Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH2:17]1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:21]([CH:18]1[CH2:19][CH2:20][C:16](=[O:15])[CH2:17]1)=[O:22])[CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCC(=O)C1

Procedure:
The product from Example 92B and 3-oxocyclopentanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ ppm 0.91 (t, J=7.5 Hz, 3H), 1.25-1.36 (m, 2H), 1.57 (s, 9H), 1.55-1.84 (m, 2H), 1.98-2.06 (m, 1H), 2.13-2.28 (m, 3H), 2.39-2.42 (m, 2H), 2.61-2.66 (m, 2H), 3.27-3.34 (m, 1H), 8.55 (s, 1H). MS (ESI+) m/z 323 (M+H)+. Anal. calcd. for C17H26N2O2S: C, 63.32; H, 8.13; N, 8.69. Found: C, 63.19; H, 8.07; N, 8.66.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][NH:8][C:9](=[O:16])[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1)([O-])=O.N#N>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][NH:8][C:9](=[O:16])[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)O[C@H]1CCOC1
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Product: Nc1cccc(CNC(=O)O[C@H]2CCOC2)c1

Procedure:
Charged 15 g of (S)-tetrahydrofuran-3-yl 3-nitrobenzylcarbamate 2c in 120 ml EtOAc to a 1L Parr bomb at room temperature under a blanket of N2. The agitator was started and the vessel pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times, then the agitator was stopped before adding 0.225 g of 5% Pd/C. The agitator was started, the vessel pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times, then the agitator was stopped. The vessel was pressurized with H2 to 2 bar, then the pressure was released. This procedure was repeated 3 times, then the vessel was pressurized with H2 to 6.75 bar. The agitator was started and the suspension stirred until complete conversion was evident by HPLC. The H2 pressure was released, the vessel re-pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times then the agitator was stopped, the reaction mixture filtered through celite and the filter cake rinsed with 30 ml EtOAc to give crude (S)-tetrahydrofuran-3-yl 3-aminobenzylcarbamate 2d as a solution in EtOAc that was used as is immediately in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:8]([C:7]1[C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cccnc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C#N)CC1

Procedure:
A mixture of 2-chloro-3-cyanopyridine (15.2 g, 0.11 mol), tert-butyl 1-piperazinecarboxylate (25 g, 0.13 mol) and triethylamine (18 ml, 0.13 mol) in toluene (200 ml), was heated under reflux for 24 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in ethyl acetate (250 ml), and washed with water (3×). The organic solution was dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with pentane, filtered and dried in vacuo, at 60° C., to afford the title compound as a cream coloured solid, 24.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[OH:12])=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:12][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH2:10][CH2:9][CH:8]([O:23][S:35]([CH3:34])(=[O:37])=[O:36])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=1)(=[O:37])=[O:36]
Reactant: O=[N+]([O-])c1cc(C(O)CCC(O)c2ccc(Cl)c([N+](=O)[O-])c2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
The product of Example 28B (4.81 g, 11.99 mmol) and triethylamine (5.85 mL, 42.0 mmol) were dissolved in dichloromethane (80 mL) at room temperature and treated with methanesulfonyl chloride (2.34 mL, 30.0 mmol) dropwise over 10 minutes. The resulting solution was stirred for 2 h then concentrated to dryness and used directly in the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:32]([O:34][C:35]([C@@:37]1([NH2:42])[CH2:39][C@H:38]1[CH:40]=[CH2:41])=[O:36])[CH3:33]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:42][C@:37]1([C:35]([O:34][CH2:32][CH3:33])=[O:36])[CH2:39][C@H:38]1[CH:40]=[CH2:41])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: -23 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4.87 g (21.0 mmol) of Boc-(2S,4R)-hydroxyproline in 25 mL of THF was added 2.03 mL (20.0 mmol) of N-methylmorpholine. A suspension formed. The mixture was cooled to −23° C. and 2.85 g (20.0 mmol) of isobutylchloroformate was added. After stirring for 10 min additional 4.25 g (42.0 mmol) of N-methylmorpholine was added. To this mixture was added the solution of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 1 at a temperature of −15° C. within 5 min. The reaction mixture was stirred for 2.5 h at 0° C. The salts were filtered off and the filtrate was treated with 20 mL of aqueous HCl (0.5 N). The solvents were removed at 50° C. under reduced pressure using a rotary evaporator and the residue was extracted twice with 50 mL of ethyl acetate. The extract was washed with 40 mL of water and 40 mL of aqueous sodium carbonate solution (10% w/w), and dried over sodium sulfate. Finally the solvent was removed completely to give 8.19 g of (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][N:5]=1)=O.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]1>CCO>[CH3:26][S:23]([CH2:22][CH2:21][CH2:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[C:8]1[CH:7]=[CH:6][N:5]=[C:4]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]2)[N:9]=1)(=[O:25])=[O:24]
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Reactant: NC1CCC(CO)CC1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(CO)CC2)n1
Yield: 49.1 %

Procedure:
1-(2-Methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (5.0 g, 13 mmol) and (4-amino-cyclohexyl)-methanol hydrochloride (2.46 g, 19 mmol) were heated at reflux in EtOH (100 mL) under N2 for 16 h. The reaction mixture was then cooled, the suspension filtered, the filtrate volume reduced by half, diluted with EtOAc and washed with water, dried over sodium sulfate, filtered and concentrated until precipitate formed. This suspension was filtered, and the filtrate concentrated again until precipitation, and the suspension filtered, and both precipitates were combined and solvent removed in vacuo to yield (4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanol (Compound 214, 2.93 g), as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][NH:12]2)[CH2:9]1)=[O:7].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][N:12]2[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)=[O:7]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CNC2C1
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CN(C(=O)c3ccccc3)C2C1
Yield: 84 %

Procedure:
In analogy to the experimental procedure of example 1c) rac-3-(2,4-Dichloro-benzylcarbamoyl)-3,6-diaza-bicyclo[3.2.0]heptane instead of 6-(2,4-dichloro-benzylcarbamoyl)-2,6-diaza-spiro[3.3]heptane using benzoyl chloride was converted into the title compound (92 mg, 84%) which was obtained as a white solid. MS (EI) m/e: 404.2 (M+H)+.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[C:16]2[O:17][CH2:18][CH2:19][C:15]=2[C:14]2[C:13]3[CH2:12][CH2:11][NH:10][C:9](=[O:20])[C:8]=3[NH:7][C:6]=2[CH:5]=1>C(O)C>[NH2:10][CH2:11][CH2:12][C:13]1[C:14]2[C:6](=[CH:5][C:4]([F:3])=[C:16]3[C:15]=2[CH2:19][CH2:18][O:17]3)[NH:7][C:8]=1[C:9]([OH:20])=[O:1]
Reactant: O=C1NCCc2c1[nH]c1cc(F)c3c(c21)CCO3
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: NCCc1c(C(=O)O)[nH]c2cc(F)c3c(c12)CCO3
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a stirring solution of KOH (214 mg, 3.82 mmol) in ethanol (50%), compound 10 (108 mg, 0.438 mmol) was added. It was refluxed for 6 h and kept overnight at room temperature. The solvent was removed and water was added to the residue thus obtained. It was filtered and acidified with acetic acid. The solid obtained was washed with water. The filtrate was again extracted with ethyl acetate. The organic layer was concentrated to yield the desired compound 11 (55 mg, yield 47.45%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[OH:8][CH2:9][C:10]([N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:13])=[O:11]>>[OH:8][CH2:9][C:10]([N:12]([CH3:13])[CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[S:4][CH:5]=[CH:6][N:7]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)=[O:11]
Reactant: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1O
Reactant: ClCc1nccs1
Product: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1OCc1nccs1
Yield: 38 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide (obtained as described in Example 3, preparation of starting materials) to give the title compound as a white solid in 38% yield; NMR spectrum (DMSO-d6 373K) 2.27 (s, 3H), 2.98 (s, 3H), 3.91 (t, 2H), 4.07 (s, 2H), 4.47 (t, 2H), 5.44 (s, 2H), 7.09 (d, 1H), 7.16 (d, 1H), 7.34 (d, 1H), 7.54 (m, 2H), 7.67 (t, 1H), 7.70 (d, 1H), 7.83 (d, 1H), 8.41 (s, 1H), 9.63 (s, 1H); Mass spectrum MH+ 480.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.N[C:14]1[CH:15]=C(C(C)=[CH:22][CH:23]=1)C(OC)=O>>[CH3:12][C:3]1[C:2]([N:1]2[CH:22]=[CH:23][CH:14]=[CH:15]2)=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][OH:7]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: COC(=O)c1cc(N)ccc1C
Product: Cc1c(CO)cccc1-n1cccc1

Procedure:
When the same reaction as in Referential Example 18 is carried out using methyl 3-amino-2-methylbenzoate instead of the starting methyl 3-amino-6-methylbenzoate, 2-methyl-3-(1-pyrrolyl)benzyl alcohol is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.[CH3:26][N:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])[CH3:28]>>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[C:32]([NH:33][C:23](=[O:24])[CH2:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:34]=[CH:35][CH:36]=1)[CH3:26]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4cccc(CN(C)C)c4)cc3)c2cc1OC
Yield: 86 %

Procedure:
Using an analogous procedure to that described in Example 1, 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid was reacted with 3-dimethylaminomethylaniline to give the title compound in 86% yield; 1H NMR: (DMSOd6) 2.14 (s, 3H), 3.35 (s, 2H), 3.68 (s, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 6.96 (d, 1H), 7.24 (m, 1H), 7.26 (d, 2H), 7.39 (s, 1H), 7.44 (d, 2H), 7.53 (d, 1H), 7.55 (d, 1H), 7.58 (s, 1H), 8.53 (s, 1H), 10.19 (s, 1H); Mass Spectrum: M+H+ 473.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])=[O:3].[NH2:17][NH2:18]>>[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])(=[O:3])[NH:17][NH2:18]
Reactant: CC(CC(C)(C)OOC(C)(C)C)OC(=O)Cl
Reactant: NN
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)NN

Procedure:
1,3-Dimethyl-3-(t-butylperoxy)butyl carbazate was prepared by reacting 1,3-dimethyl-3-(t-butylperoxy)butyl chloroformate with 11 molar excess of 54% aqueous hydrazine.
Reaction SMILES: [CH3:1][CH:2]([NH:10][NH2:11])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.C([O:14][C:15](=O)[CH:16]([CH3:20])[C:17]([CH3:19])=O)C>C(O)C>[CH3:19][C:17]1[NH:11][N:10]([CH:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[C:15](=[O:14])[C:16]=1[CH3:20]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Cc1ccc(C(C)NN)cc1
Solvent: CCO
Product: Cc1ccc(C(C)n2[nH]c(C)c(C)c2=O)cc1

Procedure:
30 g of α-methyl-4-methylbenzylhydrazine in ethanol were added to a solution of 28.8 g (0.2 mol) of α-methyl-acetoacetic acid ethyl ester in 40 ml of ethanol under N2 gas; during the addition, the temperature rose to 70° C. After completion of the addition, the reaction mixture was heated for 2 hours under reflux.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 2.02 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 72-2 (7.54 mmol, crude form) as starting materials, respectively 0.96 g (Isomer A, colorless solid) and 1.64 g (Isomer B, pale brownish red amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH2:9]([OH:11])[CH3:10].[OH-].[Na+]>ClCCl>[CH2:9]([O:11][C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)[CH3:10]
Reactant: Nc1cccc(Br)n1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOc1cccc(N)n1
Temperature: 170 °C

Procedure:
Introduced into a microwave tube are 500 mg (2.89 mmol) of 2-amino-6-bromopyridine, to which 2 ml of ethanol and 231 mg (5.78 mmol, 2 eq) of sodium hydroxide are added. The mixture is heated for 10 hours in a microwave oven at 170° C. The reaction medium is diluted with 50 ml of dichloromethane and then washed twice with 50 ml of water. The organic phase is concentrated to dryness and the residue is purified by chromatography over silica with, as eluent, heptane/ethyl acetate (1/1). The expected product is obtained in the form of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C1C(=O)N([Br:17])C(=O)C1>>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(N)c(Br)c1

Procedure:
The title compound was prepared from 4-aminobenzonitrile (2.04 g, 17.2 mmol) and NBS (3.07 g, 17.2 mmol) according to the procedure in Example 16, step (b) (2.53 g, 75%). Mass Spectrum (ESI, m/z): Calcd. for C7H5BrN2, 196.9 (M+H), found 196.7.
Reaction SMILES: [Na].N.[C:3]([O:7][C:8](=[O:32])[NH:9][C@@:10]12[CH2:15][CH:14]1[CH2:13][N:12](S(C1C=CC(C)=CC=1)(=O)=O)[C@H:11]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8](=[O:32])[NH:9][C@@:10]12[CH2:15][CH:14]1[CH2:13][NH:12][C@H:11]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(NC(=O)OC(C)(C)C)[C@@H]2c2ccccc2)cc1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]12CC1CN[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a flame dried 250 mL rbf equipped with a dry ice condenser was added fresh sodium metal (0.32 g, 14 mmol). The flask was immersed in a −78° C. bath and ammonia gas was condensed into the flask (˜30 mL). Racemic Intermediate 47, one enantiomer being [(1S,2S)-2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (3.0 g, 7.0 mmol) in THF (7 mL, 2 mL rinse) was added to the flask in a fast dropwise fashion and the thick mixture was stirred for 5 minutes at which point tic indicated the reaction was complete. The reaction was warmed to room temperature and volatile solvents allowed to evaporate. The residue was partitioned between H2O and methylene chloride, the organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a foam (1.9 g, quantitative yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]([OH:13])=[O:12])[C:8]=1[CH3:9])(=[O:3])[CH3:2].[C:14]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C.CCOCC>CO>[C:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnn(CC(=O)O)c1C
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cn1ncc(C(C)=O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 2-(4-acetyl-5-methyl-1H-pyrazol-1-yl)acetic acid (1.17 g, 6.42 mmol, as a mixture of regioisomers from the previous step) in MeOH (8.8 ml)-Toluene (30.6 ml) was added a 2 M solution of (trimethylsilyl)diazomethane in ether (4.8 ml, 9.6 mmol) dropwise at 0° C. The resulting solution was allowed to warm to rt and stirred for 120 min. The reaction was quenched by addition of AcOH (3 ml) and the solvent was concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give the desired product along with a mixture of regioisomers (>99% yield). 1H NMR (270 MHz, CDCl3) δ 2.45 (3H, s), 2.53 (3H, s), 3.79 (3H, s), 4.90 (2H, s), 7.88 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].C(O)(=O)C.Cl>O>[NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)cc(N)c2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1c(F)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Yield: 51.3 %

Procedure:
A mixture of ethyl 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (2.68 g, 7.92 mmol), acetic acid (20 ml) and concentrated hydrochloric acid (20 ml) was heated under reflux for 3 hours. After cooling there action solution with ice, water (200 ml) was poured therein and the precipitated crystals were filtered out. After washing with excess water, a small amount of cold ethanol and excess diethyl ether in that order, the crude crystals obtained were purified by recrystallization in a mixed solvent of chloroform/methanol and then dried under a reduced pressure. 1.26 g (51%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].C(#N)C.[CH2:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.OO>O>[CH:24]1([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCCCC1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: OO
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 56 °C
Yield: 84 %

Procedure:
A solution of 0.097 g (0.359 mmol) of ferric chloride hexahydrate in 2 ml of water is added to a mixture of 5.00 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 28 ml of acetonitrile, and 19 ml of cyclohexane. The mixture is heated to 56° C. A solution of 4.70 g (69 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2.25 hours to the reaction mixture while the temperature is brought to and maintained at reflux. After the peroxide is added, the mixture is heated at reflux for 45 minutes. Work-up and purification according to the procedure of Example 5 afford 5.47 g (84% yield) of the title compound, a pale yellow syrup. GC assay is 100%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][O:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: COCCBr
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cccc([N+](=O)[O-])c1N

Procedure:
A solution of 5 g 2-Amino-3-nitro-phenol, 4.5 g 1-Bromo-2-methoxy-ethane, 4.4 g K2CO3 in 50 mL DMF were heated to 60° C. for 16 h. Then 50 mL of water were added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over MgSO4, and the solvents were removed under reduced pressure. The remaining product was pure enough for the next reaction step. Yield: 5.8 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[I:9]I>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[I:9][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1ccccc1C
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(I)cc1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 77.6 %

Procedure:
A mixture of 1,2-dimethylbenzene (1.06 g; 10 mmol), silver trifluoromethanesulfonate (2.56 g; 10 mmol) and I2 (2.53 g; 10 mmol) in CH2Cl2 (50 ml) was stirred for 7 h at room temperature, then filtered through a Celite pad, washed with fresh CH2Cl2 (2×20 ml) and combined filtrates were washed with 5% Na2SO3, H2O, brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give crude title compound (1.8 g; 78%) as brownish oil, which was used in next step without further purification. 1H-NMR (CDCl3) 2.23 (s, 6H), 6.84 (d, 1H, J=8.0 Hz); 7.39 (dd, 1H, J=1.7; 8.0 Hz); 7.46 (broad s, 1H).