Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([C:9]3[CH:14]=[C:13]([CH2:15][O:16][CH3:17])[CH:12]=[CH:11][C:10]=3[N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)=[N:8][C:4]=2[CH:3]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([N:6]1[C:5]2[CH:27]=[CH:28][C:2]([C:33]3[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[C:13]([CH2:15][O:16][CH3:17])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)([CH3:25])([CH3:26])[CH3:24]
Reactant: COCc1ccc(-n2cncn2)c(-c2nc3cc(Br)ccc3n2C(C)(C)C)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 110 °C
Yield: 79.8 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-(5-methoxymethyl-2-[1,2,4]triazol-1-yl-phenyl)-1H-benzoimidazole (34 mg, 0.08 mmol) in DMF (1.5 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (20 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) and 2M aqueous Na2CO3 (0.15 mL). The reaction mixture is heated under argon at 110° C. for 2 hours. The residue is diluted with EtOAc (20 mL), washed with brine (10 mL), dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-4% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (29 mg, 83%). LCMS (ESMS): m/z 455.44 (M++1)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.S(Cl)(Cl)(=O)=O>C(OC(C)C)(C)C.O>[C:22]([C:21]1[CH:25]=[CH:26][C:18]([NH:17][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[CH:19][CH:20]=1)([OH:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)cc1
Yield: 82.4 %

Procedure:
A mixture of 190.5 g (1 mole) of 4-toluenesulfonyl chloride in 300 ml of i-propyl ether is added dropwise at 20°-30° C. to one of 252 g (3 mole) of sodium bicarbonate and 139.1 g (1 mole) of 4-aminobenzoic acid in 2.5 l of water. The mixture is stirred vigorously for 2-4 hours, until the sulfonyl chloride has been consumed. The aqueous solution is separated off and then adjusted to pH 1 with concentrated hydrochloric acid, and the precipitate is taken up in propyl acetate. The extract is washed 2× with 2N hydrochloric acid and 1× with water, dried over sodium sulfate and evaporated. 240 g (82.5% of theory) of N-(4-carboxyphenyl)-4-toluenesulfonamide are obtained.
Reaction SMILES: [BH4-].[K+].[CH3:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].O>CO>[OH:9][CH:8]1[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:14])[N:4]1[CH3:3]
Reactant: CN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN1C(=O)c2ccccc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 44.4 %

Procedure:
3.4 g of potassium borohydride are added slowly to a suspension of 10 g of N-methylphthalimide in 220 cm3 of methanol under an inert atmosphere. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by dropwise addition of 200 cm3 of distilled water. The solvent is then partially evaporated off (about 120 cm3) under reduced pressure (2 kPa) at a temperature in the region of 35° C., and the residue is diluted with 400 cm3 of distilled water. The mixture is extracted with 400 cm3 of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. 4.5 g of 3-hydroxy-2-methyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder melting at 130° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C@@H:6](/[CH:10]=[CH:11]/[C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8].[H][H]>C1COCC1.[Pt](=O)=O>[CH:4]1([CH2:5][C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][CH:20]([O:23][CH3:24])[CH2:21][CH2:22]2)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8])[CH2:25][CH2:26][CH2:27][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: COc1ccc(C[C@@H](/C=C/[C@H](Cc2cccc(Cl)c2)C(=O)O)C(=O)O)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COC1CCC(C[C@@H](CC[C@H](CC2CCCCC2)C(=O)O)C(=O)O)CC1
Yield: 98.6 %

Procedure:
To a solution of (2S,5S,E)-2-(3-chlorobenzyl)-5-(4-methoxybenzyl)hex-3-enedioic acid (113 mg, 0.291 mmol) in THF (5 mL) was added platinum(IV) oxide (60 mg, 0.26 mmol). The reaction was stirred at 1 atm of hydrogen (balloon) for 16 h. The reaction was filtered through CELITE® and washed with MeOH. The combined filtrate and MeOH washing was concentrated to give (2R,5R)-2-(cyclohexylmethyl)-5-((4-methoxycyclohexyl)methyl)hexanedioic acid (105 mg, 0.287 mmol, 98.5 yield) as an oil. Anal. Calcd. for C20H27ClO4 m/z 366.4. found: 365.3 (M−H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(OC(=O)C)(=[O:18])C>>[C:1]1([C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: O=c1cc(-c2ccccc2)cc[nH]1
Reaction time: 2 h

Procedure:
A solution of 4-phenylpyridine-N-oxide (8.55 g, 50 mmol) in acetic anhydride (250 ml) was heated under reflux for sixteen hours. Acetic anhydride was then removed under vacuum and the residue was dissolved in absolute ethanol (200 ml) and 80% sodium hydride (1.5 g, 50 mmol) was added in small portions. The mixture was stirred for 2 hours under nitrogen, then evaporated and the residue was dissolved in ethyl acetate and dilute hydrochloric acid. The phases were separated and the aqueous phase was basified (sodium bicarbonate) and re-extracted (ethyl acetate). The aqueous phase was filtered to give the solid product which was recrystallised from ethyl acetate/methanol to give pure product, 3.76 g, Mp 226°-230° C. The combined organic extracts were evaporated to give a further quantity (1.58 g) of impure product.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C[O-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][O:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 81.1 %

Procedure:
To a solution of (25)-1-(tert-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (1.50 g) in methanol (5 ml) were added 4-chlorophenol (1.90 g) and 1M sodium methoxide in methanol (7.1 ml), followed by 19 hour' reflux at 70° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 2N sodium hydroxide, saturated ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a etude product of the title compound (1.95 g).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[OH:23][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(OC)cc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)cc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A mixture of 7-hydroxy-2-(4-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (76 mg, 0.23 mmol) and glycine (345 mg, 4.59 mmol) in 0.5 M sodium methoxide/methanol (8.7 mL) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. Water (20 mL) was added and the suspension was adjusted to pH=10 with 1N HCl (3 mL). The mixture was extracted with dichloromethane. And the remaining aqueous layer was acidified to pH=3 with 1N HCl (5 mL). The suspension was extracted with 2-isopropanol/chloroform (1:3, 50 mL). The organic layer was concentrated and dried in vacuo to give the title compound as a yellow solid (25 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.28 (s, 1H), 9.42 (t, 1H), 8.88 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 4.03 (d, J=5.6 Hz, 2H), 3.88 (s, 3H); MS: (+) m/z 359.94 (M+1), (−) m/z 357.92 (M−1).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]([C:25]1[S:29][C:28]([NH2:30])=[N:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:21]([C:25]1[S:29][C:28]([NH:30][C:15]([CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[O:17])=[N:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CC(C)(C)c1nnc(N)s1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)Nc2nnc(C(C)(C)C)s2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C18H23N3O5S [M−H]−: 392.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: CN1CCNCC1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(C)CC2)c2nccc(C)c2c1
Yield: 53.7 %

Procedure:
A mixture of 5.5 g (0.015 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 1.8 g (0.018 mole) of N-methylpiperazine in 70 ml of benzene was heated under reflux for 20 hr, treated with 2 ml of triethylamine, and heated for an additional 24 hr. The mixture was allowed to cool, filtered and the filtrate was washed with water, dried and concentrated to dryness in vacuo. The residue was recrystallized twice from n-hexane containing a little toluene and then dried in vacuo at 68° to afford 3.1 g (53%) of the title compound, mp 104°-107°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O.O1CCOCC1>[CH2:25]([O:24][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]1[C:14]([OH:16])=[O:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of (S)-4-(tert-butoxycarbonyl) piperazine-2-carboxylic acid (1.0 g, 4.34 mmol) in water (5 mL) was added solid NaHCO3 (0.73 g, 8.68 mmol) at room temperature. The reaction mixture was stirred at room temperature to get clear solution. Solution of CBZ-Cl (1.22 mL, 8.68 mmol) in 1,4-dioxane (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The aqueous layer was acidified with 0.5M aqueous HCl to pH 5 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.30 g) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[CH3:24][O:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([CH:34]=O)=[CH:28][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([O:25][CH3:24])=[N:27][CH:28]=2)[CH2:12]1)=[O:9])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: COc1ncc(C=O)c(OC)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ncc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)c(OC)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)-3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (17.2 mg, 0.04 mmol) was dissolved in THF (1 mL) and 2,4-dimethoxy-5-pyrimidine carboxaldehyde (6.7 mg, 0.04 mmol) was added followed by sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) and glacial acetic acid (2.4 mg, 0.04 mmol). The mixture was stirred at room temperature for 24 h and evaporated. The residue was then dissolved in dichloromethane (1 mL) and washed with 1 N NaOH solution (1 mL). The organic phase was recovered and evaporated then treated with 25% trifluoroacetic acid in dichloromethane (1 mL) for 1 h at room temperature and evaporated. The residue was purified using LC/MS to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(2,4-dimethoxypyrimidin-5-ylmethyl)pyrolidine (Compound No. 2175) (18.6 mg, 78%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 483 (M++H, C21H25F3N6O4).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C)C=O>[Si:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 62.5 %

Procedure:
t-Butyldimethylsilyl chloride (3.07 g, 20.4 mmol) was added in one portion to a stirred solution of benzyl (4-hydroxyphenyl)acetate (4.70 g, 19.4 mmol) and imidazole (1.39 g, 20.4 mmol) in dimethylformamide (25 mL) at room temperature under nitrogen. After stirring for 4 h the volatiles were evaporated and the residue partitioned between water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous phase washed with ethyl acetate (2×100 mL). The organic extracts were combined, dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (10% diethyl ether: cyclohexane) to give the title compound as a colourless oil (4.32 g, 62%). LC/MS: 4.13 min; z/e 374, calcd (M+18) 374. 1H NMR (400 MHz: CDCl3): 7.15 (5H), 6.95 (2H), 6.60 (2H), 4.95 (2H) 3.40 (2H), 0.8 (9H), 0.00 (6H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:15]O>>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:15])=[O:8]
Reactant: CO
Reactant: Cc1ccsc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1sccc1C
Yield: 97 %

Procedure:
To a solution of 3-Methylthiophene-2-carboxylic acid (15 g, 105 mmol, 1.0 eq) in methanol (150 mL) was added cone sulfuric acid (7.5 mL) drop wise and refluxed for 12 h. The solvent was evaporated under vacuum and the residue was taken into ethyl acetate (200 mL), washed with water (2×50 mL), saturated aqueous sodium bicarbonate solution (2×50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum to afford 20 g (97%) of the desired product as a oil. 1HNMR (400 MHz, CDCl3) δ 7.38 (d, J=5.0 Hz, 1H), 6.91 (d, J=5.0 Hz, 1H), 3.85 (s, 3H), 2.55 (s, 3H); ESI-MS [(m/z) 157 (MH)+]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=1>>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][N:21]=3)=[O:24])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Cl)cn3)cc2)C1

Procedure:
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-chloropyridine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 344.85 (C18H21CIN4O); MS (ESI): 345 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[N:10][OH:11])[CH2:2]1.[H-].[Na+].S(OC)(O[CH3:18])(=O)=O.O>CN(C)C=O>[CH3:18][O:11][N:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: ON=C1COc2ccccc21
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C1COc2ccccc21
Yield: 42 %

Procedure:
3.7 g of benzofuran-3-one oxime are dissolved in 15 ml of dimethylformamide. At 20° C., 1 g of sodium hydride (60%) is added and the mixture is stirred until the evolution of gas ceases. 3.15 g of dimethyl sulphate are then added dropwise and the mixture is stirred at 20° C. for 24 hours. The reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is chromatographed over silica gel using n-hexane/acetone (4:1). 1.7 g (42% of theory) of benzofuran-3-one O-methyl-oxime are obtained as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:30])[CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].[CH:31](OC1C=CC=CC=1NCCNCC1C=C(C(N2CCCCC2)=O)C=CC=1)(C)C>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:30])[CH2:12][CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)[CH3:31])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1N(C)CCNCc1cccc(C(=O)N2CCCCC2)c1
Reactant: CC(C)Oc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Product: CC(C)Oc1ccccc1N(C)CCN(C)Cc1cccc(C(=O)N2CCCCC2)c1

Procedure:
The title compound was prepared as in Example 27 substituting [3-({2-[(2-isopropoxy-phenyl)-methyl-amino]-ethylamino}-methyl)-phenyl]-piperidin-1-yl-methanone for (3-{[2-(2-isopropoxy-phenylamino)-ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone. MS (ESI): mass calculated for C26H37N3O2, 323.29. m/z found, 324.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 (dd, J=5.9, 3.3 Hz, 1H), 7.53 (dd, J=5.9, 3.3 Hz, 1H), 7.30-7.33 (m, 2H), 6.93-6.82 (m, 4H), 4.59 (hept, J=6.1 Hz, 1H), 3.70 (br s, 2H), 3.52 (s, 2H), 3.31 (br s, 2H), 3.25 (t, J=7.3 Hz, 2H), 2.80 (s, 3H), 2.63 (t, J=7.3 Hz, 2H), 2.19 (s, 3H), 1.67 (br s, 6H), 1.35 (d, J=6.1 Hz, 6H).
Reaction SMILES: [OH-:1].[Na+].O[NH2:4].C[O:6][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)=O>C1COCC1.CO.O>[OH:1][NH:4][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)=[O:6]
Reactant: NO
Reactant: [OH-]
Reactant: COC(=O)c1ccc2ccn(Cc3ccc(OC(F)F)cc3)c2c1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(NO)c1ccc2ccn(Cc3ccc(OC(F)F)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of sodium hydroxide (0.1 g, 2.5 mmol) and 50% aqueous hydroxyl amine (1 mL) was added 1-(4-difluoromethoxy-phenylmethyl)-1H-indole-6-carboxylic acid methyl ester (0.14 g, 0.4 mmol) dissolved in THF/MeOH (2 mL, 1:1). After stirring 3 hr at room temperature, the solution was diluted with water (4 mL) and the volatile solvents were removed in vacuo. The solution was then neutralized to pH=7-8 with 1N HCl. The resulting precipitate was isolated by filtration to provide 1-(4-difluoromethoxy-phenylmethyl)-1H-indole-6-carboxylic acid hydroxyamide as a white powder (0.1 g, 75% yield). 1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.92 (s, 1H), 7.96 (s, 1H), 7.67 (d, 1H, J=3.1 Hz), 7.59 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=8.6 Hz), 7.27 (d, 2H, J=8.6 Hz), 7.17 (d, 1H, J=18 Hz), 7.13 (d, 2H, J=8.6 Hz), 6.55 (d, 1H, J=3.1 Hz), 5.47 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[N:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N+:16]=[N-:17].[Na]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:18]([N:15]=[N+:16]=[N-:17])[C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=Cc1cc(OC)c(OC)c(OC)c1)N=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
3,4,5-Trimethoxybenzaldehyde (992 mg) and methyl azidoacetate (2.91 g) were dissolved in dry methanol (2 mL), and a dry methanol solution (10 mL) of sodium (582 mg) was added dropwise to the solution at 0° C. over 2 hours under an argon atmosphere. After stirring the reaction mixture for 30 minutes as it is, it was concentrated under reduced pressure, and water was added to the residue to collect crystals deposited by filtration. The crystals were washed with water and dried to obtain the title compound.