Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([SH:22])[CH:19]=[CH:20][CH:21]=1>C(O)C.[O-]CC.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][S:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OCC)c1ccc(Cl)cc1
Reactant: Sc1cccc(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(CSc1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of the ethyl 4-chlorophenyl-α-methyleneacetate (4.2 g), m-chlorothiophenol (2.9 g) and sodium ethoxide (0.05 g) in ethanol (20 ml) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water (150 ml) to the residue, and the mixture was extracted with ether (150 ml). The extract was washed two times with 15% aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the resulting residue were added 88% formic acid (20 ml) and methanesulfonic acid (2.1 ml), followed by heating at reflux for 8 hours. After cooling to room temperature, the mixture was poured into water (100 ml) and extracted with dichloromethane (150 ml). The aqueous layer was further washed with dichloromethane (50 ml), and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was subjected to chromatography on silica gel to give 4-chlorophenyl-α-[(3-chlorophenyl)thiomethyl]-acetic acid (yield, 5.3 g), nD23.6, 1.5627
Reaction SMILES: [Mg].[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>O1CCCC1>[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:18]([OH:23])[OH:19])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)cc1
Reaction time: 8 h
Yield: 94.9 %

Procedure:
2.40 g (99.0 mmol) of magnesium and 25.56 g (89.6 mmol) of 4-octyloxybromobenzene in 250 ml of tetrahydrofuran are used to prepare, at 60° C. for 3 hours, the solution of the Grignard compound, which is added dropwise to a solution, cooled to -70° C., of 18.62 g (99.00 mmol) of triisopropyl borate in 100 ml of tetrahydrofuran, and the mixture is stirred overnight. 130 ml of 10% strength hydrochloric acid are subsequently added dropwise, the mixture is stirred at room temperature for 1 hour and partitioned between sodium chloride solution and ether, and the organic phase is washed with sodium chloride solution, dried over sodium sulfate and evaporated, giving 21.26 g of 4-octyloxybenzeneboronic acid. ##STR14##
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18].O>C1COCC1>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH2:20][CH2:21][O:22][CH2:23][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc2cccnc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc2cccnc2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H-1) (528 mg, 3 mmol) in dried THF (5 mL) at 0° C. was added NaH (240 mg, 6 mmol). The reaction was stirred for 0.5 h under N2, and then SEMCl (526 mg, 3 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. H2O was added to quench the reaction. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated to afford the title compound (750 mg), which was used for the next step without purification. MS (m/z): 307 (M+1)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(C#N)=NOS(=O)(=O)c2ccc(Cl)cc2)cc1OC

Procedure:
As described under 1.2, 10.3 g (0.05 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 12.2 g (0.055 mol) of 4-chlorobenzenesulfonic acid chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/hexane, 15.9 g (84%) of α-(4-chlorophenyl-sulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of yellowish crystals having a melting point of 145.5-148.5° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 350 nm (ε=11660) that extends to 437 nm. Elemental analysis: C16H13ClN2O5S (380.80)
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH2:25][CH3:26])[C:5]([CH2:7][O:8][C:9](=[O:23])[CH2:10][CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)=[O:6])[CH2:2][CH3:3].C(OC(C)C)(=O)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>[Pd]>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH2:24]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][O:8][C:9](=[O:23])[CH2:10][CH2:11][NH2:12])=[O:6])[CH2:25][CH3:26]
Reactant: CCCN(CCC)C(=O)COC(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)COC(=O)CCN
Temperature: 20 °C
Reaction time: 3.5 h

Procedure:
A solution of 3-benzyloxycarbonylamino-propionic acid dipropylcarbamoylmethyl ester in isopropyl acetate (33.2 g, 91.0 mmol in 129.9 g total mass of solution) was treated with TFA (7.05 ml, 92.0 mmol) while the internal temperature was maintained at 20° C., followed by 10% Pd/C (3.3 g, 50% wet) and stirred under an atmosphere of H2 (3 atm) for 3.5 h to afford 3-amino-propionic acid dipropylcarbamoylmethyl ester trifluoroacetate. The solution was used directly in the next reaction without isolation.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([Cl:31])=[C:17]([NH:23]C(=O)OC(C)(C)C)[CH:18]=[C:19]([C:21]#[N:22])[CH:20]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[NH2:23][C:17]1[CH:18]=[C:19]([CH:20]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:14][CH2:13]2)[C:16]=1[Cl:31])[C:21]#[N:22]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
(I13B): To a round bottom flask charged with tert-butyl (3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (I13A) (3.27 g, 7.02 mmol) in dichloromethane (35.1 ml) and cooled to 0° C. was added 2,6-lutidine (2.451 ml, 21.05 mmol). Trimethylsilyl trifluoromethanesulfonate (3.80 ml, 21.05 mmol) was added dropwise over 5 min. After 1 h, the reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate and dichloromethane. The mixture was transferred to a separatory funnel and the aqueous layer was extracted with dichloromethane (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on the Isco system (120 g, 0-50% EtOAc/CH2Cl2). 3-amino-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-4-chlorobenzonitrile (I13B) (1.892 g) was isolated as a sticky yellow oil.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:16]=[CH:15]1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1([C:16]2[C:17]3[C:22](=[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CS(=O)(=O)Nc1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(c2c[nH]c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 84.3 %

Procedure:
Combine 1-ethyl-5-fluoro-indan-1-ol (502 mg, 2.79 mmol, 1.30 equivalents), N-(1H-Indol-7-yl)-methanesulfonamide (450 mg, 2.14 mmol, 1.00 equivalents), and trifluoroacetic acid (0.25 ml, 3.21 mmol, 1.50 equivalents) in dichloromethane (5 ml) and stir at room temperature under nitrogen overnight. Load the solution on silica and purify eluting with 0 to 100% ethyl acetate/hexanes over 25 minutes to obtain the title compound (672 mg, 84%). LC-MS m/z 373.0 (M++1). The racemic mixture is separated on a Chiralcel OJ 8×33 cm column eluting with methanol with 0.2% dimethylethylamine (flow: 375 ml/min, UV detection at 230 nm) to provide the individual enantiomers, Examples 1A and 1B, in 96.3% ee and 97.4% ee, respectively.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH2:24]([N:29](CCCCC)[C:30](=O)[C:31]1C=C(C=O)[CH:34]=[CH:33][C:32]=1OC)[CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:30]([N:29]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:11](=[O:13])[C:10]1[CH:14]=[C:15]([CH:18]=[O:19])[CH:16]=[CH:17][C:9]=1[O:8][CH2:7][C:6]1[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)c(C(=O)O)c1
Reactant: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OC
Product: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OCc1ccc(C(F)(F)F)cc1

Procedure:
N,N-Di-n-pentyl-2-(4-trifluoromethylbenzyloxy)-5-formylbenzamide was prepared from 2-(4-trifluoromethylbenzyloxy)-5-formylbenzoic acid (300 mg, 1 eq) using the same procedure as for N,N-di-n-pentyl-2-methoxy-5-formylbenzamide. The product was obtained as a pale brown oil (424 mg, 99%). 1H NMR (CDCl3) δ9.88 (s, 1H, O═C—H), 5.21 (s, 2H, CH2Ar), 3.72 (m, 1H, NCH2), 3.20 (m, 1H, NCH2), 3.05 (m, 2H, NCH2).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[OH:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35]>>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:9]2[N:10]=[C:11]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:6]3[S:5][C:4]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:34](=[O:35])[C:33]([OH:32])([CH3:38])[CH3:37])[CH2:28][CH2:27]4)=[C:3]([CH3:2])[C:7]=3[N:8]=2)=[CH:23][N:22]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)C(C)(C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 65.6 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 40 mg 2-hydroxy-2-methylpropanoic acid via General Procedure B to give 58.3 mg of 357 after reverse phase HPLC purification. MS (Q1) 513.3 (M)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C@@H:6]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([CH3:20])[O:13][C@H:8](OC(=O)C)[C@@H:7]1[O:21][C:22](=[O:24])[CH3:23])=[O:4].[BrH:27].C(O)(=O)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C@@H:6]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([CH3:20])[O:13][C@H:8]([Br:27])[C@@H:7]1[O:21][C:22](=[O:24])[CH3:23])=[O:4]
Reactant: CC(=O)O[C@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](NC(=O)C(F)(F)F)[C@H]1OC(C)=O
Reactant: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1[C@H](NC(=O)C(F)(F)F)[C@H](OC(C)=O)[C@H](C)O[C@@H]1Br
Reaction time: 2 h
Yield: 92 %

Procedure:
The residue obtained from the reaction mixture by evaporation in vacuo, which consists of 3-trifluoroacetamido-1,2,4-tri-O-acetyl-3,6-dideoxy-β-L-talopyranose, is dissolved in 20 ml. of a 30% hydrogen bromide-acetic acid solution. After being kept for 2 hours at room temperature, 200 ml. of chloroform is added to the reaction mixture and the chloroform solution is washed with ice and water, a cold saturated sodium hydrogen carbonate solution, and water. The solution is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to heavy syrup. The syrup is crystallized by adding ether, and recrystallization from a mixture of chloroform-ether gives 16 g. (92% yield) of 3-trifluoroacetamido-2,4-di-O-acetyl-3,6-dideoxy-β-L-talopyranosyl bromide.
Reaction SMILES: [CH:1]([N:3]([CH2:16][C:17](=O)[CH3:18])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])=O.C([O-])(=O)C.[NH4+:24].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[N:3]1[CH:16]=[C:17]([CH3:18])[N:24]=[CH:1]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A mixture of methyl 4-[formyl(2-oxopropyl)amino]-3-methoxybenzoate (32.6 g) and ammonium acetate (47.5 g) in acetic acid (65.6 mL) was stirred at 140° C. for 1 hr. After completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added under ice-cooling, and the organic layer was separated. To the aqueous layer was added ethyl acetate, and the organic layer was separated. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane) to give the title compound (16.0 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:56])=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(C)c2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(C)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.50 g) in methylene chloride (15 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.17 g) in methylene chloride (10 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 228) (151 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15]C.[CH:32]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(C)=C(C3C=CC(Cl)=CC=3Cl)N=2)CC1>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])=[N:13][C:14]([CH3:15])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:32][CH2:31]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.87-1.07, 1.18-1.23, 1.82, 2.27, 3.10-3.16, 3.47-3.57, 3.66-3.76, 4.40, 5.83, 5.98, 7.25-7.50; MS (ESI+) for C25H25Cl2N3O m/z 454 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]1[S:9](=[O:11])(=[O:10])[O:8][CH2:7][CH2:6]1>CO>[OH:2][CH2:1][CH2:3][NH:4][CH2:7][CH2:6][CH2:5][S:9]([OH:11])(=[O:10])=[O:8]
Reactant: NCCO
Reactant: O=S1(=O)CCCO1
Solvent: CO
Product: O=S(=O)(O)CCCNCCO
Reaction time: 2 h

Procedure:
N-(β-hydroxyethyl)-3-aminopropanesulfonic acid, ##STR9## was prepared as follows: 366 parts ethanolamine and 1000 parts methanol were cooled to 10° C. in a three-necked, round-bottom flask which was fitted with a stirring bar, thermometer, and a dropping funnel. 244 parts propane sultone dissolved in 1000 parts methanol were added via the dropping funnel at such a rate that the flask temperature did not increase above 20° C. After the addition was completed, the contents of the flask were stirred for two hours, concentrated to a thick slurry, and then added to 2400 parts isopropyl alcohol. The resulting solid was filtered, rinsed with 500 parts isopropyl alcohol and dried to give 240 parts of the desired product.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=O)[CH2:6]2)[CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C1(C)C(C)=CC=CC=1>O>[N:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:7](=[O:9])[CH2:6][C:4]3([CH2:3][CH2:2][CH2:1][CH2:5]3)[CH2:12][C:10]2=[O:11])=[CH:15][CH:16]=1
Reactant: Nc1ccncc1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CC2(CCCC2)CC(=O)N1c1ccncc1

Procedure:
The starting material is prepared as follows: The mixture of 200 g of 3,3-tetramethyleneglutaric anhydride, 57 g of 4-aminopyridine and 1,500 ml of xylene is stirred and refluxed on a water separator for 3 days. After cooling slightly, the xylene solution is decanted from a small amount of oily material, and after cooling in an ice bath, the collected residue dissolved in 1,500 ml of boiling ethanol, the solution cooled to 5°, filtered and the residue dried, to yield the 8-(4-pyridyl)-8-azaspiro[4,5]decan-7,9-dione melting at 208°-211°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)propylamine (243 mg, 0.90 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (210 mg, 0.90 mmol) and DIPEA (780 μL, 4.5 mmol) in n-butanol (3 mL) was heated at 100° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 205 (145 mg, 42%). LCMS (Method K): RT 2.96 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.65 (1H, s), 8.81 (1H, d, J=2.47 Hz), 8.67 (1H, br s), 8.21-8.01 (3H, m), 7.91 (1H, br s), 7.73 (1H, dd, J=8.81, 4.84 Hz), 7.56 (1H, br s), 7.18-7.08 (1H, m), 6.95 (1H, dd, J=8.88, 2.48 Hz), 5.35 (1H, br s), 2.19-2.01 (2H, m), 0.90 (3H, t, J=7.32 Hz)
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16]#[N:17])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[CH3:18][OH:19].[ClH:20]>ClCCl>[ClH:20].[CH3:18][O:19][C:16](=[NH:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1
Reactant: N#CCc1ccc2c(c1)Nc1nccnc1S2
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: COC(=N)Cc1ccc2c(c1)Nc1nccnc1S2
Temperature: -20 °C

Procedure:
480 mg of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetonitrile was suspended in a solution of dry methanol (20 ml)/dry dichloromethane and cooled to −20° C. Then dry hydrogen chloride gas was blown thereinto until saturation was attained while paying attention lest the bulk temperature exceed 0° C. Then the reaction mixture was hermetically sealed and allowed to stand under ice-cooling over day and night. Next, the solvent was distilled off under reduced pressure while maintaining the bulk temperature at room temperature or below. Then a small amount of dry methanol was added to the residue and ethyl acetate was gradually added thereto under ultrasonication. The orange crystals thus precipitated were taken up by filtration, washed with diethyl ether and dried under reduced pressure. Thus, 570 mg of the title compound was obtained.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][C:12]([CH:14]1[CH2:18][CH2:17][N:16](C=C)C1=O)=O>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][C:12]1[CH2:14][CH2:18][CH2:17][N:16]=1
Reactant: C=CN1CCC(C(=O)Cc2c(Cl)cccc2Cl)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Clc1cccc(Cl)c1CC1=NCCC1

Procedure:
To a mixture of water (45 ml) and HCl conc. (45 ml) at reflux temperature was added dropwise during 15 minutes a solution of 3-[2-(2,6-dichloro-phenyl)-acetyl]-1-vinyl-pyrrolidin-2-one (2.98 g; 10 mmol), which was prepared as described in example P19, in THF (25 ml). The solution was concentrated to dryness on a rotary evaporator. The residue was dissolved in dichloromethane (20 ml), washed with water (2×30 ml) and dried over Na2SO4 and filtered through silicagel (5 g). After removal of the solvent 2.60 g (>100% of theory) of 5-(2,6-dichloro-benzyl)-3,4-dihydro-2H-pyrrole was obtained in form of a brown liquid.