salt (0.245 g, 1 mmol) and 2-methoxy propene (4.6 mL, 49 mmol). Stir 60 min and concentrate. Dissolve in ethyl acetate and wash with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with hexanes/ethyl acetate mixtures) to give the title compound as a foam (3.49 g, 61%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C([O:6][C:7]([C:9]1[N:14]2[N:15]=[C:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])[N:17]=[C:13]2[CH:12]=[C:11]([Br:24])[CH:10]=1)=O)C.NC(N)=S>C(O)C>[CH2:1]([NH:3][C:7]([C:9]1[N:14]2[N:15]=[C:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])[N:17]=[C:13]2[CH:12]=[C:11]([Br:24])[CH:10]=1)=[O:6])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Reactant: CCN
Agent: NC(N)=S
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)NCC)n2n1

Procedure:
Ethylamine (0.300 mL, 70% solution in water) and 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester, prepared as in Example 6 (0.251 g, 0.705 mmol), was suspended in ethanol (3.00 mL) and shaken. After 20 hours the reaction was filtered and the filtrate washed with cold ethanol to afford 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethylamide MS (APCI+): m/z 356.0 (M+H).