Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:64]([NH:74][C:75](=[O:93])[CH2:76][N:77]2[C:85]3[C:84]([F:87])([F:86])[CH2:83][CH2:82][C:81]([F:89])([F:88])[C:80]=3[C:79]([CH:90]([F:92])[F:91])=[N:78]2)[CH2:65][C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[C:68]([F:73])[CH:67]=2)=[N:52][C:53]([NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH3:63])=[N:54][CH:55]=1>>[F:91][CH:90]([F:92])[C:79]1[C:80]2[C:81]([F:89])([F:88])[CH2:82][CH2:83][C:84]([F:86])([F:87])[C:85]=2[N:77]([CH2:76][C:75]([NH:74][C@H:64]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH3:63])[N:52]=2)[CH2:65][C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[C:68]([F:73])[CH:67]=2)=[O:93])[N:78]=1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: COCCOCCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: COCCOCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (17B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 17A. 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 7.52-7.31 (m, 2H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 7.01-6.56 (m, 2H), 6.44 (d, J=6.0 Hz, 2H), 5.23 (t, J=6.7 Hz, 1H), 5.05 (s, 2H), 3.84-3.63 (m, 6H), 3.57 (m, 2H), 3.37 (s, 3H), 3.17-2.90 (m, 2H), 2.65-2.39 (m, 4H). MS (m/z) 774.58 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.C[O:33][CH:34]1[CH:38]([CH:39]=O)[CH2:37][CH:36](OC)O1>CN(C=O)C.C1(C)C=CC=CC=1>[C:15]([C:12]1[N:13]=[CH:14][C:9]([NH:8][C:5]2[CH:4]=[C:3]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[C:2]([N:1]3[CH:36]=[CH:37][C:38]([CH:34]=[O:33])=[CH:39]3)=[CH:7][N:6]=2)=[N:10][CH:11]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C=O)c2)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (60 mg, 0.141 mmol) (Synthesis 101-C) was dissolved in DCE/AcOH (1/1, 5 mL). 2,5-Dimethoxytetrahydrofuran-3-carboxaldehyde (28 uL, 0.211 mmol) was added and the solution was stirred at 80° C. for 1 h. The solution was evaporated to dryness and the product (143 mg, approximately 50% purity) was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.C(O)C>C(O)(=O)C>[CH2:17]([C:16]1[NH:1][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[CH:13][C:14]=2[N:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Cc2ccccc2)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(Cc3ccccc3)[nH]c2c1
Reaction time: 40 h
Yield: 74.8 %

Procedure:
A mixture of 3.60 g of ethyl 3-nitro-4-phenylacetylaminobenzoate, 47 ml of ethanol, 23 ml of acetic acid and 6.4 g of reduced iron was heat-refluxed for 4 hours. The solid material was separated through filtration, and the filtrate was concentrated. To the residue were added 50 ml of ethanol and 5 g of 35% hydrochloric acid. The mixture was stirred for 40 hours while being heat-refluxed. The reaction solution was neutralized with sodium hydrogencarbonate, and was extracted with chloroform. The organic layer was concentrated under reduced pressure, and was purified through silica-gel column chromatography to give 2.30 g of 2-benzyl-5-ethoxycarbonylbenzimidazole (150).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:20]3[CH2:21][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:23](=[O:24])[C:19]=3[C:18]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[CH:6]=1)[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:47])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:20]3[CH2:21][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[C:23](=[O:24])[C:19]=3[C:18]([OH:33])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[CH:6]=1)[CH3:2].[C:50]([OH:52])([C:49]([F:54])([F:53])[F:48])=[O:51]
Reactant: CCOC(=O)c1cccc(-c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(-c2c3c(c(O)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 277 dissolved in dichloromethane (2 mL) was added trifluoroacetic acid (200 μl) and triethylsilane (400 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was redissolved in DMSO (1 mL) and purified by prep-HPLC to afford 3-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-benzoic acid ethyl ester 278, TFA salt, (25 mg, 0.003 mmol, 44% in two steps) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.2 (d, 1H), 8.0 (s, 1H), 7.7 (m, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (m, 2H), 7.1 (t, 2H), 4.7 (dd, 2H), 4.4(q, 2H), 4.3 (dd, 2H), 1.4 (t, 3H); MS: 457 (M+1). HPLC conditions: mobile phase A was 0.1% TFA in water, mobile phase b was 0.1% TFA in CH3CN; gradient from 5% to 60% B in 20 min; flow rate was 20 mL/min; column was Phenomenex, luna 5μ, C18 (2), 150 mm×21.1 mm.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]([F:20])=[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)[CH:8]=1.[SH:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:21][C:4]1[CH:5]=[C:6]([F:20])[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:8][C:3]=1[CH2:2][S:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cn1nc(-c2cc(CBr)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSCc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 1.62 g (4.0 mmole) 3-[5-(bromomethyl)-4-chloro-2-fluorophenyl]-4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 0.44 mL ethyl mercaptoacetate and 0.55 g K2CO3 was slurried in 25 mL of acetone. The reaction mixture was allowed to stir at room temperature overnight. After dilution with 100 mL of cold water, the mixture was extracted with ethyl acetate, the organic extracts washed with water, dried with MgSO4 and concentrated in vacuo. The residue was purified by chromatography to afford 1.7 g (96%) of (((2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl) -1H-pyrazol-3-yl)-4-fluorophenyl)methyl)thio)acetic acid, ethyl ester as a white solid; mp 63° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COCCN
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: COCCNC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2-methoxyethylamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH2:14]([O:16][C:17](=[O:28])[CH:18]([CH3:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:28])[CH:18]([CH3:27])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:2][C:3]2[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=2)=[CH:24][CH:25]=1)[CH3:15]
Reactant: Cc1cnc(SC(C)C)c(CCl)c1
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Product: CCOC(=O)C(C)Cc1ccc(OCc2cc(C)cnc2SC(C)C)cc1
Yield: 33 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-5-methyl-pyridine (0.02 g, 0.09 mmol) obtained in Step D of Preparation Example 30 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.012 g, 33%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:7][CH2:8][O:9]CC1C=CC=CC=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][CH2:5][CH:6]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:7][CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CCOCc1ccccc1)COC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCC(CCO)COC(C)=O
Yield: 91.6 %

Procedure:
To a solution of 2-acetoxymethyl-4-benzyloxy-but-1-yl acetate (55 g, 0.187 mol) in ethanol (250 ml) was added 10% palladium on carbon (2.5 g), and the mixture hydrogenated at atmospheric pressure and room temperature. When the theoretical hydrogen uptake had been achieved (18 hours), the reaction was stopped and filtered through Celite. Evaporation of the filtrate gave a colourless oil (35 g). This was purified by column chromatography on silica gel, elution with 2% methanol in chloroform affording 2-acetoxy-methyl-4-hydroxybut-1-yl acetate as a clear oil (32.9, 86%). δH (CDCl3) 1.61 (2H, q, CHCH2CH2), 2.04 (6H, s, 2×OCOCH3), 2.20 (1H, m, CH), 2.61 (1H, br s, D2O exchangeable, OH), 3.68 (2H, t, CH2OH), 4.04 (4H, d, 2×CH2OCOCH3).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=O)[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:75][CH:76]([CH3:79])[CH2:77][NH2:78]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([NH:78][CH2:77][CH:76]([OH:75])[CH3:79])=[O:40])[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(O)CN
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)CNC(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of rac {1-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54 mmol) were added followed by 2-hydroxy-2-methyl-ethylamine (Aldrich, 20 mg, 0.27 mmol) and the mixture was stirred at rt for hers. The reaction was quenched with water and the mixture was extracted with methylene chloride (3×10 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 48 mg.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1.C1COCC1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>O>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][N:7]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:2](=[O:1])[CH:3]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)=[O:9])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Reaction time: 8 h

Procedure:
To a solution of t-boc-(4-benzyloxybenzyl) piperazinone 3a (2.66 g, 6.72 ×10-3 mole) and dry THF (20 ml) under argon at room temperature is added portionwise NaH (0.30 g, 7.4 ×10-3 mole, 59% oil dispersion). After stirring 1/2hour at room temperature a solution of methyl α-bromoacetate (0.62 ml, 7.4 ×10-3 mole) is added via syringe. After stirring overnight the reaction mixture is poured into water which is subsequently extracted with Et2O (3 times). The combined ethereal extracts are washed with saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate affords a viscous oil which after column chromatography (silica gel, 10% EtOAc/CHCl3)gives a clear, colorless oil. After standing in the refrigerator this oil crystallizes. The resulting solid is triturated with hexane and collected by filtration affording 4a as colorless matted needles: 2.3 g (74%), m.p. 84°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C@H:13]([OH:15])[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17]1[C:21](S(C)(=O)=O)=[N:20][N:19]=[C:18]1[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]([O:15][C:21]3[N:17]([CH3:16])[C:18]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[N:19][N:20]=3)[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: C[C@@H](O)c1nc(-c2cccc(Cl)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1nc(-c2cccc(Cl)c2)no1
Yield: 83.3 %

Procedure:
0.57 g (2.54 mmol) (+)-(1R)-1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanol, 0.64 g (2.68 mmol) 4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine and 0.90 g (2.76 mmol) cesium carbonate were stirred at 65° C. for 6 h, followed by dilution with water. Extraction with EA, washing with aq. citric acid, drying over Na2SO4, followed by purification via chromatotron 2 mm (Hep/EA/MeOH=10/10/1) gave 0.81 g (83%) racemic 4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine. Prep. chiral separation on Chiralpak AD using 100% 2-propanol yielded 0.25 g of the title compound as the second eluting enantiomer. 1H NMR: 8.76 (d, 2 H), 8.07 (t, 1 H), 7.92-7.99 (m, 1 H), 7.60-7.68 (m, 2 H), 7.45-7.51 (m, 1 H), 7.41 (t, 1 H), 6.45 (q, 1 H), 3.66 (s, 3 H), 1.99 (d, 3 H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O[C@H:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C@@H:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1ccccc1O
Product: CC(=O)c1ccccc1O[C@H](CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure B and Scheme B1 using 1-(2-hydroxyphenyl)ethanone and N-(3-{1-[(2R)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 485.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].[H][H]>O.Cl.CO.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccccn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOC(=O)CC1CCCCN1

Procedure:
Platinum(IV) oxide (15 mg) was added to a mixture of 2-(2-pyridyl)acetic acid ethyl ester (1.652 g) in water (1.25 mL) and concentrated hydrochloric acid (1.25 mL) in methanol (15 mL), and the resultant mixture was stirred in a hydrogen atmosphere at room temperature for 15 hours. The catalyst was filtered off. The solvent was evaporated under reduced pressure, and ethanol was added to the residue, and then the solvent of the mixture was evaporated again under reduced pressure. To the residue, a small amount of water, diethyl ether (about 100 mL), and an excessive amount of potassium carbonate were added, and the resultant mixture was stirred, followed by filtration. The solvent of the filtrate was evaporated under reduced pressure, to thereby give the title compound as an oily product (1.322 g, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].Br[CH2:18][CH:19]([CH3:21])[CH3:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1
Reactant: CC(C)CBr
Reactant: CC(C)(C)c1cc(Br)ccc1CCN
Agent: [H-]
Agent: [Na+]
Product: CC(C)CNCCc1ccc(Br)cc1C(C)(C)C
Yield: 30 %

Procedure:
In a manner analogous to example 1 c, the process is carried out by a reaction of 4 g (16 mmol) of (4-bromo-2-tert-butylphenyl)ethylamine (example 1b) with 1.4 g (34 mmol) of 60% sodium hydride and with 3.7 ml (34 mmol) of 1-bromo-2-methylpropane. 1.5 g of (4-bromo-2-tert-butylphenyl)ethylisobutylamine are obtained in the form of an oil (yield=30%).
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH2:7][N:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:10][CH2:11][C:5]=2[O:4][N:3]=1.[N+](=[CH2:18])=[N-]>CCOCC>[CH3:18][O:1][C:2]1[C:6]2[CH2:7][N:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:10][CH2:11][C:5]=2[O:4][N:3]=1
Reactant: C=[N+]=[N-]
Reactant: COC(=O)N1CCCc2onc(O)c2C1
Solvent: CCOCC
Product: COC(=O)N1CCCc2onc(OC)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 490 mg (1.97 mmol) of methyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-5-carboxylate (Formula II; Z=methoxycarbonyl, R3 =R4 =hydrogen) (P. Krogsgaard-Larsen, Acta Chem. Scand. B 31 (1977) 584-588) in ether (20 ml) was added an excess of diazomethane. The mixture was stirred at room temperature for 1 hour and the excess of diazomethane was destroyed by addition of glacial acetic acid. The mixture was evaporated in vacuo and the residue submitted to flash-chromatography on silica gel (eluent: toluene-ethyl acetate containing 1% of glacial acetic acid) yielding 270 mg of the title compound as a colourless oil. The oil was crystallized from toluene-light petroleum giving the analytically pure title compound. M.P. 68°-70° C. 1H NMR (CDCl3): δ4.25 (2H, s), 3.93 (3H, s), 3.66 (5H, m), 2.83 (2H, t), 1.91 (2H, m).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:32](=[O:33])[O:34][CH:35]([CH3:37])[CH3:36])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](NC(=O)OC(C)C)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.080 g, 0.19 mmol, Preparation #BB.1*) in THF (2 mL) was added TEA (0.079 mL, 0.565 mmol) and the solution was stirred at ambient temperature for about 10 min. To the reaction was added isopropyl chloroformate (1 M in toluene, 0.18 mL, 0.18 mmol) and the reaction mixture was stirred for about 1 h. The solvent was removed under reduced pressure and DCM (5 mL) and saturated aqueous NaHCO3 (2 mL) were added. The layers were separated and the organic layer was washed with brine (2 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give crude isopropyl (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (0.080 g, 60%) which was used without further purification: LC/MS (Table 1, Method b) Rt=2.33 min; MS m/z: 511 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:45]=O>CO.O.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:32]3[CH2:36][CH2:35][N:34]([CH3:45])[CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@H]5CCNC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@H]5CCN(C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
100 mg of (S)-1-methyl-7-[4-(pyrrolidine-3-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide are dissolved in 10 ml of methanol, combined with 14 μl of a 37% solution of formaldehyde in water and 20 mg of palladium on charcoal (10%) and hydrogenated for 4 hours at 4 bar. The catalyst is filtered off, the solvents are eliminated in vacuo and the residue is chromatographed on aluminium oxide (dichloromethane/methanol 95:5 to 80:20).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH:14]([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO.C(O)(=O)C>[OH:21][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][NH:12][C:6]1[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: OC(CNc1ccnc2cc(Cl)ccc12)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC(CNc1ccnc2ccccc12)c1ccccc1

Procedure:
A mixture of 7-chloro-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine (10 g), 0.8 g of palladium on powdered charcoal (10%), 5 ml of acetic acid, 7 g of sodium acetate.3H2O and 200 ml of methanol was hydrogenated at room temperature with shaking at 30-50 psi until completion of hydrogen uptake. The catalyst was filtered and the solvent evaporated. The oil residue was dissolved in 20 ml of water and the solution made alkaline (pH=10) with and NaOH solution. The crystalline compound was filtered and recrystallized from isopropanol. The yield was 7.5 g, mp 289°-290° C.