Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCOCC5)n4c3)c3ccccc32)ccc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCOCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(O)c2)n1
Yield: 29.8 %

Procedure:
A solution of Intermediate 64a (243 mg, 0.29 mmol) and TBAF (1M in THF, 1.3 mL, 1.33 mmol) in THF (3 mL) was stirred at RT for 1 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the product. This was further purified by HPLC (XBridge C18 column, 25-98% MeCN in H2O, 0.1% NH4OH) to give the title compound (58 mg, 29%). LCMS (Method 5): Rt 4.10 min, m/z 671 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.84-2.13 (6H, m), 3.46-3.50 (4H, m), 3.81-3.92 (4H, m), 4.81-4.85 (1H, m), 5.52 (1H, t, J=4.4 Hz), 6.33 (1H, s), 6.94 (1H, dd, J=8.5, 2.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.12-7.19 (2H, m), 7.31-7.43 (4H, m), 7.43 (1H, d, J=8.5 Hz), 7.60-7.62 (2H, m), 8.12 (1H, s).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[C:28]([O:27][CH3:26])=[N:36][CH:35]=[CH:34][CH:33]=4)=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ncccc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccnc4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methoxynicotinic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:7][CH:6]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C>[C:15]1(=[O:16])[N:11]([CH2:10][C:8]2[S:9][C:5]([C:3]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]4[CH:2]=3)=[CH:6][CH:7]=2)[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]12
Reactant: O=C(CBr)c1ccc(CN2C(=O)c3ccccc3C2=O)s1
Reactant: Nc1ccccn1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2cn3ccccc3n2)s1
Yield: 48.1 %

Procedure:
5-Bromoacetyl-2-(phthalimidomethyl)thiophene (0.80 g) and 2-aminopyridine (0.23 g) were dissolved in anhydrous ethanol (50 ml) and heated under reflux for 6 hours. The resulting crystals were collected by filtration and purified by a silica gel column chromatography (chloroform:methanol=100:1) to give 0.38 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]COCC.[Mg].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]([CH3:33])([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(=O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CCOCC
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCCC(C)(O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 1.75 g of 1-(3,4-dibenzyloxyphenyl)-3-nonanone in 10 ml of tetrahydrofuran was cooled to 0° to 5° C. and then an ether solution of a Grignard reagent prepared from 0.24 g of metallic magnesium and 1.7 g of methyl iodide was added dropwise to the mixture. Thereafter, the resultant mixture was stirred for 15 minutes and after adding thereto 50 ml of an aqueous 5% hydrochloric acid solution, the product was extracted with toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 1.6 g of 1-(3,4-dibenzyloxyphenyl)-3-methyl-3-nonanol.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CCO>[CH2:18]([N:20]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1)[CH2:21][CH3:22])[CH3:19]
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), N-ethylethanamine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.3), 95 (4), 87 (6), 86 (bp), 75 (4), 58 (7).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]1[CH2:14][CH2:13]1)(=[O:10])=[O:9].C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C(Cl)Cl>[CH:12]1([N:11]2[C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH2:14][CH2:13]1
Reactant: Nc1ccccc1S(=O)(=O)NC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2S(=O)(=O)N1C1CC1
Reaction time: 12 h
Yield: 83.9 %

Procedure:
A solution of of 2-amino-N-cyclopropyl-benzenesulfonamide (6.9 g, 32.5 mmol) in CH2Cl2 (50 ml) was treated with CDI (6.5 g, 40 mmol) and stirred for 12 h at reflux. The solution was a washed with HCl (1N), dried over MgSO4 and concentrated to give 6.5 g (84%) of 2-cyclopropyl-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo[1,2,4]thiadiazin-3-one as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[N:12]=3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CCCCC1
Reaction time: 0.62 h
Yield: 91.7 %

Procedure:
Add 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (See Example 34) (0.290 g, 0.830 mmol), Pd(Ph3)4 (0.043 g, 0.037 mmol), 4-methanesulfonylphenylboronic acid (0.249 g, 1.25 mmol), 2N Na2CO3 (2.1 mL), and 1,4-dioxane (1 mL) to a microwave vessel. Microwave at 30 W, 90° C. for 30-45 minutes. Concentrate and purify on silica gel eluting with 10% 2N NH3 in methanol/dichloromethane to give 1-{2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.323 g, 92%).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([O:20][C:8]3[C:9]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=4)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=3)=[CH:23][CH:24]=[N:25]2)=[CH:30][CH:29]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2nc(C)c(C)cc2Oc2ccnc3cc(Cl)ccc23)nc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4,7-dichloroquinoline (139 mg), and cesium carbonate (228 mg), and the mixture was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (77 mg, yield 94%).
Reaction SMILES: [CH2:1]=[C:2]=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]N=O>>[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:2]([CH3:1])=[O:3]
Reactant: C=C=O
Reactant: CCCCCON=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCOC(C)=O
Reaction time: 3 h
Yield: 12.8 %

Procedure:
The procedures of Example 11 were followed, except that ketene was introduced at the rate of 32.0 ml/min (1.43 mmole/min) and that triphenylphosphine (0.066 g, 0.25 mmole) was dissolved in the further added n-amyl nitrite (50 ml). The reaction proceeded smoothly for three hours, during which no deactivation of the catalyst was observed. The reaction product was analyzed by gas chromatography, revealing that n-di-amyl malonate (165.6 mmoles, 64.5%) and n-amyl acetate (32.9 mmoles, 12.8%) were obtained.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34]N>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccc(F)cc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc(F)cc1F

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2,4-difluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=435.1 (M+H)+
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH3:33])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:34])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:36]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH3:33])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)([F:36])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:34])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: COc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Agent: Cl
Product: COc1nnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 222) but using compound 11.2 HCl salt in place of compound 1.5. m/z (ES+) 474 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:15]=[N:16][N:17]=2)[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]=[CH:9]2)[CH:7]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:3]2[N:4]([CH:15]=[N:16][N:17]=2)[N:5]=[C:6]([N:8]2[CH:9]=[CH:10][C:11](=[O:14])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: Cc1cc(N2C=CC(O)CC2)nn2cnnc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(N2C=CC(=O)CC2)nn2cnnc12

Procedure:
A solution of 116 mg of 1-(8-methyl-1,2,4-triazolo-[4,3-b]pyridazin-6-yl)-1,4,5,6-tetrahydro-4-pyridinol in 15 ml of dichloromethane was treated with 500 ml of manganese dioxide and heated to reflux. The mixture was refluxed for 64 hours and the solids were filtered off through Celite and washed well with fresh hot dichloromethane. Evaporation of the solvent from the filtrate gave 2,3-dihydro-1-(8-methyl-1,2,4-triazolo [4,3-b]pyridazin-6-yl)-4(1H)-pyridinone melting at about 264°-266° C. with decomposition. Crystallization of a portion of this material from methanol gave a purified product as pale yellow needles melting at about 270.5°-271.5° C. with decomposition. This material was identical with the product obtained in Example 5.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1cccc(F)c1CBr
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2c(F)cccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)-1,3-difluorobenzene (0.56 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.40 g, 55%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([CH:10]=[O:11])[N:7]=[CH:6]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([Si](C)(C)C)([F:21])[F:20]>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([CH:10]([OH:11])[C:19]([F:21])([F:20])[F:18])[N:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: O=Cc1cn(CC2CC2)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cn(CC2CC2)cn1)C(F)(F)F
Yield: 43.7 %

Procedure:
According to Reference Example 8-2, by use of 1-(cyclopropylmethyl)-1H-imidazole-4-carbaldehyde (133 mg, 0.886 mmol) obtained in Step 1 of Reference Example 8-49 and dissolved in N,N-dimethylformamide (2.7 mL), potassium carbonate (24 mg, 0.18 mmol) and (trifluoromethyl)trimethylsilane (0.196 mL, 1.33 mmol), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 1-(1-(cyclopropylmethyl)-1H-imidazol-4-yl)-2,2,2-trifluoroethanol (Compound DX) (85.2 mg, yield: 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=3)[N:11]([CH2:30][CH3:31])[C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCI
Reactant: N#Cc1ccc(CC23CCCC=C2N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C2=CCCCC21Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (150 mg) (0.38 mmol) in DMF (5 ml) was carefully dropped on a suspension of NaH 60% (18.2 mg) (1.2 eq) in DMF (5 ml) at RT. The reaction mixture was stirred 1 h at RT, then ethyl iodide (0.046 ml) (1.5 eq) was added. After one night, the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated to yield a solid which was purified by HPLC to give 4-[1-(3,5-Dichlorophenyl)-3-ethyl-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (18.2 mg) as a white solid. 1H NMR (CDCl3):. 7.55 (2H, d), 7.25 (2H, d), 7.10 (1H, m), 6.80 (2H, m), 4.95 (1H, m), 3.75 (1H, m), 3.15 (1H, m), 3.0 (2H, s), 2.5-1.7 (6H, m), 1.25 (3H, t).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:26]([NH2:32])[CH:27]1[O:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:32][CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][O:31]1)=[O:13])[CH2:8]2
Reactant: NCC1CCCO1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCC1CCCO1

Procedure:
Phenyl-5-[(tetrahydro-furan-2-ylmethyl)-amino]-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and tetrahydrofurfurylamine. Mass spectrum (ES) MH+=421.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:10]=1)=[O:8])[CH3:5].[CH3:27][O-:28].[Na+]>CN1CCCC1=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:7]2[O:8][C:3]([CH2:2][O:28][CH3:27])=[C:4]([CH3:5])[N:6]=2)=[N:10]1
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COCc1oc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1C
Yield: 25.6 %

Procedure:
136 mg of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (0.267 mmol) and 47 mg of sodium methylate were stirred in 0.6 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture was cooled and purified directly by column chromatography (SiO2). 24 mg (20%) of 2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-methoxymethyl-4-methyl-oxazole were isolated as yellowish crystals.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@H:7]1[CH2:24][C@@:23]2([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][C@H:16]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]2=[O:26])[CH2:9][CH2:8]1)(=[O:5])[CH3:4].O>CO>[C:3]([O:6][C@H:7]1[CH2:24][C@@:23]2([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][C@H:16]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C@@H:17]2[OH:26])[CH2:9][CH2:8]1)(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@@H]1CC[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)O[C@@H]1CC[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C1
Reaction time: 1 h
Yield: 54 %

Procedure:
Sodium borohydride (9.40 g) was added portionwise to a stirred solution of 2β-acetyloxy-16β-(1-piperidinyl)-5α-androstan-17-one (46.99 g) in methanol (235 ml). After 1 h, water (300 ml) was added to precipitate the product as a gum, which was extracted into diethyl ether (300 ml). The extract was washed neutral with water (3×300 ml), dried (MgSO4) and evaporated to dryness. Crystallisation of the residue from methanol afforded 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol 2-acetate (25.49 g), m.p. 162°-166° C., [α]D +29.1° (c 0.45 in CHCl3).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:53][CH2:52]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:54][O:55][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:52][CH2:53]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:54][OH:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CO
Solvent: CC(=O)Cl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Crude [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 1c (4.26 g, 4.92 mmol) was dissolved in 30 mL methanol, followed by addition of acetyl chloride (52 μL, 0.74 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 1d (2.3 g, yellow grease), yield: 62.2%. 1H NMR (400 MHz, CDCl3): δ 7.35 (m, 13H), 7.20 (m, 3H), 7.03 (m, 4H), 6.80 (d, 2H), 4.92 (m, 3H), 4.70 (m, 1H), 4.50 (m, 1H), 4.17 (m, 1H), 4.05 (m, 3H), 3.85 (m, 6H), 3.70 (m, 2H), 3.40 (m, 1H), 3.30 (m, 1H), 3.07 (s, 3H), 0.63 (m, 2H), 0.48 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)CCc1ccccc1
Yield: 48.8 %

Procedure:
Using the method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.2 g, 0.78 mmol) was reacted with hydrocinnamoyl chloride (0.11 mL, 0.74 mmol) to provide 0.14 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenylpropanamide as a white solid, m.p. 148-150° C. 1H NMR (500 MHz, DMSO-d6) δ8.19 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.82 (t, J=6.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 2H), 7.15 (m, 3H), 6.66 (broad s, 2H), 4.58 (t, J=7.0 Hz, 2H), 3.06 (q, J=6.0 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.31 (t, J=7.0 Hz, 2H), 1.79 (quintet, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 2H); MS (EI) m/e 387.2067 (387.2059 calcd for C23H25N5O).