Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]=O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([CH:17]=[CH:18][N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CCBr
Reactant: Nc1ncccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COc2cccn3ccnc23)cc1

Procedure:
2-Amino-3-benzyloxypyridine is reacted with bromoacetaldehye in aqueous tetrahydrofuran in the presence of sodium hydrogen carbonate, whereby the above-identified compound is obtained.
Reaction SMILES: [O:1]([C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[C:10]([NH:12][C:13]1[CH:34]=[CH:33][C:16]2[N:17]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:21][C:22]([O:24]CC)=[O:23])[CH:18]=[N:19][C:15]=2[CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C>Cl>[O:1]([C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[C:10]([NH:12][C:13]1[CH:34]=[CH:33][C:16]2[N:17]([CH:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][C:22]([OH:24])=[O:23])[CH:18]=[N:19][C:15]=2[CH:14]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3Oc3ccccc3)ccc21
Agent: Cl
Solvent: CC#N
Product: O=C(O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3Oc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 3-{5-[(2-phenoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (68 mg, 135 μmol) in a mixture of hydrochloric acid (20 mL of a 5N solution) and acetonitrile (20 mL) was stirred at room temperature for 48 hours. The solution was then concentrated in vacuo, and the resulting solid filtered off and vacuum-dried to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=2.70 min, MH+ 478].
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[C-:11]#[N:12].[Na+]>O>[C:11]([C:4]1([OH:10])[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH2:3]1)#[N:12]
Reactant: O=C1CN2CCC1CC2
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC1(O)CN2CCC1CC2
Yield: 96.6 %

Procedure:
1,420 g (8.78 mole) of quinuclidine-3-one-hydrochloride were dissolved in 1800 ml of cold water and at 15° C., 432 g (8.81 mole) of sodium cyanide and 1600 of ml water were added dropwise over one hour followed by stirring for another hour at this temperature. The mixture was filtered, washed with cold water, and dried at 60° C. to obtain 1,290 g (8.48 mole) of 3-cyano-3-hydroxy-quinuclidine (97% yield), in the form of white crystals having a melting point of 157° to 159° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[CH3:16][N:17]1[C:21]([CH3:22])=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][N:17]1[C:21]([CH3:22])=[C:20]([C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)[CH:19]=[N:18]1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(C)nc(SC)nc1-c1cnn(C)c1C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (0.179 g, 0.726 mmol), 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.242 g, 1.088 mmol), and PdCl2(dppf) (0.106 g, 0.145 mmol) were dispersed in DMA (2 mL). After 10 min, 2 N sodium carbonate (1.814 mL, 3.63 mmol) was added to the reaction mixture. The reaction mixture was purged with nitrogen, sealed in a vial, and then heated at 80° C. for 5 h. The mixture was subsequently filtered through a pad of Celite, rinsed with MeOH, and the filtrate was purified via reverse phase preparative HPLC. The fractions were concentrated in vacuo to give the title compound as tan needles (0.159 g, 71%). [M+H] calc'd for C14H18N4O2S, 307; found, 307.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[C:8]1([CH2:14][CH2:15][NH:16][NH2:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:14][CH2:15][NH:16][N:17]=[CH:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C(=NNCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.4 %

Procedure:
100 ml of aqueous 10% sodium hydroxide solution were added to an aqueous solution (50 ml) of 14.55 g of (2-phenylethyl)hydrazine sulfate, and 2.25 g of sodium hydroxide were added thereto and stirred at room temperature for one hour. The reaction solution was extracted with 250 ml of dichloromethane, dried over magnesium sulfate, concentrated under reduced pressure and dried. The resulting residue was dissolved in 100 ml of ethanol, and 5.55 g of benzaldehyde were added thereto and heated under reflux for 6 hours. This reaction solution was concentrated under reduced pressure and dried to obtain 11.38 g of a crude product of the intended compound as an yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:8]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[O:11][N:10]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Product: COC(=O)COc1ccc(-c2noc(-c3sccc3Cl)n2)cc1

Procedure:
The title compound was prepared from 4-[5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-phenol and methyl bromoacetate by a procedure similar to that of Example 37 as a white solid, (30.3 mg, 52.0%). 1H NMR (DMSO-d6): 8.18 (d, J=5.1 Hz, 1H), 8.00 (d, J=8.7 Hz, 2H), 7.42 (d, J=5.1 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 4.90 (s, 2H), 1.2 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.CN(C1CCCCC1)C1CCCCC1.Cl[CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:7]=2)[CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-tert-butyl 4-((1-(5-bromo-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (340 mg, 0.639 mmol) and N-methyldicyclohexylamine (0.205 mL, 0.958 mmol) in tetrahydrofuran (2 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (0. 159 mL, 0.894 mmol). The ice bath was removed and the reaction stirred at room temperature overnight. The reaction was poured into diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 383 mg (91%) as a foam. 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.66 (s, 1H), 7.30 (m, 2H), 7.02 (m, 2H), 6.89 (s, 1H), 5.64 (qAB, JAB=10.7, 2H), 4.92 (q, J=6.4, 1H), 3.71 (m, 2H), 3.59 (m, 2H), 3.35 (qAB, JAB=9.2, 2H), 3.05 (m, 2H), 2.18 (m, 1H), 2.06 (m, 1H), 1.93 (m, 1H), 1.86 (m, 1H), 1.42 (m, 12H), 0.90 (m, 2H), −0.07 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 162.4, 160.5, 155.1, 145.6, 138.8, 135.9, 128.9 (d, J=7.7), 124.9, 123.6, 122.2, 121.1, 116.2, 115.3, 115.2, 81.9, 79.4, 77.9, 73.9, 67.6, 41.3, 40.3 (br), 32.3, 31.9, 28.6, 22.9, 17.9, −1.3.
Reaction SMILES: [CH3:1]OC(C1CC2C(=CC=C(S)C=2)C1)=O.[CH3:15][O:16][C:17](=[O:48])[CH2:18][CH:19]1[C:27]2[C:22](=[CH:23][C:24]([S:30]CC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)=[C:25]([O:28][CH3:29])[CH:26]=2)[CH2:21][CH2:20]1>>[CH2:15]([O:16][C:17](=[O:48])[CH2:18][CH:19]1[C:27]2[C:22](=[CH:23][C:24]([SH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[CH2:21][CH2:20]1)[CH3:1]
Reactant: COC(=O)CC1CCc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)c(OC)cc21
Reactant: COC(=O)C1Cc2ccc(S)cc2C1
Product: CCOC(=O)CC1CCc2cc(S)c(OC)cc21

Procedure:
19C was prepared analogously to compound 1C. Used as unpurified oil. MS: 267 (M+1)+. Preparation of {6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-1-yl}-acetic acid methyl ester (Compound 19D)
Reaction SMILES: [C:1]1([S:19]([Cl:22])(=[O:21])=[O:20])[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[C:11](S(Cl)(=O)=O)[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[C:1]1([S:19]([Cl:22])(=[O:20])=[O:21])[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cccc2nc3cccc(S(=O)(=O)Cl)c3cc12
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1cccc2nc3ccccc3cc12

Procedure:
Add acridine (5 g, 28 mmol) in portions to chlorosulfonic acid (7 mL, 2.2 eq) over 5 minutes with efficient stirring. Heat the reaction mixture to reflux for 5 hours. Cool the reaction mixture to room temperature and add cautiously to crushed ice (200 mL). Adjust the suspension to alkaline pH (phenolphthalein indicator) with sodium bicarbonate solid added in portions. Extract with methylene chloride (100 mL), wash the organic layer with saturated aqueous sodium carbonate (100 mL), saturated aqueous sodium chloride (100 mL). Dry the organic layer (MgSO4), filter and concentrate in vacuo to give an orange solid. Chromatograph on a column of silica gel (800 mL) eluting with 3:2 ethyl acetate:hexane to give the sulfonyl chloride as an apparent mixture of isomers (2.71 g) and the acridine-1,8-disulfonyl chloride (2.28 g) side product, both as yellow solids. Rf=0.85 (mono), 0.50 (di) (100% ethyl acetate)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][CH:18]([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=O>>[F:17][CH:18]([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccccc1OC(F)F
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2OC(F)F)o1
Yield: 86 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-(difluoromethoxy)-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 294 mg, 86%) which was obtained as a white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:17](=[O:27])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:32]([O:31][C:29](=[O:30])[NH:28][C:14]1([C:17](=[O:27])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CCc1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCNCC2)cc1

Procedure:
A solution of 2.86 g (5.9 mmol) 4-tert-Butoxycarbonylamino-4-(4-ethyl-phenylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (example 132, step 1) in 70 mL methanol was hydrogenated over 290 mg Pd/C (10%) with H2 (1 bar) for 2 h at room temperature. After filtration the filtrate was evaporated to dryness to yield after drying under high vacuum 2.05 g (99%) of the title compound as off-white solid. MS (m/e): 348.3 [(M+H)+].
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[NH2:13][C:14]([CH3:21])([CH:18]([CH3:20])[CH3:19])[C:15]([NH2:17])=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:15]([C:14]([N:13]=[CH:1][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])([CH3:21])[CH:18]([CH3:20])[CH3:19])(=[O:16])[NH2:17]
Reactant: COC(=O)c1ccccc1C=O
Reactant: CC(C)C(C)(N)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1C=NC(C)(C(N)=O)C(C)C
Reaction time: 3 h

Procedure:
A mixture containing 5.0 g methyl 2-formylbenzoate [C. Brown and M. V. Sargent, J. Chem. Soc. (C), 1818 (1969)] and 4.0 g 2-amino-2,3-dimethylbutyramide and 50 mg p-toluenesulfonic acid in 100 mL toluene is heated under reflux under a Dean-Stark water separator for three hours. The mixture is filtered and concentrated in vacuo. The residue crystallizes on standing and is recrystallized from etherhexane to give analytically pure methyl o-[N-(1-carbamoyl-1,2-dimethylpropyl)formimidoyl]benzoate, mp 79°-80.5° C.
Reaction SMILES: [C:1]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:21]([N:24]([CH2:33][C@@H:34]([OH:44])[C@@H:35]([NH2:43])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.CI>CN(C=O)C.C(OCC)(=O)C>[CH:21]([N:24]([CH2:33][C@@H:34]([OH:44])[C@@H:35]([NH:43][C:18](=[O:20])[C@H:14]([CH:15]([CH3:16])[CH3:17])[NH:13][C:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])([CH3:23])[CH3:22]
Reactant: CC(C)N(C[C@@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a mixture of 0.0643 g (0.24 mmol) of the acid from Step A, 0.0797 g (0.236 mmol) of the the amine from Step B, 0.032 g (0.24 mmol) of 1-hydroxybenzotriazole in 0.5 ml of anhydrous DMF was added 0.071 g (0.24 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide. After stirring overnight at room temperature the mixture was diluted to 30 ml with ethyl acetate and Washed successively with water, 5% aqueous sodium bicarbonate, 2% aqueous potassium bisulfate solution, and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel, hexane/ethyl acetate 3:2) gave 0.091 g (65% yield) of the title compound, melting at 186°-189° C.: Rf (B)=0.19; Rf (C)=0.83; NMR (CDCl3) 1.0 (m, 12H, val and isopropyl CH3); 1.71 (s, 9H, t-butyl CH3); 2.3 (m, 1 H, val CH-β); 2.5-3.27 (m, 3H, butyl CH-3, CH2); 3.5 (m, 1 H, isopropyl CH); 4.31 (m, 2H, val CH-α, OH); 5.43 (broad s, 1 H, carbazate NH); 6.22 (broad d, 1H, butyl NH); 6.7-8.73 (m, 12H, aromatic, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O.CCOCC>CC#N>[F:14][C:10]1[C:3]([O:2][CH3:1])=[C:4]([C:7]([O:11][CH3:12])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cccc(OC)c1C=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(F)c(OC)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Commercially available 2,6-dimethoxybenzaldehyde (3.500 g; 21.10 mmol) was added to a suspension of Selectfluor (8.208 g; 23.20 mmol) in MeCN (35 ml), and the resulting mixture was stirred at rt, under nitrogen, for 16 h. Water and Et2O were added and the aq. layer was further extracted with Et2O. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=4/1) afforded 3-fluoro-2,6-dimethoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 185.10 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[NH:11][C:10]1=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Si:35]([O:42][CH2:43][CH2:44][C:45]1([S:48](Cl)(=[O:50])=[O:49])[CH2:47][CH2:46]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[N:11]([S:48]([C:45]2([CH2:44][CH2:43][O:42][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:46][CH2:47]2)(=[O:50])=[O:49])[C:10]1=[O:24]
Reactant: Cc1ncnc2c(F)c3c(cc12)[nH]c(=O)n3-c1ccc(I)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCC1(S(=O)(=O)Cl)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c3c(cc12)n(S(=O)(=O)C1(CCO[Si](C)(C)C(C)(C)C)CC1)c(=O)n3-c1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-fluoro-4-iodophenyl)-4-fluoro-8-methyl-1H-imidazo[4,5-g]quinazolin-2(3H)-one (example 34, step H) (90 mg, 0.22 mmol) in THF (5 ml) at −78° C. is added LiHMDS (0.29 ml, 1 M in THF, 0.29 mmol). The reaction mixture is stirred at −78° C. for 30 min and 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropane-1-sulfonyl chloride (99 mg, 0.33 mmol) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction is quenched with saturated aqueous NH4Cl solution (20 ml) and extracted with EtOAc (2×30 ml). The combined organic solution is washed with brine (30 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the desired product.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CC([C:9]([CH:14]([CH3:16])[CH3:15])([OH:13])[CH2:10][CH:11]=[CH2:12])C.C(=O)C1C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>CCCCC.C1COCC1.[Zn+2].[Br-].[Br-].C(OCC)C>[C:14]1([CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])[CH:15]=[CH:3][CH:2]=[CH:1][CH:16]=1
Reactant: C=CCC(O)(C(C)C)C(C)C
Reactant: [Li]CCCC
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.29 ml of a 1.4-molar solution of n-butyllithium (3.20 mmol) in pentane were added dropwise at 0° C. under argon for 2 minutes to a stirred solution of 500 mg (3.20 mmol) 2-methyl-3-isopropyl-hex-5-en-3-ol in 2 ml THF. The solution obtained was heated to room temperature, stirred for 15 minutes, and then a solution of 721 mg (3.20 mmol) ZnBr2 in 2 ml THF and subsequently 330 μl (3.20 mmol) benzaldehyde and 6 ml HMPA were added. The reaction mixture was heated to 70° C. and stirred for 6 hours at this temperature. Subsequently, it was cooled to room temperature and processed analogous to Example 1. The raw product obtained was cleaned by means of a silica column with 15% diethyl ether/light gasoline. There was obtained the alcohol as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.Cl[C:13]1([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:18])[CH:16]=[CH:15][S:14]1.CC1(C)CCCC(C)(C)N1>C(Cl)(Cl)Cl>[OH:18][C:17]1[CH:16]=[C:15]([N:9]2[C:7]3=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]3[N:11]=[CH:10]2)[S:14][C:13]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COc1ccc2[nH]cnc2n1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Agent: CC1(C)CCCC(C)(C)N1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3ccc(OC)nc32)cc1O

Procedure:
In a similar manner as described for example C2, 8.54 g of the above-synthesized 5-methoxy-1H-imidazo[4,5-b]pyridine and 4.46 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate and 13.07 g of 2,2,6,6-tetramethylpiperidine in 620 ml chloroform yield the title compounds as an isomeric mixture which was used for the next step (example B7) without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=3)([OH:15])[CH:11]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.C(O)C.C[Si](C)(C)[Cl:43].O>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(O)C.O>[ClH:43].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)([OH:15])[CH:11]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)Cl
Reactant: COc1cccc(C2(O)CCC(CCC3CCCC3)CC2CN(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN(C)CC1CC(CCC2CCCC2)CCC1(O)c1cccc(O)c1
Reaction time: 6.5 h

Procedure:
The reaction was conducted in a nitrogen atmosphere with the exclusion of moisture. 1.44 g (4 mmole) of the base of compound (52) were dissolved in 15 ml toluene. 25 ml of 20% diisobutylaluminium hydride in toluene (35 mmole) were added drop-wise with stirring. The mixture was subsequently boiled for 6.5 hours under reflux and was cooled. 5 ml ethanol, followed by 5 ml of 1:1 ethanol/water and 35 ml toluene, were added drop-wise at a temperature between 0° C. and 10° C. After stirring for one hour, the salts obtained were filtered off by suction and the solvent was removed by distillation. The oil obtained was then taken up in ethyl acetate. After adding trimethylchlorosilane/water, compound (57) was obtained in a yield of 0.35 g (23% theoretical).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: ClCCN1CCCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)CC2c1ccccc1

Procedure:
The title compound, MS: m/e=568.3 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)(O)=[O:2].[NH3:25]>C1(C)C=CC=CC=1.O=S(Cl)Cl.CO>[C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)(=[O:2])[NH2:25]
Reactant: N
Reactant: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@]12CCC(=O)CC1[C@@H](C(N)=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 85 °C
Reaction time: 5.5 h

Procedure:
To a stirred suspension of 6α-carboxyandrostane-3,17-dione (II-aq, Prepn. 17, 600 mg) in dry toluene (12 mL), SOCl2 (623 μL) was added. After stirring 5.5 h at 85° C. the solution was cooled at 0° C. and 2M NH3 solution in MeOH (2.97 mL) was added. After stirring overnight at room temperature, the mixture was evaporated to dryness. The residue was treated with CH2Cl2 and H2O and extracted with CH2Cl2. The combined organic extracts were washed with 10% K2CO3 solution, brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 50/50) to give the title compound II-ar (90 mg, 15%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.27 (bs, 1H), 6.78 (bs, 1H), 2.50-0.72 (m, 21H), 1.00 (s, 3H), 0.80 (s, 3H).