Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](Cl)[N:22]=3)[N:17]=[CH:16][C:15]=2[C:25](=[O:27])[CH3:26])[CH2:9][CH2:8]1)(=O)=O.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:21]2[N:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:25](=[O:27])[CH3:26])=[C:14]3[NH:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:8][CH2:9]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(COS(C)(=O)=O)CC1
Product: CC(=O)c1cnc2ccc(N3CCCC3)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1

Procedure:
Following general procedure V, {4-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]-cyclohexyl}methyl methanesulfonate (180 mg, 0.437 mmol) was reacted with pyrrolidine (34 mg, 0.48 mmol) to afford the desired product (34 mg, 18%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 8.63 (s, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 5.57 (br s, 1H), 3.61-3.53 (m, 4H), 2.63 (s, 6H), 2.45 (d, J=7.0 Hz, 2H), 2.30-2.18 (m, 2H), 2.14-2.04 (m, 4H), 1.98-1.91 (m, 2H), 1.89-1.80 (m, 4H), 1.68-1.55 (m, 1H), 1.40-1.28 (m, 2H), 1.18-1.08 (m, 2H); ESI MS m/z 422 [M+H]+; HPLC 97.5% (AUC), tR=9.68 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][CH:7]1[C:17]2[C:18]3[CH:10]([CH:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:8]1)=[O:4]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([CH2:5][NH:6][CH:7]1[C:17]2[C:18]3[C:10](=[C:11]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: COC(=O)CNC1CCC2c3c(cccc31)NC2c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COC(=O)CNC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Yield: 53.1 %

Procedure:
A portion (360 mg) of the compound obtained in Example 146 was dissolved in chloroform (60 ml) and to the solution was added active manganese dioxide (1.44 g). The mixture was heated to reflux for 2 hours. The manganese dioxide was filtered off and the filtrate was washed with a methylene chloride/methanol mixed solvent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6:1) to yield 190 mg (53%) of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[C@H:5]([CH2:16][CH2:17][CH3:18])[CH2:4][O:3]1.Cl.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:6]4[C@H:5]([CH2:16][CH2:17][CH3:18])[CH2:4][O:3][C:2]4=[O:1])=[CH:15][CH:14]=3)=[O:13])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: CCC[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: CCC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 28.3 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(2-oxo-4-propyloxazolidin-3-yl)benzoic acid (498 mg) described in Preparation Example 79 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (239 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: COc1ccccc1N
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccccc1Nc1ncc2c(n1)CCN(C(=O)c1cccnc1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 2-methoxyaniline (0.012 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 33.5% yield (0.011 g, 0.030 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=1)[CH:22]=[O:23].O>ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[C:21]([C:20]([N+:25]([O-:27])=[O:26])=[CH:19][CH:18]=1)[CH:22]=[O:23]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(C=O)c3)c2cc1OC
Temperature: 25 °C
Yield: 66.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (200 mg) and 5-hydroxy-2-nitrobenzaldehyde (299 mg) were suspended in chlorobenzene (2 ml), and the suspension was heated under reflux for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give 3-[(6,7-dimethoxy-4-quinolyl)oxy]-6-nitrobenzaldehyde (210 mg, yield 66%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[C:17]3[CH2:16][CH2:15][C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[C:12]([CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(O)[C:11]=3[CH:10]=[CH:9][CH:8]=2)OCC[O:3]1.Cl>C(O)C>[C:2]([C:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[CH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:1]
Reactant: CN(C)CCCC1(O)c2ccccc2CCc2c(C3(C)OCCO3)cccc21
Agent: Cl
Solvent: CCO
Product: CC(=O)c1cccc2c1CCc1ccccc1C2=CCCN(C)C

Procedure:
7.8 g. of 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene are heated with 50 ml. of ethanol and 6 ml. of 25% ethanolic hydrochloric acid over a 21/2 hour period at reflux. Thereafter, the reaction mixture is concentrated under vacuum, dissolved in water, make alkaline with dilute sodium hydroxide and extracted with ether. The extract is washed with water, dried with sodium sulfate, filtered and evaporated whereby there is obtained 1-acetyl-10,11-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene as a yellow oil, whose NMR and IR spectrum are in agreement with their constitution. Through mass chromatography, it is determined that the product is a mixture of the geometric isomers α (30%) and β (70%).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[O:24])[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[5-(fur-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.96 min, MH+ 376. NMR: δH [2H6]-DMSO 9.99,(1H, s), 9.10,(1H, s), 8.83,(1H, t), 8.38,(1H, s), 8.30,(1H, d), 7.80,(2H, s), 7.75,(1H, d), 7.66,(1H, d), 7.30, (1H, d), 3.20,(2H, t), 2.31,(3H, s), 1.06,(1H, m), 0.46,(2H, m), 0.27,(2H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][C@@H:16]([O:18][CH3:19])[C@H:15]([O:20][CH3:21])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([OH:32])=[CH:27][CH:26]=2>>[CH3:21][O:20][C@H:15]1[C@H:16]([O:18][CH3:19])[CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:32][C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:22])=[CH:31]4)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: CO[C@@H]1CN(C(=O)c2cc3nccc(Cl)c3s2)C[C@H]1OC
Reactant: Cc1cc2cc(O)ccc2[nH]1
Product: CO[C@@H]1CN(C(=O)c2cc3nccc(Oc4ccc5[nH]c(C)cc5c4)c3s2)C[C@H]1OC

Procedure:
The title compound was prepared from (3R,4R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3,4-dimethoxy-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ol by a procedure analogous to Example 1F. MS 438.3 (MH+); HPLC Rf: 5.554 min.; HPLC purity: 97%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][CH2:44][C:45]#[N:46].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[C:1]([C:5]1[CH:13]=[C:12]([CH:11]=[C:7]([C:8](=[O:10])[NH:46][CH2:45][CH2:44][C:43]#[N:42])[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: N#CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C(=O)NCCC#N)cc(C(C)(C)C)c1

Procedure:
Preparation H6, Step 2: To a soultion of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (700 mg) in DMF (15 mL) at rt was added HATU (1.2 eq), 3-aminopropanenitrile (1.2 eq), and iPr2NEt (1.2 eq). The mixture was stirred at rt for 16 h before water and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to provide methyl 3-tert-butyl-5-((2-cyanoethyl)carbamoyl)benzoate as a glassy solid (520 mg). MS found: (M+H)+=289.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.CCCCCC>C(O)C>[C:1]([C:3](=[CH:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][OH:9])=[CH:20][CH:19]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(C#N)=Cc1ccc(OCCO)cc1
Temperature: 25 °C

Procedure:
Ethyl cyanoacetate (1.1 eq.) and 4-(2-hydroxyethoxy)benzaldehyde (1 eq.) were combined in ethanol (1.2 M). The reaction mixture was stirred at RT for 48. To this was then added an equal volume of hexane and the title compound was isolated by filtration as a pale yellow solid.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:19][C:20](=[O:21])[CH3:22]
Reactant: Cc1ccccc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C=Cc1ccccc1C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
In a 250 ml single neck flask was charged 12.0 g (100 mmoles,1.0 eq) of o-tolualdehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.8 g of 4-(o-tolyl)-3-buten-2-one as a faintly yellow oil in 86.3% yield.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])[N:8]=1>Cl.CO>[Br:1][C:2]1[N:3]=[C:4]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])[N:8]=1
Reactant: C[C@@H](CNc1nccc(-c2c(Br)nc(C3CCC3)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](N)CNc1nccc(-c2[nH]c(C3CCC3)nc2Br)n1
Temperature: 80 °C
Yield: 151.4 %

Procedure:
A mixture of ((S)-tert-butyl 1-(4-(4-bromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (0.27 g, 0.47 mmol) in concentrated HCl (0.14 mL) and MeOH (4 mL) was heated to 80° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated to a yellow solid to afford the crude (S)—N1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (0.25 g) as the HCl salt which is used in next step without purification: LCMS (m/z) 351.0 (MH+), tR=0.45 minute.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
To a solution of 4-nitrobenzaldehyde (2.0 g, 0.133 mol) in acetic acid (150 mL) and water (15 mL) was added iron powder (1.48 g, 0.265 mol). The reaction was stirred overnight at room temperature. The mixture was filtered and extracted with dichloromethane (50 mL×3). Then the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% ethyl acetate in petroleum ether) to afford 1.2 g of the pure product (yield was 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CO[C:22](OC)([N:24]([CH3:26])[CH3:25])[CH3:23]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[C:22]([N:24]([CH3:26])[CH3:25])[CH3:23])[C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1Cl
Reactant: COC(C)(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2C(=O)C(=C(C)N(C)C)c3ccccc32)cc1Cl
Yield: 94.4 %

Procedure:
1-(3-Chloro-4-methoxyphenyl)-2(1H,3H)-indolone (0.67 g, 2.45 mmole), dimethylacetamide dimethylacetal (90%, 0.45 ml, 2.7 mmole) and 10 ml CHCl3 were refluxed under nitrogen for 3 hours. The reaction mixture was cooled and evaporated in vacuo to a viscous oil. The oil was column chromatographed on silica gel, eluting impurities with ethyl acetate and then product with 2-4% methanol in ethyl acetate, initially isolated as an oil (793 mg). Crystallization from ether gave purified title product, 625 mg, m.p. 138°-141°.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][NH:3]1.[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O1CCCC1.C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:7]1([S:13]([N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1NCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1S(=O)(=O)c1ccccc1

Procedure:
86 parts by weight of 2-oxo-imidazolidine, 194 parts by weight of benzenesulphonyl chloride, 800 parts by volume of tetrahydrofurane, 500 parts by volume of chloroform and 101 parts by weight of triethylamine were stirred overnight at 50°C and subsequently evaporated to dryness in vacuo. The residue was gradually added, while stirring, to 1,000 parts by volume of ice water, the mixture was filtered and the residue was recrystallized from ethanol.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C[O:54][C:55]([C:57]1([CH2:60][NH:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=2)[CH2:59][CH2:58]1)=O.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][N:61]2[C:19](=[O:21])[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)=[C:55]([OH:54])[C:57]3([CH2:58][CH2:59]3)[CH2:60]2)=[CH:68][CH:67]=1
Reactant: COC(=O)C1(CNCc2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Agent: CC[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)C3(CC3)CN(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 17 h
Yield: 13.4 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.074 g, 0.209 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.088 g, 0.231 mmol) and 4-methylmorpholine (0.046 mL, 0.418 mmol) were added sequentially to a solution of 1-[(4-fluoro-benzylamino)-methyl]-cyclopropanecarboxylic acid methyl ester (0.050 g, 0.211 mmol) in N,N-dimethylformamide (3 mL) at 25° C. The reaction mixture was stirred at 25° C. for 17 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (5 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.271 mL, 0.836 mmol) was added and the reaction mixture was heated to 60° C. for 24 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 60-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) N-{3-[5-(4-fluoro-benzyl)-8-hydroxy-6-oxo-5-aza-spiro[2.5]oct-7-en-7-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.015 g, 0.028 mmol, 13%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.80-0.90 (2H, m), 1.20-1.26 (2H, m), 2.95 (3H, s), 3.31 (2H, bs), 4.23 (2H, d, J=6.1 Hz), 4.61 (2H, s), 7.14-7.18 (3H, m), 7.32-7.36 (2H, m), 7.61 (1H, t, J=5.4 Hz). LC-MS (ESI) calculated for C21H21FN4O6S3 540.06. found 541.1 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)=[N:15][C:16]=2[NH2:25]
Reactant: COc1nc2nc(OC3CCCC3)[nH]c(N)c-2n1
Reactant: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC3CCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclopentyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[S:2].[CH3:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>CO.C(Cl)Cl>[P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[N:30][NH:29][C:27](=[O:28])[C:26]2[CH:31]=[CH:32][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH:15]=1)([O:3][CH2:4][CH2:5][CH2:6][CH3:7])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[S:2]
Reactant: Cc1ccc(C(=O)NN)cc1
Reactant: CCCCOP(=S)(OCCCC)Oc1cccc(C=O)c1
Solvent: CO
Solvent: ClCCl
Product: CCCCOP(=S)(OCCCC)Oc1cccc(C=NNC(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O,O-dibutyl O-(3-formylphenyl) thiophosphate (0.02 mole) in methanol (50 ml) and 4-methylbenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product O,O-dibutyl O-[3-(4-methylbenzoylhydrazonomethyl)phenyl] thiophosphate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([NH2:21])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:22](COCC[Si](C)(C)C)[N:23]=[C:24]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])[CH2:28][CH2:27]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([NH2:21])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:22][N:23]=[C:24]([NH:25][CH:26]3[CH2:27][CH2:28][N:29]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])[CH2:30][CH2:31]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2nc(-c3c(F)cccc3F)c3cc(C(N)=O)ccc3c21
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(=O)(=O)C(F)(F)F)CC3)n[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
A 50 ml round-bottom flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 300 mg of 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide in 8 ml of DCM. 3 ml of TFA are added and the mixture is stirred at RT for 2 h. It is concentrated under RP and the solid obtained is taken up in 30 ml of water and 2 ml of 0.75M aqueous ammonia solution. The product is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. Chromatography on silica gel (15-40 μm), eluting with AcOEt, gives 30 mg of 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide (pale yellow solid). MS (E/I): m/z=554 (M+); 1H NMR: 1.69 (m, 2H); 2.17 (m, 2H); 3.38 (m, 2H); 3.83 (m, 2H); 3.93 (m, 1H); 6.24 (m, 1H); 7.33 (t, J=8.0 Hz, 2H); 7.58 (broad s, 1H); 7.69 (m, 1H); 8.17 (broad s, 1H); 8.23 (broad s, 1H); 8.36 (broad d, J=8.5 Hz, 1H); 8.44 (d, J=8.5 Hz, 1H); 12.9 (broad s, 1H).
Reaction SMILES: [ClH:1].[CH2:2]=O.Cl.Cl.[CH3:6][C:7]1[CH:8]=[C:9]([CH2:16][N:17]2[C:21]([CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24])=[CH:20][N:19]=[CH:18]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>>[ClH:1].[ClH:1].[CH3:6][C:7]1[CH:8]=[C:9]([CH2:16][N:17]2[C:21]3[CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH:24][CH2:2][C:20]=3[N:19]=[CH:18]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: C=O
Reactant: Cc1cc(Cn2cncc2C[C@H](N)C(=O)O)ccc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)O)NC3)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A 1N hydrochloric acid solution (13.7 ml) and a 37% formaldehyde solution (0.74 ml, 0.00907 mol) were added to 3-(3-methyl-4-nitrophenyl)methyl-L-histidine dihydrochloride (VIII-2) (1.1406 g, 0.00302 mol), and the mixture was stirred first at room temperature for half an hour and then on a 120° C. oil bath for 1.5 hours. The mixture was then cooled and concentrated to obtain the objective compound (VII-2) (1.1538 g; yield: 98.0%) as yellowish brown crystals (decomposed at 256.5°-258° C).