Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(C(C)C)C(C)C.[CH2:33]([O:35][C:36](=[O:48])[CH2:37][CH2:38][NH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:34]>C1COCC1>[CH2:33]([O:35][C:36](=[O:48])[CH2:37][CH2:38][N:39]([C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:34]
Reactant: Cc1ccnc(CC(=O)O)c1
Reactant: CCOC(=O)CCNCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(CCc1ccccc1)C(=O)Cc1cc(C)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
(4-Methyl-pyridin-2-yl)-acetic acid (1.0 g), carbonyldiimidazole (CDI, 1.07 g) and DIPEA (0.856 g) were added to THF (15 ml) and the light brown suspension was allowed to stir at RT for 1 hour. To the mixture was added 3-phenethylamino-propionic acid ethyl ester (0.898 g) dropwise and the resulting mixture was stirred at 55° over night. The mixture was poured into ice/water and the pH was adjusted to 5.0. The mixture was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/hexanes 2:1) to give the desired product as a light brown liquid (0.462 g). MS (ESI): 355.0 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]S([O-])(=O)=O.[Mg+2].C([BH3-])#N.[Na+]>C(Cl)Cl.C(O)(=O)C.C1COCC1>[CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1
Reactant: CN(C)c1nncc2cc(C=O)ccc12
Reactant: Nc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)c1nncc2cc(CNc3ccccc3)ccc12
Temperature: 25 °C

Procedure:
A mixture of 1-dimethylamino-phthalazine-6-carbaldehyde (25 mg, 0.13 mmol), aniline (14 μL, 0.15 mmol), THF (1 mL) and MgSO4 (43 mg, 0.357 mmol) were stirred at room temperature. To this mixture was added acetic acid (8 μL) followed by sodium cyanoborohydride (13 mg, 0.207 mmol) and the reaction stirred for 15 h. The reaction was diluted with CH2Cl2, washed with aq. NaHCO3, dried (Na2SO4) and concentrated. Purification by prep. HPLC yielded the desired compound. m/z 279.22 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](N)=[O:10])=[C:7]([OH:14])[N:6]=1)[CH2:2][CH:3]=[CH2:4].Cl.[OH-:16].[K+]>>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:16])=[O:10])=[C:7]([OH:14])[N:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: [OH-]
Reactant: C=CCCc1ccc(C(N)=O)c(O)n1
Agent: Cl
Agent: [K+]
Product: C=CCCc1ccc(C(=O)O)c(O)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of b1 (12.38 g, 70.1 mmol) in 10% aqueous KOH (350 mL) was heated to reflux for 20 h and subsequently cooled to room temperature. The reaction mixture was acidified with 12 M HCl to pH 2-3, and the resulting precipitate was filtered, washed with water (2×50 mL), and dried under vacuum to afford c1 as a yellow solid (12.46 g, 92%): mp=151-155° C.; IR(cm−1) 2905 (br), 1736, 1652; 1H NMR (DMSO-d6) δ 2.34-2.29(m, 2H), 2.73 (t, 2H, J=7.6), 4.96-5.07 (m, 2H), 5.72-5.85 (m, 1H), 6.56 (d, 1H, J=7.5), 8.28 (d, 1H, J=7.5), 13.26 (s, br, 1H), 14.64 (s, br, 1H); Anal. C10H11NO3·0.10H2O: C, H, N.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[O:3][C@@H:4]([C@@H:6]1[C@@H:9]([C@@H:10]2[C:15](=[O:16])[S:14][CH2:13][CH2:12][S:11]2)[NH:8][C:7]1=[O:17])[CH3:5].N1C=CC=CC=1.Cl[C:27](=[O:34])[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29].C(O)C>ClCCl.CCOCC>[O:17]=[C:7]1[C@H:6]([C@H:4]([O:3][Si:2]([CH3:18])([CH3:1])[CH3:19])[CH3:5])[C@@H:9]([C@@H:10]2[C:15](=[O:16])[S:14][CH2:13][CH2:12][S:11]2)[N:8]1[C:27](=[O:34])[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29]
Reactant: C=CCOC(=O)C(=O)Cl
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N[C@@H]1[C@H]1SCCSC1=O
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCO
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]1[C@H]1SCCSC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A solution of (3S,4S)-3-[(R)-1-(trimethylsilyloxy)-ethyl]-4-[(R)-3-oxo-1,4-dithian-2-yl]azetidin-2-one (650 mg), prepared in Reference Example 14, in dichloromethane (10 ml) was cooled at 0° C. and a solution of pyridine (483 mg) in dichloromethane (2 ml) and a solution of allyl chloroglyoxylate (603 g) in dichloromethane (3 ml) were added. The mixture was stirred at the same temperature for 2 hours. To this mixture was added ethanol (187 mg) at 0° C. and the mixture was stirred for 10 minutes, after which ether (30 ml) was added. The organic layer was washed with water, saturated copper sulfate solution and saturated aqueous sodium chloride solution in the order mentioned and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (packing: silica gel; ethyl acetate-hexane=1:5). The procedure gave allyl [(3S,4S)-2-oxo-4-[ (R)-3-oxo-1,4-dithian-2-yl]-3-[(R)-1-(trimethylsilyloxy)ethyl]azetidin-1-yl]glyoxylate as a colorless oil (853 mg).
Reaction SMILES: [C:1]([C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[C:32]([C:33]([O:35]CC)=S)=[CH:31][N:30]=[C:29](C)[N:28]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[SH:41][CH2:42]C(O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]2[CH2:21][C@H:22]3[N:23]([CH2:24][CH2:25][CH2:26]3)[C:27]3[N:28]=[C:29]([S:41][CH3:42])[N:30]=[CH:31][C:32]=3[C:33]2=[O:35])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=S)c1cnc(C)nc1N1CCC[C@H]1CN(Cc1ccc(C#N)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)CS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(C#N)cc1)C2=O
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
Ethyl (S)-4-(2-{[(4-cyanobenzyl)(2-nitrobenzenesulfonyl)amino]methyl}pyrrolidin-1-yl)-2-methylthiopyrimidine-5-carboxylate (1.85 g, 3.10 mmol) obtained in Step 1 was dissolved in DMF/ethanol=1/1 (20 mL), and the mixture was stirred at 75° C. for 1.5 hours after adding mercaptoacetic acid (0.647 mL, 9.30 mmol) and DBU (2.78 mL, 18.6 mmol). The reaction mixture was diluted with ethyl acetate, and washed with an aqueous sodium bicarbonate solution and saturated brine. The organic layer was then dried over anhydrous magnesium sulfate. The residue obtained upon concentration was purified by silica gel column chromatography to give (S)-5-(4-cyanobenzyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (1.12 g, quantitative).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH2:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].[C:29]1([S:35][C:36]2([S:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:40][CH:39]([O:41]CC)[NH:38][C:37]2=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH:24][CH:37]3[C:36]([S:35][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([S:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:40][C:39](=[O:41])[NH:38]3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: CCOC1CC(Sc2ccccc2)(Sc2ccccc2)C(=O)N1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4NC(=O)CC4(Sc4ccccc4)Sc4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 55.7 %

Procedure:
Adenosine 2',3',5'-triacetate (110 mg) and 3,3-diphenylthio-5-ethoxy-2-pyrrolidinone (155 mg) were heated in toluene (10 ml) under reflux for 5 hours, at the end of which the reaction solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform-acetone (5:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give crystals which were recrystallized from ethanol. By the above procedure was obtained N6 -(3,3-diphenylthio-5-oxo-2-pyrrolidinyl)adenosine 2',3',5'-triacetate as colorless needles (108 mg).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:7]([N:9]1[CH2:34][CH2:33][CH2:32][C@H:10]1[C:11]([NH:13][C@H:14]([C:22]([S:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:42]>>[NH2:1][C@@H:2]([C:7]([N:9]1[CH2:34][CH2:33][CH2:32][C@H:10]1[C:11]([NH:13][C@H:14]([C:22]([S:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:21])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[ClH:42].[ClH:42]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)SCc1ccccc1
Agent: Cl
Product: CC(C)C[C@@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)SCc1ccccc1

Procedure:
Boc-D-Leu-Pro-Arg-S-Bzl (0.845 g), prepared in Step E above, is mixed with HCl for approximately 30 minutes to remove the Boc protecting group. The product is precipitated with ether to give 0.713 g of pure H-D-Leu-Pro-Arg-S-Bzl.2HCl.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[C:15]([N+:18]([O-:20])=[O:19])=[C:14]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)[N:13]=[C:12]1[CH3:34])(C)(C)C.F>C(#N)C.ClCCl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:14]3[N:13]=[C:12]([CH3:34])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][OH:6])[C:16](=[O:17])[C:15]=3[N+:18]([O-:20])=[O:19])[CH2:22][CH2:23]2)=[CH:28][CH:29]=1
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)n1CCCCO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)n1CCCCO

Procedure:
In analogy the procedure described in example 17b, the 3-[4-(tert-butyl-dimethyl-silanyloxy)-butyl]-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H pyrimidin-4-one (example 17a) was treated with hydrofluoric acid (47-51% in water) in acetonitrile and dichloromethane at room temperature to yield the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-3-(4-hydroxy-butyl)-2-methyl-5-nitro-3H-pyrimidin-4-one as a yellow solid; m.p. 154-156° C.; MS: [M+H]+=405
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:23])([CH3:22])[C:20]#[N:21]>>[C:20]([C:19]([NH:18][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)([CH3:23])[CH3:22])#[N:21]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)C#N
Product: CC(C)(C#N)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2-methyl-propanenitrile, (CAN 19355-69-2) as starting materials, LC-MS (UV peak area/ESI) 89%, 300.1702 (M+H)+.
Reaction SMILES: COS([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH:8]=1)(=O)=O.[C-:22]#[N:23].[Na+]>CN(C=O)C>[N:13]1([C:9]2[CH:8]=[C:7]([CH2:6][C:22]#[N:23])[CH:12]=[CH:11][CH:10]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: COS(=O)(=O)Cc1cccc(N2CCc3ccccc32)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc(N2CCc3ccccc32)c1
Yield: 80.7 %

Procedure:
A mixture of 10.2 g (ca. 33.8 mmole) of 3-(1-indolinyl)benzenemethanesulfonic acid methyl ester of Example 20c and 4.97 g (101.4 mmole, 3.0 equiv.) sodium cyanide in 200 ml sieve dried DMF was heated at 60°-70° C. for 50 minutes. The product was concentrated under high vacuum at 50°-60° C. and the residue was partitioned between chloroform (200 ml) and water (200 ml). The organic portion was washed twice with 200 ml water, 200 ml brine, dried over Na2SO4 and concentrated under vacuum to give 6.39 g (80.7%) of product. Kugelrohr distillation of a 0.8 g sample gave 0.6 g of an oil of 3-(1-indolinyl)benzeneacetonitrile, b.p. 189°-192° C./0.15 mm.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[S:7])C=1.[C:13]([O:17][C:18](=[O:33])[N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH2:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18](=[O:33])[N:19]([CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]=[C:6]=[S:7])=[CH:30][CH:31]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CCN(CCCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a cooled (−20° C.) solution of 1,1-thiocarbonyldiimidazole (811 mg, 4.415 mmol) (Aldrich) in N,N-dimethylformamide (11 mL) was added dropwise a solution of [3-(4-aminophenoxy)propyl]-ethyl-carbamic acid tert-butyl ester (1.175 g, 3.99 mmol) (from Step B above) in N,N-dimethyl-formamide (11 mL) over 25 minute. After the addition was complete, the mixture was stirred at −20° C. for 20 minutes and then at room temperature for 1 hour. Ice-water was added and the mixture was extracted with ether. The ether layer was dried (Na2SO4), filtered, and evaporated. The residue was purified on silica gel with 85:15 hexane/ethyl acetate to give ethyl-[3-(4-isothiocyanatophenoxy)propyl]carbamic acid tert-butyl ester (1.24 g, 92% yield). HRMS, Observed: 336.1496; Calcd for M+:336.1508.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH2:24][CH:25]([OH:27])[CH3:26]>>[OH:27][CH:25]([CH3:26])[CH2:24][NH:23][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4]
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)OC)s1
Reactant: CC(O)CN
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NCC(C)O)s1
Yield: 49 %

Procedure:
As described for example 53, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (100 mg, 0.31 mmol) was converted, using rac-1-amino-2-propanol instead of 2-amino-1,3-propandiol, to the title compound (65 mg, 49%) which was obtained as an off white oil. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C@@:7]([OH:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:3][CH:2]=1.[CH2:20]([O:27][CH2:28][C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]([O:13][C:29](=[O:30])[CH2:28][O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)[C@@](C)(O)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Product: COC(=O)[C@@](C)(OC(=O)COCc1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 48 h
Yield: 74.2 %

Procedure:
In a dry flask under argon, were mixed 1.3 g (5 mmol) of methyl (S)-(+)-2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionate, 1.7 mL (10 mmol) of 95% benzyloxyacetyl chloride and 6.1 mL of pyridine. The reaction stirred for 48 hours and was quenched by pouring into 100 mL of 10% aqueous HCl and 200 mL of ether. The ether fraction was separated and washed with 50 mL of 10% aqueous HCl, 50 mL of H2O, 2×50 mL of NaHCO3 solution, 50 mL of H2O, 50 mL of brine, dried (MgSO4) and concentrated. The product was purified over 250 g of SiO2 using initially EtOAc/hexanes (1/9) followed by EtOAc/hexanes (1.5/8.5) as eluant to yield 1.5 g (80% yield) of methyl (S)-(+)-2-[(1,1'-biphenyl)-4-yl]-2-(2-phenylmethoxyacetoyl)oxypropionate.
Reaction SMILES: Cl.Cl.[CH2:3]([C:9]1[NH:10][NH:11][C:12]2[N:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:26]([Cl:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C(#N)C>[ClH:34].[CH2:3]([C:9]1[NH:10][N:11]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]2[N:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCC1=Nc2cccnc2NN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCCCCCC1=Nc2cccnc2N(C(=O)c2ccccc2)N1

Procedure:
3 g (0.01 mole) of 3-hexyl-1,2-dihydropyrido-[3,2-e]-as-triazine dihydrochloride are reacted with 2 g (0.02 mole) of triethylamine in 60 ml of anhydrous acetonitrile under argon, thereafter 2.9 g (0.02 mole) of benzoylchloride are added to the reaction mixture which is boiled for an hour. Then the mixture is cooled, poured into water, neutralized and extracted with chloroform. The solvent is evaporated and the residue is reacted with anhydrous hydrochloric ethanol to form a salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[CH2:10](Br)[C:11]#[CH:12].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C.CC(C)=O>[CH2:12]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9])[C:11]#[CH:10]
Reactant: COc1ccc[nH]c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCn1cccc(OC)c1=O
Temperature: 100 °C
Yield: 60 %

Procedure:
To a stirring solution of 3-methoxy-2-pyridinone (1.00 g, 8.00 mmol) in DMF (25 mL), was added propargyl bromide (80 wt % solution in toluene, 1.5 equiv) and K2CO3 (3.313 g, 24 mmol). Reaction mixture was heated to 100° C. After overnight reaction, reaction mixture was partitioned between EtOAc (120 mL) and water (100 mL). Organic layer was separated and washed repeatedly with water (7×100 mL) and brine (1×60 mL). Organic layer was dried on Na2SO4 and evaporated under vacuo to yield dark brown crude product. Column chromatography using gradient CH2Cl2:Acetone (max 20%) gave pure 150 (0.79 g, 60%) as a slightly brownish solid. 1H NMR (CDCl3, 400 MHz) δ 2.36 (1H, t, J=2.8), 3.67 (3H, m), 4.66 (1H, d, J=2.8), 6.05 (1H, t, J=7.2), 6.50 (1H, dd, J=1.6, 7.2), 7.11 (1H, dd, J=1.6, 6.8); 13C NMR (CDCl3, 100 MHz) δ 37.2, 55.5, 74.6, 77.3, 104.8, 112.0, 126.3, 149.4, 157.1. HRMS (EI) calcd for C9H9NO2 [M]+ 163.0633. found 163.0636
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Cl[CH2:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:17][C:18](=[O:19])[NH2:20])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: NC(=O)CCl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(N)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-hydroxyisophthalic acid dimethyl ester (500 mg, 2.38 mmol) and chloroacetamide (245 mg, 2.62 mmol) in DMF (7 mL) is added potassium carbonate (986 mg, 7.14 mmol) and the mixture is stirred at room temperature for 2 days. Water is added to the mixture and then it is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over sodium sulfate. The organic solution is concentrated to one fourth volume to give a precipitate. The solid is filtered, washed with ethyl acetate and dried under reduced pressure to give 5-carbamoylmethoxyisophthalic acid dimethyl ester. MS 268.2 (M+1);); 1H-NMR (400 MHz, CDCl3); δ ppm 3.96 (s, 6H), 4.59 (s, 2H), 5.87 (s, broad, 1H), 6.55 (s, broad, 1H), 7.79 (s, 2H), 8.37 (s, 1H).
Reaction SMILES: C(O)(=O)C.[CH:5](N)=[NH:6].[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[N:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]3=[CH:22][N:21]=2)=[O:19])=[CH:14][C:10]=1[C:11](O)=[O:12].[OH-].[Na+]>C(O)C>[CH:22]1[N:21]=[C:20]([C:18]([C:15]2[CH:14]=[C:10]3[C:9](=[CH:17][CH:16]=2)[N:8]=[CH:5][NH:6][C:11]3=[O:12])=[O:19])[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: Nc1ccc(C(=O)c2ncc3ccccn23)cc1C(=O)O
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(c1ccc2nc[nH]c(=O)c2c1)c1ncc2ccccn12
Temperature: 150 °C
Yield: 25.8 %

Procedure:
0.36 g (3.6 mmol) of formamidine acetate is added to 0.2 g (0.72 mmol) of 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid (described in WO 06/097625) in 7 ml of ethanol. The reaction medium is microwave-heated at 150° C. for 25 minutes. The reaction medium is hydrolysed with a 1N aqueous solution of sodium hydroxide. The aqueous phase is extracted with dichloromethane. The heterogeneous organic phase is filtered. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 54 mg of a yellow solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15])[C:9](=[O:16])[CH:8]=[CH:7]1)=[O:4].[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([OH:16])[CH:10]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15])=[O:4]
Reactant: CC/C=C\CC1C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC/C=C\CC1C(O)CCC1CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A 180 mg quantity of 4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone and 90 mg of sodium borohydride are dissolved in 20 ml of methanol, and the solution is refluxed at 80° C. for one hour. The reaction mixture is thereafter cooled to room temperature, and 20 ml of acetic acid is added to the mixture. The resulting mixture is stirred for 30 minutes and then concentrated at reduced pressure. The concentrate is distilled in a vacuum, giving 3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol (compound (3), R2 =CH3) in a yield of 94%, b.p. 63°-67° C./0.01 mm Hg.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10](COC)[C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[C:8]=2[CH:7]=1.[ClH:25]>C(O)C>[ClH:25].[ClH:25].[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[NH:10][C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[C:8]=2[CH:7]=1
Reactant: COCn1c(=O)c2c(c3cc(CCCN(C)C)ccc31)NCCC2
Agent: Cl
Solvent: CCO
Product: CN(C)CCCc1ccc2[nH]c(=O)c3c(c2c1)NCCC3
Yield: 90 %

Procedure:
The compound (112 mg, 0.34 mmol) prepared in step 9 was dissolved in ethanol (3 ml) and added with 12 N hydrochloric acid (2 ml). The resulting mixture was refluxed for 12 hours. Once the reaction was completed, the mixture was concentrated and recrystallized from methanol/ethyl acetate to obtain the title compound (110 mg, yield: 90%, yellow solid).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:17]Br>CC(O)=O>[Br:17][C:7]1[CH:6]=[C:5]([C@H:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCC[C@H](CC(=O)OC)c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCC[C@H](CC(=O)OC)c1ccc(O)c(Br)c1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To 10.1 (50 mg, 0.23 mmol) was added Br2 (36 mg, 11.6 μl, 0.23 mmol) in AcOH (1 mL) at room temperature. After 1 hour, the red color disappeared to give a pale orange solution. The solution was concentrated and purified by silica gel chromatography (0 to 50% EtOAc/hexanes) to afford a 27.1 (0.0629 g, 90.8% yield).