Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17][C:18]([OH:20])=O)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:39]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1CCN2C(=NCCC2)CC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17][C:18]([NH:48][S:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:47])=[O:46])=[O:20])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(C)c1ccc(-c2csc(N(CCC(=O)O)Cc3cccs3)n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)c1ccc(-c2csc(N(CCC(=O)NS(=O)(=O)c3ccccc3)Cc3cccs3)n2)cc1

Procedure:
N-(3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionyl)-benzenesulfonamide was prepared following procedure K using 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid (Prepared in Example 35) (50 mg, 0.125 mmol), CDI (62 mg, 0.39 mmol), DBU (30 μl, 0.2. mmol), and benzene sulfonamide (41 mg, 0.26 mmol). Purification (Silica gel, ethyl acetate/hexane 1:4) provided the product (10 mg). LCMS m/z: 527 (M+1)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH2:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[O:24])[NH:19][N:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH2:33]([NH:35][CH2:36][CH2:37][OH:38])[CH3:34].CN(C)C(=O)C>O>[CH2:33]([N:35]([CH2:36][CH2:37][OH:38])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH2:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[O:24])[NH:19][N:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:34]
Reactant: O=C(Cc1cc(Nc2ncnc3cc(OCCCCl)ccc23)n[nH]1)Nc1cccc(F)c1
Reactant: CCNCCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCOc1ccc2c(Nc3cc(CC(=O)Nc4cccc(F)c4)[nH]n3)ncnc2c1
Temperature: 90 °C
Yield: 85 %

Procedure:
2-(3-{[7-(3-Chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide and 2-(ethylamino)ethanol (ideally 12 molar equivalents) were added to N,N-dimethylacetamide under an inert atmosphere (such as provided by nitrogen) and the mixture heated to 90° C. with stirring. After a period of 12-16 hours (ideally 12 hours) the reaction is cooled back to about 85° C. and water added in a controlled manner to maintain the temperature between 80-85° C. The batch is adjusted to 80° C. and seeded with crystals of the preferred form of the product (ideally an amount of about 1% of the expected yield). The mixture was cooled to 20° C. in a carefully controlled manner over a period of about 20 hours so as to crystallise the product in the required form and of a size sufficient to afford a good filtration rate. The product is then filtered and washed with a mixture of water/N,N-dimethylacetamide and acetonitrile and suitably deliquored to afford a hydrated form of the product. Following this, the cake is slurried in situ for a period (ideally 2 hours) with warm acetonitrile (ideally at a temperature of 40° C.) then filtered, washed with more acetonitrile and then dried (in vacuo or under a stream of nitrogen) to afford the almost anhydrous 2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide as an off-white solid in a yield of 85-90%.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[S:27]=[C:28]1[NH:32][C:31](=[O:33])[CH2:30][S:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:30]3[S:29][C:28](=[S:27])[NH:32][C:31]3=[O:33])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: O=C1CSC(=S)N1
Product: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-thioxo-thiazolidin-4-one following General Procedure B.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28](=[O:41])[C@@H:29]([CH2:31][CH2:32][CH2:33][NH:34][C:35]([NH2:40])=[N:36][N+:37]([O-:39])=[O:38])[NH2:30])=[CH:22][CH:21]=1)=[O:17].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH:27][C:28](=[O:41])[C@@H:29]([CH2:31][CH2:32][CH2:33][NH:34][C:35]([NH2:40])=[N:36][N+:37]([O-:39])=[O:38])[NH:30][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:13][CH:12]=2)=[CH:24][CH:25]=1)=[O:17]
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Reactant: CCCCc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCCCc1ccc(C(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)cc1
Yield: 33 %

Procedure:
Prepared analogously to Example 69a) from 4-butyl-benzoic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 33% of theory.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].OC(C(F)(F)F)=O.[NH2:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35].C[O-].[Na+]>CCO>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 62.3 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol), 3-Amino-2,2-dimethyl-propionic acid TFA salt (120 mg, 0.52 mmol) and NaOMe (56 mg, 1.03 mmol) in EtOH (2 mL) was heated at 150° C. for 6 h in a CEM microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as a yellow solid. MS: (+) m/z 396.15 (M+1).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:16])[N:15]=1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)(=[O:3])=[O:4])=[O:29])[N:22]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: Cn1nnc(-c2ccccc2S(N)(=O)=O)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2nnn(C)n2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To 25 mL of acetonitrile was added at ambient temperature and pressure 0.48 g of 5-(2-aminosulfonylphenyl)-2-methyl-2H-tetrazole and 0.54 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate followed by 0.3 mL of DBU. After being stirred for three hours the reaction mixture was added to 25 g of ice and acidified to pH 3 with hydrochloric acid. The precipitate thus obtained was filtered, washed with water and dried to yield 0.66 g of the desired product, m.p. 214°-222° C. Infrared absorptions at 1720, 1600 and 1580 cm-1 were consistent with the desired structure.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]2[C:20]([Cl:21])=[C:19]([CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[CH:11][C:10]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C>[Cl:21][C:20]1[C:15]([NH:14][CH2:13][C:12]2[CH:24]=[CH:25][C:9]([OH:8])=[C:10]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:11]=2)=[N:16][C:17]([CH3:23])=[N:18][C:19]=1[CH3:22]
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OCC3CC3)c2)n1
Reactant: [H][H]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc(C)c(Cl)c(NCc2ccc(O)c(OCC3CC3)c2)n1

Procedure:
A solution of 2.0 g (4.7 mmol) of (4-benzyloxy-3-cyclopropylmethoxybenzyl)(5-chloro-2,6-dimethyl-pyrimidin-4-yl)amine (from example A5) in 50 ml of methanol and 20 ml of glacial acetic acid is admixed with 250 mg of Pd-on-carbon catalyst (type 38H, Johnson Matthey) and hydrogenated by circulation with hydrogen until about 1 equivalent of hydrogen (about 190 ml) has been taken up. After filtration to remove the catalyst, the solution is concentrated and the residue is chromatographed on silica gel (mobile phase: toluene/dioxane/ammonia=2:1:0.05). The fractions with Rf=0.35 are collected and concentrated. After crystallization from diisopropyl ether, 550 mg (35%) of the title compound are isolated as a beige powder. m.p.: 123-125° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[N:9]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1)=[C:10]=[S:11]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:10]([NH:9][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1)=[S:11]
Reactant: Nc1ccncc1N
Reactant: Cc1ccc(Cn2c(CC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(CC3CCN(CCNC(=S)Nc4cnccc4N)CC3)nc3ccccc32)cc1
Yield: 100 %

Procedure:
A mixture of 5.2 parts of 3,4-pyridinediamine, 19 parts of 2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-1-[(4-methylphenyl)methyl]-1H-benzimidazole and 225 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 24 parts (100%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[1-[(4-methylphenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]thiourea (405).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[N:5][CH:4]=[C:3]1[C:19]([O:21]CC)=[O:20].[OH-].[Na+].O>C(O)(=O)C>[O:1]=[C:2]1[NH:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)=[N:5][CH:4]=[C:3]1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Ethyl 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (34.4 g) and sodium hydroxide (10 g) are added to water (300 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (300 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylic acid (21.5 g). M.p. 252°-254° C.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[S:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]=2[CH3:22])O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:17]1[S:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]=1[CH3:22]
Reactant: Cc1c(C(O)c2cccc(Br)c2)sc2ccccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cc2cccc(Br)c2)sc2ccccc12
Temperature: -10 °C

Procedure:
A solution of 1.56 M hexane (23.7 ml) of n-butyl lithium was added dropwise to a solution of 3-methyl-1-benzothiophene (5.0 g) in tetrahydrofuran (50 ml) at −78° C. under an argon atmosphere, and the mixture was stirred for half an hour at the same temperature. Then, a solution of 3-bromobenzaldehyde (6.05 g) in tetrahydrofuran (6 ml) was added dropwise to the mixture, and the mixture was stirred for half an hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous solution of saturated ammonium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (3-bromophenyl)(3-methyl-1-benzothien-2-yl) methanol (10.0 g) as achromatic oily matter. Borontrifluoride diethyl ether complex (4.42 ml) and triethylsilane (9.58 ml) were added to a solution of (3-bromophenyl)(3-methyl-1-benzothien-2-yl) methanol in dichloromethane (100 ml) at −30° C., and the mixture was stirred for half an hours. After the reaction mixture was heated to −10° C. and stirred for 10 minutes, aqueous solution of saturated sodium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-(3-bromobenzyl)-3-methyl-1-benzothiophene (6.68 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]([N+:17]([O-])=O)=[CH:4][C:3]1=2>CO.[Ni]>[CH3:12][C:9]1([CH3:13])[CH2:10][CH2:11][C:2]([CH3:1])([CH3:20])[C:3]2[CH:4]=[C:5]([NH2:17])[C:6]([NH2:14])=[CH:7][C:8]1=2
Reactant: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])c([N+](=O)[O-])cc21
Agent: [Ni]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(N)c(N)cc21
Reaction time: 48 h
Yield: 85.6 %

Procedure:
39.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2,3-dinitro-naphthalene in 1300 ml of methanol were hydrogenated with Raney-nickel in a 2 l hydrogenation flask. The H2 -uptake after 48 hours was 20.7 l (18.8 l=theory). The catalyst was removed by filtration under suction, the solution was again filtered and the filtrate was evaporated in vacuo. The residue was crystallized from isopropanol. There were obtained 26.2 g (85.5% of theory) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2,3-naphthalene-diamine of melting point 188°-189° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[N:28]([CH2:36][CH2:37][OH:38])C(=O)OC(C)(C)C)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]>O1CCOCC1>[OH:38][CH2:37][CH2:36][NH:28][C@@H:23]1[CH2:22][CH2:21][CH2:20][C:19]2[C:18]([C:15]3[N:14]=[C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:17][N:16]=3)=[CH:27][CH:26]=[CH:25][C:24]1=2
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N(CCO)C(=O)OC(C)(C)C)no2)cc1C#N
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NCCO)no2)cc1C#N
Temperature: 50 °C
Yield: 79 %

Procedure:
Prepared using General Procedure 11. To a stirred solution of (R)-tert-butyl (5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(2-hydroxyethyl)carbamate INT-23 (15 mg, 0.03 mmol) in dioxane (1 mL) was added 4N HCl/dioxanes (116 μL, 0.116 mmol). After heating at 50° C. for 18 h, the mixture was concentrated and the resulting solid was purified by preparative HPLC to provide 9.53 mg (79%) of (R)-5-(3-(5-((2-hydroxyethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxy benzonitrile 50. LCMS-ESI (m/z) calculated for C24H26N4O3: 418.5; found 419.2 [M+H]+, tR=2.52 min. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 4.88-4.70 (m, 1H), 4.54 (s, 1H), 3.78 (d, J=12.1 Hz, 2H), 3.62 (s, 2H), 3.24 (dt, J=18.0, 5.6 Hz, 1H), 3.18-2.89 (m, 3H), 2.16 (d, J=5.2 Hz, 2H), 2.10-1.75 (m, 2H), 1.47 (d, J=6.1 Hz, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH:26]1[CH:30]=[CH:29][CH:28]=[N:27]1>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:4]([CH2:3][CH2:2][N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)[CH2:8][CH2:7]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1cn[nH]c1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3cccn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p.=121° C. and MS: m/e=414.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[C:18](F)[CH:17]=[C:16](Cl)[CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].BrC1SC(C(OCC)=O)=[N:28][C:27]=1C1C=CC(F)=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:27]#[N:28])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Product: N#Cc1cccc(-c2sc(C(=O)O)nc2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 8A starting with the compound from Example 4A. 161 mg (76% of theory) of the title compound are obtained.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:21][CH2:22][C:23]([O:25][C:26](C)(C)[CH3:27])=[O:24])[CH:11]=[C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1)=[O:5])C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][C:4]([OH:5])=[O:3])[CH:13]=[C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CCc1cc(CCC(=O)OC(C)(C)C)cc(Oc2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1cc(CCC(=O)O)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
A solution of t-butyl 3-[3-(2-ethoxycarbonylethyl)-5-(3-pyridyloxy)phenyl]propanoate (Preparation 29; 7.8 g) in dichloromethane (100 ml) was treated with trifluoroacetic acid (20 ml) and the resulting solution stirred at room temperature for 20 hours and then evaporated under vacuum. The residue was azeotroped twice with toluene, and then ether (ca 100 ml) and pyridine (ca 10 ml) were added sequentially. This mixture was washed with water and then the combined aqueous washings extracted with ethyl acetate. The organic solutions were combined, washed with water, dried (MgSO4) and evaporated under vacuum to provide an oil, which crystallised on trituration with an ether: hexane mixture to give the title compound (6.56 g), m.p. 85°-87° C. Found: C,66.67; H,6.04; N,3.90. C19H21NO5 requires C,66.46; H,6.16; N,4.08%.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([OH:14])[CH2:8][C:7]1([CH3:16])[CH3:15].[OH-].[K+]>C1C=CC=CC=1>[C:1]([CH2:2][CH2:3][O:14][CH:9]1[CH2:8][C:7]([CH3:15])([CH3:16])[N:6]([CH3:5])[C:11]([CH3:13])([CH3:12])[CH2:10]1)#[N:4]
Reactant: C=CC#N
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CN1C(C)(C)CC(OCCC#N)CC1(C)C
Reaction time: 16 h

Procedure:
2.65 parts of acrylonitrile was added dropwise with stirring to a solution of 8.55 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol and 0.30 parts of 40 % potassium hydroxide solution in 80 parts of benzene. Stirring was continued at room temperature for 16 hours after which time the solution was washed with water, dried and the benzene solvent removed by distillation under reduced pressure. Fractional distillation of the residue, under reduced pressure gave 1.70 parts of 4-(2'-cyanoethoxy)-1,2,2,6,6-pentamethylpiperidine having a boiling point of 105°-6° C. at 0.1 mm of Hg and the following elemental analysis by weight:
Reaction SMILES: [NH:1]1[CH2:9][C@@H:7]([OH:8])[CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:10](ON1C(=O)CCC1=O)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11].O1CCOCC1.Cl>C(=O)([O-])O.[Na+]>[N:1]1([C:10]([O:12][CH2:13][CH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:11])[CH2:9][C@@H:7]([OH:8])[CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: O=C(O)[C@H]1C[C@H](O)CN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1C[C@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
262 mg (2.0 mmol) of D-Hyp-OH was dissolved in 5 ml of a saturated aqueous solution of sodium hydrogencarbonate under stirring and a mixture of 742 mg (2.2 mmol) of Fmoc-OSu and 10 ml of 1,4-dioxane was added dropwise under cooling with ice; thereafter, and the mixture was stirred at room temperature for 3 days. In the meantime, a saturated aqueous solution of sodium hydrogencarbonate was added as appropriate to keep the pH of the reaction mixture at 8-9. After being rendered acidic with hydrochloric acid under cooling with ice, the reaction mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting solvents were chloroform and acetic acid supplemented chloroform:methanol=10:1); to remove the acetic acid used in eluting, the fractions were once concentrated under reduced pressure and dissolved again in ethyl acetate; thereafter, the solution was washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give a colorless powder in the amount of 660 mg (93%).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[N:14]=[C:13]([I:15])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:10]2[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[CH3:29]O>>[NH2:5][C:6]1[N:14]=[C:13]([I:15])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:10]2[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:29])=[O:20]
Reactant: Nc1nc(I)nc2c1nc(-c1cccc(F)c1)n2CCCC(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCn1c(-c2cccc(F)c2)nc2c(N)nc(I)nc21
Temperature: 2.5 °C
Yield: 100 %

Procedure:
Thionyl chloride (1.2 ml) was added dropwise into a mixture of 1.41 g of 4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoic acid and 75 ml of methanol over 15 minutes during the mixture was stirred at 0-5° C. in a nitrogen stream. This was raised to room temperature and stirred for 45 minutes and the solvent was evaporated. The resulting residue was dissolved in ethyl acetate and then the solution was washed with a saturated aqueous solution of sodium bicarbonate twice and then with brine once. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 1.45 g of the title compound. The yield was 100%.