Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].[H-].[Na+]>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(C#N)cc1[N+](=O)[O-]
Yield: 39.4 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzonitrile (300 mg) and dimethyl malonate (286 mg) in DMF was added 60% NaH at 0° C., followed by reaction at room temperature to obtain dimethyl (4-cyano-2-nitrophenyl)malonate (198 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[P:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P:18](Cl)Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([P:11]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[P:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: ClP(Cl)c1ccccc1P(Cl)Cl
Solvent: C1CCOC1
Product: Fc1ccc(P(c2ccc(F)cc2)c2ccccc2P(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A THF solution (26.6 mL, 1.03 M, 27.40 mmol) of p-fluorophenylmagnesium bromide was added to a mixture of 1,2-bis(dichlorophosphino)benzene (0.96 g, 3.43 mmol) and THF (20 mL) in an argon atmosphere at −78° C. After warming to room temperature, the mixture was allowed to react overnight at 60° C. The reaction mixture was cooled to ambient temperature, and the solvent was removed under reduced pressure; subsequently, CH2Cl2 (30 mL) was added. 1N aqueous solution of hydrochloric acid (20 mL) was added to the reaction mixture, and the aqueous layer was extracted three times with CH2Cl2. The moisture contained in the combined organic extract was removed with magnesium sulfate, and the extract was filtered. After removing the solvent under reduced pressure, the resulting yellow oily substance was triturated with methanol to give a white powder, and the white powder was washed two times with methanol, giving the title compound as a white powder (1.10 g, yield 62%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][C:31]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])=[O:32].[BH3-]C#N.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:24]([F:25])([F:26])[F:27])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:28][CH2:29][CH2:30][C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[O:32])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCC(=O)NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)NS(=O)(=O)c4ccccc4)ccc3c2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N-(phenylsulfonyl)propanamide (1.19 mmol, 1.5 equiv) were dissolved in anhydrous ethanol. The mixture was stirred at 80° C. for 1 h. Then NaBH3CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80° C. for 16 h. The organic layer was concentrated and purified by preparative thin layer chromatography (mobile phase was methanol:dichloromethane 1:10) to give 3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide as a white solid. 120 mg, white solid, 53%. ESI-MS: 591.0 (M+H)+. HPLC: 98.05%. 1H NMR (400 MHz, DMSO-d6) δ: 8.22˜8.13 (m, 1H), 8.11˜8.04 (m, 2H), 7.79˜7.63 (m, 4H), 7.45˜7.30 (m, 3H), 4.63˜4.49 (m, 1H), 4.27 (s, 2H), 2.99 (t, 2H), 2.32 (t, 2H), 2.19˜2.07 (m, 2H), 1.85˜1.74 (m, 2H), 1.45˜1.30 (m, 2H), 125˜1.12 (m, 2H), 1.10˜0.97 (m, 1H), 0.86 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:29][CH2:30][CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[N:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]3=4)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: O=C(Cc1ccc(Cl)cc1)NC1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(NC(=O)Cc3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-chloro-phenyl)-N-piperidin-4-yl-acetamide (0.2 g, 0.8 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (0.095 mL, 0.8 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/20% methanol) to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=[N:23][OH:24])=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.[CH2:36]([O:38][C:39]#[CH:40])[CH3:37].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[CH:37]=[C:36]([O:38][CH2:39][CH3:40])[O:24][N:23]=3)=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1c(C=NO)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: C#COCC
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(-c2ncc3[nH]c4ccc(OCc5ccccc5)cc4c3c2COC)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.1 g (3.0 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde oxime is dissolved in 40 ml of dry DMF and combined with 0.56 g (3.1 mmol) of N-bromosuccinimide (dissolved in 5 ml of DMF). The reaction mixture is stirred for 15 minutes at room temperature and then combined with 1.5 eq. of ethoxyacetylene and 2 ml of triethylamine. The reaction mixture is agitated overnight at room temperature, then poured on ice water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, the solvent drawn off, and the residue purified by column chromatography on silica gel with ethyl acetate. Melting point: 139°-140° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3Br)[C:12](=[O:22])[NH:11][C:10](=[O:23])[CH:9]=2)[CH2:3]1.[I:24]C1C=CC=CC=1CCl>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[I:24])[C:12](=[O:22])[NH:11][C:10](=[O:23])[CH:9]=2)[CH2:3]1
Reactant: ClCc1ccccc1I
Reactant: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2Br)C1
Product: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2I)C1

Procedure:
The title compound was prepared by the procedure described in the preparation of compound 8, except that 2-iodobenzyl chloride was used as the benzylating reagent. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.76 (d, J=7.6 Hz, 1 H), 7.21 (t, J=7.3 Hz, 1 H), 6.89 (t, J=7.2 Hz, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 5.26 (s, 1 H), 4.79-4.92 (ABq, J=34.1, 6.7.0 Hz, 2H), 3.27 (m, 1 H), 3.13 (s, 1 H), 2.85 (d, J=11.6 Hz, 1 H), 2.70 (m, 1 H), 2.41 (m, 1 H), 2.02 (m, 1 H), 1.60 (m, 1 H), 1.45 (m, 2 H). MS (ES) [m+H] calc'd for C16H20IN4O2, 427.1; found, 427.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][C@H:8]2[C:16]([O:18][CH3:19])=[O:17])[C:3]1=[O:20].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)C>[CH:13]([N:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[C:3]2=[O:20])[C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)([CH3:14])[CH3:15]
Reactant: COC(=O)[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O

Procedure:
(3R,4S)-Methyl 4-((3S)-3-amino-2-oxopyrrolidin-1-yl)-1-isopropylpiperidine-3-carboxylate (50 mg, 0.176 mmol, 1 eq.), 4-chloro-6-(trifluoromethyl)-quinazoline (45 mg, 0.194 mmol, 1.1 eq.) and triethylamine (98 uL, 0.706 mmol, 4 eq.) were dissolved in ethanol (3 mL) at room temperature then microwaved at 100° C. for 1 hour. Purified by HPLC. Obtained (3R,4S)-methyl 1-isopropyl-4-(2-oxo-(3S)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)piperidine-3-carboxylate, bis TFA salt (88 mg) as a white solid. LCMS detects (M+H)+=480.39. 1H NMR (400 MHz) (CD3OD) δ 8.82 (s, 1H, J=7 Hz); 8.20 (s, 1H, J=7 Hz); 8.78 (s, 1H, J=7 Hz); 7.91 (d, 1H, J=7 Hz); 7.30-7.10 (m, 1H); 5.37 (m, 1H); 4.3-4.05 (m, 1H); 3.80-3.00 (m, 9H); 2.60-2.45 (m, 1H); 2.45-2.10 (m, 2H); 2.10-1.80 (m, 2H); 1.27 (m, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=C.[Mg].Br[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1>O1CCCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:11][CH:12]=1
Reactant: C=CCCCCBr
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A suspension of 6-bromo-1-hexene (10 g), magnesium (1 .5g), and lodoethane (1 drop) in anhydrous tetrahydrofuran was heated at reflux until all of the magnesium dissolved. The resulting Grignard reagent was cooled to about 0° C. and was treated with a 1M solution of ZnCl2 in ether (67 ml), and the mixture was allowed to warm to room temperature over 30 minutes. Tetraids(triphenylphosphine)palladium (0) (3.5 g) and 4-bromofluorobenzene (6.73 ml) were added to the reaction and the mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature, concentrated in vacuo, diluted with hexane, filtered and concentrated once more in vacuo. Chromatography on a silica gel column eluting with ether-hexane (0-5%) afforded 5 g of a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10].[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>CN(C)C=O>[CH3:8][S:9]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:20])[CH2:16][CH2:17]1)(=[O:11])=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(NC(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid (229.4 mg, 0.785 mmol, US20060014708) in N,N-dimethyl formamide (4.0 mL) was added TEA (101 mg, 1.004 mmol) and 1,1′-carbonyldiimidazole (Aldrich, 134 mg, 0.826 mmol). After it was stirred at rt for 2 hrs, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give imidazole-1-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (150.7 mg, 70.5%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[CH2:15][O:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:12])=[CH:5]2.[CH3:31][C:32]([CH3:34])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[CH2:15][O:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH:32]([CH3:34])[CH3:31])[CH2:22][CH2:23]1)=[O:12])=[CH:5]2
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COCC(NC(=O)c2cc3cc(Cl)ccc3[nH]2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, 5-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-2-carboxamide (320 mg, 0.72 mmol) and acetone (2.0 mL, 27 mmol) afforded, after purification (SiO2: 0 to 2.5% isopropylamine in 1:1 hexane:EtOAc) and recrystallization (acetonitrile), 185 mg (53%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([O:25][CH3:26])[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=5)=[CH:3][C:4]=4[O:25][CH3:26])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Product: COc1cc(-c2ccc(F)cc2)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Yield: 72 %

Procedure:
Following the procedure described in Example 76c using 4-[4-bromo-2-(methyloxy)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one and (4-fluorophenyl)boronic acid gave the title compound as a solid (60 mg, 0.137 mmol, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.27-9.05 (m, 1H), 7.58 (dd, J=5.3, 7.3 Hz, 2H), 7.34 (ddd, J=2.3, 4.0, 7.8 Hz, 1H), 7.28-7.11 (m, 3H), 4.02-3.87 (m, 3H), 3.80-3.67 (m, 1H), 3.62 (ddd, J=4.2, 8.0, 11.9 Hz, 1H), 3.49-2.96 (m, 1H), 2.77-2.36 (m, 2H), 2.32-1.99 (m, 1 H), 1.88-1.67 (m, 1H), 1.59-1.50 (m, 1H), 1.09-0.92 (m, 2H), 0.84-0.67 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N+:6]([O-:11])[CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[S:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=1)(=[O:14])=[O:13].[N+:24]([O-])([OH:26])=[O:25].CCOCC>C(O)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N+:6]([O-:11])[CH:7]=[C:8]([N+:24]([O-:26])=[O:25])[CH:9]=2)[S:4][C:3]=1[S:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=1)(=[O:13])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3c(ccc[n+]3[O-])c2Br)c1
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3c(cc([N+](=O)[O-])c[n+]3[O-])c2Br)c1

Procedure:
3-Bromo-2-(3-cyano5-fluorobenzenesulfonyl)-thieno[2,3-b]pyridin-N-oxide (prepared as described in WO 2007/072095) (7.97 g, 19.3 mmol) was boiled at 120° C. with 66% nitric acid (1.22 ml) in acetic acid (25 ml) for 4 hours. The reaction mixture was evaporated and the residue was purified by chromatography (Kieselgel 60, chloroform:methanol=5:0.1). First the starting material was isolated (3.7 g, 47%), than a yellow solid, which was treated with ether (5 ml). After filtration the title compound was isolated (0.72 g, 8.3%). LC-MS: (M+H)+ 459.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:25]([O:29][C:30]([C:32]1[S:36][C:35](Cl)=[N:34][CH:33]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl>CN(C=O)C>[C:25]([O:29][C:30]([C:32]1[S:36][C:35]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:34][CH:33]=1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=O)OC(C)(C)C)s3)cc(C)c21
Yield: 95.2 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2 g, 8 mmol), Cs2CO3 (7.82 g, 24 mmol) and t-butyl-2-chloro-1,3-thiazole-5-carboxylate (2.64 g, 12 mmol) in DMF (20 mL) was heated at 80° C. for 1 h. The reaction mixture was cooled down and acidified to pH 3 with 6N HCl, extracted with ethyl acetate and washed with water and brine. The organic layer was dried by Na2SO4 and concentrated. The residue was purified by column chromatography (silica, Hexanes/EA=8:2, then DCM/MeOH=9:1) affording the title compound (3.3 g, 89%) as a light yellow solid. 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.46 (d, 1H), 7.18 (d, 1H), 5.68 (dd, 1H), 4.21 (q, 2H), 3.11 (dd, 1H), 2.44 (m, 1H), 2.39 (s, 3H), 1.56 (s, 9H), 1.24 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CC(C)=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccccc1C(=O)OC
Yield: 50.2 %

Procedure:
A mixture of 40 g of methyl 2-hydroxybenzoate, 45.4 g of powdered potassium carbonate, 700 ml acetone and 78.2 g of 1-bromotetradecane is heated at reflux temperature for 5 days. The reaction is cooled, filtered and concentrated in vacuo. The residue is dissolved in ethyl acetate; washed with water, saturated sodium bicarbonate, 10% sodium hydroxide, water and saturated sodium chloride; dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-10% ethyl acetate/hexane) to give 46.0 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=O)=[N:9][NH:10][CH:11]=1)=[O:5].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12]([C:8]2[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:2]=3[F:1])=[CH:11][NH:10][N:9]=2)=[O:14])[CH2:22][CH2:23]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC(NC(=O)c2n[nH]cc2NC(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), 4-amino-N-methylpiperidine (50.0 μl, 0.45 mmol), EDAC (104 mg, 0.54 mmol) and HOBt (73.0 mg, 0.54 mmol) in DMF (3 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO4) and reduced in vacuo to give 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (1-methyl-piperidin-4-yl)-amide as a white solid (113 mg, 69%). (LC/MS: Rt 2.52, [M+H]+ 364.19).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C@H:7]1[CH2:12][CH2:11][C@:10]2([OH:27])[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3.[N+]([O-])(O)=O.[C:32](N1C(C)=CC(C)=N1)(=[NH:34])[NH2:33]>C(O)C>[NH:1]([CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C@H:7]1[CH2:12][CH2:11][C@:10]2([OH:27])[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)[C:32]([NH2:34])=[NH:33]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/OCCN)CC[C@]12O
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/OCCNC(=N)N)CC[C@]12O
Yield: 36 %

Procedure:
A solution of 0.95 g of (E)-17β-(2-aminoethoxyimino)methyl-5β-androstane-3β,14β-diol (I-ab) and 1.05 g of 1-amidino-3,5-dimethylpyrazole nitrate in 20 ml of ethanol was heated at reflux for 10 hrs. The solution was evaporated to dryness under reduced pressure and the crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness under reduced pressure. The residue was ground with di-iso-propyl ether/ethanol to give 0.38 g of the title compound (I-ag), as a nitrate, white solid.
Reaction SMILES: C([Mg][Cl:5])(C)C.[Br:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=1Br.C(C(Cl)C)CCCCC>O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=1[Cl:5]
Reactant: CC(C)[Mg]Cl
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: CCCCCCC(C)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(Cl)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Isopropylmagnesium chloride (1.20 ml, 2.40 mmol) was added dropwise to a solution of methyl 4,5-dibromo-2-furancarboxylate (568 mg, 2.0 mmol) in Tetrahydrofuran (THF) (16 ml) at 0° C. The resulting mixture was stirred at this temperature for 30 min and then cooled to −78° C. A solution of hexylchloroethane (568 mg, 2.401 mmol) in THF (1 mL) was added dropwise, and the resulting mixture was stirred at this temperature for 1 hr. The reaction was quenched with addition of NH4Cl (sat. aq) and the resulting mixture was stirred at rt overnight. Ether and water were added and the aqueous layer was discarded. The organic layer was washed with brine, dried (Na2SO4) and concentrated to give 0.34 g of the product containing its isopropyl ester.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([S:23][C:24]3[C@H:25]([CH3:48])[C@@H:26]4[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]4[C:28]=3[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[CH2:20]2)[S:17][CH:18]=1)=[O:13])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:20][CH:21]([S:23][C:24]3[C@H:25]([CH3:48])[C@@H:26]4[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]4[C:28]=3[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[CH2:22]2)[S:17][CH:18]=1)=[O:13]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cs4)C3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCCO)cs4)C3)[C@H](C)[C@H]12
Yield: 75.7 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl]azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (605.3 mg, 0.84 mmol) in tetrahydrofuran (30 ml) were added acetic acid (0.15 ml, 2.6 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (2.5 ml, 2.5 mmol) in an ice bath and the mixture was stirred for 1 hour at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by: chromatography on a silica gel column using toluene: acetonitrile (2:3) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(2-hydroxyethylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (383.7 mg, yield 75%) as a pale yellow solid.