Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(Cc2ccc(C=O)cc2)o1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc(Cc2ccc(/C=C/[N+](=O)[O-])cc2)o1
Temperature: 100 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
To a mixture of 4-(5-methyl-furan-2-ylmethyl)-benzaldehyde (96 mg, 0.48 mmol) described in Manufacturing Example 46-1-3 and acetic acid (1 mL) were added nitromethane (190 μL, 3.6 mmol) and ammonium acetate (110 mg, 1.4 mmol) at room temperature, which was stirred for 3 hours at 100° C. The reaction mixture was cooled to room temperature, and extracted by addition of water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The filtrate was concentrated under a reduced pressure to obtain the title compound (120 mg) as a crude product. This compound was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:38](=[O:43])[C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[O:43]=[C:38]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:3]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.508 mmol) was dissolved in DCM (5 mL) and pyridine (0.0820 mL, 1.02 mmol) was added, followed by the addition of methyl 2-chloro-2-oxoacetate (0.0620 g, 0.508 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of water (10 mL) and the mixture extracted with CH2Cl2 (4×10 mL). The combined organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2-oxo-2-((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)amino)acetate (0.180 g, 70.2%). The residue was taken for the next step without further purification. LCMS Condition B-80: retention time 2.32 min, [M+1]=480.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.90 (s, 3H), 4.93 (d, J=4.7 Hz, 2H), 6.83 (d, J=2.8 Hz, 1H), 7.25-7.39 (m, 2H), 7.44-7.63 (m, 6H), 7.79 (td, J=7.7 Hz, J=1.8 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 8.36-8.41 (m, 1H), 8.95-9.05 (m, 2H), 9.19 (d, J=1.8 Hz, 1H), 11.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([N:9]([C:14]1[C:15](=[O:28])[C:16]2[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:18][C:17]=2[C:25](=[O:27])[CH:26]=1)[CH2:10][CH2:11][O:12][CH3:13])(=[O:8])[CH3:7]>O1CCCC1>[C:6]([N:9]([C:14]1[C:15](=[O:28])[C:16]2[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:18][C:17]=2[C:25](=[O:27])[C:26]=1[NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:11][O:12][CH3:13])(=[O:8])[CH3:7]
Reactant: COCCN(C(C)=O)C1=CC(=O)c2sc(C(=O)OC)cc2C1=O
Reactant: COCCN
Solvent: C1CCOC1
Product: COCCNC1=C(N(CCOC)C(C)=O)C(=O)c2cc(C(=O)OC)sc2C1=O
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
2-Methoxyethylamine (0.15 ml) was added to a solution of methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 6.5 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with hexane-ethyl acetate 50:1 solution) to give methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-6-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) as a reddish purple oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([CH:14]=[O:15])[CH:3]=1.O.P([O-])(O)(O)=[O:18].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([OH:18])=[O:15])[CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: COc1c(C=O)cc(F)c2ccccc12
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1c(C(=O)O)cc(F)c2ccccc12
Reaction time: 2.5 h
Yield: 280.5 %

Procedure:
9.3 g of 4-fluoro-1-methoxynaphthalene-2-carbaldehyde were dissolved in 100 mL of acetonitrile. 2.1 g sodium dihydrogenphosphate monohydrate in 10 mL of water were added, followed by the addition of 9.5 mL hydrogen peroxide (30%). 8.9 g sodium chlorite, dissolved in 20 mL water were added dropwise while maintaining an internal temperature between 5° C. and 15° C. The reaction was then allowed to come to room temp over 2.5 h. The precipitated solid was filtered with suction, and the solid was washed with water, and dried in vacuo at 40° C. to yield 9.4 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid. The filtrate was treated with 60 mL of cold 10% aqueous sodium bisulfite solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was washed with 0.2 N NaOH twice. The washes were acidified with 6 N HCl to pH 3, whereupon crystallization occurred. The precipitating product was filtered, washed with water and dried in vacuo at 40° C. to yield a second batch of 1.0 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.CN(C)[CH:19]=[C:20]([C:26]1[N:27]=[N:28][N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:30]=1)[C:21](OCC)=[O:22]>O>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:29]2[N:28]=[N:27][C:26]([C:20]3[C:21](=[O:22])[N:12]4[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]4=[N:1][CH:19]=3)=[N:30]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(=CN(C)C)c1nnn(Cc2ccc(OC)cc2)n1
Reactant: CCOC(=O)c1ccnc(N)c1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccn2c(=O)c(-c3nnn(Cc4ccc(OC)cc4)n3)cnc2c1
Temperature: 130 °C
Yield: 53.9 %

Procedure:
Ethyl 2-aminoisonicotinate (6.5 g, 39.23 mmol) was added with acetic acid (500 ml) and ethyl 3-(dimethylamino)-2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-2-propenoate (13 g, 39.23 mmol) and refluxed by heating at 130° C. for 5 hours. The reaction solution was returned to room temperature and poured into water, and this was extracted with chloroform. The resulting organic layer was washed with saturated brine, and the collected organic layer was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure and subjected to azeotropy with toluene, and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=80:1→50:1→30:1) to obtain 8.6 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](O)=[O:21])=[O:17])=[CH:10]2>>[CH2:23]([CH:19]([NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17])[C:20](=[O:21])[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C1CCNC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Pyrrolidine (0.35 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.31 mmol) were coupled according to procedure A (0-25° C. reaction temperature, 140 hour reaction time) and the crude product triturated with ether: Yield 89 mg, 71%; HPLC (70/30) 7.57 minutes (98%); PBMS 396/398 (MH+, 100/80%);
Reaction SMILES: [OH:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:3]([OH:5])=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36](O)[CH2:35]2>C1COCC1.C(OCC)(=O)C>[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36]([O:4][C:3](=[O:5])[C:2]([OH:1])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:35]2
Reactant: COc1cccc(C(O)(C(=O)O)c2cccc(OC)c2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1

Procedure:
To a stirred solution of hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) (1.384 g, 4.8 mmol) in dry THF (2.0 ml) is added CDI (0.870 g, 5.3 mmol) and the mixture is heated to reflux for 90 minutes. (R)-1-aza-bicyclo[2.2.2]octan-3-ol (0.67 g, 5.3 mmol) is then added. After refluxing for 16 hours, the reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is then extracted with 2M HCl and the aqueous portion is treated with potassium carbonate to basify the solution. The aqueous portion is re-extracted with ethyl acetate. The organic portions are combined, dried over MgSO4 and concentrated in vacuo to yield a crude residue which is purified using C-18 reverse phase column chromatography (eluent: water-acetonitrile), to afford the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17]>O>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH:17][CH:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[NH:3][C:4]([CH3:10])([CH3:9])[CH2:5]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: CN(C)CCCN
Solvent: O
Product: CN(C)CCCNC1CC(C)(C)NC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
1808.9 g (11.65 mol) of 2,2,6,6-tetramethyl-4-piperidinone and 1191.1 g (11.66 mol) of N1,N1-dimethyl-1,3-propanediamine are combined in a 4 l reactor and stirred for 2 hours at 60° C. Then, the reaction water is distilled off in vacuum. Thereafter the reaction solution is transferred to an autoclave and admixed with 76 g of Raney nickel. The autoclave is flushed 3 times with 5 bar nitrogen each time. Then, the hydrogenation is carried out by repeated pressurization with 50 bar hydrogen, wherein the reaction mixture is stirred vigorously during the entire reaction time. Then, the reaction mixture is separated by fractional distillation. The product has a boiling point of 130° C. at 4.5 mbar. 2062 g of product could be isolated having a purity of 98.6% and a yield of 72% of theory.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([N:23]2[CH2:29][CH:28]3[NH:30][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)[C:3]=1[C:31](=[O:33])[CH3:32].[N:34]1[N:35]=[C:36]([C:39](O)=[O:40])[NH:37][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:34]1[N:35]=[C:36]([C:39]([N:30]2[CH:28]3[CH2:27][CH2:26][CH:25]2[CH2:24][N:23]([C:4]2[C:3]([C:31](=[O:33])[CH3:32])=[C:2]([NH2:1])[N:7]4[N:8]=[CH:9][C:10]([C:11]5[CH:12]=[N:13][C:14]([C:17]6[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=6)=[CH:15][CH:16]=5)=[C:6]4[N:5]=2)[CH2:29]3)=[O:40])[NH:37][CH:38]=1
Reactant: CC(=O)c1c(N2CC3CCC(C2)N3)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: O=C(O)c1nnc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1c(N2CC3CCC(C2)N3C(=O)c2nnc[nH]2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(7-amino-5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (11 mg, 0.025 mmol), 4H-1,2,4-triazole-3-carboxylic acid (3.1 mg, 0.027 mmol), EDCI (9.5 mg, 0.05 mmol), HOBt (6.75 mg, 0.05 mmol) and DIEA (26 ul, 0.15 mmol) in DMF (1 ml) was stirred at room temperature overnight. Purification with prep-LC provided 1-(5-(8-(4H-1,2,4-triazole-3-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone, LCMS tR=3.31 Min (10 min run, UV 254 nm). Mass calculated for M+H 535.2, observed LC/MS m/z 534.95 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([NH:38][CH3:39])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41].O1CCOCC1>O1CCOCC1>[ClH:41].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([NH:38][CH3:39])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CNc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 60 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(N-methylamino)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature for 3 hours. The resulting solid was filtered to give 30 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-(N-methylamino)quinolin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.O>CN(C)C=O>[Cl:20][C:19]1[C:14]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:10])([F:9])[F:8])[N:4]=[CH:5]2)=[N:15][CH:16]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:18]=1
Reactant: Cc1[nH]cnc1C(F)(F)F
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
To a solution of 0.50 g (3 m mol) of 5-methyl-4-trifluoromethylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 133 mg (3 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.62 g (3 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 8 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.48 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methyl-4-trifluoromethylimidazole.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10](=[O:45])[CH:11]([NH:37]C(OC(C)(C)C)=O)[CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([CH3:36])[CH:27]=3)=[CH:20][CH:19]=2)[CH2:14]1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10](=[O:45])[CH:11]([NH2:37])[CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([CH3:36])[CH:27]=3)=[CH:22][CH:23]=2)[CH2:14]1
Reactant: COC(=O)C(CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 2-tert-butoxycarbonylamino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester from Example step 8c in methylene chloride at room temperature. After stirring for 1 h, the reaction was concentrated in vacuo to give 2-amino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester trifluoroacetate salt (0.1 g, 100%) as an oil. MS found: (M+H)+=420.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([OH:27])=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([O:27][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
Benzyl bromide (4.34 g, 25.4 mmol) and potassium carbonate (4.80 g, 34.7 mmol) were added to 1-(tert-butoxycarbonyl)nipecotic acid (5.30 g, 23.1 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature for 6 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The organic layer washed sequentially with water and brine and was dried over sodium sulfate. The solvent was then evaporated to give 7.11 g (96%) of the desired compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:17]([OH:21])[C:18](O)=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:30]([NH:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)([CH3:33])([CH3:32])[CH3:31].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]([C@@H:16]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:17]([OH:21])[C:18]([N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:35]([NH:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:41])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 5 h

Procedure:
14.0 g (37.0 mmol) of (2S, 3S)-3-(N,N-dibenzylamino)-2-hydroxy-4-phenylbutyric acid [prepared as described in step (a) above] and the whole of the N-t-butyl-L-prolinamide hydrochloride were suspended in 250 ml of methylene chloride, and 6.7 g (41.1 mmol) of diethyl cyanophosphate and 11.2 g (110.9 mmol) of triethylamine were slowly added dropwise to the suspension. The mixture was then stirred for 5 hours. At the end of this time, the reaction mixture was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The mixture was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from hexane, to give 16.6 g of the title compound as colorless crystals, melting at 122°-123° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.[CH2:20]([N:22](CC)CC)C>ClCCl>[CH3:20][NH:22][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid (120 g, 519 mmol) in dichloromethane (800 mL) is added 1,1-carbonyldiimidazole (88.4 g, 545 mmol). The resulting solution is stirred at 25° C. for 1 h and methylamine hydrochloride (52.5 g, 779 mmol) and triethylamine (157.3 g, 1557 mmol) are added and the reaction is stirred for an additional 18 h. The mixture is diluted with dichloromethane (600 mL) and washed with 1 M hydrochloric acid and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid methylamide as a white solid (126 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:28])[C:15]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:5]OS(C)(=O)=O.[C-:29]#[N:30].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:29]#[N:30])[CH:11]=[CH:12][C:13]=1[CH:14]([CH3:28])[C:15]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17]
Reactant: [C-]#N
Reactant: CC(c1ccc(COS(C)(=O)=O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1ccc(CC#N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
Methanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzyl ester (66 mg) was dissolved in DMF at RT under argon. Sodium cyanide (18 mg) was added and the mixture was warmed to 85° C. and allowed to stir for 1.5 hours. The mixture was diluted with ethyl acetate and washed with water and brine.
Reaction SMILES: N1CCOCC1.[OH:7][CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11].[CH2:15]([C:18]#[N:19])[C:16]#[N:17]>CN(C)C=O>[NH2:19][C:18]1[O:7][CH:8]=[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]=1[C:16]#[N:17]
Reactant: CC(C)(C)C(=O)CO
Reactant: N#CCC#N
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CC(C)(C)c1coc(N)c1C#N
Temperature: 0 °C
Yield: 51.8 %

Procedure:
174 g (2 moles) of morpholine were added dropwise to a solution of 232 g (2 moles) of hydroxy-pinacolone and 132 g (2 moles) of malonic acid dinitrile in 500 ml of dimethylformamide, while cooling, in a manner such that the internal temperature did not rise above 40° C. After the reaction had ended, the reaction mixture was stirred into 5 liters of ice-water. The solid product which thereby precipitated was filtered off, washed with water and dried. 170 g of 2-amino-3-cyano-4-tert.-butyl-furan of melting point 86° C. were obtained in this manner.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[S-:20][C:21]#[N:22].[K+].O1CCCC1>O>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:6]=[C:7]([S:20][C:21]#[N:22])[C:3]([CH3:2])=[N:4]1
Reactant: N#C[S-]
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1SC#N

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole (9.55 g), potassium thiocyanate (1 g) and tetrahydrofuran (50 ml) were heated under reflux for 3 hours. The mixture was poured into water, solid collected and recrystallised from ethyl aceteate/hexane to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-thiocyanato-methyl-2H-1,2,3-triazole, m.p. 115°-117°. (Compound 23)