Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[C:12]=2[CH:16]2C[CH2:17]2)[CH:7]=1)([CH3:5])[CH2:3][OH:4].C([C@H]1CC[C@H](OC2C(C=C)=C3C(=CC=2)C=C([C@]2(C)COC(=O)N2)C=C3)CC1)(C)(C)C>>[NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[C:12]=2[CH:16]=[CH2:17])[CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C2CC2)CC1
Agent: C=Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@]3(C)COC(=O)N3)ccc12
Product: C=Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@@](C)(N)CO)ccc12

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-vinylnaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-cyclopropylnaphthalen-2-yl)propan-1-ol (Example 215) in 76% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-vinylnaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=365.48 [M−16]+. 1H NMR (MeOD) δ: 8.29 (d, J=9.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.55 (dd, J=9.0, 2.3 Hz, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.11 (dd, J=17.9, 11.7 Hz, 1H), 5.66-5.79 (m, 2H), 4.28-4.41 (m, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.18-2.27 (m, 2H), 1.87-1.95 (m, 2H), 1.80 (s, 3H), 1.41-1.55 (m, 2H), 1.09-1.29 (m, 3H), 0.92 (s, 9H)
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][OH:8])[C:5](=[O:9])[CH2:4][N:3]1[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][CH:32]([CH:36]([CH3:38])[CH3:37])[C:33](O)=[O:34]>CCOCC>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][CH:32]([CH:36]([CH3:38])[CH3:37])[C:33]([O:8][CH2:7][N:6]1[C:5](=[O:9])[CH2:4][N:3]([CH2:10][C:11]#[CH:12])[C:2]1=[O:1])=[O:34]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: C#CCN1CC(=O)N(CO)C1=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C#CCN1CC(=O)N(COC(=O)C(Nc2ccc(C(F)(F)F)cc2Cl)C(C)C)C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol (0.99 mmol) and triethylamine (1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20% ether/hexane, gives (2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][C:12]=3[C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1)(=O)=O.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:35])[C:33]=1[F:34].[OH-].[NH3+]N>O.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:22]([CH:19]1[CH2:18][C:12]2[C:13](=[O:17])[O:14][C:15]3[C:10]([C:11]=2[CH2:21][CH2:20]1)=[CH:9][CH:8]=[C:7]([C:30]1[CH:29]=[C:28]([F:27])[C:33]([F:34])=[C:32]([F:35])[CH:31]=1)[CH:16]=3)[CH2:23][CH3:24]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: CCCC1CCc2c(c(=O)oc3cc(OS(=O)(=O)C(F)(F)F)ccc23)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N[NH3+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCc2c(c(=O)oc3cc(-c4cc(F)c(F)c(F)c4)ccc23)C1

Procedure:
10 g (25.6 mmol) of 6-oxo-8-propyl-7,8,9,10-tetrahydro-6H-benzo[c]-chromen-3-yl trifluoromethanesulfonate, 4.50 g (25.6 mmol) of 3,4,5-trifluorobenzeneboronic acid, 10.6 g (38.4 mmol) of sodium metaborate octahydrate, 360 mg (0.51 mmol) of bis(triphenylphosphine)palladium chloride and 50 μl of hydrazinium hydroxide are dissolved in 15 ml of water and 250 ml of THF, and the mixture is refluxed overnight. Water is added to the batch, which is extracted three times with dichloromethane. The combined org. phases are dried over sodium sulfate, the solvent is removed under reduced pressure, and the residue is filtered through silica gel and recrystallised, giving 8-propyl-3-(3,4,5-trifluorophenyl)-7,8,9,10-tetrahydrobenzo[c]chromen-6-one.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(CC)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-ethyl-cyclopentane carboxylate (4.90 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.22 ml) was slowly added, then benzoyl chloride (4.68 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours; Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed in turn using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 8.86 g of yellow liquid. MS: m/e 290(M+″), 261, 216, 185, 168, 139, 105(base), 77.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[O:9][C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[CH:7][CH:6]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH3:15][C:10]1([C:8]2[O:9][C:5]([CH2:4][C:16]#[N:17])=[CH:6][CH:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: [C-]#N
Reactant: CC1(c2ccc(CCl)o2)OCCO1
Agent: N#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(c2ccc(CC#N)o2)OCCO1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(5-chloromethyl-furan-2-yl)-2-methyl-[1,3]dioxolane (2.37 mg, 11.68 mmol) in DMSO (50 mL) was treated with sodium cyanide (2.29 g, 46.72 mmol) and the reaction mixture was stirred at 80° C. for 45 min. Water (100 mL) was added to the cooled reaction mixture and the product was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a yellow oil. LC-MS-conditions 02: tR=0.83 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:43][C:44](=[O:48])[CH2:45][NH:46][CH3:47])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([N:46]([CH3:47])[CH2:45][C:44]([OH:43])=[O:48])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)N(C)CC(=O)O)cc2)cc1

Procedure:
The product from Example 104A and sarcosine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.15-7.38 (m, 8 H), 7.02 (m, 4 H), 6.87 (m, 4 H), 4.12 (s, 1 H), 4.06 (s, 2 H), 4.01 (s, 2 H), 3.99 (s, 1 H), 2.99 (s, 2 H), 2.91 (s, 3 H), 2.82 (s, 1 H), 2.76 (m, 2 H), 2.62 (m, 2 H), 2.39 (s, 3 H); MS (ESI) m/z 616 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.N(CCO)CCO>C1COCC1>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: OC(CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 209.3 %

Procedure:
2-Chloroacetophenone (3 g., 19.4 mmol) was treated with (−) DIP-chloride (6.7 g., 20.9 mmol) in anhydrous THF (20 mL) at dry-ice bath temperature and left overnight. The temperature was raised to room temperature and THF was removed in vacuo. The residue was dissolved in ether (100 mL). The diethanolamine (4.58 g., 42.6 mmol) was added and the mixture stirred at room temperature for 5 hrs. The separated solid was filtered and the filtered cake was washed with hexane (40 mL) and ether (30 mL). The combined filtrates were evaporated to dryness to give 6.36 g of crude product. This was purified by silica gel column chromatography using 1% ether and petroleum ether 1.71 g (56%) of the desired product was obtained as an oil.
Reaction SMILES: [H-].[K+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH:6]=[CH:5][CH:4]=1.[Cl-:22].[Cr+3:23].[Cl-].[Cl-]>C1COCC1>[Cl-:22].[Cl-:22].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14]2[Cr+2:23])[CH:6]=[CH:5][CH:4]=1
Reactant: C1=CC(c2cccc3cccnc23)c2ccccc21
Reactant: [Cr+3]
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: [Cr+2]C1=Cc2ccccc2C1c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
0.05 g of potassium hydride (1.23 mmol) was suspended in 20 ml of THF, and 0.3 g of 1-(8-quinolyl)indene (1.23 mmol) was slowly added. The resultant violet suspension was stirred at room temperature for three hours and then added dropwise to a mixture of 0.46 g of chromium(III)chloride 3THF (1.23 mmol) in 50 ml of THF and, when the addition was complete, the mixture was stirred for a further 16 hours. The solvent was removed under reduced presssure, and the resultant solid was extracted with hot toluene. After the solvent had been distilled off from the combined extracts, the product was obtained as a green powder, which was washed a number of times with hexane and dried under a high vacuum, giving 0.22 g of 1-(8-quinolyl)indenylchromium(III) dichloride (50%).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl)([O-:24])=[O:23]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc([N+](=O)[O-])c1

Procedure:
The intermediate silyl protected alcohol was prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Method F, alkylating with 3-nitrobenzyl chloride. Deprotection to the indicated product was carried out by method I.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:12][C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.I[CH2:25][CH3:26]>O>[Br:12][C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[C:17]([S:19]([CH2:25][CH3:26])(=[O:21])=[O:20])[CH:18]=1
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: CCI
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCS(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Sodium sulfite (1.755 g, 13.92 mmol) and sodium bicarbonate (1.231 g, 14.65 mmol) were dissolved in water (37 mL) to give a colorless solution. The mixture was heated at 75° C. 3-Bromo-2-chloropyridine-5-sulfonyl chloride (2.132 g, 7.33 mmol) was added portionwise over 1 hour. The reaction mixture was stirred at 75° C. for 1 hour. The mixture was concentrated and N,N-dimethylformamide (13.88 mL) was added. Sodium bicarbonate (1.231 g, 14.65 mmol) and iodoethane (0.589 mL, 7.33 mmol) were added. The resulting mixture was heated to 75° C. for 2 hours and then cooled to ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to provide the title compound.
Reaction SMILES: FC(F)(F)C1C=C[C:6]([C:7](O)=[O:8])=[CH:5]C=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25](C(=O)C)=[CH:24][CH:23]=2)=[N:19][CH:20]=1>>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:27]=2[CH2:5][CH2:6][C:7]3=[O:8])=[N:19][CH:20]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1ccc(Oc2ccc(N)cn2)cc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-(trifluoromethyl)benzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 1-{4-[(5-amino-2-pyridinyl)oxy]phenyl}-1-ethanone obtained in Reference Example 24 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2].S(Cl)(Cl)=O.Cl[CH2:18]Cl>>[CH3:18][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([CH3:12])[CH:5]=1
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C#N)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 4-cyano-3-methyl-benzoic acid from Example E2d (1.5 g, 9.3 mmol) and thionyl chloride (5 ml, 68.5 mmol) in dichloromethane (20 ml) was heated at re-flux for 2 h then solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (25 ml). Methanol (10 ml) was added and the solution was stirred at room temperature for 2 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield the title compound (1.6 g, 100%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH2:8]([S:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CN(C=O)C.CCOC(C)=O>[CH2:8]([S:15][C:16]1[N:21]=[C:20]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:19]=[C:18]([Cl:23])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(N)(=O)=O
Reactant: Clc1cc(Cl)nc(SCc2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(Cl)nc(SCc2ccccc2)n1
Reaction time: 1 h

Procedure:
To methane sulphonamide (1.47 g) in DMF (30 ml) was added 60% sodium hydride (0.59 g) at room temperature and stirred for 1 h. To this mixture was then added the subtitle product of step ii) and the mixture stirred at room temperature for 6 h. To the reaction mixture was added EtOAc (50 ml) and aqueous hydrochloric acid (50 ml, 1M). The organic layer was separated and washed with brine (20 ml), combined, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (20 to 50% EtOAc/iso-hexane) to afford the subtitle compound as a yellow oil. Yield: 1.60 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.[N:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:35][C:29]1([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH2:30][CH2:31][N:32]([C:19](=[O:21])[CH2:18][O:17][CH2:16][CH2:15][N:13]([CH3:14])[S:10]([C:6]2[C:5]([CH3:22])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:33][CH2:34]1
Reactant: OC1(c2ccncc2)CCNCC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(c3ccncc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (77 mg, 0.475 mmol) was added to a solution of 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetic acid (acid unit S2) (150 mg, 0.453 mmol) in methylene chloride (7 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-4-yl)piperidin-4-ol (A4) (80 mg, 0.453 mmol) in methylene chloride (3 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/methanol/hexane/ammonia solution (25% aq.) (100:10:10:1).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH:14]=[C:13]([C@@H:15]([NH:18]S(C(C)(C)C)=O)[CH2:16][CH3:17])[CH:12]=[N:11]2)(=O)=O)=CC=1.Cl>CO.O1CCOCC1>[NH:10]1[CH:14]=[C:13]([C@@H:15]([NH2:18])[CH2:16][CH3:17])[CH:12]=[N:11]1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cnn(S(=O)(=O)c2ccc(C)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1cn[nH]c1
Reaction time: 12 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {(S)-1-[1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-propyl}-amide (2.00 g, 5.22 mmol) in MeOH was added a 4 M solution of HCl (5.0 mL, 20 mmol) in dioxane. After 12 hours, the solvent was concentrated in vacuo. The residue was made basic with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]1[C:10](=[O:15])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1c1ccc(Cl)c(Cl)c1
Product: CN(C)C=C1CCCC(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
2-(3,4-Dichloro-phenyl)-cyclohexanone (101 mg, 0.42 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (119 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 298.0 [(M+H)+].
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCCCN1CCOCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCCN3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 4-(3-chloropropyl)morpholine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].ClC1C=CC(S[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=2)=[O:30])=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29](=[O:30])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[N:32]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: O=C(Sc1ccc(Cl)cc1)c1cccc(C(F)(F)F)n1
Reactant: N#CCc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC(C(=O)c1cccc(C(F)(F)F)n1)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of 4-fluorophenylacetonitrile (0.12 mL, 1.0 mmol) in dry tetrahydrofuran (2 mL) is treated dropwise with potassium bis(trimethylsilyl)amide (0.5 M toluene, 3.0 mL, 1.5 mmol) at 0° C. under an atmosphere of nitrogen. The mixture is stirred 10 min then 6-trifluoromethyl-pyridine-2-carbothioic acid S-(4-chloro-phenyl) ester is added all at once. The mixture is allowed to warn to room temperature then warmed to reflux for 10 min, at which time the reaction is complete by TLC (methylene chloride). The mixture is allowed to cool then poured into 10% citric acid and extracted into methylene chloride. The methylene chloride solution is dried over magnesium sulfate and concentrated in vacuo. The residue is purified on a silica gel cartridge prepared with hexane then eluted with methylene chloride to yield 204 mg (66%) 2-(4-fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrile. MS ES− m/z 307 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13].S(=O)(=O)(O)O.[OH-].[Na+]>O.C(O)(=O)C>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:10]([CH3:9])=[CH:11][C:12]([CH3:13])=[N:1]2)=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c2ccc(N)nc2n1
Reaction time: 24 h

Procedure:
2,6-Diaminopyridine (43.6 g., 0.4 mole), 40.0 g (0.4 mole) of 2,4-pentanedione, 200 ml. of glacial acetic acid and 5 ml. of 96% sulfuric acid were mixed, then refluxed with stirring for 24 hours. The cold solution was added slowly with good stirring and ice bath cooling to 160 g of sodium hydroxide in enough water to make 600 ml. The brown solid, which crystallized, was filtered after the solution had been cooled overnight at 5°, washed twice with cold water and dried, 25.3 g., m.p. 125°-200°. This crude material was dissolved in 130 ml. of boiling 95% ethanol and the solution chilled overnight at -15°, 19.5 g. (28%), m.p. 215°-220°. This material was suitable for the following experiment.
Reaction SMILES: [CH2:1]([CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH2:26]=[O:27].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:18]([C:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:26][OH:27])#[N:19]
Reactant: C=O
Reactant: CCCCCCCCC(C#N)c1ccc(Cl)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an ice cold stirred solution of α-n-octyl-2,4-dichlorobenzyl cyanide (40 g., 0.14 mole) in 250 ml. of pyridine containing a suspension of paraformaldehyde (21 g., 0.7 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 72 hours. The reaction mixture is poured into 2 liters of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 40 g. of a thick oil.