Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=1)=[O:4].[C@H:19]12[CH2:25][C@H:22]([CH2:23][CH2:24]1)[CH2:21][C:20]2=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[N:10]1[CH2:11][CH2:12][C:7]2([C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6]2)[CH2:8][CH2:9]1
Reactant: CNC(=O)C1=CC2(CCNCC2)c2ccccc21
Reactant: O=C1C[C@H]2CC[C@@H]1C2
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: CC(Cl)Cl
Product: CNC(=O)C1=CC2(CCN(C3CC4CCC3C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (C6) (0.015 g, 0.073 mmol), titanium (IV) isopropoxide (0.065 mL, 0.22 mmol) and (1R,4S)-bicyclo[2.2.1]heptan-2-one (3 eq) was stirred at room temperature for 18 h in dichloroethane (0.5 mL). Sodium triacetoxyborohydride (0.013 g, 0.073 mmol) was added and the reaction stirred at room temperature for 1 h. The solvent was evaporated and 6N NaOH (0.5 mL) and methanol (1 mL) was added and triturated to give a white solid. The solid was washed with methanol (1 mL) and EtOAc (1 mL). The filtrate was concentrated under reduced pressure to afford the crude product that was purified by reverse phase preparative HPLC to afford 1′-(bicyclo[2.2.1]heptan-2-yl)-N-methylspiro[indene-1,4′-piperidine]-3-carboxamide (Compound No. 38) (0.012 g) as an oil. LC/MS (10-90% over 3 min with 0.9% FA) m/z 337.2 (M+1), Rt 1.7 minutes. 1HNMR (500 MHz, CD3OD): δ 7.74 (d, 1H), 7.35 (m, 4H), 3.73 (m, 2H), 3.55 (m, 1H), 3.30 (m, 2H), 2.91 (s, 3H), 2.42-2.74 (m, 5H), 2.19 (m, 2H), 1.54-1.74 (m, 8H), 1.31 (m, 1H)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:11][CH:12]2[CH2:18][CH:17]3[N:19](C(OC(C)(C)C)=O)[CH:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])[N:3]=[N:2]1.Cl>O1CCOCC1>[CH:17]12[NH:19][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[N:2][NH:1][CH:5]=1)[CH2:18]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(NC(=O)CCCc1c[nH]nn1)C2
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCCc1c[nH]nn1)NC1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reaction mixture comprising of tert-butyl 3-(4-(1H-1,2,3-triazol-4-yl)butanamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (401 mg, 1.103 mmol) in dioxane (5 ml) was treated with 4M HCl in dioxane (0.827 ml, 3.31 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound. The material was taken on to the next step without further purification.
Reaction SMILES: CC(C)([O-])C.[K+:6].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH:12]=[CH:13][CH:14]=1>CC(N(C)C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O-:23])[CH:12]=[CH:13][CH:14]=1.[K+:6]
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2[O-])c1
Reaction time: 0.5 h

Procedure:
9.83 g of potassium t-butoxide were added, whilst ice-cooling and stirring, to a solution of 20.0 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20) in 50 ml of dimethylacetamide, and the resulting mixture was stirred at the same temperature for 30 minutes, to give potassium 2-[2-(3-methoxyphenyl)ethyl]phenolate.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH2:8])=[S:7])(=[O:3])[CH3:2].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=[O:12].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:4][CH2:5][C:6]1[S:7][CH2:13][C:11]([CH2:10][Cl:9])([OH:12])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(N)=S
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)OCC1=NC(O)(CCl)CS1
Temperature: 25 °C
Reaction time: 87 h
Yield: 92 %

Procedure:
A mixture of 5.33 g of 2-acetoxythioacetamide prepared according to Example 2, 5.21 g of 1,3-dichloroacetone, 6.88 g of sodium bicarbonate and 20 ml of 1,2-dichloroethane was stirred at room temperature for 87 hours. The mixture was filtered to remove insoluble inorganics and concentrated under reduced pressure to an oil. The oil was taken up in 4 mls of 1,2-dichloroethane and 25 mls of cyclohexane added dropwise. The slurry was stirred for 1 hour at 0° C. and then filtered. The precipitate was washed with cyclohexane and dried at room temperature under reduced pressure. The product, 2-acetoxymethyl-4-chloromethyl-4-hydroxy-thiazoline was obtained in 92% yield (8.25 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(C(C)C)C(C)C)C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C1COCC1.C(OCC)(=O)C.O>[Cl:11][C:4]1[N:3]=[C:2]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:29][CH2:30][CH2:31]3)=[CH:24][CH:23]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(N)cc2)CCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (54 g) in THF (1200 mL), were added ethyl diisopropylamine (1.05 eq.) and tert-butyl [1-(4-aminophenyl)cyclobutyl]carbamate (74 g) at −14° C. and the mixture was warmed up to 25° C. The mixture was stirred for 24 h and diluted with ethyl acetate (1 L) and water (750 mL). The separated organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was solidified with ethyl acetate/hexane (1:1) to give tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (89 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][OH:19].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:24]([O:19][CH2:18][C:3]1[CH:4]=[C:5]([Cl:17])[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[Br:1])[CH:23]=[CH2:22]
Reactant: CCc1ccc(Cc2cc(Br)c(CO)cc2Cl)cc1
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Temperature: -10 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of (2-bromo-5-chloro-4-(4-ethylbenzyl)phenyl)methanol (3.4 g, 10 mmol) in DMF (50 mL) was added NaH (0.8 g, 20 mmol, 60% in miner oil) in portions at −5° C. After being stirred for 1 h at the same temperature, the reaction mixture was cooled to −10° C., TBAI (0.37 g, 1 mmol) and a solution of allyl bromide (1.45 g, 12 mmol) in DMF (10 mL) was added. The reaction mixture was stirred for another 1 h prior to quenching by ice water and extracted 3× with EtOAc. The combined organic layers were washed with brine and then dried over Na2SO4. Concentration gave the crude product, which was purified by silica column chromatography (elution with PE:EtOAc=10:1) to afford the title compound (3.22 g, yield 84.8%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH2:15]([CH2:17][NH2:18])[OH:16]>C(O)C>[OH:16][CH2:15][CH2:17][NH:18][C:2]1[N:7]2[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Cl)n2ncc([N+](=O)[O-])c2n1
Reactant: NCCO
Solvent: CCO
Product: Cc1cc(NCCO)n2ncc([N+](=O)[O-])c2n1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
15 g of 7-chloro-5-methyl-3-nitropyrazolo[1,5-a]pyrimidine in 100 cc of ethanol were introduced into a 250 cc three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer and a condenser. 5 g of ethanolamine were added dropwise and the medium was refluxed for 30 minutes. After cooling to room temperature, the yellow precipitate was filtered off. This precipitate was rinsed with diisopropyl ether. After drying under vacuum over phosphorus pentoxide, 14.2 g of 7-β-hydroxyethylamino-5-methyl-3-nitropyrazolo[1,5-a]pyrimidine were obtained in the form of yellow crystals. (Yield=86%, melting point=231° C.).
Reaction SMILES: C([O-])=O.[NH4+].[Na+].O=[C:7]([C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])[C:8]([O-:10])=[O:9].N.C1C=[N+:21]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.N[C@H](C(O)=O)CC(C)C.C([O-])=O.C>O>[CH3:14][C:11]([CH2:12][CH3:13])([CH3:15])[C@@H:7]([C:8]([OH:10])=[O:9])[NH2:21]
Reactant: CCC(C)(C)C(=O)C(=O)[O-]
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: CC(C)C[C@H](N)C(=O)O
Agent: N
Agent: O=C[O-]
Solvent: O
Product: CCC(C)(C)[C@H](N)C(=O)O

Procedure:
6.3 g (0.1 mole) ammonium formate and 1.67 g (10 mmoles) 2-keto-3,3-dimethyl pentanoic acid sodium salt are suspended in 80 ml of water, the pH value is adjusted with ammonia to 8.2, so that the solids dissolve and the volume is adjusted to 100 ml. Subsequently, 14.34 mg (0.02 mmole) NAD+.3H2O cofactor as well as 800 U of leucine dehydrogenase (LeuDH) and 500 U of formate dehydrogenase (FDH) are added. The temperature is set to 32° C. During the reaction the system is gently stirred and the pH value is adjusted to 8.2 via a pH stat unit. After at most 72 h it is demonstrated via determination of degree of conversion by HPLC that the reaction is finished. The reaction solution is adjusted to pH 9.5 with ammonia and subsequently clarified with 2% active charcoal. The almost colourless solution is concentrated at a rotary evaporator, the amino acid is crystallized, is separated via a funnel, is washed three times with little ethanol and is dried overnight under vacuum at 50° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34]C1C=CC=CC=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1(N)[CH:46]=[CH:45][C:44](OCC)=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:16])[NH:12][CH2:13][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccc(N)cc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCc1ccccc1

Procedure:
Synthesis was performed performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and phenetylamine (38 uL) according to Method A to give the title compound (57 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.36 (dd, J=1.9 Hz, J=8.3 Hz, 1H), 7.28-7.15 (m, 10H), 7.00 (d, J=8.7 Hz, 1H), 4.79 (s, 2H), 4.50 (t, J=6.8 Hz, 1H), ), 4.25 (dd, J=5.1 Hz, J=9.4 Hz, 1H), 3.40 (m, 1H), 3.02 (m 2H), 2.90 (dd, J=7.7 Hz, J=13.6 Hz, 1H), 1.36 (s, 9H); (KBr) 3297, 2979, 1728, 1688, 1645 cm−1; HRMS m/z 633.2660 (calc. of monoisotopic mass for C34H39N3O9 gives 633.2686).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:21])[C:7](=[N:12][C@H](C1C=CC=CC=1)C)[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][C:6](=[O:21])[C@H:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[NH2:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N=C(C(=O)NC(C)(C)C)C(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H](N)C(C)(C)C
Reaction time: 51 h
Yield: 60.4 %

Procedure:
A solution of 20.0 g (69.3 mmol) of (S)-N-tert-butyl-3,3-dimethyl-2-(1-phenylethylimino)-butyramide in 155 ml of methanol was hydrogenated in a low pressure hydrogenation apparatus in the presence of 12.5 g of 5 percent Pd/C at 40° C. and normal pressure for 51 hours. After cooling the catalyst was filtered off and the filtrate was evaporated to dryness: 11.9 g (92.2%) of white crystals containing 94.4% (S)-N-tert-butyl-tert-leucinamide, 92.5% e.e. Recrystallization from 50 ml of hexane yielded 7.8 g (66.0%) of (S)-N-tert-butyl-tert-leucinamide as white crystals, m.p. 78°-80° C., [α]=-32.2 (c=1, CHCl3), >98% e.e.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:22])[C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N-].[BrH:23].C(O)(=O)C>CCOCC>[Br:23][CH2:3][C:4](=[O:22])[C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)C=[N+]=[N-]
Reactant: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)CBr
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution comprised of tert-butyl(S)-3-diazo-2-oxo-1-phenethylpropylcarbamate (7.09 g, 23.4 mmol) in ether (100 mL) was cooled to −10° C. and a solution comprised of hydrogen bromide/acetic acid (4.66 mL, 30% by weight) in ether (30 mL) was added dropwise. The mixture was stirred for 30 minutes and then ether (200 mL) was added. The mixture was washed with brine (50 mL), saturated aqueous sodium bicarbonate (150 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated. Product was crystallized from hexane, to provide tert-butyl (S)-3-bromo-2-oxo-1-phenethylpropylcarbamate (5.29 g, 14.7 mmol). 1H NMR (CDCl3): δ 1.44 (9H, s, t-Bu), δ 1.86 (1H, m, one CH2CH2C6H5), δ 2.18 (1H, m, other CH2CH2C6H5), δ 2.67 (2H, t, J=7.7 Hz, CH2CH2C6H5), δ 3.99 (2H, 2×d, J=13 Hz, CH2Br), δ 4.53 (1H, m, CHNH), δ 5.08 (1H, br.D, 5 Hz, NH), δ 7.17-7.29 (5H, m, aromatic H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:35])[NH:27][C:26](=[O:28])[CH:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:32]3[CH2:33][CH2:34][CH:29]([CH:25]4[CH2:24][C:23]([CH3:22])([CH3:35])[NH:27][C:26]4=[O:28])[CH2:30][CH2:31]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CC(C2CCNCC2)C(=O)N1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(C2CCN(C(=O)c3ccc(N4CC(F)(F)C4)c(OCC4CC4)n3)CC2)C(=O)N1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5,5-dimethyl-3-(piperidin-4-yl)pyrrolidin-2-one hydrochloride in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=463.6 [MH+].
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[CH:15]=[C:16]([I:17])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.FC1C=C(N)C(N)=C(I)C=1.[OH-].[Na+]>C(O)=O>[F:18][C:14]1[CH:15]=[C:16]([I:17])[C:11]2[N:10]=[CH:9][NH:8][C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cnc2c(I)cc(F)cc21
Agent: Nc1cc(F)cc(I)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Fc1cc(I)c2nc[nH]c2c1
Reaction time: 3 h
Yield: 86 %

Procedure:
The 6-fluoro-4-iodo-benzoimidazole-1-carboxylic acid tert-butyl ester used in this step was prepared from 5-fluoro-3-iodo-benzene-1,2-diamine according to the procedure of Weber et al., WO 9400124. Briefly, a mixture of 5-fluoro-3-iodo-benzene-1,2-diamine (1.3 grams, 5.16 mmoles) and 1.5 mL of 96% formic acid was stirred at 100° for 3 hours, then cooled, and 35 mL 5% sodium hydroxide was added. The mixture was cooled in an ice bath and the resulting solid was collected, washed with water and dried in vacuo to provide 1.16 grams (86%) 6-fluoro-4-iodo-1H-benzoimidazole, m.p. 210-211° C. A mixture of 1.0 gram (3.8 mmoles) of this benzimidazole, di-tert-butyl dicarbonate (0.92 grams, 4.2 mmole), and 5 mg dimethylaminopyridine in 15 mL dioxane was stirred at 80° C. for 20 hours, then concentrated under reduced pressure. Purification of the residue by column chromatography over silica gel 230-400 mesh eluting with 30% ethyl acetate in hexane gave 6-fluoro-4-iodo-benzoimidazole-1-carboxylic acid tert-butyl ester as a crystalline solid, 1.38 grams (100%), m.p. 73-74° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([OH:15])=O)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH2:35].C(N1CCOCC1)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH:35][C:13](=[O:15])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1c1ccccc1
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1Cl)[C@@H]1CCC(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 40.1 %

Procedure:
5-oxo-1-phenyl-proline (0.047 g, 0.23 mmol, prepared as described below) was dissolved in dichloromethane (˜2 ml) and dimethylformamide (1 ml) and to this was added 1-hydroxybenzotriazole (0.034 g, 0.25 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.040 g, 0.25 mmol), N-ethyl morpholine (0.032 ml, 0.25 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.048 g, 0.25 mmol). The mixture was stirred at room temperature for 4.5 hrs. The mixture was diluted with more dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-5-oxo-1-phenyl-prolinamide (0.032 g) as a white solid. LC/MS [M+H]+=347.1, retention time=2.51 minutes.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([OH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>O>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Yield: 95.3 %

Procedure:
20 ml of pyridine was added to 5.02 g (49.2 mM) of n-hexanol, followed by stirring below 0° C. To the mixture, 11.24 g (59.0 mM) of p-toluenesulfonyl chloride was added. The mixture was stirred for 6 hours below 0° C. After the reaction, the reaction mixture was poured into iced water and acidified with conc. HCl, followed by two times of extraction with dichloromethane, two times of washing with water, drying with sodium sulfate and distilling-off of the solvent to obtain 12.0 g (46.8 mM) of an objective product (yield: 95.0%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[O:16][CH3:17].B(OB=O)=O.[Cl:23][C:24]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:25]=1[CH:26]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:23][C:24]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:25]=1/[CH:26]=[CH:13]/[C:12](=[O:14])[CH2:11][C:10](=[O:15])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:16][CH3:17])[CH:4]=1
Reactant: COc1cc(C=CC(=O)CC(C)=O)ccc1O
Reactant: O=Cc1ccc(O)cc1Cl
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCN
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2Cl)ccc1O
Reaction time: 1 h
Yield: 25.2 %

Procedure:
6-(4-Hydroxy-3-methoxyphenyl)hex-5-ene-2,4-dione (20 mg, 85 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring mixture at 80° C. was added a solution of 2-chloro-4-hydroxybenzaldehyde (17 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol), sequentially. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution (1 mL) of 1N HCl and brine at room temperature, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound (8.0 mg, 25%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:35]=[C:36]=[O:37])[CH2:32][CH2:33][CH3:34]>C(#N)C>[CH2:31]([NH:35][C:36]([NH:14][S:11]([C:10]1[N:9]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:12])=[O:37])[CH2:32][CH2:33][CH3:34]
Reactant: CCOC(=O)c1cnn(-c2ccc3ccccc3n2)c1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNC(=O)NS(=O)(=O)c1c(C(=O)OCC)cnn1-c1ccc2ccccc2n1
Yield: 90.7 %

Procedure:
To a mixture of 6 g of 4-ethoxycarbonyl-1-(2-quinolyl)pyrazole-5-sulfonamide and 3.6 g of anhydrous potassium carbonate dissolved in 40 ml of acetonitrile, was added 1.9 g of n-butylisocyanate at room temperature, followed by heating under reflux for 1.5 hours. After the reaction was completed, acetonitrile was evaporated under reduced pressure, and then the residue was poured into ice water to filter insolubles off, and then the filtrate was precipitated with hydrochloric acid. Crystals precipitated were filtered, washed with water and dried to obtain 7 g of N-(n-butylcarbamoyl)-4-ethoxycarbonyl-1-(2-quinolyl)pyrazole-5-sulfonamide. m.p: 140° to 142° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@H:8]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[Cl:36][CH2:37][C:38]([CH2:40]Cl)=[CH2:39]>CC#N>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@H:8]([N:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:40][C:38]([CH2:37][Cl:36])=[CH2:39])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)C[C@H](NCc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CCl)CN(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 81 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
Part 2: A mixture of (2S)-benzylamino-succinic acid 1-benzyl ester 4-tert-butyl ester (12.1 g, 32.6 mmol), K2CO3 (14 g, 3 equiv.), NaI (3.0 g, 20 mmol) and 3-chloro-2-chloromethyl-1-propene (5.1 g, 40.8 mmol) in MeCN (150 mL) was stirred at 81° C. for 16 h. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by Combiflash (hexane and ethyl acetate: gradient 0 to 8% during 12 min) afforded (2S)-[benzyl-(2-chloromethyl-allyl)-amino]-succinic acid 1-benzyl ester 4-tert-butyl ester (8.7 g, 58%). MS (ESI): 458 (M+H+).