Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:4]=1)=O.[CH:37]([NH2:40])([CH3:39])[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:37]([NH:40][CH2:1][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:4]=1)([CH3:39])[CH3:38]
Reactant: CCOC(=O)CCCCCCn1cc(C=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCn1cc(CNC(C)C)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 7-(7-formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Intermediate C)(50 mg, 0.103 mmol) in DCE (1 ml) was treated with iso-propylamine (0.027 ml, 0.310 mmol) and stirred at RT for 30 minutes. Sodium triacetoxyborohydride (65.7 mg, 0.310 mmol) was added and stirring continued at RT for 16 hours. The mixture was extracted with DCM (30 ml) and the organic extract was washed with water (×2) and concentrated under reduced pressure to afford the titled compound as an orange oil;
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:17][C:16]=2[F:35])=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[NH:10][NH2:11])(=[O:3])[NH2:2].[CH3:36]OC(OC)OC>CN(C)C=O>[C:1]([C:4]1[C:9]2[N:8]([CH:36]=[N:11][N:10]=2)[C:7]([S:12][CH3:13])=[N:6][C:5]=1[NH:14][C:15]1[C:16]([F:35])=[CH:17][C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]2)=[CH:19][C:20]=1[F:21])(=[O:3])[NH2:2]
Reactant: CSc1nc(NN)c(C(N)=O)c(Nc2c(F)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Reactant: COC(OC)OC
Solvent: CN(C)C=O
Product: CSc1nc(Nc2c(F)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(C(N)=O)c2nncn12

Procedure:
A solution of the product of Example 16F (615 mg, 1.2 mmol) and trimethoxymethane (5 g, 46.9 mmol) in N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 1 hour and at 55° C. for 3 hours. The mixture was filtered to give the title compound. MS: 495 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[N:6]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:9][CH:8]=2)[N:6]=1
Reactant: OB(O)c1cccs1
Reactant: Cc1nc(-c2ccc(Br)cc2)c(-c2ccc(S(C)(=O)=O)cc2)o1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc(-c2ccc(-c3cccs3)cc2)c(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a stirred solution of 2-methyl-5-[4-(methylsulfonyl)phenyl]-4-(4-bromophenyl)-oxazole (0.314 g, 0.8 mmol) in DME (10 mL) was added thiophene-2-boronic acid (0.123 g,0.96 mmol), bis(triphenylphosphine)palladium(II)chloride (0.064 g, 0.09 mmol) and saturated NaHCO3 solution (3.2 mL) at room temperature under nitrogen. The mixture was heated at reflux temperature for 4.5 hours, and cooled down to room temperature. The reaction mixture was filtered through celite, the filtrate was poured into water and the whole was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3/2). The resulting solid was recrystallized from ethyl acetate/hexane to give the title compound (0.225 g, 71.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:6]=[CH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[O:32][CH2:31][CH2:30][O:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:6](/[C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[O:29][CH2:30][CH2:31][O:32]3)=[CH:24][CH:23]=2)=[CH:7]\[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C=CC(=O)N2CCOCC2)cc1OC
Reactant: Brc1ccc(C2OCCO2)cc1
Product: COc1ccc(/C(=C\C(=O)N2CCOCC2)c2ccc(C3OCCO3)cc2)cc1OC

Procedure:
This compound was obtained in analogy to the preceding Examples from 3,4-dimethoxycinnamic acid morpholide and 2-(4-bromophenyl)-1,3-dioxolane.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](Cl)=[O:11]>>[CH3:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: Oc1ccccc1
Reactant: CC(Cc1ccccc1)C(=O)Cl
Product: CC(Cc1ccccc1)C(=O)Oc1ccccc1

Procedure:
The procedure as described in Example 4a) was repeated with phenol (30.5 mmol) and 2-methyl-3-phenylpropanoyl chloride (30.5 mmol). The crude product (5.51 g, 75%) was used without further purification in the next step.
Reaction SMILES: [BrH:1].O[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>O>[Br:1][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: Br
Solvent: O
Product: Oc1ccc(CCCBr)cc1
Yield: 83.8 %

Procedure:
To 48% hydrobromic acid solution (110 g) was added 4-(3-hydroxypropyl)phenol (25 g) and heated on a steam bath for 3 hours. After cooling, water (500 ml) was added, the oil was extracted with ether, washed with water and then with dilute sodium bicarbonate solution. The etheral extract was dried over potassium carbonate, evaporated and the residue was distilled in a Kugelrohr apparatus giving 29.6 g (84%) of 4-(3-bromopropyl)phenol, bp 180° (2 mm). The product was 92.6% pure by gas chromatography and mass spectrum was compatible with 4-(3-bromopropyl)phenol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.O.C(=O)(O)[O-].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C(COC)OC>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
2-Chloropyridine-4-carbonitrile 19 (2.96 g, 21.35 mmol) was dissolved in 100 ml of dimethoxyethane. The solution was added with 70 ml of water, sodium bicarbonate (3 equiv., 5.38 g), [4-(trifluoromethyl)phenyl]boronic acid (1.2 equiv., 4.87 g) and the mixture was then stirred at rt for 5′. The mixture was degassed and placed under argon. A catalytic amount of tetrakispalladium was added and the mixture heated at 100° C. overnight. The solvents were evaporated off and the resulting residue dissolved with ethyl acetate and then washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give a beige solid. (2.5 g, 47% yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([O:18][CH3:19])[C:9]([C:14]([O:16]C)=[O:15])=[CH:10][C:11]=2[Cl:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[OH-].[Na+].CO>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([O:18][CH3:19])[C:9]([C:14]([OH:16])=[O:15])=[CH:10][C:11]=2[Cl:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c2c(c1OC)CCN2C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)cc(Cl)c2c1CCN2C(C)=O

Procedure:
A mixture of the indole ester of step 9 above (0.8 g) and 10% aqueous NaOH/MeOH (20 ml/80 ml) is stirred under reflux for 2 hours. The reaction mixture is concentrated and the aqueous residue is diluted with water and extracted with CHCl3. The organic layer is dried (MgSO4) and evaporated affording an off-white solid which is determined to be the desired compound by NMR.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][SH:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>O.C(O)C>[CH2:12]([S:7][CH2:6][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: CC(CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCSCC(C)C(=O)O
Temperature: 0 °C

Procedure:
3-Allylsulfanyl-2-methyl-propanoic acid was prepared as described by Zhou et al. J. Org. Chem. 2004, 69, 7072. An ice-cold mixture of 2-methyl-3-sulfanyl-propanoic acid (5 g, 42 mmol) and sodium hydroxide (3.33 g, 83 mmol) in water (50 mL) was treated with a solution of allyl bromide (5.98 g, 49 mmol) in ethanol (100 mL) over 30 minutes. Ice bath was removed after 45 minutes and after 14 hours at room temperature, volatiles were removed under reduced pressure. The residue was cooled in ice, acidified to pH 6 with 1N HCl and extracted with ethyl acetate, washed with water, dried over MgSO4, concentrated under reduced pressure and dried in vacuo at room temperature for 14 hours to leave a clear liquid. Acidification of the aqueous layer to pH 4 afforded an additional 2.7 g of material. Total yield 4.44 g (74%): IR (KBr thin film) 1708 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.83-5.73 (m, 1H), 5.14-5.13 (m, 1H), 5.10-5.09 (m, 1H), 3.15 (d, J=7.3 Hz, 2H), 2.80 (dd, J=13.2, 7.0 Hz, 2H), 2.69 (sextet, J=7.1 Hz, 1H), 2.53 (dd, J=12.8, 6.5 Hz, 1H), 1.28 (d, J=7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 179.01, 131.63, 114.92, 37.38, 32.72, 31.00, 14.19; EIMS m/z 160.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16](NC(=O)C(C3N=C(N)SC=3)=NOC)[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(OCC1CS[C@@H]2C(NC(=O)C(C3N=C(N)SC=3)=NOC(C)C)C(=O)N2C=1C(O)=O)(=O)C>>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH2:16][C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)C)c3csc(N)n3)[C@H]2SC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1

Procedure:
Gelues were prepared with 250 mg of 3-acetoxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid or sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxylmino-acetamido]-ceph-3-eme-4-carboxylate or 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(1-methylethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid or the syn isomer of 7-2(2-amino-4-thiazolyl)-2-hydroxy-imino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylic acid and sufficient excipient to obtain a final weight of 400 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1CCN2C(=NCCC2)CC1>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(OCC)(=O)C>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1

Procedure:
A solution of 2-chloro-5-nitropyridine (1.58 g, 10.0 mmol) in DMF (15 mL) was treated with 1-Boc-piperazine (1.96 g, 10.5 mmol) in the presence of DBU (3 mL) and Bu4NI (0.185 g, 0.5 mmol) at 80° C. for 18 h. The reaction mixture was diluted with ethyl acetate at 25° C. The organic phase was washed with H2O, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford 4-(5-nitropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester as a yellow solid which was used for next step reaction without further purification. MS (ES+) m/z 309.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:22].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:22])[C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)c2ccccc2N(C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (0.10 g, 0.36 mmol) and iodomethane (0.50 mL, 8.0 mmol) in DMF (4 mL) was added NaH (60% in mineral oil, 20 mg, 0.50 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded 90 mg (86%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2,3-trimethyl-4-quinolinone as a colorless oil. The oil (90 mg, 0.32 mmol) was treated with NaBH4 (50 mg, 1.3 mmol) in methanol (5 mL) for 1 h and the reaction mixture was concentrated. Filtration from the inorganic material through a silica gel pad provided a colorless oil, which was then subjected to hydrogenation over 10% Pd/C (10 mg) in EtOAc (5 mL) under a hydrogen balloon for 15 h. Filtration from the catalyst through a Celite™ pad followed by removal of solvent gave 70 mg (82%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil. The crude oil (70 mg, 0.26 mmol) was treated with TFA (0.50 mL, 6.5 mmol) in CH2Cl2 for 30 min. and was quenched with 5% NaOH (6 mL). The mixture was extracted with EtOAc (2×15 mL) and was concentrated. Chromatography on silica gel using a 10% mixture of EtOAc and hexane afforded 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil (40 mg, 89%). Data for 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.00-6.91 (m, 2H), 6.60 (t, J=7.3, 1H), 6.45 (d, J=7.3, 1H), 3.61 (br s, 1H), 2.74 (dd, J=16.6, 5.3, 1H), 2.47 (dd, J=16.6, 10.3, 1H), 1.82 (m, 1H), 1.20 (s, 3H), 1.05 (s, 3H), 0.97 (d, J=7.2, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 1-benzyl-4-piperidone (5.6 mL, 30.0 mmol) in 50 mL THF was added a solution of methyllithium in THF (24.0 mL, 36 mmol) dropwise at 0° C. over 15 min. The reaction mixture was allowed to warm to room temperature over 3 h and then quenched with 30 mL of sat. NH4Cl solution. The organic layer was extracted with diethyl ether (2×100 mL) and the combined organic layer was washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain yellow gum. It was purified by column chromatography over silica gel with 9:1 EtOAc-MeOH as the eluting system to obtain 1-benzyl-4-methyl-4-piperidinol as a yellow thick oil (3.6 g, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH2:15]3)=[O:10])[NH2:8])=[CH:4][CH:3]=1.[C:35]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C:43]1=O)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([NH:8][CH:45]2[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:43][CH2:44]2)[C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])[CH2:15]3)=[O:10])=[CH:33][CH:34]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@H](N)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
0.41 g of N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea is dissolved in 4 ml of dichloromethane under N2 in the presence of 0.17 g of N-BOC-piperidone and of 0.23 g of sodium triacetoxyborohydride, and the mixture is stirred at ambient temperature for 16 h. After evaporation and hydrolysis, extraction is carried out with ethyl acetate until the aqueous phase is completely depleted. The organic phase is washed with H2O and then with a saturated aqueous sodium chloride solution. Drying over MgSO4 and concentration to dryness are carried out. The crude is chromatographed on silica gel, elution being carried out with a 98/2 mixture of dichloromethane and methanol. 0.37 g of tert-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo-[3.2.1]oct-8-yl)-2-oxoethyl]amino}piperidine-1-carboxylate is then obtained.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11](=[O:31])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:20](=[O:29])[CH2:19][O:18][C:17]=2[N:30]=1)[CH3:10])C)(C)(C)C.Cl>>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]2[C:20](=[O:29])[CH2:19][O:18][C:17]3[N:30]=[C:13]([NH:12][C:11](=[O:31])[C@@H:9]([NH:7][CH3:6])[CH3:10])[CH:14]=[CH:15][C:16]2=3)=[CH:23][CH:24]=1
Reactant: C[C@@H](C(=O)Nc1ccc2c(n1)OCC(=O)N2c1ccc(Cl)cc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Product: CN[C@@H](C)C(=O)Nc1ccc2c(n1)OCC(=O)N2c1ccc(Cl)cc1
Yield: 80.7 %

Procedure:
{(S)-1-[1-(4-Chloro-phenyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (23 mg) was treated with HCl, according to General procedure 3 (HCl deprotection), to give the title compound (8 mg). 1H NMR (400 MHz, DMSO-d6): 11.10 (1H, s), 9.20 (1H, br), 8.94 (1H, br), 7.71-7.59 (3H, m), 7.47-7.38 (2H, m), 6.86 (1H, d), 5.03 (2H, s), 4.01-3.92 (1H, m), 2.58-2.53 (3H, m), 1.47 (3H, d). MS: [M+H]+ 361.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:26][CH3:27])=[N:19][N:20]3[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1>>[CH2:1]([C@@H:8]1[N:13]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:26][CH3:27])=[N:19][N:20]3[CH:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(C(C)C)c2cc(N3CCNC(Cc4ccccc4)C3)ccc12
Reactant: Clc1cnccn1
Product: CCc1nn(C(C)C)c2cc(N3CCN(c4cnccn4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 12 %

Procedure:
Prepared using the same procedure described in Example 410 from 6-(3-benzyl-piperazin-1-yl)-3-ethyl-1-isopropyl-1H-indazole and chloropyrazine to afford the title compound as a yellow solid (7 mg, 12%). LC/MS (Method B) 4.47 min, [M+1]+ 441.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[BrH:14]>>[Br:14][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1
Reactant: Br
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Product: Cc1nc(C(F)(F)F)ccc1CBr
Temperature: 135 °C
Yield: 71 %

Procedure:
A mixture of (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (1.677 g, 8.77 mmol, 76% pure) in 48% aq. HBr (10 mL) was heated to reflux (oil bath temperature, 135° C.) for 24 h. The volatile components of the resulting biphasic mixture were distilled under vacuum to remove most of the hydrogen bromide (sodium hydroxide trap). The residue was partitioned between 2:1 EtOAc/THF and water (at pH 3) and the organic phase was dried (MgSO4), filtered and evaporated. The solid residue was re-evaporated after addition of dichloromethane/hexanes to obtain the title compound as a tan solid, 1.19 g, 71% yield (based on the purity of the starting material). HPLC/MS: retention time=2.15 min, [M+H]30 =254.
Reaction SMILES: CC(C)([S@@]([NH:6][C@@H:7]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:10][CH:9]=1)=O)C.[ClH:28].O1CCOCC1>>[ClH:28].[NH2:6][C@@H:7]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: CCOP(C)(=O)c1ccc([C@@H](N[S@@](=O)C(C)(C)C)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(C)(=O)c1ccc([C@@H](N)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 4-((S)—((S)-1,1-dimethylethylsulfinamido)(4-fluorophenyl)-methyl)phenyl(methyl)phosphinate, 19-c, (10.6 g, 27 mmol) was dissolved in HCl/dioxane (100 ml) and the mixture was stirred at room temperature for about 3 h. The mixture was then concentrated under vacuum and the residue was washed with ethyl acetate to provide the product, 19-d, (6.66 g, 80%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[OH:20][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccccc1)C1CCCN1
Yield: 69 %

Procedure:
N-Boc-pyrrolidine (5.0 g) is dissolved in diethyl ether (60 mL) and the solution is cooled to −78° C. N,N,N′,N′-Tetramethylethylenediamine (TMEDA) (4.4 mL) is added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below 60° C. After 2 h, benzaldehyde (3.6 mL) is added and the mixture is stirred at −70° C. for an additional 30 mL The reaction mixture is allowed to warm to room temperature and is then quenched with water and poured into EtOAc (200 mL). The separated organic layer is washed with saturated aq. ammonium chloride (3×50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated. The crude product is purified by column chromatography (heptane/EtOAc, 8/1; 6/1) to afford 6.3 g of N-Boc-2-(hydroxy(phenyl)methyl)-pyrrolidine as a mixture of diasteromers. The resulting N-Boc-2-(hydroxy(phenyl)-methyl)pyrrolidine (5.6 g) is dissolved in dichloromethane (500 mL) and trifluoroacetic acid (60 mL) is added. The mixture is concentrated, dissolved in dichloromethane (200 mL), and washed with saturated aq. sodium bicarbonate (3×100 DL). The aqueous layers are extracted with dichloromethane (4×50 mL) and the combined organic layers are concentrated. The crude product is distilled in a Kugelrohr apparatus (150-175° C., 0.2 Torr) to afford 2.47 g of the title compound as a mixture of diasteromers. Physical characteristics. MS (ESI+) m/z 178 (M+H)+.