Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cc(Br)ccc1OCCN1CCCC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 6.00 g (29.85 mmol) of 5-bromo-2-hydroxybenzaldehyde, 5.84 g (3.43 mmol) of 1-(2-chloroethyl)pyrrolidine, and 12.38 g (89.54 mmol) of potassium carbonate was stirred for 2 hours at 50° C. and for 2 hours at 75° C., cooled to RT, filtered, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, gradient EtOAc/MeOH 100:0→85:15). Yield: 5.89 g (66% of theoretical); C13H16BrNO2 (M=298.176); calc.: molpeak (M+H)+: 298/300 (Br); found: molpeak (M+H)+: 298/300 (Br); HPLC-MS: 4.82 minutes (method A).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][C:30]#[CH:31]>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:31]#[C:30][CH2:29][O:28][CH3:27])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(Br)cc12
Reactant: C#CCOC
Product: COCC#Cc1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Yield: 39 %

Procedure:
6-(3-Methoxy-prop-1-ynyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 39% yield using the procedure described in example 23A, starting from 6-bromo-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (tert-butyl protected oxime of example 66) and 3-Methoxy-propyne. The title compound was isolated as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[C:29]([CH2:43][O:44][CH3:45])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([CH2:43][O:44][CH3:45])=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COCc1ncc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COCc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC(C)C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 191.1.1) to give the title compound as a white foam. (HPLC: tR 2.41 min (Method A); M+H=473 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.27-8.25 (m, 1H), 8.15-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.62-7.60 (m, 1H), 7.42-7.40 (m, 1H), 4.77 (hp, 1H), 4.47 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.31 (s, 3H), 1.97 (s, 3H), 1.37-1.32 (m, 6H))
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-])=O)[CH:14]=2)[CH2:8][C:7]1=[O:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[O:25]1CC[CH2:27][CH2:26]1>[Pd].[C]>[C:26]([NH:21][C:15]1[CH:14]=[C:13]([CH:9]2[CH2:10][C:11](=[O:12])[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:7]([OH:24])[CH2:8]2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20])(=[O:25])[CH3:27]
Reactant: C1CCOC1
Reactant: CCCC(=O)C1C(=O)CC(c2ccc(OC)c([N+](=O)[O-])c2)CC1=O
Agent: [Pd]
Product: CCCC(=O)C1=C(O)CC(c2ccc(OC)c(NC(C)=O)c2)CC1=O
Reaction time: 16 h
Yield: 55 %

Procedure:
5.3 g of 2-butyryl-5-(3-nitro-4-methoxyphenyl)cyclohexane-1,3-dione in 300 ml of tetrahydrofuran were hydrogenated in the presence of 3 g of Pd/carbon (10%) under atmospheric pressure at 25° C. After 0.9 l of hydrogen had been absorbed, the mixture was dried over sodium sulfate and filtered, 1.3 g of sodium bicarbonate were added and the mixture was reacted with 1.2 g of acetyl chloride. After the mixture had been stirred for 16 hours, it was filtered and evaporated down. The remaining oil was brought to crystallization with diethyl ether, and the crystals were filtered off under suction. 3 g (55% yield) of 5-(3-acetylamino-4-methoxyphenyl)-2-butyryl-3-hydroxycyclohex-2-en-1-one of melting point 102°-106° C. were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][C:11]3=[N:21][N:22]([CH3:24])[CH:23]=[C:10]3[C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:5]=[CH:4][N:3]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:9]2[C:10]3[C:11](=[N:21][N:22]([CH3:24])[CH:23]=3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:40])=[O:41])=[CH:35][CH:34]=3)[CH:7]=2)=[CH:26][CH:27]=1
Reactant: Cn1cc2c(-c3ccc(F)cc3)c(-c3ccnc(Cl)c3)c(-c3ccc(F)cc3)nc2n1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: Cn1cc2c(-c3ccc(F)cc3)c(-c3ccnc(Nc4ccc(S(N)(=O)=O)cc4)c3)c(-c3ccc(F)cc3)nc2n1
Temperature: 190 °C
Yield: 17.6 %

Procedure:
A mixture of 5-(2-chloropyridin-4-yl)-4,6-bis(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridine (100 mg, 0.23 mmol, obtained in example 190) and 4-aminobenzenesulfonamide (46 mg, 0.27 mmol) was heated at 190° C. overnight. It was allowed to cool and the crude product obtained was purified by chromatography on silica gel using EtOAc as eluent, to afford 23 mg of the desired compound (yield: 17%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]([OH:22])=O)[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:2]=1.[Cl:23]CCl>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]([Cl:23])=[O:22])[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:2]=1
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a suspension of 3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid (15b) (0.28 g, 0.88 mmol) in dichloromethane (3.5 ml) oxalyl chloride (0.23 ml, 2.64 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.29 g, 98%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].O>C(#N)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)N1CCN(CCC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Isopropylpiperazine (650 mg) is dissolved in acetonitrile (7 ml) and thereto is added t-butyl acrylate (743 μl) under ice-cooling. The reaction solution is warmed to room temperature and stirred for 4 hours, and thereto is added additional t-butyl acrylate (148 μl), and then the mixture is stirred at room temperature for another 10 hours. Additional t-butyl acrylate (222 μl) is added to the reaction solution, and the mixture is stirred for 6 hours, thereto is poured water and the solution is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 followed by 10/1) to give t-butyl 3-(4-isopropylpiperazin-1-yl)propionate (1.18 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:27])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][O:25][C:23](=[O:24])[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]([C@H:9]2[CH2:10][C@@H:11]([O:13][CH3:14])[CH2:12][NH:8]2)=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Into a solution of 7 (12.5 g, 33.0 mmol) in anhydrous CH2Cl2 (70 mL) was added TFA (20 mL). The solution was stirred at RT overnight before concentrating under reduced pressure to give 8 (9.19 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[F:15])[CH3:5].P([O-])([O-])([O-])=O.Cl>C(Cl)Cl>[F:15][C:8]1[C:9]([F:14])=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[NH:6][C@H:4]([CH3:5])[C:3]([OH:16])=[O:2]
Reactant: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: C[C@@H](Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 30 °C

Procedure:
Methyl2-(2,3,4-trifluoroanilino)propionate (1.0 g) was suspended in a 0.1 M phosphate buffer solution (pH 6.5; 200 ml). After adding α-chymotrypsin (manufactured by Sigma; 0.2 g), the mixture was gently stirred. The mixture was further stirred for 16 hours while maintaining at 30° C. After adding methylene chloride, the liquid reaction mixture was filtered through celite to eliminate denatured protein and then separated. The organic layer was washed with a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. Next, the solvent was evaporated under reduced pressure to thereby give methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (0.43 g). The optical purity of this product was 98% ee. On the other hand, the all aqueous layers obtained by the separation were combined and adjusted to pH 2 with 10% hydrochloric acid followed by extraction with IPE. The organic layer was dried over anhydrous magnesium sulfate and evaporated. Thus, the title compound was obtained as a crude product (0.47 g). The optical purity of this product was 92% ee. Further, the crude product was recrystallized from a solvent mixture of isopropyl ether with hexane. Thus, the title compound of 100% ee was obtained. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 29.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[Cl-:5].[Cl-].[CH2:7]([Zr:11]([CH3:33])(=[SiH2:32])([CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:31])[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH3:21])[CH2:8][CH:9]=[CH2:10]>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:5].[Cl:1][Si:2]([Cl:4])([Cl:3])[CH2:10][CH2:9][CH2:8][CH2:7][Zr:11]([CH3:33])(=[SiH2:32])([CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:31])[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH3:21]
Reactant: C=CCC[Zr](C)(=[SiH2])(C1C(C)=Cc2ccccc21)C1C(C)=Cc2ccccc21
Reactant: Cl[SiH](Cl)Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1=Cc2ccccc2C1[Zr](C)(=[SiH2])(CCCC[Si](Cl)(Cl)Cl)C1C(C)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.4 g (3 mmol) of trichlorosilane and 10 mg of H2PtCl6.6H2 O were added to a solution of 0.52 g (1 mmol) of (3-butenyl)(methyl)silanediyl[bis(2-methylindenyl)]zirconium dichloride in 5 ml of toluene. After stirring for 24 hours at room temperature, the excess trichlorosilane and the toluene were removed in an oil pump vacuum. This gives 0.69 g of an oil which no longer shows any resonance signals of the vinyl protons in the 1H-NMR spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([S:22]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[C:12]([O:14][CH3:15])=[O:13])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1c(N)ccc2ncccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2ncccc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of Example 96B (0.233 g, 1.20 mmol) in pyridine (4 mL) was treated with benzenesulfonyl chloride (0.20 mL, 1.6 mmol), and stirred for 7 hours at ambient temperature. The mixture was concentrated and the residue was purified by C18 reverse-phase HPLC with acetonitrile/water/0.5 mM ammonium acetate to provide the desired product. MS (ESI(+)) m/e 343 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([CH:5]2[CH2:9][CH:8]([O:10][CH3:11])[CH2:7][N:6]2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:4][CH2:3]1.[CH3:22]I.[H-].[Na+]>C1COCC1>[CH3:11][O:10][CH:8]1[CH2:7][N:6]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH:5]([C:2]2([O:1][CH3:22])[CH2:3][CH2:4]2)[CH2:9]1
Reactant: COC1CC(C2(O)CC2)N(C(=O)OCc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC(C2(OC)CC2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of benzyl 2-(1-hydroxycyclopropyl)-4-methoxypyrrolidine-1-carboxylate (312 mg, 1.07 mmol) dissolved in THF (3.6 mL) at 0° C. was added methyl iodide (0.23 mL, 3.68 mmol) followed by sodium hydride (56.5 mg, 2.36 mmol). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice, and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% methanol/dichloromethane, linear gradient) to afford benzyl 4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine-1-carboxylate. MS ES I calc'd. for C17H23NO4 [M+H]+ 306. found 306.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]2[NH:17][N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[C:13]=2[CH2:12]1)(=[O:10])=[O:9].Br[CH2:31][CH2:32][CH2:33][OH:34].CO>CN(C=O)C.O>[CH3:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]([CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[C:13]=2[CH2:12]1)(=[O:9])=[O:10]
Reactant: OCCCBr
Reactant: CS(=O)(=O)N1CCc2[nH]nc(-c3ccc(C(F)(F)F)cc3)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCO)C1
Reaction time: 0.42 h
Yield: 46 %

Procedure:
Cs2CO3 (33.74 g, 103.5 mmol) was added to a solution of 5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (29.8 g, 86.3 mmol) in anhydrous DMF (70 mL) and stirred for 25 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) was added and stirred under N2 at room temperature for 18 h. Water (500 mL) was added to the reaction and stirred for 5 min. The precipitated material was filtered out and washed with water (4×100 mL) and dried in a Freeze Drying System. The crude material (31.0 g) was taken up in anhydrous DMF (65 mL) and Cs2CO3 (33.74 g, 103.5 mmol) was added, and stirred for 10 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) and MeOH (6.0 mL, 4.75 g, 148 mmol) were added and stirring continued under N2 at room temperature for 15 h. Water (500 mL) was added to the reaction and stirred for 10 min. The precipitated material was filtered and washed with water (3×100 mL). The filter cake was dissolved in CH2Cl2 (200 mL) and washed with brine (50 mL), dried (Na2SO4), and concentrated. The solid was triturated with Et2O (200 mL), filtered, washed with Et2O, and dried to furnish 16.0 g of the desired compound. The mother liquor was chromatographed (silica, 0-10% acetone/EtOAc) to obtain an additional 3.0 g of the title compound. The combined yield was 54.6%. MS (electrospray): calculated for C17H20F3N3O3S, 403.12; m/z found, 404.0 [M+H]+, 426.0 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.71 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 4.55 (s, 2H), 4.23 (t, J=6.5 Hz, 2H), 3.70-3.63 (m, 4H), 2.90 (s, 3H), 2.90 (t, J=5.1 Hz, 2H), 2.62 (t, J=5.9 Hz, 1H), 2.06 (q, J=6.1 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](O)=O)[CH:10]=2)[NH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C([O:56][C:57](=[O:72])[C:58]1[CH:63]=[CH:62][C:61]([NH:64][CH:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)=[C:60]([NH2:71])[CH:59]=1)C.[OH-].[Na+]>CN(C=O)C>[CH:65]1([N:64]2[C:61]3[CH:62]=[CH:63][C:58]([C:57]([OH:56])=[O:72])=[CH:59][C:60]=3[N:71]=[C:12]2[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:3][C:2]3=[O:1])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3[nH]c(-c4ccccc4)cc(=O)c3c1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Oxo-2-phenyl-1,4-dihydro-quinoline-6-carboxylic acid (298.5 mg, 1.05 mmol), (Compound 481c), was dissolved in DMF (5 mL), and HATU (440 mg, 1.1 eq.) and diisopropyl ethylamine (402 μL) were added. After stirring at room temperature for 15 minutes, 3-amino-4-cyclohexylamino-benzoic acid ethyl ester (303 mg, 1.1 eq.) dissolved in 2 mL DMF was added. After stirring overnight, the reaction was evaporated, dissolved in ethyl acetate and washed with water and brine, dried with sodium sulfate, evaporated and dried overnight. The product was then refluxed in acetic acid for 4 hr, evaporated to dryness, and coevaporated 2 more times with toluene. Saponification proceeded by dissolving the residue in ethanol (10 mL), adding 10 eq. of 1N NaOH solution and stirring at 40° C. for 4 hr. The ethanol was evaporated, and water was added and acidified. The resulting precipitate is purified via reverse-phase HPLC. Yield: 47 mg.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[Cl:20])(C)(C)C>O1CCOCC1>[Cl:20][C:10]1[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:16][CH3:17])=[C:14]([CH3:15])[C:9]=1[NH2:8]
Reactant: COc1cc(OC)c(Cl)c(NC(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(N)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HCl (91 mL, 360 mmol, 8 equiv, 4N in dioxane) is added dropwise to a cooled (10° C.) solution of (2-chloro-3,5-dimethoxy-6-methyl-phenyl)-carbamic acid tert-butyl ester (13.8 g, 45.7 mmol) in dioxane (150 mL), under an argon atmosphere. The reaction mixture is allowed to warm to RT, stirred for 24 h and concentrated. The residue is diluted with EtOAc, washed with a saturated aqueous solution of NaHCO3, and brine, dried (Na2SO4), filtered and concentrated. The residue is purified by crystallization from DCM/Hex to afford the title compound. ESI-MS: 202.0 [MH]+, TLC: Rf=0.37 (DCM).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Temperature: 20 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (1.5 g, 5.74 mmol, 1.0 equiv.), t-BuNH2 (1.26 g, 17.22 mmol, 3.0 equiv.) in 1,4-dioxane (50 ml) was stirred at 20° C. for 4 h under nitrogen atmosphere. The reaction mixture was concentrated to give a residue, which was purified by silica gel chromatography (PE/EA 100:1 to 10:1 as eluent) to afford 5-bromo-N-tert-butylthiophene-2-sulfonamide (1.614 g, 94.3%) as solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7](OCC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:18]>O>[ClH:18].[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: Cc1nc[nH]c1CO

Procedure:
In U.S. Pat. No. 3,984,293, there is described the state of the art as background to the electrochemical reduction of 4-imidazole carboxylic acids. That invention is useful, however, it necessitates an extra chemical step prior to reduction, namely, hydrolysis of the ester intermediate to form the free carboxylic acid. Also, U.S. Pat. No. 4,055,573 teaches a method for preparing 4-(hydroxymethyl)-imidazoles and their lower alkyl ethers by electrochemical reduction in concentrated sulfuric acid in concentrated solutions using standard electrochemical cells with yields up to 80%. It should be noted that, although the imidazole alcohol is produced, an equally important product is imidazole ethyl ether. Subsequent reaction of the mixed alcoholalkyl ether with cysteamine hydrochloride produces the thioamine in about 60% yield. Further, in British Pat. No. 1,341,376 the reduction of 4-methyl-5-carbethoxyimidazole with lithium aluminum hydride, followed by addition of water, filtration and acidification with hydrochloric acid, affords 4-methyl-5-hydroxymethylimidazole hydrochloride. Although the yield is not given, it appears to amount to about 60%. Subsequent reactions produced 4-methyl-5-(2-aminoethyl)-imidazole.
Reaction SMILES: [OH:1]S([O-])(=O)=O.[K+].[F:7][C:8]([F:26])([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:9][CH2:10][S:11]([CH2:13][C:14]#[N:15])=[O:12].S([O-])([O-])=O.[Na+].[Na+]>O.CO>[F:26][C:8]([F:7])([C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])[CH2:9][CH2:10][S:11]([CH2:13][C:14]#[N:15])(=[O:1])=[O:12]
Reactant: N#CCS(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)([O-])O
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 8 h

Procedure:
To a suspension of 9.21 g of a double salt of 2KHSO5.KHSO4.K2SO4 (Oxone, registered trade mark) in 50 ml of water was added dropwise a solution of 6.80 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfinyl)acetonitrile in 50 ml of methanol at room temperature over 60 minutes under a nitrogen atmosphere, and the mixture was stirred overnight. To the reaction mixture was added 25 ml of an aqueous 10% sodium sulfite solution, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 25 ml of an aqueous 10% sodium sulfite solution and 50 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under rescued pressure. The residue was subjected to silica gel column chromatography to obtain 5.4 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)acetonitrile represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:4][N:3]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:4][N:3]=1
Reactant: Clc1ncc(C#CCCn2ccnn2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Clc1ncc(CCCCn2ccnn2)cn1

Procedure:
2-Chloro-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine (2.52 g, 10.8 mmol) is dissolved in ethyl acetate (210 ml) and hydrogenated for 2.5 h at r.t. in the presence of palladium on calcium carbonate (10%, 2.55 g). The reaction mixture is filtered and concentrated in vacuo to yield 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine as a colorless solid. Yield 2.15 g (84%)