Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[S:29]([CH3:28])(=[O:31])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(S(C)(=O)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
A solution of the bis-hydrochloride salt of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (50 mg, 0.11 mmol) in pyridine (1 mL) was treated with methanesulfonyl chloride (26 μL, 0.34 mmol) and stirred at room temperature for 16 h. The reaction mixture was evaporated and partitioned between EtOAc (2 mL) and a saturated aqueous NaHCO3 solution (2 mL). The organic component was separated, dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 30% then 40% EtOAc/hexane as eluant to afford the title compound as an oil (46 mg, 91%). 1H NMR (CDCl3) 7.36-7.23 (m, 5H), 6.78 (d, J=8.6, 1H), 6.48 (br s, 1H), 6.42 (br d, J=8.1, 1H), 4.71 (m, 1H), 4.30 (br t, 1H), 3.80 (s, 3H), 3.77 (m, 1H), 3.56-3.19 (m, 5H), 2.80-2.76 (m, 2H), 2.55 (s, 3H), 2.04-1.90 (m, 2H), 1.87-1.84 (m, 4H), 1.62-1.60 (m, 2H). LC/MS (Method A) 7.25 min, [M+1]+ 445.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:15]=[C:16]([S:20]([CH2:23][CH2:24][S:25][C:26]2[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.CCCCCC>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH:32][C:31]1[C:26]([S:25][CH2:24][CH2:23][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:33])([F:34])[F:12])[CH:15]=2)(=[O:22])=[O:21])=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:10]
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cc1ccccn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C(Cc1ccccn1)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 32 %

Procedure:
302 mg (2.0 mmol) methyl 2-(pyridin-2-yl)acetate were added to a solution of 362 mg (1.0 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) in xylene (4 ml) and the mixture was then heated for 7 h at 150° C. After cooling to RT the mixture was diluted with EtOAc and the phases were separated. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 6:4) of the residue yielded 154 mg (0.32 mmol, 32%) 2-pyridin-2-yl-N-[2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]acetamide. MS: m/z 482.1 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.C1(NC(C2C3C=C(C4C([Cl:25])=CN=C(NCCCN5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:37]1([NH:40][C:41]([C:43]2[C:51]3[CH:50]=[C:49]([C:52]4[C:57]([Br:58])=[CH:56][N:55]=[C:54]([Cl:59])[N:53]=4)[S:48][C:47]=3[CH:46]=[CH:45][CH:44]=2)=[O:42])[CH2:39][CH2:38]1.[CH3:60][C:61]1([CH3:72])[CH2:66][C:65](=[CH:67][CH2:68][NH2:69])[CH2:64][C:63]([CH3:71])([CH3:70])[NH:62]1>>[ClH:25].[ClH:59].[CH:37]1([NH:40][C:41]([C:43]2[C:51]3[CH:50]=[C:49]([C:52]4[C:57]([Br:58])=[CH:56][N:55]=[C:54]([NH:69][CH2:68][CH:67]=[C:65]5[CH2:66][C:61]([CH3:72])([CH3:60])[NH:62][C:63]([CH3:71])([CH3:70])[CH2:64]5)[N:53]=4)[S:48][C:47]=3[CH:46]=[CH:45][CH:44]=2)=[O:42])[CH2:39][CH2:38]1
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CC1(C)CC(=CCN)CC(C)(C)N1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Agent: Cl
Product: CC1(C)CC(=CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC(C)(C)N1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 2-(2,2,6,6-tetramethylpiperidin-4-ylidene)-ethylamine and isolated as a yellow solid. ES+(m/z) 554 (79Br) and 556 (81Br) [M(free base)+H].
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[PH2:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C.C([O:27][CH2:28][CH3:29])(=O)C>>[OH:9][CH:8]([P:12](=[O:13])([O:27][CH2:28][CH3:29])[O:14][CH2:15][CH3:16])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Reactant: CCO[PH2]=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-nitrobenzaldehyde (8.56 g) and ethyl hypophosphite (7.81 g) was gradually added triethylamine (1.5 mL). After stirring for 1 hr., the reaction mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and diethyl α-hydroxy-4-nitrobenzylphosphonate was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). Recrystallization from ethyl acetate-hexane gave yellow prism crystals (4.62 g, yield 28%). melting point: 94–95° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[Cl:10][Sn]Cl.CO[C:15](OC)(OC)[CH3:16]>CCO>[Br:1][C:2]1[C:3]2[N:9]=[C:15]([CH3:16])[NH:8][C:4]=2[CH:5]=[C:6]([Cl:10])[CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: COC(C)(OC)OC
Reactant: Nc1cccc(Br)c1N
Solvent: CCO
Product: Cc1nc2c(Br)cc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.7 %

Procedure:
A suspension of 3-bromobenzene-1,2-diamine (4.0 g, 15.90 mmol) and SnCl2 (17.9 g, 79.50 mmol) in EtOH (40 mL) was heated at reflux for 4 h. After cooling to RT, 1,1,1-trimethoxyethane (12.9 g, 79.50 mmol) was added to the mixture. The reaction mixture was stirred at 120° C. for 14 h, then cooled to RT and concentrated in vacuo. The residue was diluted with EtOAc (100 mL), treated with satd. aq. NaHCO3 (200 mL), filtered with Celite®, and washed with EtOAc (50 mL×3). The filtrate was washed with satd. aq. NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 4-bromo-6-chloro-2-methyl-1H-benzo[d]imidazole as a yellow solid (3.5 g, 89.7%). MS (ESI): m/z=244.9 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:44][C:41]1[CH:40]=[CH:39][C:38]([CH:31]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)[N:32]2[CH2:33][CH2:34][N:35]([CH2:22][CH2:21][CH2:20][C:11]3[CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=3)[CH2:36][CH2:37]2)=[CH:43][CH:42]=1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
127 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (75 mg, 0.261 mmol), DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)3 (166 mg, 0.783 mmol).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>C(OCC)(=O)C>[C:1]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)O
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
Acetic acid (0.3 g), triethylamine (0.7 ml) and aniline (0.5 g) are dissolved in ethyl acetate (10 ml), and thereto is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.05 g), and the mixture is stirred at room temperature for 1 hour. After allowing to stand overnight, the reaction mixture is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give acetanilide (0.7 g). The product recrystallized from water has a melting point of 110°-112° C.
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:33])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[C:11]([O:24][CH3:25])[CH:10]=2)[N:5]1C(OC(C)(C)C)=O)=[O:3].C([Cl:37])(C)=O>C(OCC)(=O)C.CO>[ClH:37].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:6]2[NH:5][C@:4]([CH3:33])([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]2)=[CH:10][C:11]=1[O:24][CH3:25]
Reactant: COc1cc([C@H]2CC[C@@](C)(C(N)=O)N2C(=O)OC(C)(C)C)ccc1OCc1ccccc1F
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc([C@H]2CC[C@@](C)(C(N)=O)N2)ccc1OCc1ccccc1F
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-2-methyl-1-pyrrolidinecarboxylate (D61, 110 mg, 0.24 mmol) in a mixture of ethyl acetate (2.7 ml) and methanol (0.3 ml) at 0° C. was added AcCl (110 μl, 1.54 mmol). The mixture was stirred for 1 hour at room temperature. Two further additions of AcCl (110 μl and after 1 h another 110 μl plus additional stirring for 2 h) were required, before the reaction was complete (as shown by HPLC). The mixture was evaporated and the residue was triturated with Et2O to afford the title compound as a white solid (80 mg, 84%); Rt (HPLC) 3.41 min; MS: (ES/+) m/z: 359[MH]+ C20H23FN2O3 requires 358; 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.82-10.05 (br.s, 1H); 8.02-8.27 (br.s, 1H); 8.05-8.10 (br.s, 1H); 7.80-7.90 (br.s, 1H); 7.47-7.53 (m, 1H); 7.35-7.43 (m, 1H); 7.17-7.24 (m, 2H); 7.15 (d, 1H); 7.07 (d, 1H); 6.95 (dd, 1H); 5.08 (s, 2H); 4.57-4.72 (m, 1H); 3.70-3.78 (s, 3H); 2.39-2.51 (m, 1H); 2.19-2.32 (m, 1H); 1.95-2.08 (m, 1H); 1.81-1.95 (m, 1H); 1.62 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([CH2:10][CH:11]=[CH2:12])[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(OCC)(=[O:40])C.Cl>C(OCC)C>[C:1]1([C:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([CH2:10][CH:11]=[CH2:12])[CH:8]=[O:40])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: C=CCC(C#N)(COCC[Si](C)(C)C)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCC(C=O)(COCC[Si](C)(C)C)c1ccccc1
Reaction time: 2.5 h
Yield: 39.2 %

Procedure:
A solution of 2-phenyl-2-(2-(trimethylsilyl)ethoxymethyl)-pent-4-enenitrile (354 mg, 1.23 mmol) in ethyl ether (1.0 mL) was cooled in an ice bath and a 1.5 M solution of diisobutylaluminum hydride in toluene (1.25 mL, 1.88 mmol) was added. After 2.5 h, ethyl acetate (0.30 mL, 270 mg, 3.1 mmol) was added and the mixture was transferred to a stirred mixture of 30 mL of ethyl ether and 10 mL of 2 N aqueous HCl at 0° C. After 10 min, the layers were separated and the aqueous layer was stirred for 0.5 h with another 30 mL of ethyl ether. The two organic layers were washed in succession with 10 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The combined organic layers were dried over sodium sulfate and evaporated. The residue was dissolved in 5.0 mL of THF and 0.7 mL of water was added followed by 1.0 g of silica gel. After stirring for 40 min at RT, the mixture was filtered and the silica gel was washed with additional THF. The filtrate was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with 2% ethyl ether in hexane, to give 140 mg of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 9.56 (s, 1H), 7.35 (t, 2H, J=7 Hz), 7.26 (t, 1H, J=7 Hz), 7.16 (d, 2H, J=7 Hz), 5.47 (ddt, 1H, J=17, 10, 7 Hz), 5.06-4.96 (m, 2H), 3.98 (d, 1H, J=9 Hz), 3.80 (d, 1H, J=9 Hz), 3.58-3.47 (m, 2H), 2.73 (d, 2H, J=7 Hz), 0.88 (t, 2H, J=8 Hz), -0.03 (s, 9 H). Mass spectrum (CI): m/z=263 (M-27, 100%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[C:13]1([C:19](=O)[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][N:10]=[C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: NNc1ccccc1C(F)(F)F
Product: O=C(C(=NNc1ccccc1C(F)(F)F)c1ccccc1)c1ccccc1

Procedure:
1,2-Diphenylethane-1,2-dione [2-(trifluoromethyl)phenyl]hydrazone was prepared from 2-trifluoromethylphenyl hydrazine and 1,2-diphenyl-ethane-1,2-dione according to the procedure of Step 1 Example 2. MS (ESI) m/z 369; MS (ESI) m/z 367;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCOC(=O)c1c(C=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C=O)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-formyl-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (600 mg, 1.26 mmol; see step (a) above), 2-bromo-5-(trifluoromethyl)pyridine (426 mg, 1.89 mmol), Na2CO3 (aq, 2 M, 1.89 mL, 3.78 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), EtOH (5 mL) and toluene (20 mL) was heated at 80° C. for 24 h, allowed to cool, poured into H2O and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. Yield 500 mg (80%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-:10].[Na+].[Na][Na]>O>[OH:10][CH:2]([C:7]([OH:9])=[O:8])[CH:3]([NH:1][CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8])[C:4]([OH:6])=[O:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: [OH-]
Agent: [Na+]
Agent: [Na][Na]
Solvent: O
Product: O=C(O)CC(NC(C(=O)O)C(O)C(=O)O)C(=O)O

Procedure:
In one particularly preferred embodiment of the production process, aspartic acid is initially introduced into water in such a quantity that a 20% by weight to 30% by weight solution or suspension is formed and approximately 2 mol equivalents of an alkali metal hydroxide, preferably sodium hydroxide, and then approximately 1 mol equivalent epoxysuccinic acid dialkali metal salt, preferably disodium salt, are added to the resulting solution or suspension. The mixture is then stirred, preferably until the reactants have completely reacted, which generally takes about 1 to 8 hours. To accelerate the reaction, elevated temperatures, for example in the range from 80° to 100° C., may be applied. After removal of the solvent, for example in a rotary evaporator, the tetraalkali metal salt of 3-hydroxy-2,2'-iminodisuccinic acid is obtained as a more or less colorless solid in a substantially quantitative yield. The 3-hydroxy-2,2'-iminodisuccinic acid can be released from this solid or from the solvent-containing crude product in known manner by addition of typical acids, for example hydrochloric acid or sulfuric acid. The acidification step may be omitted if the salt is to be subsequently used as such. The solvent removal step can be omitted if the product is to be incorporated in liquid formulations or intermediates, for example in pastes or slurries.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:31][CH2:32][CH:33]=[CH:34][C:35]1[CH2:42][S:41][C@H:40]2[N:37]([C:38](=[O:44])[C@H:39]2[NH2:43])[C:36]=1[C:45]([OH:47])=[O:46])(=[O:30])[CH3:29]>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([O:31][CH2:32]/[CH:33]=[CH:34]\[C:35]1[CH2:42][S:41][C@H:40]2[N:37]([C:38](=[O:44])[C@H:39]2[NH:43][C:13](=[O:15])[CH2:12][S:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:36]=1[C:45]([OH:47])=[O:46])(=[O:30])[CH3:29]
Reactant: CC(=O)OCC=CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CSc1ccc2ccccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)OC/C=C\C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CSc3ccc4ccccc4c3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 10.5 g (48 mmol) of naphthalen-2-ylsulfanyl-acetic acid in 80 ml of N,N-dimethylacetamide were added 7.8 g (48 mmol) of 1,1′-carbonyldiimidazole and the reaction mixture was stirred for 0.5 h at 20° under an atmosphere of argon. To the yellow solution were added 11.93 g (0.5 mmol) of (Z and E)-(6R,7R)-3-(3-acetoxy-propenyl)-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid and stirring was continued for 3 h at 20°. The brown solution was diluted with ethyl acetate (0.5 1), washed with 1 N hydrochloric acid (0.2 1) and with water (5×0.1 1), dried over sodium sulfate and evaporated in vacuo. The remaining material was crystallized from ethyl acetate to give 11.7 g (58%) of (Z)-(6R,7R)-3-(3-acetoxy-propenyl)-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a light brown solid.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C([O:9][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]3)=[N:16][N:15]2[CH:38]=1)=O)C>>[CH2:1]([NH:6][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:34])([F:36])[F:35])[CH2:24][CH2:25]3)=[N:16][N:15]2[CH:38]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Reactant: CCCCCN
Product: CCCCCNC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 56 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use n-pentylamine in place of isoamylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 56% yield (0.062 g). m.p. 179-180° C. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.75-7.5 (m, 4H), 7.38-7.27 (s, 2H), 6.89 (d, J=9.6 Hz, 1H), 4.07-3.8 (m, 2H), 3.7-3.51 (m, 2H), 3.5-3.28 (m, 6H), 1.68-1.52 (m, 2H), 1.45-1.28 (m, 4H), 0.89 (t, J=2.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 162.3, 154.8, 138.2, 134.3, 134.2, 132.4, 129.5, 127.1, 126.8, 126.8, 126.2, 125.4, 121.8, 118.2, 111.9, 46.2, 41.2, 39.1, 29.4, 29.1, 22.4, 13.9. MS (ES+) m/z 489.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([N+:21]([O-])=O)[CH:12]=3)[N:10]=2)[CH:7]=1.CC(O)=O>[Fe].C(O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[C:13]([CH:12]=3)[NH2:21])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Iron (0.726 g) is added to a mixture of 6-chloro-2-[3-nitro-4-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrazine (0.891 g), HOAc (1.19 mL), and EtOH—H2O (10 mL, 4:1). The mixture is stirred at 80° C. for 2 hours, cooled, concentrated and taken up into sat. aqueous NaHCO3 and extracted with EtOAc and CH2Cl2. Organic layer is dried and concentrated to give the title compound (813 mg), which is used without further purification. LCMS m/z=313.4 [M+H]+, tR=2.29 min.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:19][CH:20]=[CH2:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O:37]1CCCC1>>[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:19][CH2:20][CH2:21][OH:37])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: C=CCC(CCCCCCCCCc1ccccc1)OCc1ccccc1
Agent: B1C2CCCC1CCC2
Product: OCCCC(CCCCCCCCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a 0.5M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (253 ml) was added dropwise, under nitrogen, a solution of 41.8 g of 4-benzyloxy-13-phenyl-1-tridecene in 100 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 3 hours, quenched by the sequential addition of 72 ml of ethanol, 24 ml of 6N solution of sodium hydroxide, and 48 ml of a 30% solution of hydrogen peroxide. The mixture was heated at 50° for 2.5 hours. Upon standing at room temperature overnight, the mixture separated into aqueous and organic layers. The organic layer was washed with 100 ml of a 10% aqueous solution of sodium sulfite and 100 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous potassium carbonate and concentrated. The concentrate was taken up in 20% diethyl ether/hexane, filtered and concentrated to an oil. The oil was purified by high pressure liquid chromatography using as an eluent hexane/diethyl ether (2:1 by volume) to give 32.7 g (75%) 4-benzyloxy-13-phenyl-tridecan-1-ol as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[NH2:12].Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(=O)(O)[O-].[Na+]>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:4][C:3]=1[N:12]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: ClCCNCCCl
Reactant: CS(=O)(=O)c1ccc(F)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CS(=O)(=O)c1ccc(F)c(N2CCNCC2)c1
Yield: 39 %

Procedure:
10 mL solution of 432 mg 2-fluoro-5-methylsulfonylphenylamine (compound in Production Example 338) and 490 mg bis(2-chloroethyl)amine hydrochloride in 1,2-dichlorobenzene was stirred at 200° C. for 9 hours. The reaction mixture was neutralized by adding an aqueous saturated sodium bicarbonate solution and then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 230 mg of the title compound (dark brown solid).