Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[CH:4]([CH2:9][C:10]1[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1NC(CC)CC)[C:5]([O:7]C)=O.P(=O)(O)(O)O.[OH2:39]>>[CH2:4]([CH:9]([O:39][C:15]1[CH:14]=[C:13]([CH3:22])[N:12]=[C:11]2[C:10]=1[CH2:9][CH2:4][C:5](=[O:7])[N:23]2[C:24]1[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=1[CH3:32])[CH2:10][CH3:15])[CH3:5]
Reactant: O
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CC(C(=O)OC)C(=O)OC
Agent: O=P(O)(O)O
Product: CCC(CC)Oc1cc(C)nc2c1CCC(=O)N2c1c(C)cc(C)cc1C
Temperature: 25 °C

Procedure:
A mixture of 2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic acid dimethyl ester (100 mg, 0.219 mmol), 85% phosphoric acid (3 ml) and water (3 ml) was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to dryness to give 91 mg of a clear oil. The oil was purified through silca gel column chromatography using 10% methanol (MeOH) in methylene chloride (CHCl2) as eluent to give a tan crystals, mp 138-140° C. 1H NMR (CDCl3) δ 6.93(s,2H), 6.31(s,1H), 4.21(m,1H), 2.93(m,2H), 2.76(m,2H), 2.31(s,3H), 2.19(s,3H), 1.99(s,6H), 1.71(m,4H), 0.96(t,6H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21](C(OC4C=CC=CC=4)=O)[C:22](=O)[O:23]C4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[N:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:49]4[CH2:50][CH2:51][CH:46]([N:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)[CH2:47][CH2:48]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 9 h
Yield: 28.3 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (15.5 g, 29.7 mmol) synthesized in Production example 5-2 was dissolved in dimethylformamide (180 ml); 4-piperidinopiperidine (20.0 g, 119 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 9 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and concentrated to about 100 ml. The residue was allowed to be kept cool at 5° C. overnight to precipitate crystals. The crystals were filtered off and washed with ethyl acetate to yield the title compound (4.0 g, 8.4 mmol, 28%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:22])C(=O)C1>ClCCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Yield: 47.9 %

Procedure:
A solution of methyl 2-methyl-6-nitrobenzoate (TL (1996) 37 5425, 15.6 g, 80 mmol), NBS (21.4 g, 120 mmol) and benzoyl peroxide (200 mg, 0.82 mmol) in 1,2-dichloroethane (250 mL) was heated at reflux for 8 h. The reaction mixture was concentrated to dryness and the crude mixture purified by chromatography over silica gel eluting with 2% ethyl acetate/hexanes to afford 10.5 g of methyl 2-(bromomethyl)-6-nitrobenzoate (XXXVI, yield: 65%). 1H NMR (CDCl3, 400 MHz): δ 3.98 (s, 3H), 4.57 (s, 2H), 7.59 (dd, 1H, J=7.8, 8.4 Hz), 7.78 (d, 1H, J=7.8 Hz), 8.1 (d, 1H, J=8.4 Hz).
Reaction SMILES: [CH3:1][C@:2]1([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:4][O:3]1.[Cl:23][C:24]1[NH:25][CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1.C(=O)([O-])O.[Na+].O>C(#N)C>[Cl:23][C:24]1[N:25]([CH2:4][C@@:2]([CH3:1])([OH:3])[CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: C[C@]1(CN2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C[C@](O)(CN1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 31.5 %

Procedure:
To a suspension of (S)-1-(2-methyloxiran-2-ylmethyl)-4-(4-trifluoromethoxyphenyl)piperazine (0.43 g, 1.37 mmol) and 2-chloro-4-nitro-1H-imidazole (0.22 g, 1.51 mmol) in acetonitrile (4 ml), sodium hydrogencarbonate (0.17 g, 2.06 mmol) was added followed by stirring under reflux for 9 hours. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol (0.20 g, yield 31%) as a light yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[C:35]([O:39][C:40](=[O:52])[N:41]([CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH2:51])[CH3:42])([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][CH2:19][C:20](=[O:21])[NH:51][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[CH2:44][CH2:43][N:41]([C:40]([O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:52])[CH3:42])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CN(CCc1ccccc1N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CCc1ccccc1NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
2-(((9-Fluorenyl)methoxycarbonyl)amino)acetic acid (2.49 g, 2.79 mmol) was suspended in dichloromethane (40 ml). The suspension was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (802 mg, 4.19 mmol) was added. The reaction mixture was stirred for 30 min at 0° C. A solution of N-(2-(2-aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (698 mg, 2.79 mmol) in dichloromethane (15 ml) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with dichloromethane (100 ml) and washed with brine (100 ml). The aqueous solution was extracted with dichloromethane (2×30 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane (1:1) as eluent, to give 1.412 g of ({2-[2-(N-(tert-butoxycarbonyl)-N-methylamino)ethyl]phenylcarbamoyl}methyl)carbamic acid ((9-fluorenyl)methyl) ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1CC#N)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH2:23][C:24]#[N:25])[N:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH:23]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:24]#[N:25])[N:16]=1
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Reactant: COc1cc(OC)nc(CC#N)n1
Product: COc1cc(OC)nc(C(C#N)c2ccccc2[N+](=O)[O-])n1

Procedure:
The compound of the general formula (II) can be produced, for example, as follows. A 2-nitrophenylacetonitrile derivative is reacted with a 2-halogeno- or alkylsulfonyl-4,6-dimethoxypyrimidine in the presence of a base, or a 2-halogeno-nitrobenzene derivative is reacted with 2-(4,6-dimethoxypyrimidine-2-yl)acetonitrile in the presence of a base, to obtain 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile (IV). The compound (IV) is subjected to oxidative decyanation to obtain a compound of the general formula (V). The nitro group of the compound (V) is reduced to convert it into an amino group to obtain a compound of the general formula (VI). The carbonyl group of the compound (VI) is reduced to a hydroxymethyl group to obtain a compound of the general formula (II).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:26]([O:28][CH2:29][C:30](Cl)=O)[CH3:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:26]([O:28][CH2:29][C:30]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:27]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (18.04 g, 52.1 mmol) in 180 mL of pyridine was treated with 50 mg of 4-dimethylaminopyridine and chilled in an ice water bath. 2-ethoxyacetyl chloride (6.44 g, 52.6 mmol) was added dropwise to the solution. The reaction was stirred at room temperature for 3 h. The reaction was then heated to reflux with stirring. After 18 h the reaction was cooled and then concentrated. The residue was partitioned between CHCl3 (150 mL) and water (150 mL) and the layers were separated. The aqueous portion was extracted with CHCl3 (3×50 mL). The combined organic portions were washed with brine, dried over Na2SO4, filtered and concentrated to yield 15.47 g of tert-butyl 2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a sticky yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c2cc(F)c(OCc3ccccc3)cc2n1
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c2cc(F)c(OCc3ccccc3)cc2n1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
A mixture of 3.1 g of (10.9 mmol) of 7-benzyloxy-4-chloro-6-fluoro-2-methyl-quinoline and 18.1 ml (21.8 mmol) pyrrolidine was heated at 80° C. (oil bath temperature) under an argon atmosphere for 6 h. The reaction mixture was concentrated in vacuo, the residue taken up in methylene chloride, which was washed with water, saturated NaCl solution and then dried over magnesium sulphate. The solvent was removed in vacuo, the residue purified by flash chromatography on silica gel with CH2Cl2/MeOH (100:0 to 90:10 over 1 h) as eluent. Combination of the purified fractions and concentration in vacuo gave 1.7 g (46.2%) of the 7-benzyloxy-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline as a brown crystalline solid. ISP mass spectrum, m/e: 337.4 (M+1 calculated for C21H21FN2O: 337).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:27](=[O:30])[CH2:28][CH3:29])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: CCC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and propanoyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:37]([OH:40])([CH3:39])[CH3:38].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:38][C:37](=[O:40])[CH3:39])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O
Reactant: CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(c1ccc(C)cc1)c1cc(Br)ccc1CC(C)=O
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a cold solution (0° C.) of 125 mg (0.4 mmol) of 4-bromo-2-[(1-p-tolyl)vinyl]phenol (Compound R) in 5 mL of tetrahydrofuran was added 125 mg (0.5 mmol) of triphenylphosphine and 0.04 mL (31 mg, 0.5 mmol) of isopropanol followed by 0.07 mL (82 mg, 0.5 mmol) of diethylazodicarboxylate. The dark yellow solution was removed from the ice bath, allowed to warm to ambient temperature on its own and stirred overnight (22.5 hours). The reaction mixture was concentrated in vacuo to a gummy yellow solid. Purification by flash chromatography (silica, 1% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:16]([O:18]C(C)(C)C)=[O:17])[C:11](=[O:30])[CH:10]=1.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[C:16]([OH:18])=[O:17])[C:11](=[O:30])[CH:10]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
1.7 g (purity 89%, 3.2 mmol) of tert-butyl 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoate (racemate) were hydrolysed with TFA according to General Method 6A. After work-up, the residue was triturated with diethyl ether and the solid was filtered off and dried under reduced pressure. Yield: 1.8 g (purity 76%, 99% of theory)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 435 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](Cl)=[CH:4][C:5]([F:8])([F:7])[F:6].[H][H].[OH-].[K+]>C(O)C.[Ni]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)CCC(F)(F)F
Yield: 47.8 %

Procedure:
In a stainless steel autoclave, 40 g of 1,1,1,4,4,4-hexafluoro-2-chloro-2-butene in 300 ml of ethanol were hydrogenated with hydrogen in the presence of 12 g of potassium hydroxide and 25 g of Raney nickel for 3 hours at 20° C. and another 1 hour at 100° C. at a pressure of from 30 to 40 bar. The solid components were then removed from the reaction mixture by filtration and the remaining liquid was distilled to give 16 g of 1,1,1,4,4,4-hexafluorobutane having a boiling point of 25°-30° C. at 1013 mbar. The mass spectrum showed a molecular ion at m/e 166.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH2:25]([OH:27])[CH3:26]>[Pd]>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:25](=[O:27])[CH3:26])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Product: CC(=O)Nc1ccc2c(c1)C(n1cncc1C(=O)OC(C)C)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(7-nitro-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester, which can be prepared as described in Example 5, (3.24 g, 9.84 mmol) in ethanol (125 mL) is added palladium on carbon (10% wt., 0.65 g, 0.61 mmol). The flask is flushed with hydrogen and stirred under balloon pressure at room temperature overnight. The catalyst is then filtered through Celite®. The Celite® cake is washed with methanol and the combined filtrate is concentrated to afford 3-(7-acetylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, J=6.3 Hz, 3 H), 1.38 (d, J=6.3 Hz, 3 H), 1.62-1.83 (m, 2 H), 2.01-2.08 (m, 1 H), 2.13-2.21 (m, 1 H), 2.67-2.84 (m, 2 H), 5.22 (sept, J=6.3 Hz, 1 H), 6.17 (t, J=5.1 Hz, 1 H), 6.31 (d, J=2.5 Hz, 1 H), 6.62 (dd, J=8.2, 2.5 Hz, 1 H), 6.98 (d, J=8.2 Hz, 1 H), 7.21 (s, 1 H), 7.77 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 48 h
Yield: 73.7 %

Procedure:
2,5-Diamino-benzenesulfonamide (4.20 kg, 22.4 mol) was dissolved in dichloromethane (120 L) and pyridine (8.00 kg, 89.9 mol), and the resulting solution was cooled to 0° C. Methanesulfonyl chloride (2.80 kg, 24.4 mol) was added slowly, and the resulting mixture was allowed to warm to 23° C. and stirred for 2 days. The mixture was filtered and the resulting solid was washed with dichloromethane (2×20 L). The solid was diluted with water (100 L) and 1.0 M aqueous hydrochloric acid solution (25 L), and was then stirred at 23° C. for 1 h. The mixture was filtered and the resulting solid was washed with water (20 L) and then with methyl-tert-butyl ether (2×10 L). The solid was further dried in vacuo at 45° C. to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (4.39 kg, 16.5 mol, 73%) as a pale pink solid. 1H NMR (400 MHz, CD3OD) δ: 2.89 (3H, s), 6.82 (1H, d, J=8.5 Hz), 7.20 (1H, dd, J1=8.5 Hz, J2=2.5 Hz), 7.58 (1H, d, J=2.5 Hz). LC-MS (ESI) calcd for C7H11N3O4S2 265.02, found 266.0 [M+H+].
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][S:14]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[C:24][C:25](OCC)([O:29]CC)[O:26][CH2:27][CH3:28])[CH:22]=1)(=[O:16])=[O:15]>C1(C)C=CC=CC=1>[CH2:27]([O:26][C:25](=[O:29])[C:24]#[C:23][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([S:14]([CH3:13])(=[O:15])=[O:16])[CH:22]=1)[CH3:28]
Reactant: CCOC(C#Cc1cncc(S(C)(=O)=O)c1)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C#Cc1cncc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
p-Toluenesulfonic acid monohydrate (1.39 g, 0.73 mmol) was added to a solution of 3-methanesulfonyl-5-triethoxyprop-1-ynyl-pyridine (1.20 g, 3.70 mmol) in toluene (40 mL). After stirring overnight at room temperature, the solvent was removed under reduced pressure. The crude product was chromatographed on silica (30% ethyl acetate/hexanes) to give the title compound (0.55 g, 53% yield) as a white solid. 1H NMR (CDCl3) δ 9.17 (d, 1H, J=2.4 Hz), 9.03 (d, 1H J=2.0), 8.40 (t, 1H, J=2.0 Hz), 4.35 (q, 6H, J=8.0), 3.14 (s, 3H), 1.38 (t, 9H, J=8.0).
Reaction SMILES: N1CCCCC1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH:16]([C:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:20])[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)C(=O)Cc1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)C(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
0.9 ml of piperidine is added to 24.8 g (0.2 mol) of 4-fluorobenzaldehyde and 32.4 g (0.2 mol) of benzyl isopropyl ketone in 150 ml of toluene and the mixture is heated to reflux overnight. After cooling to room temperature, the mixture is extracted several times using water and the organic phase is dried over magnesium sulphate and concentrated in vacuo. The residue is subjected to incipient distillation up to a bath temperature of 150° C. at 0.1 mbar in a high vacuum and 43.8 g of crude product are obtained in the distillation residue.
Reaction SMILES: CN(C)/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C@H:22]([CH3:25])[CH2:23][OH:24]>C1COCC1>[OH:24][CH2:23][C@H:22]([N:21]1[C:12]2[C:11](=[CH:16][C:15]([I:17])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1)[CH3:25]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: C[C@@H](N)CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn([C@H](C)CO)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (Intermediate 24, 1 g, 2.56 mmol) dissolved in THF (10 mL) was added (R)-2-aminopropan -1-ol (300 mg, 2.56 mmol). The reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in DMF (10 mL). Potassium carbonate was added (1.06 g, 7.67 mmol, 3 equiv.), and the reaction mixture was stirred at 70° C. for 18 h. The reaction mixture was cooled down to room temperature and quenched with 1 N HCl. The precipitate that formed was collected by filtration, washed with water and hexanes to provide (R)-ethyl 1-(1-hydroxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (446 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[N:10][CH:11]=1.O1CCCC1>[C].[Pd].CO>[CH3:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[N:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:16]=[CH:17][C:18]=1[NH2:19]
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of 5-(3-methyl-4-nitrophenoxy)-2-(methylsulfonyl)pyridine (12.58 g), 10% palladium carbon (2.5 g, containing water (50%)), tetrahydrofuran (200 mL), and methanol (50 mL) was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 18 hr. The catalyst was filtered off, and the obtained filtrate was concentrated under reduced pressure to give the title compound (11.4 g, yield 100%) as a pale-yellow oil.