Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[C:5]([CH3:19])[CH:4]=2)=[CH:23][CH:22]=1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCc2ccc(F)cc2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, part D) (0.600 g, 2.33 mmol), 2-(4-fluorophenyl)ethylamine (0.325 g, 2.33 mmol) and 3 Å molecular sieves in a vial. Add methanol (11.7 mL), cap and stir overnight. Add NaBH4 (0.088 g, 2.33 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2× 25 mL), dry it over Na2SO4 and concentrate it to give the title compound (0.478 g, 54.0%): TOF MS ES+ 381.2 (M+H)+, HRMS calcd for C21H22N4O2F 381.1727 (M+H)+, found 381.1729, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=11.3 min. 97.8% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>CCOCC>[OH:9][CH2:8][C:7]1[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:11]
Reactant: COc1ccc(O)c(C=O)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Under ice cooling, the solution of 5-methoxysalicylaldehyde (5 g) in ether (20 ml) was slowly added dropwise to the suspension of LiAlH4 (0.75 g) in ether (50 ml). After stirring at room temperature for 2 hours, another addition of LiAlH4 (0.5 g) was carried out under ice cooling, with subsequent stirring at room temperature for 30 minutes. To the reaction solution was added ice carefully, followed by sequential addition of 1N HCl and ether. After filtering off insoluble materials using Celite™, the ether layer was separated from the filtrate, and then, the aqueous phase was further extracted with ether. The combined ether layers were washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was washed with ether-hexane and filtered to give the title compound (3.9 g; 77%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][C:8]([CH2:10][CH3:11])=O.C(O)C>O.[Pd]>[CH:8]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([CH2:10][CH3:11])[CH3:7]
Reactant: CCC(C)=O
Reactant: C[C@H](N)C(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCC(C)N[C@@H](C)C(=O)O

Procedure:
356 g of alanine (4 mols) is dissolved in 1.5 liters of deionized water and put into a 1-gallon autoclave. 25 g of 10% Pd on carbon, wet with water, 423 g of methylethylketone (5.85 mols) and 250 ml of ethanol are added. The autoclave is closed and hydrogenation is carried out at 90°-105° C. and 63.3-77.3 kg/cm2. A pressure drop corresponding to 83.3 kg/cm2 is observed in the course of 4 hours. The autoclave is allowed to cool overnight.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].[NH2:11][C:12]1[C:13]([C:18](O)=O)=[N:14][CH:15]=[CH:16][N:17]=1>C(OCC)C>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:18]1[C:13]1[C:12]([NH2:11])=[N:17][CH:16]=[CH:15][N:14]=1)[CH3:2]
Reactant: CCNc1ccncc1N
Reactant: Nc1nccnc1C(=O)O
Solvent: CCOCC
Product: CCn1c(-c2nccnc2N)nc2cnccc21
Temperature: 195 °C
Yield: 5.5 %

Procedure:
To polyphosphoric acid, preheated to 130° C., was added in one portion an intimate mixture of the product of Example 1 Step 2 (206 mg, 1.5 mmol) and 3-aminopyrazine-2-carboxylic acid (230 mg, 1.65 mmol). The temperature was increased to 195° C. for 1 hour and then cooled back to 130° C. for a further 1 hour. The viscous oil was poured on to ice containing saturated sodium carbonate solution and diethyl ether (5 ml) and the aqueous solution was extracted with chloroform (×5). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude solid was purified by silica gel chromatography eluting with a gradient of dichloromethane to 0.880 ammonia:ethanol:dichloromethane (1:9:40), to afford the title compound, (20 mg, 6%); MS (ES+) m/e 241 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:32][CH:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:41][CH2:42][CH:33]2[CH3:32])=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: CC1CCc2ccccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC1CCc2ccccc2N1C(=O)c1cccnc1Oc1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 18.1 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (34.1 mg, 0.12 mmol, 1.0 equiv; Example 31, Step 1) in thionyl chloride (492 mg, 300 μL, 4.14 mmol, 34.5 equiv; [CAS RN 7719-09-7]) was heated to 100° C. over night. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (155 mg, 204 μL, 1.20 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydro-quinoline (22.1 mg, 0.15 mmol, 1.25 equiv; [CAS RN 1780-19-4]) and the reaction mixture heated by microwave irradiation to 100° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9 mg (18%) of the title compound. MS (ISP): 412.9 [M+H]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH:23]([F:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1.Cl[C:32]([O:34][CH3:35])=[O:33].[Cl-].[NH4+]>O1CCCC1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([C:23]([F:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:32]([O:34][CH3:35])=[O:33])[N:18]=1
Reactant: COc1cc(OC)nc(C(F)c2ccccc2)n1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(F)(c1ccccc1)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M in hexane, 1.7 ml) was added to diisopropylamine (0.59 ml) under nitrogen in dry tetrahydrofuran (15 ml) at -78° C. This solution was stirred for 30 minutes, then a solution of the product of stage (a) above (1.0 g) in tetrahydrofuran (10 ml) was added over 20 minutes. Methyl chloroformate (0.4 g) in dry tetrahydrofuran (10 ml) was added over 15 minutes at -78° C., and the reaction mixture was allowed to warm slowly to room temperature, after which it was added to aqueous ammonium chloride solution. The mixture was extracted with ether, the extracts being washed with water, dried over magnesium sulfate, and evaporated to dryness to give 1.08 g of the desired product, identical to that of Method A above.
Reaction SMILES: C(Br)Br.[C:4](Cl)(=O)C.[C:8]1([O:17][CH3:18])[CH:16]=[CH:15][C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][CH:9]=1.CC(OC)(C)C>C(OCC)C.[Zn].Cl[Cu]>[CH:13]1([CH2:12][C:11]2[CH:15]=[CH:16][C:8]([O:17][CH3:18])=[CH:9][CH:10]=2)[CH2:4][CH2:14]1
Reactant: C=CCc1ccc(OC)cc1
Reactant: CC(=O)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: COC(C)(C)C
Solvent: BrCBr
Product: COc1ccc(CC2CC2)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 589.7 %

Procedure:
CH2Br2 (220 g) was added to a slurry of zinc powder (340 g) and CuCl (54 g) in diethyl ether (450 ml). The reaction was started by the addition of acetyl chloride (8 g). The reaction mixture was heated to 45° C. and a solution of estragol (192 g) in ether (150 ml) was added during 25 minutes. Additional CH2Br2 (456 g) dissolved in ether (150 ml) was dropped into the grey-red suspension during 45 minutes. Afterwards, the mixture was stirred at 50° C. for 12 hours. The suspension was cooled to room temperature and MTBE (900 ml) was added. The mixture was filtered through celite, and the filtrate was washed with saturated NH4Cl, water, saturated NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled (b.p. 90-95° C./0.1 Torr) to yield 97.5 g (46%) of a colorless oil, which was found to have the following characteristics, NMR and MS spectra.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:14]2[CH2:19][CH:18]([CH2:20]O)[CH2:17][N:16](/[C:22](=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15]2)[NH:9][C:10](=[O:13])[C:11]=1[OH:12])=[O:5])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH2:26]([O:25][C:23](=[O:24])[C:22]([N:16]1[CH2:17][CH:18]2[CH2:19][CH:14]([C:8]3[N:9]([C:10](=[O:13])[C:11]([OH:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=3)[CH2:20]2)[CH2:15]1)=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:27]
Reactant: CCOC(=O)/C=C(\C(=O)OCC)N1CC(CO)CC(c2nc(C(=O)OCC)c(O)c(=O)[nH]2)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C(=O)OCC)N1CC2CC(C1)c1nc(C(=O)OCC)c(O)c(=O)n1C2
Temperature: 23 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
To diethyl 2-(3-(4-(ethoxycarbonyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-5-(hydroxymethyl)piperidin-1-yl)maleate (1.05 g, 2.32 mmol) in THF at 0° C. was added triethylamine (0.975 mL, 6.99 mmol) and methanesulfonyl chloride (0.541 mL, 6.99 mmol). The reaction mixture was stirred at 23° C. for 3 hours. H2O (50 mL) was then added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. To the crude material dissolved in EtOH (40 mL) were added K2CO3 (0.643 g, 4.66 mmol) and H2O (1.7 mL). The reaction mixture was stirred at 23° C. for 36 hours. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography (Biotage flash chromatography system) using a gradient of ethyl acetate:methanol:AcOH (95:4:1) to (40:40:10) to afford 1.05 g (33% yield) of the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.83-4.26 (7 H, m), 2.68-3.40 (6H, m), 2.02 (1 H, m), 1.79-1.89 (2 H, m), 1.07-1.31 (10 H, m). LCMS (+ESI, M+H+) m/z: 450.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([NH:11][CH2:12][C:13]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:14][C:15]3([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[O:25]C)[CH2:17][CH2:16]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>ClCCl>[N:1]1[C:10]2[C:5](=[C:6]([NH:11][CH2:12][C:13]([C:28]([F:31])([F:29])[F:30])([OH:27])[CH2:14][C:15]3([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[OH:25])[CH2:17][CH2:16]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3ncccc23)C(F)(F)F)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(F)cc1C1(CC(O)(CNc2cccc3ncccc23)C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
Analogously to Example 38, 330 mg (0.76 mmol) of 1-(quinolin-5-ylamino)-3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-(trifluoromethyl)propan-2-ol is reacted with 3.80 ml (3.80 mmol) of a 1 M boron tribromide solution in 6.90 ml of dichloromethane. After 2 hours, the reaction is halted. The recrystallization from ethyl acetate and methanol yields 292 mg (91% of theory) of the product.
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)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)[N:3]=1.[CH:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([O:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH:22]4[CH2:24][CH2:23]4)[NH:19][N:18]=3)[N:3]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: OC1CCC1
Reactant: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(OC3CCC3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine and cyclobutanol to give (1-Cyclobutoxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 381(MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.O[Li].O>O1CCOCC1>[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)#[N:27]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C#N)CC1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCN(C#N)CC2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
3-[(1-cyano-piperidin-4-yl)-(4-methyl cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (150 mg, 0.32 mmol) was dissolved in a 4:1 mixture of dioxane: H2O (3.2 ml) and treated with LiOH.H2O (20 mg, 0.48 mmol). After 2 hours of stirring at 50° C., the solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (5% MeOH/CH2Cl2) to provide 3-[(1-Cyano-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (114.3 mg, 78% yield) as pale green foam. 1H NMR (DMSO-d6, 400 MHz): 7.80 (m, 2H), 7.45 (m, 4H), 4.44 (m, 1H), 3.35 (m, 2H), 3.13 (m, 2H), 1.96 (t, 1H), 1.88 (d, 1H), 1.75 (m, 1H), 1.70-1.40 (m, 6H), 1.20 (m, 3H), 0.70 (d, 3H), 0.60 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]2[CH:9]=[C:8]([O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]3[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[O:35]=[C:33]1[N:1]([C@H:2]2[C@@H:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10]3[CH:9]=[C:8]([O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]4[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=4)(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3]2)[C:8](=[O:20])[CH:7]2[CH:34]1[CH2:6]2
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N)CC3)c1
Reactant: CC(=O)Cl
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N2C(=O)C4CC4C2=O)CC3)c1

Procedure:
cis-N-(2-{[7-Amino-8-(2-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide (60 mg, 0.105 mmol) in acetyl chloride (2 mL, 28.1 mmol) was heated under reflux for 30 min. The acetyl chloride was evaporated in vacuo. The crude product dissolved in dichloromethane and washed successively with saturated sodium bicarbonate and saturated sodium chloride and dried (magnesium sulfate). The crude product was used for next step without further purification. Yield: 38 mg (colorless foam).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:44])[N:28](CO)[C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.ClC(Cl)(Cl)C#N.C(OP(=O)(O)OC(C)(C)C)(C)(C)C>C(#N)C.CCOC(C)=O.C1CCCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:44])[NH:28][C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)N(CO)C3=O)c[nH]c12
Agent: CC(C)(C)OP(=O)(O)OC(C)(C)C
Solvent: CC#N
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)NC3=O)c[nH]c12

Procedure:
To a solution of 7-{1-[1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (7.30 g, 12.30 mmol) in acetonitrile (60 mL) was added dropwise a solution of DBU (0.374 g, 0.371 mL, 2.46 mmol) in trichloroacetonitrile (17.8 g, 12.3 mL, 123 mmol) at r.t. under argon. The reaction mixture was stirred for 5 h at r.t. until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated complete conversion. The reaction mixture was evaporated to dryness at reduced pressure and the residue was suspended in acetonitrile (60 mL). Phosphoric acid di-tert-butyl ester (3.36 g, 15.99 mmol) was added and the reaction mixture was stirred for approximately 3.5 h at r.t. under argon until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated that the reaction was complete. The reaction mixture was concentrated at reduced pressure and the residue was partitioned between EtOAc and water. The layers were separated and the organic phase was washed with water (5 times). The organic phase was dried over Na2SO4 and concentrated at reduced pressure to afford a red solid. The crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80) to yield the title compound as a red solid. 1H-NMR (400 MHz, DMSO-d6): 12.03 (s, 1H), 8.08 (d, 1H), 7.70-7.65 (m, 2H), 7.47 (t, 1H), 7.11 (s, 1H), 7.11-7.07 (m, 1H), 6.77 (d, 1H), 6.44 (t, 1H), 5.97 (d, 1H), 5.39 (d, 1H), 3.49-3.08 (m, 6H), 2.39 (s, 3H), 1.45 (s, 18H), 1.41 (s, 9H), 0.87-0.56 (m, 4H). 31P-NMR (162 MHz, DMSO-d6): −12.1. LCMS: [M+1]+=786.4, Rt(1)=2.53 min., Rt(2)=1.62 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:17]=[O:18]>>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH:17]=[O:18]
Reactant: COc1ccsc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccsc1C=O
Reaction time: 1 h

Procedure:
1.03 ml of 3-methoxythiophene were dissolved in 2.3 ml of dimethylformamide. While cooling in ice, 1.06 ml of phosphoryl chloride were added. After 1 h, the reaction solution was added to ice, and the solution was neutralized with 5 molar sodium hydroxide solution. The aqueous phase was extracted 3 times with 25 ml of diethyl ether each time, and the combined organic phases were then washed with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. 840 mg of the product with the molecular mass of 142.18 (C6H7O2S) were obtained. MS (ESI): 143.0 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH2:12][N:13]=[N+]=[N-])[CH:6]=1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:12][NH2:13]
Reactant: [N-]=[N+]=NCc1cc(Cl)cc(CN=[N+]=[N-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cc(Cl)cc(CN)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
The solution of 3.50 g of 1,3-bis(azidomethyl)-5-chlorobenzene in THF (20 mL) was added slowly to the LAH (1.33 g, 35.0 mmol) suspension in THF at 0° C. The resulting reaction mixture was stirred at RT for 1 hr. and then at reflux for another hour. Slow addition of 2 mL of 5% NaOH solution resulted a precipitate, which was removed by filtration. The product on solid was rinsed off with THF. The solvent was evaporated in vacuo to yield 2.60 g of 3-(aminomethyl)-5-chlorobenzylamine. 1H NMR (500 MHz, CD3OD) δ 7.25 (s, 2 H), 7.21 (s, 1 H), 3.76 (s, 4 H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[S:10][N:11]=[C:12]2[CH:17]=[C:16]([CH:18]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:19]([O:21]CC)=[O:20])[CH:15]=[CH:14][C:13]=12.C(=O)([O-])[O-].[K+].[K+].S(=NC1C=CC=CC=1)=O.[Na]>CC(C)=O.C1(C)C=CC=CC=1.CO.C(O)(=O)C>[N:9]1[S:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18]3[C:19](=[O:21])[O:20][C:25]([OH:26])([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[C:24]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:15]=[CH:14][C:13]=12
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(CC(=O)c1ccc(OC)cc1)c1ccc2nsnc2c1
Agent: O=C([O-])[O-]
Agent: O=S=Nc1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C2(O)OC(=O)C(c3ccc4nsnc4c3)=C2Cc2ccccc2)cc1

Procedure:
0.38 g of benzaldehyde and 120 g of ethyl 2-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxyphenyl)-4-oxo-butanoate ("A"), m.p. 89°, (obtainable by reaction of 5.5 g of ethyl 2-(2,1,3-benzothiadiazol-5-yl) acetate with 5.5 g of 2'-bromo-4-methoxyacetophenone and 4 g of potassium carbonate in 200 ml of acetone, 18 hours under reflux; ethyl 2-(2,1,3-benzothiadiazol-5-yl) acetate, m.p. 40-41°, is obtained by reaction of 24.3 g of ethyl 3,4-diaminophenyl acetate and 26.9 ml of thionylaniline in 80 ml of toluene, 4 hours under reflux) are added to a solution of 80 mg of sodium in 5 ml of methanol and the mixture is heated under reflux for one hour. After addition of 5 ml of acetic acid, it is heated for a further 16 hours. The solvent is removed and the residue is worked up in the customary manner. 3-(2,1,3-Benzothiadiazol-5-yl)-4-benzyl-5-hydroxy-5-(4-methoxy-phenyl)-5H-furan-2-one, FAB 431, is obtained.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][CH:8]=[CH:9][CH:2]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>C1COCC1>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][CH:4]1[C:5](=[O:6])[O:1][CH:2]2[CH:9]=[CH:8][CH2:7][CH:3]12
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C1CC2CC=CC2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2C=CCC2C1Cc1ccc2ccccc2c1

Procedure:
Analogously to the procedure of Example 1, the title compound was prepared from 0.31 g (2.5 mmol) of 3,3a,4,6a-tetrahydro-cyclopenta[b]furan-2-one, 2.5 ml of a 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 0.55 g (2.5 mmol) of 2-(bromomethyl)-naphthalene in 10 ml of THF. Yield: 498 mg (75.4%) of a pale yellow oil (Example 21). Diastereomer mixture: 94:6 (HPLC) MS (EI): m/e=264 [M+] The separation into the diastereomers and enantiomers is carried out using preparative HPLC: Example 22, 23, 24 and 25.