Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)C.[O:17]=[C:18]1[N:29]([C@@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([CH:36]=O)[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1.O>O1CCCC1>[O:17]=[C:18]1[N:29]([C@@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32](/[CH:36]=[CH:7]/[C:6]([OH:5])=[O:16])[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C[C@H]1CCC[C@@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/[C@H]1CCC[C@@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% in oil) (15 mg) in tetrahydrofuran (1 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (84 μl). After stirring at ambient temperature for 5 minutes, cis-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (100 mg) was added and stirred at ambient temperature for overnight. The reaction mixture was poured into water, and extracted with EtOAc and tetrahydrofuran. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by praparative thin layer chromatography eluting with dichloromethane:methanol=10:1. The fractions containing desired compound were combined and evaporated. The residue was dissolved in dioxane (500 μl), and 1M NaOH solution (352 μl) was added, then stirred at 100° C. for 2 hours. After cooling to the ambient temperature, 1M HCl (352 μl) and pH 4 buffer (10 ml) was added to the reaction mixture. Resulting precipitates were collected by filtration and washed with water to give (2E)-3-[cis-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexyl]acrylic acid (21 mg) as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6](Cl)=O)[CH3:2].C(OC1C=CC=CC=1C(O)=O)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([CH3:62])[C:40]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)([CH3:41])[NH:39]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:37]2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([CH3:62])[C:40]([C:42]3[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=3)([CH3:41])[NH:39][C:6]([C:5]3[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:4]=3[O:3][CH2:1][CH3:2])=[N:37]2)=[CH:32][CH:31]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CCOc1ccc(S(C)(=O)=O)cc1C(=O)Cl
Agent: CCOc1ccccc1C(=O)O
Product: CCOc1ccc(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methanesulfonyl-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 2-ethoxy-5-methanesulfonyl-benzoyl chloride (prepared from 2-ethoxy-benzoic acid in an analogous as described in example 59) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:64]/[O:65][CH3:66])/[C:27]([NH:29][CH:30]2[C:62](=[O:63])[N:32]3[C:33]([C:46]([O:48]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:47])=[C:34]([C:37]4[O:38][C:39]5[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=5[N:41]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:64]/[O:65][CH3:66])/[C:27]([NH:29][CH:30]2[C:62](=[O:63])[N:32]3[C:33]([C:46]([OH:48])=[S:47])=[C:34]([C:37]4[O:38][C:39]5[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=5[N:41]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4o3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(O)=S)=C(c3nc4ccccc4o3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
A 272 mg portion of diphenylmethyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido }-3-(benzoxazol-2-yl)thio-3-cephem-4-carboxylate was dissolved in 1.4 ml of anisole. Under cooling on an ice bath, the resulting solution was mixed with 2.7 ml of trifluoroacetic acid and stirred for 30 minutes at the same temperature. The resulting reaction mixture was added dropwise to 14 ml of diisopropyl ether, and the formed precipitate was recovered by filtration and dried. The thus dried product was suspended in 3 ml of distilled water, and the suspension was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution. Thereafter, this solution was chromatographed using 10 ml of HP-20 resin and freeze-dried to obtain 73 mg of the title compound as a sodium salt (yield, 46%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])=[CH:37][CH:36]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with 4-methoxybenzylamine (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 9 mg of the title compound as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:34])/[C:5](/[F:33])=[C:6](\[CH3:32])/[CH:7]=[CH:8]/[C:9](/[F:31])=[C:10](\[C:13]1[C:22]([O:23][CH2:24][O:25][CH3:26])=[CH:21][C:20]2[C:19]([CH3:28])([CH3:27])[CH2:18][CH2:17][C:16]([CH3:30])([CH3:29])[C:15]=2[CH:14]=1)/[CH2:11][CH3:12])C.[OH-].[Na+]>CCO>[F:33]/[C:5](=[C:6](/[CH3:32])\[CH:7]=[CH:8]\[C:9](\[F:31])=[C:10](/[C:13]1[C:22]([O:23][CH2:24][O:25][CH3:26])=[CH:21][C:20]2[C:19]([CH3:28])([CH3:27])[CH2:18][CH2:17][C:16]([CH3:30])([CH3:29])[C:15]=2[CH:14]=1)\[CH2:11][CH3:12])/[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)/C(F)=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC/C(=C(F)/C=C/C(C)=C(\F)C(=O)O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure E and using (2Z,4E,6E)-2,6-difluoro-7-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-nona-2,4,6-trienoic acid ethyl ester (Compound 20, 314 mg, 0.66 mmol), 1M NaOH (2.0 mL) and EtOH (5 mL) at 40° C. for overnight followed by flash column chromatography on silica gel (10%→50% EtOAc-hexane), the title compound was obtained as a yellow solid (282 mg, 95%). 1H NMR (300 MHz, CDCl3): δ0.98 (t, J=7.6 Hz, 3H), 1.23 (s, 6H), 1.29 (s, 6H), 1.67 (s, 4H), 2.06 (d, J=3.2 Hz, 3H), 2.47 (m, 1H), 2.68 (m, 1H), 3.44 (s, 3H), 5.12 (s, 2H), 6.35 (dd, J=26.1, 15.8 Hz, 1H), 6.94 (s, 1H), 7.01 (dd, J=15.8, 1.8 Hz, 1H), 7.02 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:29][CH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)=[O:24])[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reactant: CNC(=O)c1ccc(CN)cc1
Product: CNC(=O)c1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)cc(F)c4C)ccc32)cc1

Procedure:
Example 135 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-H-indazol-1-yl)acetate (Example 123) and 4-(aminomethyl)-N-methylbenzamide to give the title compound (0.005 g).
Reaction SMILES: [CH:1]1([C:4]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[F:13])[CH3:5])[CH2:3][CH2:2]1.CC(C(C1C2C(=C(CS(C)=[O:53])C=CC=2)NC=1)C1C=CC(C(F)(F)F)=CC=1)CC#N>>[CH:1]1([C:4]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:53])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[F:13])[CH3:5])[CH2:3][CH2:2]1
Reactant: CSCc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3)c[nH]c12
Reactant: CC(CC#N)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 217 mg (94% purity, 0.61 mmol) of the compound from Example 96 in analogy to the synthesis of the compound from Example 91. 212 mg (99% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20]>CN(C)C=O.C(OCC)(=O)C.O.[Cl-].[Na+].O>[Br:17][C:18]([F:25])([F:24])[C:19]([NH:1][CH2:2][C:3]1([OH:16])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1)=[O:20]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CNC(=O)C(F)(F)Br)CC1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of tert-butyl 4-(aminomethyl)-4-hydroxy-piperidine-1-carboxylate (3.00 g, 13.0 mmol) in N,N-dimethylformamide (30 mL) was added ethyl 2-bromo-2,2-difluoro-acetate (2.65 g, 13.0 mmol) and the reaction mixture stirred for 1 h under nitrogen. The reaction mixture was mixture diluted with ethyl acetate and water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated to provide tert-butyl 4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (4.98 g, 12.9 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J=5.9 Hz, 1H), 4.66 (s, 1H), 3.65 (d, J=12.7 Hz, 2H), 3.16 (d, J=6.1 Hz, 2H), 3.02 (s, 2H), 1.38 (m, 13H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][CH2:22][C:23]1[CH:28]=CC=C[CH:24]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(C1CC1)#C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][CH2:22][CH:23]1[CH2:28][CH2:24]1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2nc(CCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: C#CC1CC1
Product: Cc1cc2nc(CCC3CC3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(2-cyclopropylethyl)-7-methylquinolin-6-yl)acetic acid (39) (5.7 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl)acetic acid of Example 37 except using ethynylcyclopropane instead of ethynylbenzene. 1H-NMR 400 MHz (CD3OD) δ 8.17 (d, J=8.4 Hz, 1 H), 7.91 (s, 1 H), 7.66 (d, J=8.8 Hz, 1 H), 7.6-7.5 (m, 3 H), 7.31 (m, 1 H), 5.18 (s, 1 H), 3.21 (m, 2 H), 2.71 (s, 3 H), 1.72 (m, 2 H), 0.92 (s, 9 H), 0.75 (m, 1 H), 0.41 (m, 2 H), 0.02 (m, 2 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C27H31ClNO3: 452.2. Found: 452.2.
Reaction SMILES: O.C1(=O)CCCCC1.[N+:9]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]2[CH2:23][O:22][CH2:21][CH2:20][O:19]2)=[CH:14][CH:13]=1)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].C(O)(=O)C>[NH2:9][C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]2[CH2:23][O:22][CH2:21][CH2:20][O:19]2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCC2COCCO2)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: O=C1CCCCC1
Product: Nc1ccc(OCC2COCCO2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
46.2 g of iron filings, 46 ml of water and 9 ml of glacial acetic acid are stirred for 30 minutes at 95° C. Then 150 ml of cyclohexanone are added and, when the temperature has again risen to 95° C., 36.8 g of (p-nitrophenoxy)methyl-1,4-dioxane (known from British patent specification 749 713) are added in portions. The batch is then stirred for 31/2 hours at 95° C. and, after addition of 9.0 g of sodium carbonate in portions, filtered hot. The residue is washed with cyclohexanone and the filtrate is subjected to steam distillation. After cooling, the product precipitates in the form of white crystals which are separated from a dark oil and recrystallised from water with the addition of animal charcoal. The crystals are dried in vacuo at 60° C., affording 16.3 g (51% of theory) of (p-aminophenoxy)methyl-1,4-dioxane of the formula ##STR33## with a melting point of 86°-87° C.
Reaction SMILES: C(COC1C=C(OC)C=CC=1CN1C2C(=CC(O)=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O)(OCC)=O.[CH2:41]([O:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:60]=1[O:67][CH2:68][C:69]([O:71]CC)=[O:70])[C:53]([C:74]([O:76]CC)=[O:75])=[C:52]2[C:79]1[CH:84]=[CH:83][C:82]2[O:85][CH2:86][O:87][C:81]=2[CH:80]=1)[C:42]1C=CC=C[CH:43]=1>>[C:69]([CH2:68][O:67][C:60]1[CH:61]=[C:62]([O:65][CH3:66])[CH:63]=[CH:64][C:59]=1[CH2:58][N:54]1[C:55]2[C:51](=[CH:50][C:49]([O:48][CH2:41][CH2:42][CH3:43])=[CH:57][CH:56]=2)[C:52]([C:79]2[CH:84]=[CH:83][C:82]3[O:85][CH2:86][O:87][C:81]=3[CH:80]=2)=[C:53]1[C:74]([OH:76])=[O:75])([OH:71])=[O:70]
Reactant: CCOC(=O)COc1cc(OC)ccc1Cn1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2cc(OCc3ccccc3)ccc21
Agent: CCOC(=O)COc1cc(OC)ccc1Cn1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2cc(O)ccc21
Product: CCCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)O)n2Cc1ccc(OC)cc1OCC(=O)O

Procedure:
Ethyl 1-(2-carboethoxymethoxy-4-methoxybenzyl)-5-hydroxy-3-(3,4-methlenedioxyphenyl)indole-2-carboxylate. The title compound was prepared from ethyl 5-benzyloxy-1-(2-carboethoxymethoxy-4-methoxybenzyl)-3-(3,4-methylenedioxyphenyl)indole-2-carboxylate (460 mg, 0.735 mmol) by the method given in example 6; m.p. 128°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[C:19]#[CH:20].C([O-])([O-])=O.[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH2:20][C:19]#[CH:18])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)ncn2-c1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccccc1-n1cnc2cc(N)ccc21
Temperature: 70 °C
Reaction time: 18.5 h
Yield: 36.6 %

Procedure:
A suspension of 5-amino-1-(2-hydroxyphenyl)benzimidazole (4) (499 mg, 2.21 mmol), 80% propargyl bromide (2.43 mmol) in toluene (271 μL), K2CO3 (398 mg, 2.88 mmol), and acetone (15 mL) is stirred at 70° C. under argon for 18.5 h and then cooled to room temperature. The mixture is concentrated, diluted with H2O (35 mL), and extracted with ethyl acetate (100 mL and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (2% to 7% methanol/ethyl acetate) to give 213 mg (39%) of 5 as a light-brown solid, mp 40-42° C. IR 3379, 2966, 1512, 1239 cm−1; 1H NMR (CDCl3) δ 2.51 (t, J=2.4 Hz, 1H, C≡CH), 3.09 (bs, 2H, NH2), 4.68 (d, J=2.4 Hz, 2H, CH2C≡CH), 6.74 (dd, J=8.4 Hz, 2.1 Hz, 1H, 6-BenzimidH), 7.14 (d, J=8.4 Hz, 1H, 7-BenzimidH), 7.16 (d, J=2.1 Hz, 1H, 4-BenzimidH), 7.19 (m, 1H, 3-PhH), 7.29 (m, 1H, 5-PhH), 7.42-7.49 (m, 2H, 4,6-PhH), 8.01 ppm (s, 1H, 2-BenzimidH). HRMS calcd C16H13N3O [M+H]+ 264.1137. found 264.1129.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.S(=O)(=O)(O)[OH:13]>[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]([OH:13])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: O=S(=O)(O)O
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Agent: [Cr+6]
Agent: [O-2]
Product: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of 63.3 g (0.3 mol) of 2,4,6-trichloro-5-formylpyrimidine in 300 ml of fuming sulfuric acid (SO3 content 25%) are added in flake form 24 g (0.24 mol) of chromium trioxide, and the mixture is stirred for 20 hours. The temperature rises within about one hour to 45°-50° C., and then falls again to room temperature (20°-25° C.). The reaction solution is poured into ice water, and the precipitate is filtered off and washed with a small amount of ice-water. The reaction product is dissolved in diethyl ether; the solution is then dried over sodium sulfate and subsequently evaporated to dryness. The yield is 55.4 g (81.2%) of 2,4,6-trichloropyrimidine-5-carboxylic acid, m.p. about 150° C. The melting point can be raised to 155°-157° C. by recrystallisation of the product from chloroform.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH2:18]([NH:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCC=O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCCCCCCN[C@@H](CC(C)C)C(=O)OC
Yield: 51 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-leucine methyl ester hydrochloride (1 gm, 5.5 mmol), THF (20 mL), MgSO4 (1.12 gm, 9.35 mmol), decanal (2.06 mL, 11.0 mmol), Et3N (767 μL, 5.5 mmol), sodium borohydride (416 mg, 11.0 mmol), and methanol (25 mL) to give 11b (800 mg, 51%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.88-0.98 (9H, m), 1.2-1.37 (15H, m), 1.42-1.54 (4H, m), 1.71 (1H, heptet), 2.42-2.5 (1H, m), 2.53-2.6 (1H, m), 3.29 (1H, t, J=7.32 Hz), 3.74 (3H, s). ESI-MS: 308.1 (M+23).
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([CH:13]2[O:15]C2)=[CH:11][CH:10]=1>>[C:9]1([CH3:8])[CH:17]=[CH:16][C:12]([CH:13]=[O:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C2CO2)cc1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Product: Cc1ccc(C=O)cc1

Procedure:
Following the procedure of Example 16 and employing 4.84 g. (0.115 mol) of 57% sodium hydride, 23.5 g. (0.115 mol) of trimethylsulfonium iodide and 11.9 g. (0.099 mol) of p-tolualdehyde there is obtained p-methylstyrene oxide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>C(O)C>[N:16]1[C:3]([C:5]2[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)=[CH:2][N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18][C:17]=12
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2cn3c(n2)sc2ccccc23)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of 1.95 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, 1.06 g of 2-aminobenzothiazole and 50 ml of ethanol is heated to boiling under reflux for 17 hours. The reaction mixture is then cooled to room temperature, whereupon the crystals are removed by filtration under suction. There is obtained 5-(imidazo[2,1-b]benzothiazol-2-yl)-3-nitropyrocatechol of m.p. 303°-305° (from N,N-dimethylformamide/methanol).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].C(N(CC)CC)C.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C1COCC1>[C:1]([CH:3]1[CH2:5][N:4]1[C:14]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:15])#[N:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#CC1CN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1CN1C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 33 %

Procedure:
A solution of 175 mg of 2-cyanoaziridine and 0.36 mL of triethylamine in 5 mL of THF was cooled and stirred in an ice bath. A solution of 550 mg of 4-Nitrophenyl chloroformate in 2.5 mL of THF was added at a rate that kept the temperature below 10° C. When the addition was complete, the solution was stirred 2 hours at room temperature and then filtered to remove triethylamine hydrochloride. The filtrate was concentrated under reduced pressure and the residual oil was stirred with 5 mL of toluene for 30 minutes. The pale yellow precipitate that formed was washed with toluene (2×5 mL) and dried under vacuum to afford a 33% yield of 4-nitrophenyl 2-cyanoaziridine-1-carboxylate, m.p. 100-104°C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][C:20]=1[O:27][CH2:28][O:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CS(C)=O.[Cl-].[Na+].O.O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:21]=1)=[O:6]
Reactant: COCOc1cc(CN)ccc1OCc1ccccc1
Reactant: Nc1ncccc1C(=O)O
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COCOc1cc(CNC(=O)c2cccnc2N)ccc1OCc1ccccc1

Procedure:
Next, a solution of 2-amino-nicotinic acid (16 mg, 0.116 mmol), 4-benzyloxy-3-methoxymethoxy-benzylamine (15 mg, 0.0549 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (55 mg, 0.124 mmol) and triethylamine (0.08 mL, 0.574 mmol) in dimethylsulfoxide (4 mL) was stirred under nitrogen atmosphere at room temperature for 24 hours. Water (100 mL) and brine (50 mL) were added to the reaction solution, which was then extracted with ethyl acetate (100 mL) twice, and washed with water twice. The organic layer was dried over anhydrous magnesium sulfate, which was then filtered, the filtrate was evaporated in vacuo, and 2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide was obtained as a pale yellow oil. This was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then hexane:ethyl acetate=3:7), and 2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide) (9.4 mg, 0.0239 mmol, 43.5%) was obtained as a pale yellow oil. A solution of the resulting 2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide (7.8 mg, 0.0198 mmol) and 2M hydrochloric acid (2 mL) in methanol (3 mL) was stirred for 21 hour at room temperature. Sodium bicarbonate (600 mg, 7.14 mmol) was added to the reaction mixture to basify it, which was then filtered, evaporation in vacuo was carried out, then, the obtained residue was purified by thin layer NH silica gel chromatography (methanol:ethyl acetate=5:95), and the title compound (2.0 mg, 0.0057 mmol, 29%) was obtained as a white solid.