Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[OH:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([O:11][Si:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10].C(N(CC)CC)C>C(OCC)C>[Cl:4][C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([O:11][Si:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([CH3:16])([CH3:14])[CH3:15])=[O:10])=[S:2]
Reactant: CC(C)(C)[Si](OC(=O)c1cccc(O)c1)(c1ccccc1)c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC(=O)c1cccc(OC(=S)Cl)c1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 130 ml of thiophosgene in 250 ml of dry diethyl ether at -78° C. was added dropwise a mixture of 72 g of diphenyl- (2-methylprop-2-yl)silyl 3-hydroxybenzoate and 29 ml of triethylamine in 200 ml of dry diethyl ether. The mixture was stirred at -78° C. for 30 minutes, at room temperature for 120 minutes, and then partitioned between diethyl ether and water. The organic layer was washed with cold water and with brine, and was dried over anhydrous calcium chloride. Evaporation in vacuo, and repeated addition of dry diethyl ether and re-evaporation in vacuo afforded 86.5 g of the title compound as a viscous orange oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:10]#N)=[CH:6][C:7]=1C#N.[H-].C([Al+]CC(C)C)C(C)C.[CH3:22][OH:23].S(=O)(=O)(O)[OH:25]>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[S:4][C:5]([CH:10]=[O:25])=[CH:6][C:7]=1[CH:22]=[O:23]
Reactant: CSc1sc(C#N)cc1C#N
Reactant: O=S(=O)(O)O
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CSc1sc(C=O)cc1C=O
Reaction time: 2 h

Procedure:
To a suspension of 7.20 g of 2-methylthio-3,5-dicyanothiophene, obtained according to Example IV (a), in 120 ml of dry toluene is added, while stirring and under a nitrogen blanket, 75 ml of a 20% solution of diisobutyl aluminumhydride in toluene. The reaction mixture is stirred for two hours, after which 12 ml of methanol is added under cooling in ice. The reaction mixture is stirred in ice plus conc. sulphuric acid till a clear solution. The toluene phase is separated and the water phase washed twice with toluene. The combined organic phase is washed with water, dried, filtered and evaporated. The residue is recrystallized from ethanol yielding 2-methylthio-3,5-diformylthiophene in a quantity of 3.0 g; melting point 135°-137° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[ClH:10].[CH2:11](O)[CH3:12]>>[ClH:10].[OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH2:11][CH3:12])=[O:8])[CH2:3]1
Reactant: CCO
Reactant: O=C(O)[C@@H]1CC(O)CN1
Agent: Cl
Product: CCOC(=O)[C@@H]1CC(O)CN1
Yield: 95 %

Procedure:
A slurry of 100 g (760 mmol) of 4-hydroxy-L-proline in 600 mL of absolute ethanol was treated with dry hydrogen chloride until homogeneous. The solution was heated to the reflux temperature for 2 h. Upon cooling in the refrigerator, the product was obtained as white needles which were filtered, washed well with ether, and dried under reduced pressure to yield 141 g (95%) of (5): mp 153°-153.5° C. (lit. mp-147°-148° C.). 1H NMR (DMSO d6) δ1.25 (t, 3H, J=7 Hz), 4,20 (q, 2H, J=7 Hz). 13C NMR (D2O) 24.1, 47.1, 63.6, 68.7, 73.8, 79.1, 177.5; IR (KBr) 3320, 1735 cm-1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[C:2]=1[NH2:12].[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[NH:12]1[C:2]2[CH:1]=[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][C:3]=2[NH:11][C:14](=[O:15])[C:13]1=[O:17]
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc2ccccc2cc1N
Agent: Cl
Product: O=c1[nH]c2cc3ccccc3cc2[nH]c1=O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A mixture of 603 mg (3.81 mmol) of 2,3-naphthalenediamine and 382 mg (4.24 mmol) of oxalic acid in 5 mL of 2N HCl was refluxed for 3 h and cooled to room temperature. The mixture was filtered, washed with water, and dried to leave a brown solid 803 mg (99%); mp>250° C.; 1H NMR (DMSO-d6), 7.382 (dd, 2, J=3.16, 6.17), 7.525 (s, 2), 7.815 (dd, 2, J=3.22, 6.18), 12.088 (s, 2).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:28][C:29]1[CH:56]=[CH:55][CH:54]=[CH:53][C:30]=1[CH2:31][N:32]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52])[C@@H:33]([CH2:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=1)[CH:34]=[O:35]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C@@H:34]([OH:35])[C@@H:33]([N:32]([CH2:31][C:30]1[CH:53]=[CH:54][CH:55]=[CH:56][C:29]=1[CH3:28])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@H](C=O)Cc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)n1cccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)c1cccn1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Add n-butyllithium (3.30 mL, 8.25 mmol, 2.5 M in hexanes) to a solution of 2,2,6,6-tetramethylpiperidine (1.40 mL, 8.18 mmol) in tetrahydrofuran (THF) (30 mL) at −78° C. over 2 min. Stir 5 min, then warm to −10° C. and stir 5 min, then cool to −78° C. Add N-tert-butoxycarbonylpyrrole (1.37 mL, 8.25 mmol) in THF (1.6 mL) over 3 min. Stir 30 min and add 2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-propionaldehyde (2.96 g, 7.44 mmol) in THF (15 mL) over 5 min. Stir 60 min at −78° C., warm to 0° C. and stir 60 min. Cool −78° C. and quench with saturated aqueous ammonium chloride solution. Extract with ethyl acetate, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and dichloromethane) to give the title compound as a foam (0.416 g, 10%).
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][C:5]=1Cl)(=[O:3])[CH3:2].[OH-:33].[Na+].[CH3:35]O>>[C:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][C:5]=1[O:33][CH3:35])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: CO
Agent: [Na+]
Product: COc1nc(-c2ccccc2)n(Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C(C)=O

Procedure:
760 mg of 4′-(5-acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamide and 650 mg of NaOH are refluxed for 22 h in 10 ml of methanol. The solvent is then removed in vacuo, the residue is taken up in 20 ml of water, and the solution is adjusted to pH=6 using a 10% aqueous HCl solution and extracted 3 times using 50 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using MTB/DIP 1:1 yields 230 mg of a viscous oil.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:14][CH2:13][N:12]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH2:11][CH2:10]1)C.[Li+].[OH-]>C(O)C>[C:19]([CH2:18][N:15]1[CH2:14][CH2:13][N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:34])=[O:3])[CH2:17][CH2:16]1)([OH:21])=[O:20]
Reactant: CCOC(=O)CCCCN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCN1CCN(CC(=O)O)CCN(CC(=O)O)CC1

Procedure:
The ethanol (0.6 mL) liquid of the 4,7-bis(tert-butoxycarbonyl methyl)-1,4,7-triazonane-1-pentanoic acid ethyl ester (0.036 g, 0.0741 mmol) prepared at Step 1 was added with LiOH (0.0053 g, 0.222 mmol), and allowed to react at 50° C. for 24 hr. After confirming the conclusion of the hydrolysis reaction with the ESI-MASS, the reaction mixture was filtered through the Whatman syringe filter (0.45 μm) and dried under reduced pressure. The product was separated with RP-HPLC (10 mM HCl/EtOH; concentration increase from 0 to 40% for 20 min), and the filtrate underwent lyophilization to give final product.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[OH:31])[CH:26]=O)[CH3:21].[OH-].[Na+]>C(Cl)Cl.O>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:26][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:28]=[CH:29][C:30]=1[OH:31])[CH3:21]
Reactant: C1CCNC1
Reactant: CCOc1cc(C=O)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(CN2CCCC2)ccc1O
Yield: 72.3 %

Procedure:
NaB(OAc)3H (8 g, 0.038 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.1 mL, 0.038 mol) and 3-ethoxy-4-hydroxybenzaldehyde (5 g, 0.03 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 12 h and cooled with an ice bath. 10N NaOH (3.8 mL) and water (30 mL) were added. The organic layer was separated. The aqueous one was extracted with chloroform (2×100 mL). The extracts were evaporated. The residue was purified by chromatography (silica gel 40-63μ, 100 g, CCl4—CHCl3, CHCl3/MeOH 100:0→90:10) to give the title compound (4.8 g, 73%) was obtained as dark-yellow crystals. 1H NMR data (DMSO-d6): 8.65 (s, 1H ArOH), 6.81 (d, 1H, J=1.71, Ar—H), 6.70 (d, 1H, J=7.8, Ar—H); 6.65 (dd, 1H, J1=7.8, J2=1.7, Ar—H), 3.98 (q, 2H, CH2CH3), 3.42 (s, 2H, ArCH2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N), 1.59-1.73 (m, 4H, CH2CH2CH2CH2); 1.31 (t, 3H, J=6.9, CH2CH3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[C:36]([C:37]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)OCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 572.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][C:20]3=[O:21])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:40])C=1.C(=O)([O-])O.[Na+]>ClCCl>[O:40]1[CH2:5][CH:4]1[CH2:3][CH2:2][CH2:1][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][C:20]3=[O:21])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(OCCCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
1-{1-[4-(4-Pentenyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) is dissolved in dichloromethane (50 ml) and thereto is added gradually m-chloroperbenzoic acid (1.6 g) at room temperature. The mixture is stirred under the same conditions overnight and the reaction mixture is poured into aqueous sodium hydrogen carbonate solution and the mixture is extracted with chloroform and dried with magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give 1-{1-[4-(3-oxiranylpropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.5 g).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1)=[O:20]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1Cc2cccc3c2N1CCC3
Product: O=C(CCCCCl)c1cc2c3c(c1)CC(=O)N3CCC2
Yield: 64.9 %

Procedure:
Using 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (3.46 g) and 5-chlorovaleryl chloride (3.4 g) according to the same method as that of Reference Example 1, the title compound (3.78 g) was obtained as pale yellow crystals having a melting point of 89 to 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]([O:16]CC)=[O:15])=[CH:11][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C#N)c2)c(-c2cc(F)cc(Cl)c2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(-c2cc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg (0.34 mmol) of the compound from Example 11A are provided in 6.1 ml of tetrahydrofuran, and 80.7 mg (3.37 mmol) of lithium hydroxide and 2.0 ml of water are added at room temperature. The mixture is stirred at room temperature overnight, a 1N aqueous HCl solution is subsequently added until an acidic pH is obtained, the mixture is extracted with ethyl acetate and the extract is dried over sodium sulfate, filtered and concentrated. 119 mg (89% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][NH2:11])=[CH:6][CH:5]=1)=[O:3].[O:14]1[CH:16]([CH2:17][O:18][C:19]2[S:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH3:32])=[O:25])=[CH:22][N:23]=2)[CH2:15]1>C(O)C>[NH2:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][NH:11][CH2:15][CH:16]([OH:14])[CH2:17][O:18][C:19]2[S:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH3:32])=[O:25])=[CH:22][N:23]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: NCCOc1ccc(C(N)=O)cc1
Reactant: CCC(C)CCCNC(=O)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: CCC(C)CCCNC(=O)c1cnc(OCC(O)CNCCOc2ccc(C(N)=O)cc2)s1

Procedure:
This example illustrates further methods according to the invention of preparing further compounds of formula I of the invention. In this example 1 g. of β-(4-aminocarbonylphenoxy)-ethylamine (Cox et al, J. Med. Chem., v. 16, No. 11 (1973) is added to a solution containing 0.4 g. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20° C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of the 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue which is then further purified by thin-layer chromatography on silica gel yielding 1-[β-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(OCC)=O)C.[H-].[Na+].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O>C1COCC1>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1/[CH:32]=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Reactant: O=Cc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of methyl 4-[(diethoxyphosphoryl)methyl]benzoate (916 mg, 3.20 mmol; see Preparation 4(i) above) in THF (20 mL, dry) under nitrogen atmosphere was added a sodium hydride (520 mg, 60% dispersion in oil, 13.00 mmol) at 0° C. 2-Naphthaldehyde (500 mg, 3.20 mmol) was dissolved in THF (10 mL, dry) then added dropwise to the reaction mixture at 0° C. under N2 and the reaction mixture stirred at room temperature for 1 h followed by quenching with water. The pH level of the mixture was adjusted to pH 4 by the dropwise addition of HCl(conc.) with stirring at 0° C. TLC analysis showed that it was the required product (282 mg). Extraction of the water layer with ethyl acetate followed by drying (MgSO4) gave the sub-title compound (total amount 846 mg, 92%), m.p.=195-198° C.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH:20]([C:31]2C=C(F)[CH:34]=[CH:33][C:32]=2[F:38])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:15][N:14]=1)=[O:12])(C)(C)C.[C:40](OC(=O)C)(=O)C.C(N(CC)CC)C.F[C:55]([F:60])(F)[C:56](O)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH:20]([C:31]2[CH:56]=[C:55]([F:60])[CH:34]=[CH:33][C:32]=2[F:38])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:15][N:14]=1)=[O:12])(=[O:5])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)NCCNC(=O)OC(C)(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
To a solution of tert-butyl[2-[[[5-[(2,5-difluorophenyl) [(4-fluorophenyl)sulfonyl]meth yl]-4-methylpyridin-2-yl]carbonyl]amino]ethyl]carbamate (90 mg, 0.160 mmol) in methylene chloride (5 ml), trifluoroacetic acid (2 ml) was added, and the resulting mixture was stirred for 2.5 hours at room temperature. The reaction solution was concentrated under reduced pressure, and methylene chloride and a 0.5 N aqueous sodium hydroxide were added thereto. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was dissolved in methylene chloride (5 ml), and acetic anhydride (23 μl, 0.240 mmol), triethylamine (26 μl, 0.240 mmol) and a catalytic amount of 4-dimethylaminopyridine were added thereto. The reaction solution was stirred for 20 hours at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:20) was concentrated under reduced pressure, to obtain the title compound (79 mg, 0.156 mmol, 98%) as an amorphous substance.
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH2:8][C:7]3([CH3:15])[CH2:13][NH:14][C:5]([C:6]=23)=[CH:4][CH:3]=1.[Cu][C:17]#[N:18]>CN(C=O)C.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>[CH3:15][C:7]12[CH2:13][NH:14][C:5]3=[C:6]1[C:11](=[C:2]([C:17]#[N:18])[CH:3]=[CH:4]3)[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: CC12CNc3ccc(Br)c(c31)NC(=O)C2
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC12CNc3ccc(C#N)c(c31)NC(=O)C2
Temperature: 150 °C

Procedure:
A mixture of (±)-6-bromo-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one (53 mg, 0.20 mmol, described in Intermediate 47), tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol), and copper(I) cyanide (27 mg, 0.30 mmol) in DMF (2 mL) was heated at 150° C. for 3 h. The cooled reaction mixture was quenched with aqueous NaHCO3 (10 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—60:40 to 0:100, to give the title compound in sufficient purity for use in the next step. MS: m/z=214 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:7][N:6]=1
Reactant: c1nc[nH]n1
Reactant: Clc1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cnc(-n2cncn2)cn1

Procedure:
2,5-Dichloropyrazine (298 mg, 2.0 mmol) and 1,2,4-triazole (145 mg, 2.1 mmol) were added in DMF (10 mL), then cesium carbonate was added and the reaction was at room temperature over night. Water (20mL) was added, extracted with ethyl acetate (30 mL), second wash with brine (20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 22% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[N:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]=[O:21].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:20]([NH:19][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCN=C=O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), ethyl 3-isocyanatopropionate (286 mg), triethylamine (0.418 mL), and tetrahydrofuran (20 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (470 mg, 95%) as a colorless solid.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]([CH:9]([CH3:11])[CH3:10])[C@H:5]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16])[CH2:4]1.C(O)(C)C.[CH:24]([NH2:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]([CH:9]([CH3:11])[CH3:10])[C@H:5]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][NH:27][CH:24]([CH3:26])[CH3:25])[CH3:16])[CH2:4]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCCl
Reactant: CC(C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)NCCN(C)CCO[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Yield: 100 %

Procedure:
5 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-chloro ethyl)-N-methylamine hydrochloride were added to a mixture of 50 ml isopropanol and 50 ml water. 1.9 g of isopropylamine and 7.7 g of potassium carbonate were then added, and the reaction mixture was heated under reflux for 5 hours. The reaction mixture was worked up by diluting it with 100 ml of water and extracting the solution with ethyl acetate. The organic phase was worked up as described in Example 1 C). 4.78 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclo hex-3-yloxy)ethyl]-N-[2-(isopropylamino)ethyl]-N-methylamine were obtained. The free base was then converted into the corresponding hydrochloride analogously to Example 1 D). 5.1 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcycl ohex-3-yloxy)ethyl]-N-[2-(isopropylamino)ethyl]-N-methylamine dihydrochloride having a melting point of 156° C.-158° C. were obtained.