Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:12]=C[C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])#N.Cl.O.[C:18]([OH:24])([C:20](F)(F)F)=[O:19]>CC#N>[C:18]([C:20]1[CH:12]=[C:5]([CH:4]=[CH:3][C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])([OH:24])=[O:19]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1cc(C[C@H](N)C(=O)O)ccc1O
Agent: Cl
Solvent: O
Solvent: CC#N
Product: N[C@@H](Cc1ccc(O)c(C(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A 250 mL 3-necked flask equipped with a magnetic stirrer and a condenser was charged with 4.1 g of 3-cyano-L-tyrosine and 100 mL of 6N aqueous HCl. The mixture was heated to reflux with stirring. After 36 h, HPLC (C18, 90:10:0.1 H2O:MeCN:TFA) indicated no remaining starting material at k′=1.33 and a major new component at k′=1.69. The reaction mixture was cooled to RT, filtered to remove solids, and concentrated in vacuo to dryness. The residue was dissolved in 100 mL of 8:2 H2O:MeOH and the solution was passed through two C18 plugs (3.5×4.5 cm, EM separations LiChroprep RP-18) washing with 8:2 H2O:MeOH. The filtrate was concentrated in vacuo to dryness to afford 4.5 g of 3-carboxytyrosine as a brown solid. A portion of this material (1.30 g) was dissolved in 40 mL of 1,4dioxane with 2 mL of concentrated H2SO4 and the solution was added to 30 mL of isobutylene (condensed at −78° C.) in a 300 mL pressure bottle equipped with a magnetic stirrer. The vessel was stoppered, warmed to RT and stirred. After 48 h, the bottle was cooled to 0° C. in an ice water bath, opened, and the mixture was treated with 20 g of NaHCO3. After allowing the isobutylene to evaporate, the mixture was suspended in 300 mL of water and extracted with CH2Cl2 (4×100 mL). The combined CH2Cl2 extracts were washed with 5% aqueous NaHCO3 (2×50 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give a yellow-brown oil. Analysis by tlc (SiO2, 97:3 CH2Cl2:MeOH) indicated a major component at Rf=0.41 and three minor components at Rf=0.30, 0.25 and 0.0. The crude material was purified by flash chromatography on 75 g of silica gel (94:6 CH2Cl2:MeOH) to give 1.2 g of a light yellow oil. The oil was dissolved in 40 mL of ether and treated with 3.9 mL of 1M ethereal HCl. A precipitate formed which was collected by filtration and dried in vacuo to afford 1.14 g (53%) of tert-butyl 3-(tert-butoxycarbonyl)-L-tyrosinate HCl as a fluffy white solid. An analytical sample (26 mg) was prepared by recrystallization from MeOH-ether, m.p. 205° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(-c2ncccc2C(F)(F)F)ccc1C(=O)O

Procedure:
Hydrogenate the solution of 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid (3.84 mmol) in 95% EtOH (100 mL) with 10% Pd-C (150 mg) for over night. Filter through a celite pad and concentrate the filtrate to give 2-amino-4(3-trifluoromethyl-pyridin-2-yl)-benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[CH:23]([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.28 mmol) and isobutyraldehyde (0.14 g, 1.92 mmol) in dichloroethane was added sodium triacetoxy borohydride (0.81 g, 3.85 mmol) and catalytic acetic acid. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCl3) δ: 0.80 (6H, 2×d), 1.45 (9H, s), 1.60–1.90 (2H, m), 2.20 (2H, d), 3.00–3.70 (7H, m), 7.20 (4H,s). ESI-MS m/z: 367 (M+1), UV retention time: 1.89 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5](=[O:29])[C@@H:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[C:9]1=[O:28])[CH3:7].N1C=CC=CC=1.[S:39](Cl)([CH3:42])(=[O:41])=[O:40].Cl>C(Cl)Cl>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([NH:13][C@H:10]1[CH2:11][CH2:12][N:8]([C@@H:6]([CH3:7])[C:5]([N:4]([CH:30]([CH3:32])[CH3:31])[CH2:3][CH2:2][NH:1][S:39]([CH3:42])(=[O:41])=[O:40])=[O:29])[C:9]1=[O:28])(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N(CCN)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N(CCNS(C)(=O)=O)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (0.04 g) was dissolved in DCM (3 ml) at 0° C. and was treated with pyridine (0.027 ml) and mesyl chloride (0.03 ml). The reaction mixture was allowed to reach room temperature and then stirred at room temperature for 3 h. Additional DCM (3 ml) followed by hydrochloric acid (5 ml) was added. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with DCM, diethyl ether, ethyl acetate:10% aqueous NH3) to give the title compound (0.024 g) as gum.
Reaction SMILES: [CH2:1]([NH2:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[Cl-].[CH2:13]([O:15][C:16](=[O:20])[C:17](O)=[O:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:20])[C:17]([NH:11][CH2:1]/[CH:2]=[C:3](\[CH3:4])/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:18])[CH3:14]
Reactant: CCOC(=O)C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CN
Agent: [Cl-]
Product: CCOC(=O)C(=O)NC/C=C(\C)CCC=C(C)C

Procedure:
Said substance is manufactured according to AAV 1, by converting geranylamine and oxalic acid monoethylester chloride with each other and the product is purified by column chromatography (pentane/diethyl ether=2/1).
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[OH-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O>[C:15]([NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:11])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(OC)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
1.06 g of 3-aminobenzaldehyde dimethyl acetal was dissolved in a mixture of 5 ml of toluene and 10 ml of water containing 0.8 g of sodium hydroxide, and 5 ml of a toluene solution of 1.3 g of benzoyl chloride was added. The mixture was stirred at room temperature for 2 hours. The organic layer was separated, and evaporated under reduced pressure. The residue was dissolved in a mixture of 10 ml of methanol and 10 ml of 10% hydrochloric acid, and heated at 90° C. for 30 minutes. Water (20 ml) was added to the reaction mixture to allow it to cool. There was obtained 1.16 g (yield 87.3%) of 3-benzoylaminobenzaldehyde as colorless needles having a melting point of 122° to 123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of N-p-nitrobenzyloxycarbonyl-4-hydroxymethylpiperidine (20 g) in dry pyridine (127 ml) was added p-toluenesulfonyl chloride (25.8 g) with ice-cooling, and the reaction mixture was kept overnight at the same temperature, diluted with ice water and extracted with diethyl ether dichloromethane. The extract was washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate and again water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was crystallized from methanol to give N-p-nitrobenzyloxycarbonyl-4-p-toluenesulfonyloxymethylpiperidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](Cl)[C:12]=3[S:11][C:10]=2[CH3:20])=[C:4]([CH3:21])[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]4)[C:12]=3[S:11][C:10]=2[CH3:20])=[C:4]([CH3:21])[CH:3]=1
Reactant: OCC1CCNCC1
Reactant: Cc1nc(Cl)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCC(CO)CC2)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of 7-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2,6-dimethyl-thieno[3,2-d]pyrimidine (500 mg), piperidin-4-ylmethanol (226 mg), N,N-diisopropylethylamine (253 mg) in ethanol (1.5 mL) was heated at reflux for 1 day. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with EtOAc. The organic layer washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/EtOAc=3:1) to obtain {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol as a white solid (568 mg).
Reaction SMILES: [CH2:1]([P:7](=[O:10])([OH:9])[OH:8])[CH2:2][P:3](=[O:6])([OH:5])[OH:4].C(Cl)(=O)C(Cl)=O.[F:17][C:18]1([F:34])[C@H:22]([OH:23])[C@@H:21]([CH2:24]O)[O:20][C@H:19]1[N:26]1[CH:33]=[CH:32][C:30]([NH2:31])=[N:29][C:27]1=[O:28]>CN(C=O)C>[CH2:1]([P:7]([O:9][CH2:24][C@H:21]1[O:20][C@@H:19]([N:26]2[CH:33]=[CH:32][C:30]([NH2:31])=[N:29][C:27]2=[O:28])[C:18]([F:17])([F:34])[C@@H:22]1[OH:23])(=[O:8])[OH:10])[CH2:2][P:3](=[O:5])([OH:4])[OH:6]
Reactant: O=P(O)(O)CCP(=O)(O)O
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)CCP(=O)(O)O)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.9 %

Procedure:
Ethylenediphosphonic acid (173 mg, 0.91 mmol) was treated with oxalyl chloride (2 mL, as solvent) and anhydrous DMF (0.1 ml, cat.). After heating at reflux for 10 minutes under argon, a solution was obtained and after a further 3 h the reaction mixture was cooled to room temperature and evacuated in vacuo. The residue was co-evaporated with anhydrous acetonitrile (3×10 ml). The residue was dissolved in anhydrous trimethyl phosphate (2 mL), cooled to −15° C. and 2′deoxy-2′,2′-difluorocytidine (93 mg, 0.46 mmol) was added under argon. After stirring for 2 h the reaction mixture was quenched with ice-cold TEAB solution (1.0 M, 5 mL) and stirred for 30 minutes. Purification by HPLC gave 7.8 mg of the titled compound 81.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Cl:11][C:12]1[C:13]([NH2:21])=[C:14]([NH2:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]>Cl>[Cl:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]2[C:13]=1[NH:21][C:2](=[O:4])[C:1](=[O:8])[NH:20]2
Reactant: Nc1cc(F)c(F)c(Cl)c1N
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Product: O=c1[nH]c2cc(F)c(F)c(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (981 mg, 6.72 mmol) and 3-chloro-4,5-difluoro-1,2-diaminobenzene (120 mg, 0.670 mmol) was heated to reflux under N2 for 15 h. The reaction was allowed to cool to room temperature and the gray solid collected by vacuum filtration and rinsed with ice-cold EtOH (10 mL) and air dried. The solid was taken and dissolved in 5 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 1N HCl (pH=1). A white powder formed in the solution at pH=6, but a few drops 1N NaOH cleared the solution and upon addition of a few drops 1N HCl white needles slowly formed in the solution. These were collected by vacuum filtration, rinsed with 20 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 24.9 (16%) of pale yellow needles. 1H NMR (d6 -DMSO) δ 7.05 (dd, 1H, J =10.5, H-8), 11.6 (br s, 1H, NH), 12.0 (br s, 1H, NH). There was 13% 6,7-difluoro-1,4-dihydro-2,3-quinoxalinedione present by NMR.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:17]2(=[O:29])=[O:28])=[C:12]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:11]=1)(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[S:17](=[O:29])(=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:19](=[O:21])[CH2:20]2)=[C:12]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester (1.5 g, 2.67 mmol) (from Example 59, step B) in 10 mL of CH2Cl2 is added TFA (4.0 mL). The mixture stirred for 30 min and then evaporated and azeotroped with toluene to afford the title compound as an orange foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:12]=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1(/[CH:12]=[CH:19]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1(NC(=O)OC(C)(C)C)CC1
Yield: 61 %

Procedure:
1-Tert-butoxycarbonylaminocyclopropane carbaldehyde (10.99 g, 59.3 mmol) and (carbethoxymethylene) triphenylphosphorane (27.6 g, 75.2 mmol) were dissolved in dichloromethane (300 ml) and heated under reflux for 4 hours. After evaporating the solvent, the resulting residue was applied to a silica gel chromatography column and eluted with an eluant of n-hexane:ethyl acetate=9:1, to thereby obtain 9.23 g (61%) of the title compound.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][OH:14])(C)(C)C.O>C1COCC1>[CH3:6][NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][OH:14]
Reactant: CC(C)(C)OC(=O)NCCCNCCO
Solvent: C1CCOC1
Solvent: O
Product: CNCCCNCCO
Yield: 60 %

Procedure:
To a solution of [3-(2-Hydroxy-ethylamino)-propyl]-carbamic acid tert-butyl ester (900 mg, 4.1 mmol) in THF (20 mL) was added a 1M solution of BH3 in THF. The mixture was refluxed for 24 hours under nitrogen. The reaction was allowed to cool down and water (5 mL) was carefully added with vigorous stirring. The reaction mixture was concentrated to low volume and treated with a 6M aqueous solution of HCl (60 mL). The mixture was refluxed for 24 h. The mixture was concentrated to dryness then co-evaporated several time with methanol to give the desired 2-(3-methylamino-propylamino)-ethanol (399 mg, 2.46 mmol)
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:26][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:25][CH2:24][CH2:23]1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: NC1CCC1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC2CCC2)s1
Yield: 15 %

Procedure:
As described for example 108, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (400 mg, 1.3 mmol) was converted, using cyclobutylamine instead of 3,3-difluoroazetidine hydrochloride, to the title compound (68 mg, 15%) which was obtained as a white solid. MS: m/e=360.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[N:6][C:5]([NH:16][C:17](=[O:30])[C:18]([CH3:29])([S:20]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:22])=[O:21])[CH3:19])=[N:4]1)[CH3:2].[Br-].[Br-].[Br-].[Al+3]>C(S)C>[CH2:1]([N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][C:5]([NH:16][C:17](=[O:30])[C:18]([CH3:29])([S:20]([CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)(=[O:22])=[O:21])[CH3:19])=[N:4]1)[CH3:2]
Reactant: CCn1nc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)nc1-c1ccc(OC)cc1
Agent: [Al+3]
Agent: [Br-]
Solvent: CCS
Product: CCn1nc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)nc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
To a solution of 446 mg (1.02 mmol) of N-[1-ethyl-5-(4-methoxy-phenyl)-1H[1,2,4]triazol-3-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide in ethanethiol (5 mL) are added 801 mg (3.01 mmol) of aluminium tribromide. The reaction is stirred at room temperature for 3 h. The reaction is quenched by addition of 6M aqueous HCl solution (2 mL). The resulting precipitate is isolated by filtration, washed with methanol and retreteated with 801 mg (3.01 mmol) of aluminium tribromide in ethanethiol (5 mL) at room temperature for further 3 h. The reaction is quenched by addition of 6M aqueous HCl solution (2 mL). The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by mass-directed preparative HPLC (neutral method) to afford 110 mg of N-[1-ethyl-5-(4-hydroxy-phenyl)-1H-[1,2,4]triazol-3-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide. Yield: 26%, ES-MS: m/z 423 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(O)c2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF (116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 185° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.00 (s, 2 H), 6.66 (s, 1 H), 6.92 (m, 1 H), 7.21 (m, 7 H), 7.32 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1)=[O:4].C(OCC)(=O)C>[Pd].CN(C)C=O>[OH:15][CH:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:16])([F:17])[F:1])[CH:14]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCc2ccc(NC(=O)C(F)(F)F)cc21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)C(O)CC2)C(F)(F)F
Reaction time: 72 h
Yield: 56.1 %

Procedure:
A mixture of 10% (w/w) palladium on carbon (2.34 g), 6-(trifluoroacetamido)indan-1-one (7.79 g), ethyl acetate (53 ml) and dimethylformamide (11 ml) was hydrogenated at atmospheric pressure for 72 h. The reaction mixture was filtered through diatomaceous earth with ethyl acetate wash and evaporated. The residue was flash chromatographed, eluting with 95:5 methylene chloride:methanol, and triturated with ether to give 1-hydroxy-6-(trifluoroacetamido)indane (4.41 g, 56%) as a colorless solid; mp 123.0°-124.5° C.; MS(EI), m/e=245(M+.).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:28]([C:23]2([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:29])=[N:7][CH:6]=1
Reactant: COc1ccc(C2(C(=O)O)CCCC2)cc1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3ncc(Cc4ccccc4Cl)s3)CCCC2)cc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (45 mg, 0.20 mmol) and 1-(4-Methoxy-phenyl)-cyclopentanecarboxylic acid (44 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL) containing triethylamine (84.1 L, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography. ESI-MS m/z calc. 426.1. found; 427.2 (M+1)+ Retention time 3.97 minutes. 1H NMR (400 MHz, MeOD) d 1.62-1.84 (m, 4H), 1.95-2.17 (m, 2H), 2.41-2.62 (m, 2H), 3.78 (s, 3H), 4.22 (s, 2H), 6.90 (d, J=8.8 Hz, 2H), 7.03-7.49 (m, 7H).