Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20](O)[CH3:21])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20]([N:46]2[C:42](=[O:52])[C:43]3[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:45]2=[O:47])[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cccc2nc(C(C)O)c(-c3cccc(F)c3)c(=O)n12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(-c3cccc(F)c3)c(=O)n12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 3-(3-fluorophenyl)-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (0.6500 g, 2.179 mmol), triphenylphosphine (0.6858 g, 2.615 mmol), phthalimide (0.3847 g, 2.615 mmol), and THF (14.53 mL) was stirred at rt for 5 min to dissolve all reactants. The mixture was then cooled to 0° C. and to the cooled homogenous mixture was added dropwise over 3 min to diisopropyl azodicarboxylate (0.5148 mL, 2.615 mmol) at 0° C. The reaction mixture was allowed to warm to rt and stirred at rt. After 5 h, the mixture was concd under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc for 10 min as eluent to give 2-(1-(3-(3-fluorophenyl)-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethypisoindoline-1,3-dione as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75-7.82 (2 H, m), 7.65-7.74 (3 H, m), 7.35-7.42 (1 H, m), 7.13-7.24 (1 H, m), 6.90-7.01 (4 H, m), 5.43 (1 H, q, J=7.0 Hz), 2.89 (3 H, s), 1.62 (3 H, d, J=7.4 Hz); Mass Spectrum (ESI) m/e=427.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:34]1[CH2:35][CH:36]=[C:37]([C:2]2[C:3]([O:8][C@H:9]3[CH2:14][CH2:13][C@H:12]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3Cl)CC2)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: COCCOC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3C3=CCOCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
trans-4-(3-Chloropyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine (0.810 g, 1.73 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.455 g, 2.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.087 mmol) were mixed in DME (2 mL) under a nitrogen atmosphere. Sodium carbonate (2.60 mL, 5.19 mmol, 2 M in water) was added via syringe, and the reaction mixture was then heated to 80° C. and stirred for 5 h. The mixture was cooled to RT and partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine as a light yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[CH:15][NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:27]=[CH:26][C:25]([N:14]2[CH:15]=[C:16]([C:17]#[N:18])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[N:13]2)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1ccc(Nc2n[nH]cc2C#N)cc1
Product: CC(=O)c1ccc(-n2cc(C#N)c(Nc3ccc(S(C)(=O)=O)cc3)n2)cc1

Procedure:
1-(4-acetylphenyl)-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile was prepared according to the general procedure in Example 15 Step 4 using 3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile (0.24 g, 0.915 mmol) and (4-acetylphenyl)boronic acid (0.300 g, 1.830 mmol) as the starting materials.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>>[Br:21][C:20]([Br:24])=[CH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1
Reactant: COc1ccc(C=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C=C(Br)Br)cc1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Triphenylphosphine (57.8 g, 220 mmol) was dissolved in dichromomethane (200 ml) in nitrogen atmosphere, and carbon tetrabromide (36.5 g, 110 mmol) was added little by little under cooling with ice, followed by stirring for 30 minutes. Then, p-anisic aldehyde (10.0 g, 73.4 mmol) was dropwise added under cooling with ice, followed by stirring for 10 minutes. The reaction solution was subjected to filtration, silica gel (50 g) was added to the filtrate, and the filtrate was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired compound 1-(2,2-dibromovinyl)-4-methoxybenzene (21.4 g, quant.) as pale yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:25][O:26][C:27](=[O:42])[NH:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]1[O:38][C:39](=[O:41])[CH3:40].C(=O)(O)N>C(Cl)Cl.O>[CH3:25][O:26][C:27](=[O:42])[NH:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][C:33]([N+:1]([O-:4])=[O:2])=[CH:34][CH:35]=2)[CH:30]1[O:38][C:39](=[O:41])[CH3:40]
Reactant: COC(=O)NC1Cc2ccccc2C1OC(C)=O
Reactant: O=[N+]([O-])O
Agent: NC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)NC1Cc2ccc([N+](=O)[O-])cc2C1OC(C)=O
Temperature: 0 °C

Procedure:
To 90% HNO3 (55.1 mL, 0.8 mol) under nitrogen at −30° C. is added 100 mL of trifluoroacetic acid followed by the addition of trifluoroacetic anhydride (100 g, 0.476 mol) over 5 minutes. The above carbamate (1-acetyloxy-indan-2-yl)-carbamic acid methyl ester (1S-trans)) (20.0 g, 0.08 mol) in 34 mL of methylene chloride is added slowly (over 90 min.) keeping the temperature between −30 and −35° C. The reaction is worked up by adding 100 mL of water and warmed to 0° C. to give two layers. The layers are separated and the aqueous layer extracted with methylene chloride. The combined organic extracts are washed with 100 mL of water (pH is adjusted to 8.5 with sodium bicarbonate), and with cold water. The organic layer is dried over MgSO4, filtered and evaporated to give crude product. The crude product is crystallized from ethyl acetate and further precipitated by the addition of heptane to give (1-acetyloxy-6-nitro-indan-2-yl)-carbamic acid methyl ester (1S-trans); mp 164-167° C.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29](Cl)=[O:30])[CH:24]=1>N1C=CC=CC=1>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:20][CH2:19][N:15]2[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]3[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:29]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)=[O:30])[C:4](=[O:22])[CH2:5]3)[CH2:17][C:16]2=[O:18])=[O:30])[CH:24]=1
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: O=C(OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)c3cccnc3)C(=O)C2)CC1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
A mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.31 g, 1.0 m mol), 3-pyridylcarbonyl chloride (0.28 g, 2.0 m mol) and pyridine (10 ml) was stirred for 18 hours at room temperature. The solvent was removed from the reaction mixture under reduced pressure and the residue was extracted with chloroform. The extract solution was washed with saturated sodium bicarbonate aqueous solution successively with water, and was dried over magnesium sulfate. The residue obtained by removing the solvent under reduced pressure from the extract solution was purified by silica gel column chromatography (chloroform:ether:methanol=6:1:1, Rf value=0.3) to give the titled compound (0.12 g; yield 24%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[C:10][CH2:11][CH2:12][NH:13]C(=O)OCC2C=CC=CC=2)=[C:4]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1>CCO.[Pd]>[NH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:5]1[C:4]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:3][C:2]([NH2:1])=[N:7][C:6]=1[CH3:8]
Reactant: CCCCCNc1nc(N)nc(C)c1C#CCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCNc1nc(N)nc(C)c1CCCCN
Reaction time: 3 h
Yield: 44.7 %

Procedure:
The product from step (i) (0.2 g) was dissolved in EtOH (20 mL) then 5% Pd/C (100 mg) in EtOH (5 mL) was added. The reaction mixture was hydrogenated at 4 bar overnight. The catalyst was filtered off then 20% Pd(OH)2/C (100 mg) in EtOH (5 ml) was added and the reaction mixture hydrogenated at 4 bar for 3 h. The catalyst was filtered off and the solvents evaporated to give the subtitle compound 0.06 g.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(N(CC)C(C)C)(C)C.Br[C:19]([CH3:26])([CH3:25])[C:20](OCC)=[O:21].O>CN(C)C=O>[CH3:25][C:19]1([CH3:26])[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][C:20]1=[O:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Nc2ccccc2NC1=O
Temperature: 110 °C
Yield: 57.5 %

Procedure:
To a solution of 1,2-phenylenediamine (16.96 g) in N,N-dimethylformamide (80 ml) were added successively N,N-diisopropylethylamine (36.4 mL) and ethyl α-bromoisobutyrate (39.8 g), and the mixture was heated at 110° C. for 3 days. After cooling, to the reaction mixture was added cold water and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed successively with an aqueous 10% HCl solution, water, an aqueous saturated sodium hydrogencarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was recrystallized from dichloromethane-n-hexane to give 3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (15.90 g) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[Sn](Cl)Cl>O1CCOCC1.Cl>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Product: Nc1cccc(Br)c1F
Temperature: 70 °C

Procedure:
2.0 g (9.09 mmol) of 3-bromo-2-fluoronitrobenzene were dissolved in 10 ml of dioxane, and 8.62 g (45.45 mmol) of tin(II) chloride were added at RT. After addition of a few drops of 1 N hydrochloric acid, the mixture was heated at 70° C. for 2 h. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate. The solution was washed successively twice with 1N aqueous sodium hydroxide solution, water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 997 mg (57.7% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12]([OH:14])=O)=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][N:49]([CH3:60])[CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:48][N:49]([CH3:60])[CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][C:12](=[O:14])/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:55][CH:54]=1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Method A; To a mixture of 3 (2.50 g, 8.00 mmol), EDC.HCl (1.84 g, 9.60 mmol) and HOBt (1.30 g, 9.62 mmol) in DMF (50 ml) was added a solution of 4-(2-(dimethylamino)ethoxy)benzene-amine dihydrochloride (2.23 g, 8.81 mmol) and N,N-Diisopropylethylamine (4.13 g, 32.0 mmol) under ice cooling, and the mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with AcOEt, the organic layer was washed with H2O×2, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: AcOEt then CHCl3/MeOH, 10:1) and recystallization from AcOEt-hexanes gave 4 (43%). 4: colorless powder; 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.4), 2.33 (6H, s), 2.71 (2H, t, J=5.7 Hz), 2.77 (2H, q, J=7.4 Hz), 3.43 (3H, s), 4.04 (2H, t, J=5.7 Hz), 5.09 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=9.0 Hz), 7.00 (2H, d, J=8.8 Hz), 7.00 (1H, brs) 7.06 (2H, m), 7.12-7.23 (3H, m), 7.41 (2H, d, J=9.0 Hz).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:12])[C:8]=1[C:9](=[O:11])[CH3:10].I[CH3:14].O>CS(C)=O>[CH3:14][N:5]1[CH:6]=[C:7]([CH3:12])[C:8]([C:9](=[O:11])[CH3:10])=[C:4]1[CH3:3]
Reactant: CI
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1c(C)cn(C)c1C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
KOH (818 mg, 14.6 mmol) was partially dissolved in DMSO (115 mL) and stirred for 5 min. 1-(2,4-dimethyl-1H-pyrrol-3-yl)-ethanone (1 g, 7.3 mmol) was added in small portions and the mixture was stirred for 45 min. Iodomethane (0.54 mL, 8.75 mmol) was added dropwise at such a rate as to maintain the internal temperature ≦30° C. The mixture was stirred for a further 45 min then poured into H2O (50 mL) and extracted with Et2O (3×60 mL). The combined organic extracts were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo to afford 1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-ethanone (1.06 g) as a pink solid. This was suspended in 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one (3.6 mL, 17.5 mmol) in a N2-flushed flask and heated at 70° C. for 36 h. The mixture was evaporated in vacuo and the residue triturated in EtOAc. The titled compound (973 mg) was obtained as a reddish solid. 1H-NMR (DMSO-d6) δ: 1.30 (s, 3H, CH3), 1.51 (s, 3H, CH3), 2.20 (br. s, 6H, CH3), 2.66 (s, 3H, CH3), 4.57 (d, 1H, J=12.5 Hz, CH), 5.53 (s, 1H, pyrrolyl-H), 6.72 (d, 1H, J=12.7 Hz, CH).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[C:18]([CH3:26])[CH:17]=1)[CH3:14].CN(CC1OC(CSC[CH2:39][NH:40][C:41]2[C:45](OC)=[N:44][S:43](=[O:49])(=[O:48])[N:42]=2)=C(C)C=1)C.CN>CO>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:45]2[C:41]([NH:40][CH3:39])=[N:42][S:43](=[O:49])(=[O:48])[N:44]=2)=[C:18]([CH3:26])[CH:17]=1)[CH3:12]
Reactant: Cc1cc(CN(C)C)oc1CSCCN
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1oc(CN(C)C)cc1C
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1oc(CN(C)C)cc1C

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamine [prepared in Step B] and the resultant 3-{2-[(5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with an excess of methylamine, the title compound is thereby produced.
Reaction SMILES: C([O:3][C:4](=O)[C@@H:5]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH:9]=1)[CH3:6])C.[BH4-].[Na+]>C(O)C>[Br:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][OH:3])[CH:17]=[CH:16]2
Reactant: CCOC(=O)[C@H](C)Oc1ccc2cc(Br)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](CO)Oc1ccc2cc(Br)ccc2c1
Yield: 96.9 %

Procedure:
Prepared according to the method described in Example 4b) from (2S)-2-(6-bromonaphthalen-2-yloxy)-propionic acid ethyl ester (12.45 g, Example 10a)) and sodium borohydride (1.6 g) in ethanol (150 ml). The crude material was purified by column chromatography over silica eluting with ethanol:dichloromethane (1:99) to give the sub-title compound as a solid (10.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][OH:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester as a brown oil, MS: 377 (M, 1Cl).
Reaction SMILES: C(OC([N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]1([C:18]([O:20]C)=[O:19])[CH2:14][CH:13]1[CH:15]([F:17])[F:16])=O)C1C=CC=CC=1.C(OC(NC1(C(OC)=O)CC1C(F)F)=O)(C)(C)C.[OH-].[Na+]>CO>[C:25]([O:24][C:22]([NH:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:14][CH:13]1[CH:15]([F:17])[F:16])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)C1(N(C(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CC1C(F)F
Agent: COC(=O)C1(NC(=O)OC(C)(C)C)CC1C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CC1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 151.3 %

Procedure:
A mixture of methyl 1-((benzyloxycarbonyl)(tert-butoxycarbonyl)amino)-2-(difluoromethyl)cyclopropanecarboxylate (1.05 g, 2.63 mmol), methyl 1-(tert-butoxycarbonylamino)-2-(difluoromethyl)cyclopropanecarboxylate (1.43 g, 5.39 mmol) in MeOH (20 mL) and sodium hydroxide (10 mL, 40.0 mmol) was stirred at rt for 18 h. The reaction mixture was concentrated and adjusted to pH=4 using 1N HCl. A white solid precipitated from the solution and was collected by filteration. The filter cake was washed with water to yield 1.2 g of the crude product as a white solid. Crystallization from hexane/EtOAc gave 1.0 g (50%) of 1-(tert-butoxycarbonylamino)-2-(difluoromethyl)cyclopropanecarboxylic acid as a white solid. This intermediate was isolated as a single diastereoisomer wherein the CF2H substituent is syn to the carboxyl group.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.[C:19]1(=O)[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21](=[O:28])[O:20]1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[C:19](=[O:20])[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]2=[O:28])=[N:2]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccccc1/C=C/c1n[nH]c2ccccc12
Yield: 47.7 %

Procedure:
To a solution of Compound 2 (50 mg, 0.21 mmol) in acetic acid (1.0 mL), 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (39 mg, 0.26 mmol) was added followed by heating under reflux for 1.0 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) and crystallized from ethyl acetate to obtain Compound 203 (37 mg, 46%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=4[C:7]=3[CH:6]=2)(=[O:4])=[O:3])[CH2:25][CH2:24]1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CN1CCNCC1
Product: CN1CCN(S(=O)(=O)c2ccc3[nH]c(=O)c4[nH]cc(C(=O)O)c4c3c2)CC1

Procedure:
8-(4-Methyl-piperazine-1-sulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is prepared according to synthesis 25, from 440 mg (0.75 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 164 μl (1.48 mmol) of 1-methyl-piperazine to give, after washing with water, 340 mg (65%) of 8-(4-methyl-piperazine-1-sulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC3CC3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2nc3c(N4CCN(CC5CC5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-4-(4-cyclopropylmethyl-piperazin-1-yl)-3-nitro-pyridin-2-ylamine (0.043 g, 0.12 mmol) and EtOH (3 ml) was added 4-methoxybenzaldehyde (0.027 g, 0.18 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was stirred at 70° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 4%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.012 g, 23%). 1H-NMR (500 MHz, DMSO-d6) 0.12 (m, 2H) and 0.50 (m, 2H) (cyclopropyl CH2), 0.90 (m, 1H, cyclopropyl CH), 2.27 (d, J=6.4 Hz, 2H, N—CH2cyclopropyl), 2.67 (br s, 4H, piperazine N(CH2)2), 3.66 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.8 Hz, 2H) and 8.14 (d, J=8.8 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H);