Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:48])[C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]([F:47])([F:46])[F:45])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:48])[C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]([F:47])([F:45])[F:46])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)Nc3ccccc3C(F)(F)F)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)Nc3ccccc3C(F)(F)F)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 5 from tert.butyl 4'-[(2-n-butyl-6-(N-(2-trifluoromethylphenyl-aminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[F:16][C:17]([F:35])([F:34])[C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1>C1COCC1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:30]1([OH:33])[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]3[N:22]([C:18]([C:17]([F:35])([F:34])[F:16])=[N:19][N:20]=3)[N:23]=2)[CH2:28][CH2:29]1
Reactant: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: Clc1ccccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2Cl)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (1.0M in THF, 10 mL, 10.00 mmol) was added dropwise to 1-bromo-2-chlorobenzene (1.91 g, 9.98 mmol) in THF (2.0 mL) cooled to 0° C. over a period of 10 minutes. The resulting solution was stirred at 0° C. for 1 hour then a 2.0 mL aliquot was added dropwise to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (400 mg, 1.40 mmol) in THF (10 mL) cooled to 0° C. over a period of 10 minutes. The resulting solution was stirred at 0° C. for 10 minutes then allowed to warm slowly to room temperature and stirred for a further hour. The reaction mixture was then quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc. The extract was washed with saturated brine, dried over MgSO4 and concentrated by evaporation, then purified by flash silica chromatography, eluting with EtOAc. Pure fractions were evaporated to dryness to afford 4-(2-chlorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (230 mg, 41%) as a colourless solid.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]I>O1CCCC1>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([NH:2][CH3:1])[CH3:28]
Reactant: CN
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2=O
Solvent: C1CCOC1
Product: CNC(C)CCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
718 mg of methylamine are condensed at −78° C. into a solution of 960 mg of 11β-fluoro-3-hydroxy-7α-(6-iodo-hexyl)oestra-1,3,5(10)-trien-17-one in 9 ml of anhydrous tetrahydrofuran and the mixture is stirred overnight at room temperature in a pressure reactor. After the pressure reactor has been opened at −20° C., it is allowed to come to room temperature in order to allow excess methylamine to evaporate. The reaction solution is then added to saturated sodium hydrogencarbonate solution, extracted 3 times with ethyl acetate, dried over sodium sulphate and concentrated in vacuo. 763 mg of 11β-fluoro-3-hydroxy-7α-[5-(methylamino)hexyl]oestra-1,3,5(10)-trien-17-one are obtained as a crude product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:13][CH2:14][CH2:15][NH2:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.Cl[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].[H-].[Na+]>ClCCl.O1CCCC1.CN(C)C=O.CCCCCC.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH:12]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:13][CH2:14][CH2:15][N:16]2[CH2:33][CH2:34][CH2:35][C:36]2=[O:37])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: O=C1CCCN1CCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a dichloromethane solution (6 ml) of the 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butylamine hydrochloride (120 mg, 0.303 mmol) obtained in Example 227 were added N-methylmorpholine (250 μl, 2.69 mmol) and 4-chlorobutyric acid chloride (40.7 μl, 0.364 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with dichloromethane, washed successively with a saturated aqueous solution of ammonium chloride, water and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was dissolved in tetrahydrofuran (5 ml), followed by the addition of sodium hydride (60% dispersion in mineral oil, 14.2 mg, 0.356 mmol) and N,N-dimethylformamide (2 drops). The resulting mixture was stirred at room temperature for 24 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated, whereby the title compound (105 mg, 0.245 mmol, 82%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:14][O+:15](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:14][OH:15])[CH:3]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: OCc1cc(Cl)ccn1
Yield: 43.3 %

Procedure:
A solution of 4-chloropyridine N-oxide (5 g, 38.6 mmol) and trimethyloxonium tetrafluoroborate (5.94 g, 40.1 mmol) in CH2Cl2 (115 mL) was stirred for two hours at ambient temperature. The solvent was evaporated and the residue taken up in MeOH (115 mL) and heated to near boiling. Ammonium persulfate (1.76 g, 7.72 mmol) dissolved in H2O (7.7 mL) was added and the mixture was heated to reflux for 30 min. A second portion of ammonium persulfate (0.88 g) in H2O (3.9 mL) was added and the mixture was refluxed for another 30 min. The solvent was evaporated and the residue was partitioned between CH2Cl2 and aqueous Na2CO3 (10% w/v). The organic layer was washed with H2O, dried over MgSO4, and evaporated leaving 2.4 g (43%) of the title compound. 1H NMR (CDCl3) δ 8.20 (d, 1H, J=5.0 Hz, H-6); 7.31 (s, 1H, H-3); 7.04 (d, 1H, J=5.0 Hz, H-5); 5.46 (s, 1H, OH); 4.61 (s, 2H, CH2).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.[I-].[K+].[NH2:11][C:12]1[C:31]([Cl:32])=[CH:30][C:15]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][C@H:20]2[O:28][CH3:29])=[O:17])=[C:14]([O:33][CH3:34])[CH:13]=1.[OH-].[NH4+]>ClCCl.O>[NH2:11][C:12]1[C:31]([Cl:32])=[CH:30][C:15]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:2]3[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=3)[CH2:21][C@H:20]2[O:28][CH3:29])=[O:17])=[C:14]([O:33][CH3:34])[CH:13]=1
Reactant: Cc1nccnc1Br
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Agent: [I-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2nccnc2C)C[C@H]1OC
Temperature: 120 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of 8.56 parts of 2-bromo-3-methylpyrazine and 0.1 parts of potassium iodide was pulverized and 2 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide were added. The whole was stirred for 3 hours at 120° C. The reaction mixture was taken up in dichloromethane and water and made alkaline with ammonium hydroxide. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The first fractions was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.95 parts (36%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl]benzamide; mp. 169.5° C. (compound 27).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][C:22](=[O:31])[C:23]([F:30])([F:29])[CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:7]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][CH:22]([OH:31])[C:23]([F:29])([F:30])[CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:7]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC[C@H](C)CC(F)(F)C(=O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Reaction time: 0.58 h
Yield: 100.3 %

Procedure:
A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((6S)-4,4-difluoro-6-methyl-3-oxooctyl)-3-(2-tetrahydro pyranyloxy)cyclopentyl]heptanate (D) (72.56 g, 132.7=1) in methanol (290 ml) was cooled to approximately −20° C., and sodium borohydride (5.00 g, 132.2 mmol) was added thereto. After stirring for approximately 35 minutes, acetic acid (7.5 ml, 131=1) was added dropwise, and the reaction mixture was concentrated under reduced pressure. The residue was supplemented with water (326 ml) and extracted three times with ethyl acetate (226 ml). The organic layers were combined, washed with 3% aqueous sodium chloride (323 ml) and saturated aqueous sodium chloride (323 ml), and dried with anhydrous magnesium sulfate (40.6 g). The solution was concentrated under reduced pressure to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((6S)-4,4-difluoro-6-methyl-3-hydroxyoctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (E) (73.01 g; quantitative yield) as a colorless oil.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32](OC(F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:40]C1C=CC(B(O)O)=CC=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([Cl:40])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(Cl)cc2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-chlorophenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 76% yield using 4-chlorophenylboronic acid as the reagent.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]1[CH2:11][CH2:10]2)(=O)=O.[CH3:25][N:26](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:25]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]1[CH2:11][CH2:10]2)#[N:26]
Reactant: CCOC(=O)C1C2CCc3cc(OS(=O)(=O)C(F)(F)F)ccc3C21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)C1C2CCc3cc(C#N)ccc3C21
Temperature: 100 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
Ethyl 5-{[(trifluoromethyl)sulfonyl]oxy}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate (0.2 g, 0.5 mmol) was mixed with Zn(CN)2 (0.82 mmol) and Pd(Ph3P)4 (56 mg, 10 mol %) in DMF (4 ml), bubbled with argon for 5 min and heated at stirring in a closed vial for 14 h at 100° C. Reaction was monitored by GC. The reaction mixture was concentrated by rotary evaporation, mixed with saturated NH4Cl and extracted into ethylacetate (3×15 ml). Organic extract was washed with water and brine, dried under Na2SO4. Concentration gave 0.12 g of product as an oil (yield 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][N:8]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][N:8]=1
Reactant: COc1ncc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](N)C1
Yield: 39.9 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidyl]carbamate (75 mg, 0.15 mmol) in dichloromethane 4.0 ml and trifluoroacetic acid (0.80 mL, 10 mmol) was stirred at RT 4 h. The reaction was concentrated and submitted for reverse phase HPLC to give 222 (25 mg) in 41% yield. MS (ESI) m/z: 418.2. 1H NMR (400 MHz, DMSO) δ 9.45 (s, 2H), 9.32 (s, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 4.24 (d, J=10.2 Hz, 1H), 4.06 (d, J=13.3 Hz, 1H), 4.00 (s, 3H), 3.09 (dd, J=24.2, 12.0 Hz, 3H), 2.63 (s, 3H), 1.94 (d, J=15.0 Hz, 2H), 1.76 (d, J=10.0 Hz, 1H), 1.49 (d, J=10.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:37]=[CH:36][CH:35]=[C:30]([C:31](OC)=[O:32])[CH:29]=1>O1CCCC1>[CH3:25][O:26][C:27]([C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1)=[O:32])=[O:38]
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cccc(C(=O)OC)c2)n1
Yield: 15.9 %

Procedure:
Under the conditions of example 1B, 652 mg of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 3 ml of tetrahydrofuran is mixed with 2.75 ml of n-butyllithium (1.6 molar in hexane) and 427 mg of isophthalic acid dimethyl ester in 3 ml of tetrahydrofuran, worked up and chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 130 mg of an oily crude product is obtained, which is subjected to complete purification of the high-pressure liquid chromatography on silanized silica gel (RP18 material) with methanol/H2O=85/15. 58 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. The reaction mixture was then treated with phenyl isocyanate (247 μL, 2.28 mmol) and Et3N (0.64 mL, 4.56 mmol) and allowed to warm slowly to room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to yield a yellow solid. The yellow solid was dissolved in a minimum amount of CH2Cl2 and EtOAc was added until the solution became turbid. The mixture was placed in a freezer overnight and white crystal formed. The crystals were isolated by filtration and were dried under vacuum to give 126 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea. mp 171.0-174.0° C.;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([Cl:26])([F:25])[F:24])=[N:21][N:22]=2)[N:19]=1>>[Cl:26][C:23]([F:24])([F:25])[C:20]1[N:18]2[N:19]=[C:14]([N:10]3[CH2:9][CH2:8][N:7]([CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:12][CH2:11]3)[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: c1csc(CN2CCNCC2)c1
Product: FC(F)(Cl)c1nnc2ccc(N3CCN(Cc4cccs4)CC3)nn12
Yield: 74 %

Procedure:
A mixture of 1-(thiophen-2-ylmethyl)piperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(thiophen-2-ylmethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 74% yield.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Si:7]([O:14][C@H:15]1[C@H:19]2[O:20][CH2:21][C:22](=O)[C@H:18]2[O:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[C:10]([Si:7]([CH3:8])([CH3:9])[O:14][C@@H:15]1[CH2:16][O:17][C@@H:18]2[C:22](=[CH2:1])[CH2:21][O:20][C@H:19]12)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=O)CO[C@@H]21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 234.7 %

Procedure:
A stirred suspension of methyltriphenylphosphonium bromide (1.84 g, 5.16 mmol) and potassium tert-butoxide (578 mg, 5.16 mmol) in tetrahydrofuran (15 mL) was heated at reflux under an atmosphere of argon for 3 hours then allowed to cool to ambient temperature. A solution of ketone (87) (888 mg, 3.44 mmol) in tetrahydrofuran (7.5 mL) was added then heating at reflux continued for 2.25 hours. The mixture was diluted with water (30 mL) then the product extracted into diethyl ether (2×30 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered and reduced in vacuo to leave residue (2.07 g). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 15:85 gave alkene (88) as a colourless oil (799 mg, 91%).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH:12](CO)[CH2:13][C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1.[CH2:28]([OH:30])[CH3:29]>[OH-].[OH-].[Pd+2]>[OH:30][CH2:28][CH2:29][CH:12]1[CH2:11][CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])([OH:17])[CH2:13]1
Reactant: CCO
Reactant: COc1ccccc1C1(O)CC(CO)CC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Product: COc1ccccc1C1(O)CC(CCO)CC2CNCC21
Reaction time: 3 h

Procedure:
A suspension of 3.1 g of (3aRS,4RS,6SR,7aSR)-2-benzyl-6-hydroxymethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol and 0.5 g of 20% palladium hydroxide on charcoal in 75 cm3 of ethanol is hydrogenated at atmospheric pressure for 3 hours at 60° C. The reaction mixture is subsequently filtered and evaporated to dryness under reduced pressure (2.7 kPa). 3.0 g of (3aRS,4RS, 6SR, 7aSR)-6-hydroxyethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained in the form of a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([Cl:15])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc(Br)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
The raw material meta-bromophenylacetic acid (100 g, 0.47 mol, 1.0 eq) was dissolved in dichloromethane (500 ml), then was cooled to 0° C. in ice-salt bath. Oxalyl chloride (120 g, 0.95 mol, 2.0 eq) was added dropwise to the reaction mixture with temperature maintaining 0° C. After the dropping was finished, the reaction temperature was changed to room temperature and reacted for two hours. The reaction mixture was concentrated under reduced pressure to obtain meta-bromophenylacetyl chloride (110 g, 0.47 mol) after the reaction completed. The obtained meta-bromophenylacetyl chloride was dissolved in dichloromethane (200 ml) for further use.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H].C(OC(C)C)(C)C>[Pd].CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Yield: 66.4 %

Procedure:
A Parr bottle was charged with (4-nitrobenzyl)-methy-carbarnic acid tert-butyl ester (30.0 g, 113 mmol), 150 mL EtOAc, and 10% Pd/C (3.0 g, 10 wt %), and shaken under 40 psi hydrogen for 90 min. When hydrogen uptake ceased, the reaction vessel was purged with nitrogen, filtered through celite, and concentrated to provide a tan solid, which was granulated with 300 mL of isopropyl ether to provide the title compound as an off-white solid (17.7 g in two crops, 75 mmol, 66% yield):