Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[C:26]([Br:27])=[CH:25][N:24]([CH3:28])[N:23]=2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:27][C:26]1[C:22]([C:18]2[CH:17]=[C:16]([NH:15][C:8]([C:7]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)=[O:9])[CH:21]=[CH:20][CH:19]=2)=[N:23][N:24]([CH3:28])[CH:25]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3ccc(OC(F)(F)F)cc3)c2)n1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To 4-(trifluoromethoxy)benzoyl chloride (19 μL, 0.12 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)4-bromo-1-methylpyrazole (30 mg, 0.12 mmol) and triethylamine (17 μL, 0.12 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (40 mg, 76%), m.p. 138.6-139.6° C. (EtOAc/hexane).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>>[N:36]1([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[CH:32]=[CH:31][S:30][CH:29]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Yield: 49.1 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.13 mmol) and morpholine (0.069 mL, 0.65 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.65 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (33 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:10]12([C:20](=O)[CH2:21][C:22](OCC)=[O:23])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>>[C:10]12([C:20]3[S:9][C:6]4[C:7]([C:22](=[O:23])[CH:21]=3)=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][CH:12]([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: CCOC(=O)CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(S)cc1
Product: COc1ccc2sc(C34CC5CC(CC(C5)C3)C4)cc(=O)c2c1
Reaction time: 1.5 h

Procedure:
1.4 g 4-methoxythiophenol is added to 10 g of polyphosphoric acid preheated to about 90°. Then 2.5 g ethyl 3-(1-adamantyl)-3-oxopropionate is added slowly, and the mixture is stirred for altogether 1.5 hours at 90°. The mixture is poured onto ice/water, vigorously stirred and extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 6/1). 2-(1-adamantyl)-6-methoxy-4H-thiochromen-4-one is obtained (colourless crystals; mp 140°). b) Under argon 14 ml of 1M boron tribromide solution in dichloromethane are added at room temperature to a solution of 1.12 g 2-(1-adamantyl)-6-methoxy-4H-thiochromen-4-one in dry dichloromethane. After stirring for 1 hour the mixture is poured onto ice/water and extracted with dichloromethane. The combined organic layers are washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The title compound is obtained (colourless crystals; mp 257° after chromatography on silica gel using cyclohexane/ethyl acetate 4/1 as an eluant).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][CH:21]([C:24]1([CH3:28])[CH2:27][O:26][CH2:25]1)[C:22]#[N:23]>>[C:22]([CH:21]([C:24]1([CH3:28])[CH2:27][O:26][CH2:25]1)[NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])#[N:23]
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: CC1(C(N)C#N)COC1
Product: C[C@H](Oc1cc(C(=O)NC(C#N)C2(C)COC2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and 2-amino-2-(3-methyloxetan-3-yl)acetonitrile (example 251b) as starting materials and isolated (180 mg, 83%); MS (ESI, m/z): 384.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].CS(C)=O>C(OCC)(=O)C>[C:10]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:24][CH2:23][N:15]([C:16]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:22])[CH2:14][CH2:13]1)#[N:11]
Reactant: N#CCc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.9 %

Procedure:
2-(2,3-dichlorophenyl)acetonitrile (2.49 g crude, est. 83% purity, 11 mmol), 2.70 g tert-butyl bis(2-chloroethyl)carbamate (J. Med. Chem. 1992, 35, 11, 2033-2039) (11 mmol), 19.5 g aesium carbonate (60 mmol) and 200 ml DMSO were combined in a round bottom flask and stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and the organic layer washed with 1M aq. KHSO4 solution, and then saturated aq. NaHCO3 solution, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography on silica, using a gradient from 5% to 35% ethyl acetate in hexanes as eluent. 2.3 g of the title compound were isolated as an oil (59% yield)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Br[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23]>C(#N)C>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: CS(=O)(=O)NCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)NCCN1CCC(CO)CC1
Yield: 54.8 %

Procedure:
4-Piperidine methanol (1.60 g) was dissolved in dry acetonitrile (40 ml), N,N-diisopropylethylamine (5 ml) was added, followed by N-(2-bromoethyl)methanesulphonamide (2.95 g) in acetonitrile (10 ml), and the resulting mixture heated at reflux for 2 h. The solvent was removed in vacuo to leave a gum. This was purified by FCC eluting with System A (75:8:1) to give the title compound (1.80 g) as a solid, m.p. 81°-82°.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][CH:15]([CH3:28])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])(O)=O.[Na+]>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH2:16][CH:15]([CH3:14])[CH3:28])=[C:19]([O:26][CH3:27])[CH:20]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1cc(C=O)ccc1OCC(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCC(C)C
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 2.2 g (11.8 mmol) of N-Boc-piperazine and 2.5 g (about 12 mmol) of crude 4-(2-methylpropyloxy)-3-methoxybenzaldehyde are mixed in 50 ml of dry of dichloromethane. After dissolution 2 drops of acetic acid is added, then 4.25 g (20 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 20 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off, concentrated in vacuum at 50÷80° C. The residue (3.3 g of oil)-crude N-(tert-butyloxycarbonyl)-N′-(4-(2-methylpropyloxy)-3-methoxybenzyl)piperazine is used on the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2([C:14]#N)[CH2:13][CH2:12][S:11][CH2:10][CH2:9]2)[CH2:3]1.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=C1[Mg]Br>CCOCC>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:14]1[C:8]1([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]2)[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: CC1CCCN(C2(C#N)CCSCC2)C1
Reactant: Br[Mg]c1cc2ccccc2s1
Solvent: CCOCC
Product: CC1CCCN(C2(c3cc4ccccc4s3)CCSCC2)C1

Procedure:
4-(3-methyl-piperidino)-tetrahydro-4H-thiopyran-4-carbonitrile (2 g, 8.9 mmoles) dissolved in 50 ml of anhydrous ether is introduced dropwise into a 2-benzothiophenylmagnesium bromide (44.7 mmoles) solution. Ether is heated under reflux for 20 hours. After the usual treatment, a brown oil is obtained (1.7 g) which is chromatographed on 60 g of alumina eluting with an EP/EA (95/5) mixture. In this way, a white solid is obtained (1.2 g, 40%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2.[CH3:47][Si:48]([C:51]#[CH:52])([CH3:50])[CH3:49]>C(N(CC)CC)C.C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:47][Si:48]([CH3:50])([CH3:49])[C:51]#[C:52][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(C#C[Si](C)(C)C)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.5 g) in triethylamine (5 mL) were added trimethylsilylacetylene (0.2 mL), tetrakis (triphenylphosphine) palladium (0) (81 mg) and copper (I) iodide (27 mg), and the mixture was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The insoluble material was removed by filtration. The filtrate was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1-2/1) to give 4-(2-trimethylsilylethynyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.4 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added tetra(n-butyl) ammonium fluoride (0.15 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH:37]([N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH:37]([CH3:39])[CH3:38])[CH3:50])=[O:49])[CH2:48][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)N(C)C(=O)CN1CCNCC1
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin 1-yl)-N-isopropyl-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 16c) in an analogous manner as described in example 25. LR-MS: 703.4 [(M+H)+]
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[C:8](O)(=[O:10])[CH3:9]>>[CH3:9][C:8]([CH:6]1[C:1](=[O:3])[O:4][C:5]1=[O:7])=[O:10]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)C1C(=O)OC1=O
Yield: 86 %

Procedure:
To a solution of 60 ml of acetic acid and 43 ml of acetic anhydride at 0° C., was added slowly 40 g (0.27 mol) of acetone-dicarboxylic acid. The mixture was stirred and the temperature was not allowed to rise above 10° C. The acid was dissolved slowly and a pale yellow precipitate formed. After 3 h the product was filtered, washed with 30 ml of glacial acetic acid and 100 ml of benzene. The white powder obtained was dried at high vacuum to afford 30 g of acetonedicarboxylic acid anhydride (yield 86%). Mp 137-138° C.
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:22]([N:39]([CH2:47]COCCO)[CH2:40][C:41]1C=CC=[CH:43][CH:42]=1)([O:24][CH2:25][CH:26]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23].N1C=CC=CC=1.CO>C1COCC1>[C:22]([N:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:47]1)([O:24][CH2:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:23]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N(CCOCCO)Cc1ccccc1
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCCC1
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
THF (15 ml) was added to 2-Chlorotrityl chloride resin (4.0 g, 1.2 mmol/g) and the mixture was agitated for 25 min. FmocN(Bn)CH2CH2OCH2CH2OH (6.1 g, 14.7 mmol) in THF (25 ml) was added followed by pyridine (850 μl, 10.5 mmol) and the mixture was heated to 65° C. for 15 h. MeOH (5 ml) was added and heating was continued for 35 min. The resin was filtered, washed with DMF (3×), CH2Cl2 (3×). MeOH (3×) and Et2O (3×) to give 5.0 g. A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.45 mmol/g.
Reaction SMILES: F[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.C([O-])(=[O:15])C.[Na+].C(OCC)(=O)C.O>CN(C)C=O>[F:8][C:5]1[N:4]=[C:3]([C:9]([O:11][CH3:12])=[O:10])[C:2](=[O:15])[NH:7][CH:6]=1
Reactant: COC(=O)c1nc(F)cnc1F
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(F)c[nH]c1=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 10.1 %

Procedure:
In 3.0 mL of N,N-dimethylformamide was dissolved 0.3 g of methyl 3,6-difluoro-2-pyrazinecarboxylate. After adding 0.16 g of sodium acetate at an ice-cooled temperature, the mixture thus obtained was stirred at 50° C. for 2.5 hours. The reaction mixture was poured into a mixture of 50 mL of ethyl acetate and 30 mL of water, and the organic layer was separated. The remaining aqueous phase was extracted with three 25 mL portions of ethyl acetate. The organic layers were united, washed successively with 15 mL of water and 15 ml of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate=1:2] to obtain 0.03 g of methyl 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a colorless solid product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19]O)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>C(#N)CC.O>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19][N:49]3[CH2:48][CH2:47][N:46]([C:43]4[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][CH:44]=4)[CH2:51][CH2:50]3)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C1CN(Cc2ccccc2)c2ncc(CO)cc2N1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CN(Cc2ccccc2)c2ncc(CN3CCN(c4ccc(Cl)cc4)CC3)cc2N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (66.6 mg, 40%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.33 (d, J=4.5 Hz, 4H), 7.25-7.30 (m, 1H), 7.19-7.24 (m, 2H), 7.01 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.72 (s, 2H), 3.86 (s, 2H), 3.36 (s, 2H), 3.07-3.15 (m, 4H), 2.44-2.49 (m, 4H). [M+H] calc'd for C25H26ClN5O, 448. found, 448.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1([CH2:21][OH:22])[CH2:19][CH2:18][CH:17]1[CH3:20].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1([CH:21]=[O:22])[CH2:19][CH2:18][CH:17]1[CH3:20]
Reactant: CC1CCC1(CO)c1cccs1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1CCC1(C=O)c1cccs1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (50 mL, 0.10 mmol) was added to CH2Cl2 (150 mL) at 23° C. and was cooled to −78° C. DMSO (16 g, 0.20 mmol) was added dropwise to the mixture and stirring was continued for 15 min. A solution of alcohol 4 (7.9 g, 0.041 mmol) in CH2Cl2 (50 mL) was then added dropwise, after which Et3N (44 g, 0.44 mmol) was added and the mixture was warmed to 23° C. After 1 h, the mixture was poured into saturated aqueous NaHCO3 and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic portions were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by FCC (silica gel, hexane; 2:1, hexane/CH2Cl2) to afford the above named aldehyde 5.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](Cl)[N:10]=[N:9][C:8]=2[Cl:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Cl:14][C:8]1[N:9]=[N:10][C:11]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1nnc(-c2cccnc2)cc1-c1ccccc1
Temperature: 10 °C

Procedure:
4-Phenyl-3,6-dichloropyridazine (1-1; 113 mg, 0.5 mmol) was dissolved in dry dioxane (2 mL). Then pyridine-3-boronic acid (99 mg, 0.8 mmol), 2 M aqueous Na2CO3 (0.75 mL) and palladium(0) tetrakis-triphenylphosphine (60 mg, 0.04 mmol) were added. This mixture was degassed, the vessel sealed and heated at 10° C. for 9 hours. The cooled reaction was diluted with water and the product mixture extracted into ethyl acetate, the extract dried over anhydrous NaSO4, filtered and evaporated. The product was purified by chromatography on silica gel and elution with a 20-70% ethyl acetate/hexane gradient to give 3-chloro-4-phenyl-6-pyridin-3-ylpyridazine (3-1). NMR (CDCl3): δ9.26 (1H, s), 8.78 (1H, d, J=4.6 Hz), 8.51 (1H, d, J=8 Hz), 7.86 (1H, s), 7.55-7.58 (5H, m), 7.51 (1H, dd, J=8 Hz, J=4.5 Hz); m/e (m+1): 268.1.
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH3:18])[NH:11][C:10](=O)[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].B#B.Cl>O1CCCC1>[CH2:1]([C:5]1([CH2:17][CH3:18])[NH:11][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC)CSc2ccccc2C(=O)N1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC1(CC)CSc2ccccc2CN1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
A solution of the product from step (a) (46.5 g,) in tetrahydrofuran (260 ml) was cooled to 0° C., and 1M diborane (450 ml, Aldrich) in THF was slowly added. The resulting mixture was heated to reflux for 48 hours, cooled to 0° C., and treated carefully with 6M aqueous HCl. The mixture was heated to reflux for 1.5 hours, concentrated to 400 ml and extracted twice with diethyl ether. The organic layers were dried and concentrated to afford the title product (44.0 g) as a colorless oil. 1H NMR consistent with the proposed structure.
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na+]>O>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
An alkaline solution of 4 g of sodium stearate in 100 ml of water is metered into a suspension of 100 g of Iriodin 300 (TiO2 /Fe2O3, mica having a particle size of 10-60 μm from E. Merck, Darmstadt) in 1000 ml of water at a pH of 6, resulting in the precipitation of stearic acid while keeping the pH constant with 5% hydrochloric acid. The product is then filtered off, dried and pyrolysed at 800° C. in an N2 gas stream.