Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.Cl.[NH:16]1[CH2:21][CH2:20][C:19]2([C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH2:23][O:22]2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:16]3[CH2:17][CH2:18][C:19]4([C:25]5=[N:26][CH:27]=[CH:28][CH:29]=[C:24]5[CH2:23][O:22]4)[CH2:20][CH2:21]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: c1cnc2c(c1)COC21CCNCC1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)OCc3cccnc34)nn2)n1

Procedure:
The object product (72 mg, 28%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg), 5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine] dihydrochloride (86 mg) and potassium carbonate (290 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][O:9][C:10]1[C:11]([F:31])=[C:12]([F:30])[C:13]2[C:14](=[O:29])[C:15]3[C:20]([O:21][C:22]=2[C:23]=1[F:24])=[C:19]([F:25])[C:18]([OH:26])=[C:17]([F:27])[C:16]=3[F:28].O>C(Cl)Cl>[CH3:8][O:9][C:10]1[C:11]([F:31])=[C:12]([F:30])[C:13]2[C:14](=[O:29])[C:15]3[C:20]([O:21][C:22]=2[C:23]=1[F:24])=[C:19]([F:25])[C:18]([O:26][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:17]([F:27])[C:16]=3[F:28]
Reactant: COCCOCCl
Reactant: COc1c(F)c(F)c2c(=O)c3c(F)c(F)c(O)c(F)c3oc2c1F
Solvent: ClCCl
Solvent: O
Product: COCCOCOc1c(F)c(F)c2c(=O)c3c(F)c(F)c(OC)c(F)c3oc2c1F
Reaction time: 1 h

Procedure:
Methoxyethoxymethyl chloride (150 mg, 1.2 mmol) is added to a solution of Compound 47 in 10 mL dry CH2Cl2 at 20° C. The reaction mixture is stirred for 1 hour and poured into 50 mL water. The product is extracted with diethyl ether (30 mL×2) and ethyl acetate (30 mL). The combined organic extracts are washed with 5% citric acid solution (50 mL), and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield 425 mg yellow oil. The crude oil is then recrystallized from isopropyl alcohol to yield 240 mg (51%) of Compound 48 as a colorless solid. 1H-NMR (d6-DMSO) 5.48 (s, 2H); 4.36 (s, 3H); 3.99 (t, J=Hz, 2H); 3.58 (t, J=Hz, 2H); 3.36 (s, 3H). 19F-NMR (d6-DMSO) 142.90 (d, J=12.7, 1F); 142.97 (d, J=12.4 Hz, 1F); 153.12 (d, J=13.5 Hz, 1F); 155.54 (d, J=19.7 Hz, 1F); 155.82 (d, J=11.3 Hz, 1F); 157.13 (d, J=19.5 Hz, 1F).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:18]=[CH:19]OCC)[S:16][CH:17]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[NH:24][NH2:25]>C(O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([N:18]=[CH:19][NH:25][NH:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[S:16][CH:17]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC=Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NNC=Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Reaction time: 18 h
Yield: 87 %

Procedure:
A mixture consisting of 4-(4-cyclohexylphenyl)-2-ethoxymethyleneaminothiazole (500 mg), ethyl carbazate (170 mg) and ethanol (10 ml) was stirred under ice-cooling for 1 hour and then at room temperature (about 15° C.) for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crystals were collected by filtration with hexane to give ethyl 3-[4-(4-cyclohexylphenyl)-2-thiazolyliminomethyl]carbazate (515 mg, yield of 87 %). Recrystallization from dimethylforamide-water produced colorless prisms, mp of 188 to 189° C.
Reaction SMILES: Cl.[NH2:2]O.[CH:4]([C:6]1[S:10][CH:9]=[C:8]([N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:4]([C:6]1[S:10][CH:9]=[C:8]([N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1)#[N:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C=O)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
Hydroxylamine hydrochloride (0.766 g, 11.03 mmol) was added to a solution of compound 11 (1.888 g, 5.51 mmol) in pyridine (5.5 mL). The solution was heated to 90 degrees for 10 minutes and then cooled to room temperature. Acetic anhydride (3.23 mL, 34.2 mmol) was then added to the solution. It was then stirred at room temperature for 30 minutes and then at 80 degrees for 1 hour. The reaction was concentrated to half the volume under reduced pressure and then diluted with 300 mL of water, extracted into ethyl acetate (3×), washed with brine, dried over Na2SO4, filtered and then concentrated. The resulting yellow oil was then purified by silica gel chromatography through a 40M Biotage column with gradient of 12-24% ethyl acetate in hexanes to give compound 12 (1.39 g, 74%) as a white crusty solid. LRMS (ESI): calc. 339.13; found 338.1 (M-H)−.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:1]([C:3]3[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=3)[N:2]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccc(C(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-hydrazinobenzoic acid as described for compound 35. Purified by chromatography and crystallized from ethyl acetate. M.p. 198°-199° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=2)=[N:3]1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:27](O)=[O:28].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:27]=[O:28])[C:4]([C:7]2[O:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=2)=[N:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1ccc(-c2ccc([N+](=O)[O-])o2)n1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Heat 1.0 g of 1-methyl-3-(5-nitro-2-furyl)pyrazole together with 0.73 g of hexamethylenetetramine and 11.6 g of trifluoroacetic acid for 4.5 hours at boiling point. Add the resulting 4-pyrazolylmethyleneammonium-salt-containing solution to 31 ml of ice water. Stir the thus-obtained admixture for 15 minutes, and make it alkaline with concentrated sodium carbonate solution. Filter off the precipitate and wash it with water until it is neutral to obtain 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde [melting point: 181° to 182° C] with a yield of 79%.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[C:7]([Cl:24])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=[C:7]([Cl:24])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1
Reactant: CCOC(=O)c1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.5 %

Procedure:
To a solution of 3,5-dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-benzoic acid ethyl ester (prepared as described in Example 1, Step A) (100 mg, 0.26 mmol) in methylene chloride (3 mL) at −78° C. under nitrogen was added diisobutylaluminum hydride (1M in hexane, 0.6 ml, 0.6 mmol). The reaction mixture was warmed to room temperature and stirred for about 19 hours. The reaction was quenched with methanol (1 ml) and sodium potassium tartrate (0.5M aqueous solution, 2 ml). After stirring for about 15 minutes, the solution was extracted with methylene chloride (3×10 mL). The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried, filtered, and concentrated. The crude product was purified by preparative TLC (methylene chloride) to afford the title compound (75 mg) as a solid. NMR (400 MHz, CDCl3) δ7.39 (s, 2H), 6.85 (d, 1H), 6.69 (d, 1H), 6.43-6.46 (dd, 1H), 4.68 (s, 2H), 3.77 (s, 3H), 3.26-3.30 (sept, 1H), 2.03 (bs, 1H), 1.18 (d, 6H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5](=[O:26])[CH2:6][PH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:27][B-:28]([F:31])([F:30])[F:29].[CH2:32]([O+](CC)CC)C>C(Cl)Cl.C(=O)=O.CC(C)=O>[F:27][B-:28]([F:31])([F:30])[F:29].[C:8]1([P+:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:5]2[CH2:4][CH2:3][CH:2]([CH3:32])[O:26]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC[O+](CC)CC
Reactant: O=C(CCCO)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC1CCC(=C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.5 g of (5-hydroxy-2-oxopentyl)triphenylphosphorane was dissolved in 20 ml of methylene chloride under a nitrogen atmosphere, cooled in dry ice/acetone bath and 15 ml of triethyloxonium tetrafluoroborate as a 1 M solution in methylene chloride was added. The reaction mixture was stirred at about -78° C. for 0.5 hour and allowed to warm to room temperature over about 2 hours, decanted into ice water and stirred vigorously with the addition of an additional 30 ml of methylene chloride. The extraction was repeated twice, the extracts combined, dried over sodium sulfate, the solvent removed under nitrogen gas followed by warming to 40° C. for 2 hours at 0.5 mm. Crystallization from ethyl acetate gave 700 mg of the desired product, m.p. 118.5°-122.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH:12]([C:15]1[S:16][C:17]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][C:26]2([O:25][CH2:24][CH2:23][N:22]([C:20]([C:17]3[S:16][C:15]([CH:12]([CH3:13])[CH3:14])=[N:19][CH:18]=3)=[O:21])[CH2:27]2)[CH2:28][CH2:29]1
Reactant: CC(C)c1ncc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: OCCCCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 9-bromo-1-nonanol (0.446 g) in MeCN (3.9 mL) was added to solution of (2-isopropylthiazol-5-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 114, step b) (0.395 g) and triethylamine (0.36 mL) in MeCN (8.6 mL). The resulting mixture was stirred at 60° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM (25 mL), washed with brine (20 mL) and water (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as a white solid. Yield 0.329 g.
Reaction SMILES: [CH:1]([C:5]1[C:10]([O:11][CH2:12][C:13](O)=[O:14])=[C:9]([Cl:16])[CH:8]=[C:7]([Cl:17])[CH:6]=1)([CH2:3][CH3:4])[CH3:2].S(Cl)([Cl:20])=O>>[CH:1]([C:5]1[C:10]([O:11][CH2:12][C:13]([Cl:20])=[O:14])=[C:9]([Cl:16])[CH:8]=[C:7]([Cl:17])[CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)O
Product: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)Cl

Procedure:
A mixture of 5.8 g of the product of Step C and 40 ml of thionyl chloride was refluxed for 2 hours and was evaporated to dryness under reduced pressure. The oil residue was washed with benzene and evaporated to dryness under reduced pressure to obtain 6.2 g of the desired product which was used as is for the next step.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:39][O:40][CH3:41].[Cl-].[NH4+]>ClCCl>[CH3:39][O:40][CH2:41][O:27][CH:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1
Reactant: COCCl
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
In dichloromethane (45 mL), 7-dehydrocholesterol (2.0 g, 5.2 mmol) was dissolved, then N,N-diisopropylethylamine (2.70 mL, 15.6 mmol) and chloromethylmethylether (1.00 mL, 13.2 mmol) were sequentially added under ice-cooling, followed by stirring at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with dilute aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated to yied a residue. To the residue, methanol was added to triturate to obtain the title compound (1.9 g, 83%).
Reaction SMILES: [ClH:1].[CH:2]1([C:5]2[CH:6]=[C:7]([F:21])[C:8]3[NH:12][C:11](=[O:13])[N:10]([CH:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:9]=3[CH:20]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[CH:2]1([C:5]2[CH:6]=[C:7]([F:21])[C:8]3[NH:12][C:11](=[O:13])[N:10]([CH:14]4[CH2:15][CH2:16][N:17]([CH:32]5[CH2:33][CH2:34][O:29][CH2:30][CH2:31]5)[CH2:18][CH2:19]4)[C:9]=3[CH:20]=2)[CH2:3][CH2:4]1
Reactant: O=C1CCOCC1
Reactant: O=c1[nH]c2c(F)cc(C3CC3)cc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(F)cc(C3CC3)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Cyclopropyl-4-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D29, 0.28 mmol, 86 mg), was dissolved in 1,2-dichloroethane (3 ml) and triethylamine (3 eq., 0.83 mmol, 0.086 g), tetrahydro-4H-pyran-4-one (7 eq., 1.99 mmol, 0.2 g) and sodium triacetoxyborohydride (3 eq., 0.83 mmol, 0.052 g) were added at room temperature and the mixture was stirred at room temperature for one overnight. The reaction mixture was quenched with NaHCO3 (saturated solution) and diluted with dichloromethane, then the two phases were separated by hydrophobic filter and the aqueous was washed with dichloromethane again. The organic phases were combined and the solvent was evaporated to afford the crude product which was purified by chromatography (methanol-NH3-dichloromethane) to afford the free base of the title compound, 100 mg, 98%, M++H=360. This material was dissolved in methanol (2 ml) and HCl (3 eq., 0.046 ml from a 1M solution in diethyl ether) was added at room temperature and the mixture was stirred at room temperature for 5 minutes. The solvent was subsequently evaporated to afford the title compound, 90 mg, 82%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:5]=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:12][CH2:13][N:14]([C:17]5[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:15][CH2:16]4)[NH:7][C:6]=3[CH:5]=[C:4]([C:35]([F:37])([F:38])[F:36])[CH:3]=2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2c(Br)cc(C(F)(F)F)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cc3[nH]c(N4CCN(c5ncccc5C(F)(F)F)CC4)nc23)CC1

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole from Example 146a reacted with piperazine-1-carboxylic acid tert-butyl ester under the conditions of Example 127b to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([CH2:14][O:15][CH3:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 24.6 mg (0.74 mmol, 60% dispersion in mineral oil) NaH in 5 mL THF at 0° C. was added 0.115 g (0.61 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (prepared using route 15 step a) in 1 mL THF dropwise over 10 minutes, and the reaction was stirred at 0° C. for 30 minutes. 46 μL (0.74 mmol) methyl iodide was added and the reaction was stirred at room temperature for 2 hours. 20 mg (0.61 mmol, 60% dispersion in mineral oil) of NaH followed by 38 μL (0.61 mmol) of methyl iodide were added and the reaction mixture was stirred at room temperature for 16 hours. 5 mL of H2O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO4. After filtration, the solvent was evaporated to give the desired product which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][C@H:9]([OH:12])[C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc([C@@H](O)CO)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 116 %

Procedure:
To a stirred solution of (R)-1-(6-methoxypyridin-3-yl)ethane-1,2-diol (2.7 g, 0.016 mol) and pyridine (10 mL) in CH2Cl2 (100 mL) at 0° C. was added p-toluenesulfonyl chloride (3.6 g, 0.019 mol) in small portions. The mixture was slowly warmed to rt and stirred for 24 h, and then diluted with CH2Cl2 (100 mL). The organic phase was washed with aq. NaHCO3, brine, dried (Na2SO4), and concentrated to give a solid (6.0 g). LC-MS: 324.0 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.CS(Cl)(=O)=O.[C:42](O)([C:44](F)(F)F)=[O:43]>CN(C=O)C>[C:42]([N:24]1[CH2:23][CH2:22][C:21]2([C:16]3[C:17](=[CH:18][C:13]([C:11]4[N:10]=[C:9]([O:28][C@@H:29]([C@@H:31]5[CH2:35][C:34](=[O:36])[NH:33][CH2:32]5)[CH3:30])[C:8]5[N:4]([CH:1]6[CH2:2][CH2:3]6)[CH:5]=[N:6][C:7]=5[CH:12]=4)=[CH:14][CH:15]=3)[NH:19][C:20]2=[O:27])[CH2:26][CH2:25]1)(=[O:43])[CH3:44]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCNCC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC2(CC1)C(=O)Nc1cc(-c3cc4ncn(C5CC5)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To solution of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one: (0.094 g, 0.193 mmol) in DMF was added TEA (0.119 g, 1 mmol), then followed by the addition of methanesulfonyl chloride (0.022 g, 0.193 mmol). Reaction was stirred at 0° C. for 10 minutes; LC-MS showed reaction was complete. TFA was added, and the crude material was purified by HPLC.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20])=[CH2:2].FC(F)(F)C(O)=O.[CH2:28]([N:35]([CH2:39][Si](C)(C)C)[CH2:36]OC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[F:20][C:4]1[CH:5]=[C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:7]=[CH:8][C:3]=1[CH:1]1[CH2:2][CH2:36][N:35]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:39]1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(Cc4ccccc4)C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (S)-(−)-N-[[3-[4-vinyl-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 41, Step 1, 3.50 g) and trifluoroacetic acid (0.23 mL) in dry methylene chloride under N2 is treated with a solution of N-benzyl-N-(methoxymethyl) trimethylsilylmethylamine (6.10 g) in dry methylene chloride (50 mL) dropwise over 4.5 hours, and the resulting solution was stirred at ambient temperature for 17 hours. The reaction mixture is then washed with saturated aqueous sodium bicarbonate (30 mL), water (30 mL) and saline (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which is chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of methanol/methylene chloride (1/99-10/90). Pooling and concentration of those fractions with an Rf=0.19 by TLC (methanol/chloroform, 10/90) and trituration with methanol/diethyl ether gives the title compound, NMR (CDCl3, 400 MHz) 7.35, 7.25, 7.13, 6.08, 4.78, 4.03, 3.76, 3.69, 3.62, 2.97, 2.78, 2.56, 2.33, 2.02, 1.85δ.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1.[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCCl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy)ethylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60° C. and treated with 10 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was treated with an additional 1 mL concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHCl13. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (2×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a brown foam.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15]>>[Cl:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCCCl
Reactant: BrCc1ccccc1
Product: ClCCOCCOCc1ccccc1

Procedure:
is prepared from benzyl bromide and 2-(2-chloroethoxy)ethanol by the method described in literature (Bessodes, 1996).