Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C(O)=O.O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][CH2:7][CH2:6][CH:2]=[O:1]
Reactant: OCCCCSCCC1OCCO1
Solvent: O=CO
Solvent: O
Product: O=CCCSCCCCO
Temperature: 25 °C

Procedure:
4-(2-(1,3-Dioxolan-2-yl)ethylthio)butan-1-ol (example 281, step a) (500 mg) was dissolved in an 80% solution of aqueous formic acid (6 mL) and the reaction mixture was stirred at room temperature over the weekend. The mixture was diluted with water (10 mL) and extracted with ether (3×10 mL) then the organics were washed with brine (10 mL), dried over sodium sulphate, filtered and evaporated to afford 3-(4-hydroxy-butylsulfanyl)-propionaldehyde as an oil. This was dissolved in dry methanol and (2-isopropyl-thiazol-4-yl)-(1-oxa-4,9-diaza-spiro[5.5]undec-4-yl)-methanone trifluoroacetate (Example 22, step b) (606 mg) and 3 Å molecular sieves were added. Acetic acid (0.2 mL) was added and the mixture stirred for 5 minutes under argon before cooling to 0° C. and addition of sodium triacetoxyborohydride (633 mg). The cooling bath was removed and the reaction mixture stirred at room temperature overnight. The mixture was filtered then applied directly to an SCX-2 cartridge and washed with methanol before eluting the product with 2N ammonia in methanol. Further purification was by silica gel chromatography eluting with 10% methanol in DCM to afford the subtitled compound as a pale green oil. Yield 0.37 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:17]=[C:15]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:30])([F:32])[F:31])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCCC3)ccc21
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-oxo-2-pyrrolidin-1-yl-ethyl)amide (46 mg) was prepared by following General Procedure F using {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetic acid (47 mg), pyrrolidine (0.14 ml), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 520. 1H NMR (DMSO-d6, 400 MHz): δ 8.32 (t, 1H), 7.82 (s, 1H), 7.61 (m, 2H), 7.52 (d, 1H), 7.28 (m, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 4.02 (d, 2H), 3.57 (s, 3H), 3.49 (t, 2H), 3.34 (m 2H), 1.91 (p, 2H), and 1.79 (p, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14](=[O:27])[CH2:15][CH2:16]S(C1C=CC(C)=CC=1)(=O)=O)=O)(C)(C)C.Cl.O1CCOCC1>CO>[CH2:10]1[CH:9]2[N:8]([CH2:16][CH2:15][C:14](=[O:27])[CH2:13]2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)CCC(=O)CC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1CCN2CCCC2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
(±)-1-(t-Butoxycarbonyl)-2-[4-(p-toluenesulfonyl)-2-oxobutyl]pyrrolidine (322 mg (0.814 mmol), prepared as described in 1)) was dissolved in methanol (3.2 ml). To the solution was added a solution of 4N hydrochloric acid/dioxane (0.61 ml, 2.44 mmol), and the resulting mixture was stirred at 50° C. for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to remove solvents and any excess of hydrochloric acid. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and this was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through alumina (eluent, ethyl acetate), to give the title compound (74 mg) as a light brown oil (yield 65%).
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[ClH:18]>C(O)(=O)C>[ClH:18].[F:17][C:14]([F:15])([F:16])[C:11]1[CH:10]=[CH:9][C:8]([C:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCNCC1
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(C2=CCNCC2)cc1

Procedure:
A solution of 4.9 g. of 4-hydroxy-4-(α,α,α-trifluoro-p-tolyl)piperidine in 33 ml. of 37% hydrochloric acid solution and 66 ml. of acetic acid is stirred at reflux temperature for 18 hours. The solution is evaporated and the residue is triturated with acetone to give white crystals, m.p. 213°-215°C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:10][CH2:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:1]
Reactant: C=C(C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: C=C(CBr)c1ccccc1
Yield: 51.5 %

Procedure:
Benzene (120 ml), was mixed with 9.00 g (76.2 mmol), of α-methylstyrene, 14.2 g (80.0 mmol), of N-bromosuccinimide, and 300 mg of benzoyl peroxide and the mixture was refluxed for 24 hours. After the solvent was distilled off under reduced pressure, carbon tetrachloride was added and the resulting crystals were filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane 100%), to obtain the target compound. The yield, % yield and NMR spectrum were as follows. Yield: 7.72 g, % yield: 51.5%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[IH:11]>O.C(=O)([O-])[O-].[K+].[K+]>[NH2:1][C:2]1[N:7]=[C:6]([I:11])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: COc1cc(Cl)nc(N)n1
Reactant: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(I)nc(N)n1
Reaction time: 65 h

Procedure:
18.0 g of 2-amino-4-chloro-6-methoxypyrimidine was added to 65 mL of 57% aqueous hydroiodic acid with ice bath cooling. The resulting thick mixture was kept at ambient temperature for 65 hours, diluted with water and neutralized with potassium carbonate. The solid was collected and recrystallized from aqueous ethanol to give 5.0 g of white crystals, m.p. 141.5°-144° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:20][C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:18]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:53]=[O:54]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH:20]([CH2:53][OH:54])[C:19]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:18]([C:37](=[O:42])[C:38]([F:40])([F:39])[F:41])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N1N=C(c2cc(F)ccc2OCc2ccccc2)CC1(CCCOC1CCCCO1)c1ccccc1)C(F)(F)F
Reactant: C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N1N=C(c2cc(F)ccc2OCc2ccccc2)C(CO)C1(CCCOC1CCCCO1)c1ccccc1)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
To a solution of 13.0 g (22.2 mmol) 3-5 in 150 ml of THF at −78° C. was added dropwise a solution of 22.2 ml (44.4 mmol) 2 M NaHMDS in THF. After the addition was complete, the solution was warmed to −40° C. and stirred for 45 min. In a separate flask, 40 g of paraformaldehyde was mixed with 100 ml of mineral oil and heated at 140° C. A stream of argon was passed over the paraformaldehyde/mineral oil mixture and the resulting formaldehyde gas was bubbled into the above solution of C-5 still at −40° C. for 15 minutes. The cold solution was quenched with 100 ml of saturated aqueous NH4Cl and allowed to warm to room temperature. The mixture was dumped into a separatory funnel with EtOAc and the layers were separated. The aqueous was extracted with EtOAc, the combined organics were washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography with EtOAc/hexanes to provide 3-6 as an amber gum. Data for 3-6: LC-MS: rt=3.1 min, m/z=531 (M−THP+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[H][H]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: Fc1ccc(C=C[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1

Procedure:
A solution of 1 g of β-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl ]-4-fluorostyrene in 10 ml of toluene and 5 ml of ethanol is hydrogenated with 500 mg of 5 percent palladium-charcoal at room temperature and normal pressure until the hydrogen uptake comes to a standstill. The black suspension is subsequently filtered. Evaporation of the filtrate gives 1-[2-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]ethyl]-4 -fluorobenzene.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].O>O1CCCC1.CN(C)C=O>[F:1][C:2]1[C:3]([OH:26])=[CH:4][CH:5]=[C:6]([F:25])[C:7]=1[C:8]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)=[O:24]
Reactant: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To 2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol (P-0009, 45.0 mg, 1.27 mmol) in tetrahydrofuran (15 mL) and N,N-dimethylformamide (5 mL) was added dichlorodicyanoquinone (87 mg, 3.8 mmol). The reaction was stirred at room temperature for 50 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0066, 7 mg, 15.6%). MS (ESI) [M+H+]+=352.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]2[CH2:17][CH:16]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])[CH2:15][CH2:14][CH:13]2[NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:38])([F:37])[F:36])[C:28]=3[N:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:40]([O:42]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:41]>C1(C)C=CC=CC=1.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>[C:40]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[CH2:17][C@H:16]([N:18]([CH:20]([CH3:21])[CH3:22])[CH3:19])[CH2:15][CH2:14][C@@H:13]2[NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:28]=3[N:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:42])[CH3:41]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)N(C)C1CCC(NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)C(CS(=O)(=O)c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(S(=O)(=O)C[C@@H]2C[C@H](N(C)C(C)C)CC[C@@H]2NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1S,2R,4R)-(N-[2-(4-Bromo-benzenesulfonylmethyl)-4-(isopropyl-methyl-amino)-cyclohexyl]-2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetamide, Example 3, (50 mg) was dissolved in toluene (1 ml) prior to the addition of 1-ethoxyvinyltri-n-butyltin (0.5 ml), Pd(PPh3)4 (20 mg) and a few crystals of 2,6-tert-butyl-4-methyl phenol. The resulting solution was heated to reflux overnight. After cooling, the palladium catalyst was filtered off and the solution was concentrated. The residue was dissolved in dioxane (1 ml) prior to the addition of 1N HCl. The resulting solution was stirred at rt for 2 h. The solution was concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (8 mg). MS found: (M+H)+=593.5.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[CH2:12](O)[CH:13]=[CH2:14].C([O-])(=O)C.[Na+]>>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH2:2][CH2:14][CH:13]=[CH2:12]
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: C=CCO
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CCCC(=O)C1CCCC(C)(C)C1
Temperature: 150 °C

Procedure:
Into a 2 liter autoclave is placed 672 grams of the dimethyl ketal of 1-acetyl-3,3-dimethyl cyclohexane prepared according to Example I; 348 grams of allyl alcohol; and 15 grams of sodium acetate. The autoclave is sealed and the contents are heated to 150° C. and maintained at 150° C. for a period of five hours. At the end of the five hour period the autoclave contents are cooled and the autoclave is opened. The resulting product is distilled on a 12" Goodloe column yielding the following fractions:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH:35]([CH2:47][CH2:48][CH3:49])[CH2:36][CH2:37][N:38]([CH3:46])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].[C:50]([OH:58])(=[S:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[CH3:42][C:41]([O:40][C:39](=[O:45])[N:38]([CH2:37][CH2:36][CH:35]([S:57][C:50](=[O:58])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:47][CH2:48][CH3:49])[CH3:46])([CH3:44])[CH3:43]
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: OC(=S)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)SC(=O)c1ccccc1
Temperature: 0 °C
Yield: 55.3 %

Procedure:
To a stirred solution of triphenylphosphine (1.13 g, 4.32 mmol) in dry tetrahydrofuran (12 ml) was added diisopropyl azodicarboxylate (0.88 ml, 4.32 mmol) dropwise with stirring at 0° C. under nitrogen. After stirring for 0.5 h, a solution of (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester (500 mg, 2.16 mmol) and thiobenzoic acid (0.51 ml, 4.3 mmol) in dry tetrahydrofuran (10 ml) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 h, and then stirred at room temperature overnight. The mixture was evaporated, the residue dissolved in toluene and eluted down a flash chromatography column using 10% ether/isohexane as eluent to give 420 mg (55%) of product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 58.5 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (60 mg, 0.15 mmol, 1.0 equiv; Example 122) in anhydrous DMF (0.5 mL) was added N-ethyldiisopropylamine (96 mg, 129 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and ethyl bromoacetate (55.1 mg, 37 μL, 0.33 mmol, 2.2 equiv; [CAS RN 105-36-2]) and the reaction mixture heated by microwave irradiation to 100° C. for 2 h. Removal of the solvent 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 42.7 mg (62%) of the title compound as a light yellow powder. MS (ISP): 486.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19].N1CCCCC1>C1COCC1.O.[Cu]I>[CH3:17][C:4]1[C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)cnc1NC(=O)CN1CCCC1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1cc(C#C[Si](C)(C)C)cnc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere 35 mg (0.03 mmol) tetrakis-triphenylphosphane-palladium and 5.7 mg (0.03 mmol) CuI are added to a solution of 447 mg (1.5 mmol) N-(5-bromo-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide and 0.23 mL (1.65 mmol) ethynyl-trimethyl-silane in 0.45 mL (4.5 mmol) piperidine and 10 mL THF and the reaction mixture is stirred for 14 h at RT. To complete the reaction a further 35 mg tetrakis-triphenylphosphane-palladium are added and the reaction mixture is heated to 50° C. for 4 h. It is diluted with water, extracted exhaustively with EtOAc, the combined organic phases are washed with saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4]Cl.[OH-:6].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:4]([O:6][CH2:4][CH:2]1[O:3][CH2:1]1)[CH:2]1[O:3][CH2:1]1
Reactant: ClC[C@H]1CO1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2.01 g of R-(-)-epichlorohydrin and 16 mg of benzyl triethyl ammonium chloride (the latter two compounds were the same ones as used in Preparation 1) were mixed and heated to 70° C. To the mixture was dropwise added 650 mg of 24% by weight sodium hydroxide aqueous solution. The resultant was stirred for 2 hours at 70° C., and cooled to room temperature. The mixture was extracted trice with chloroform, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from hexane to obtain 380 mg of an S isomer of glycidyl ether of the following formula: ##STR42## mp: 65° C. [α]D25 : +1.90° (C=0.46, CH2Cl2)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2C(OC(C)(C)C)=O)=[O:29])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][NH:31]2)=[O:29])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1)[C@@H]1Cc2ccccc2CN1
Yield: 123.6 %

Procedure:
The titled compound was prepared from tert-butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-nitrophenyl) piperazinyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (120 mg, 0.18 mmol, Preparation VIII) by treatment with 5 mL of a satd soln of HCl in EtOAc. This was purified by preparative HPLC (TFA buffer) to give the title compound as white solid (65 mg). MS (ESI, pos. ion) m/z: 548 (M+H). Calc'd for C29H30ClN5O4: 547.20.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH:4]=[N:3]1.[BH4-].[Na+].B(O)(O)O>CO>[CH3:1][N:2]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: CN1N=CCc2c(-c3ccccc3)ncnc21
Agent: OB(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1NCCc2c(-c3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.8 %

Procedure:
To a stirred solution of 1-methyl-5-phenyl-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg) in dry methanol (15.0 mL), sodium borohydride (296 mg, 7.81 mmol) was added slowly, followed by boric acid (480 mg) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 24 hours and solvents were removed under reduced pressure. The resulting oil was diluted with dichloromethane (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a residue which was purified by column chromatography using EtOAc/hexane (1.4:8.6) as eluent to afford 1-methyl-5-phenyl-1,2,3,4-tetrahydropyrimido[4,5-c]pyridazine (130 mg) as gummy liquid. 1H NMR (DMSO-d6): δ 2.66-2.69 (t, 2H), 2.88-2.91 (t, 2H), 3.22 (s, 3H), 5.46-5.50 (t, 1H), 7.41-7.47 (m, 3H), 7.53-7.55 (m, 2H), 8.36 (s, 1H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=3)[C:14]([CH2:16][CH3:17])=[N:15][C:11]=2[CH:10]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[NH2:5][S:6]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=4)(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=3)[C:14]([CH2:16][CH3:17])=[N:15][C:11]=2[CH:10]=1)(=[O:7])=[O:8]
Reactant: CCc1nc2cc(S(=O)(=O)NC(C)(C)C)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2cc(S(N)(=O)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 72.2 %

Procedure:
A solution of 5-[(tert-butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (Example 87, 330 mg, 0.55 mmol) in trifluoroacetic acid (10 mL) was heated at 80° C. for 2 h. The mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford 215 mg (73%) of the title compound: MS (ESI) m/z 542 (M+H)+; 1H-NMR (CDCl3) δ 8.32 (1H, d, J=1.3 Hz), 7.77–7.69 (3H, m), 7.41(2H, d, J=8.3 Hz), 7.33–7.25 (4H, m), 7.11 (1H, d, J=8.6 Hz), 6.65 (1H, br.s), 4.59 (1H, s), 3.63–3.53 (2H, m), 2.95 (2H, t, J=7.0 Hz), 2.80 (2H, q, J=7.6 Hz), 2.41 (3H, s), 1.36 (3H, t, J=7.6 Hz) 1.23 (9H, s).