Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][N+:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[Cl:18][C:19]1[CH:20]=[N:21][N:22]([CH2:6][CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][C:2]([OH:1])([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:11][CH2:10]2)[CH:23]=1
Reactant: Clc1cn[nH]c1
Reactant: OC1(c2ccccc2)CC[N+]2(CCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OC1(c2ccccc2)CCN(CCCCn2cc(Cl)cn2)CC1
Yield: 77.3 %

Procedure:
A mixture of 15.0 g (48 mmol) of 8-hydroxy-8-phenyl-5-azoniaspiro[4,5]decane, 5.4 g (53 mmol) of 4-chloropyrazole and 13.2 g of potassium carbonate in 200 ml of dimethylformamide is heated at reflux for 20 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporation is carried out at reduced pressure, a crude product being obtained which is suspended in ethyl ether, which is filtered while cold and which is washed with ethyl ether. 12.4 g (37.1 mmol) of 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidyl)butyl]-1H-pyrazole are obtained.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:38]2=[O:52])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:38]2=[O:52])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained as a white powder: 1H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.17-6.85 (m, 5H), 6.22 (s, 1H), 5.83 (s, 2H), 5.04 (t, 1H), 4.56-4.08 (m, 5H), 3.69 (m, 1H), 1.18 (t, 3H); MS (ES+) m/z 408.1 (M+23).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH:22]=[CH:21][O:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH:32]([F:34])[F:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:33][CH:32]([F:34])[O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][O:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH:22]=[CH:21][O:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cn1cc(-c2cc(O)cc(S(C)(=O)=O)c2)c2ccoc2c1=O
Reactant: FC(F)Oc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCc3ccccc3OC(F)F)cc(S(C)(=O)=O)c2)c2ccoc2c1=O
Temperature: 80 °C
Yield: 57.8 %

Procedure:
A capped mixture of 4-(3-hydroxy-5-methylsulfonylphenyl)-6-methylfuro[2,3-c]pyridin-7-one (25 mg, 0.08 mmol), 1-(bromomethyl)-2-(difluoromethoxy)benzene (28 mg, 0.12 mmol), and Cs2CO3 (50 mg, 0.15 mmol) in DMF (900 uL) was heated to 80° C. for 3 h. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (22 mg, 58%) as a white solid. LCMS (M+H)+=476.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([NH:13][C@@H:14]([C:19]([OH:21])=[O:20])[C:15]([SH:18])([CH3:17])[CH3:16])(=[O:12])[CH3:11]>Cl>[C:10]([N:13]1[C@@H:14]([C:19]([OH:21])=[O:20])[C:15]([CH3:17])([CH3:16])[S:18][C@@H:6]1[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:12])[CH3:11]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)(C)S
Agent: Cl
Product: CC(=O)N1[C@@H](c2ccc(Cl)cc2)SC(C)(C)[C@@H]1C(=O)O
Reaction time: 0.2 h
Yield: 88.4 %

Procedure:
4.2 g (30 mmoles) of 4-chlorobenzaldehyde are given to the suspension containing 5.73 g (30 mmoles) of N-acetyl-D-penicillamine in 18 ml of ethereal hydrogen chloride solution under stirring for 12 minutes. After dissolution, a product is precipitated which is filtered out and washed with ether to give 8.32 g (88.4%) of the title compound, m.p.: 197°-198° C. after recrystallization from ethyl acetate, [α]D =+230.5° (c=0.59, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:14]([CH3:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:32][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:17]3[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=3)[C:14]([CH3:32])([OH:15])[CH3:16])[CH2:10]2)=[CH:30][CH:29]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 230 mg (0.5 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)acetone in 10 mL of THF was added slowly a solution of 0.42 mL (1.25 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h, followed by adding 1 g of sodium sulfate decahydrate to quench the reaction, and stirring for 1 h at rt. The quenched reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford racemic 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol as a white solid. The enantiomers were separated by a chiral column (OJ Column with hexanes/ethyl alcohol); 1H NMR (CDCl3) δ 1.06 (s, 3H), 1.15 (S, 3H), 2.29 (t, 1H, J=7.5 Hz), 2.74 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2H), 3.62 (m, 1H), 4.20 (s, 11H), 6.67-6.73 (m, 3H), 7.21-7.33 (m, 8H); Mass Spectrum: m/e=476 (M+1 35Cl, 35Cl) and 478 (M+1 35Cl, 37Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[N:17]([C:19]([CH3:22])=[N:20][N:21]=4)[CH:18]=3)[C:11](=[O:24])[C:10](O)=[C:9]2[C:26]([CH:28]2[CH2:30][CH2:29]2)=O)=[CH:4][CH:3]=1.[NH:31]([C:33]1[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=1)[NH2:32]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:26]([CH:28]4[CH2:29][CH2:30]4)=[N:32][N:31]([C:33]4[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=4)[C:10]=3[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N2C(=O)C(O)=C(C(=O)C3CC3)C2c2ccc(Cl)cc2)cn2c(C)nnc12
Reactant: Cn1nccc1NN
Solvent: CCOCC
Product: Cc1cc(N2C(=O)c3c(c(C4CC4)nn3-c3ccnn3C)C2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Step 114.1 using 5-(4-chlorophenyl)-4-(cyclopropanecarbonyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 117.1) and 5-hydrazinyl-1-methyl-1H-pyrazole (Step 74.2). The crude material was first purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) followed by preparative achiral SFC (column Silica, gradient 23-28% in 6 min_total 11 min). A third purification was performed by preparative HPLC (Gilson gx-281. Column: Sunfire C18, 30×100 mm, 5 mm. Flow: 30 mL/min. Gradient: 30% to 60% B in min; A=0.1% TFA in H2O, B=CH3CN. Detection: UV). The fractions were combined, basified with NaHCO3, the CH3CN was removed under reduced pressure and the resulting aqueous layer was extracted with CH2Cl2, the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford, after trituration in Et2O, a white solid. tR: 0.99 min (LC-MS 2); ESI-MS: 499 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.03-0.14 (m, 1H) 0.67-0.80 (m, 2H) 0.80-0.92 (m, 1H) 1.78-1.85 (m, 1H) 2.42 (s, 3H) 2.61 (s, 3H) 3.85 (s, 3H) 6.55 (s, 1H) 6.63 (d, J=2.0 Hz, 1H) 7.30 (s, 1H) 7.37 (d, J=8.6 Hz, 2H) 7.46 (d, J=8.6 Hz, 2H) 7.56 (d, J=1.6 Hz, 1H) 8.39 (s, 1H).
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].OS(O)(=O)=O>O.C(O)C>[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]([OH:10])[C:1]#[N:2]
Reactant: O=Cc1ccccc1OC(F)F
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CC(O)c1ccccc1OC(F)F
Reaction time: 0.33 h

Procedure:
7.2 g of potassium cyanide were dissolved in 30 ml of water and 6 ml of ethanol, while cooling. 16 g of 2-difluoromethoxybenzaldehyde were then added at 0°-5° C., while cooling. After subsequently stirring the mixture between 0° and 10° C. for 20 minutes, a mixture of 7 ml of concentrated H2SO4 and 18 ml of water was added dropwise. The mixture was subsequently stirred for a further 2 hours and was thereby allowed to come to room temperature. After extracting twice with methylene chloride, the organic phase was dried and the solvent was distilled off. 2-Difluoromethoxy-α-cyano-benzyl alcohol was obtained as a colorless oil, the structure of which was confirmed by a nuclear magnetic resonance spectrum. The yield was virtually quantitative.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([O:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[F:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3cccc(F)c3c(O[C@H]3CCNC3)n2)[nH]1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Temperature: -40 °C
Yield: 52.9 %

Procedure:
To a mixture of (S)-3-(8-fluoro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (80 mg, 0.22 mmol) in DCM (5 mL) was added 2,6-dimethylpyridine (70 mg, 0.6 mmol). The mixture was cooled to −40° C. Acryloyl chloride (25 mg, 0.28 mmol) was added and the reaction mixture was warmed to 0° C. over a 30 minute period. The reaction was quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (43 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (s, 1H), 11.88 (s, 1H), 8.01 (s, 1H), 7.85-7.83 (d, J=8 Hz, 1H), 7.78-7.76 (t, J=4 Hz, 1H), 7.39 (m, 1H), 6.67-6.64 (m, 1H), 6.19-6.14 (m, 2H), 5.72-5.66 (m, 1H), 4.06 (m, 0.5H), 3.85-3.58 (m, 3.5H), 2.29-2.25 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:25]=1)[CH3:2].Br[CH2:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:27][C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33][CH3:34])=[O:32])[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:25]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)CCc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)c1cccc(CBr)c1
Product: CCc1ccc2c(c1)CCc1oc(C)nc1C2c1cn(Cc2cccc(C(=O)OC)c2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of step (ii) (0.38 g) and methyl 3-[bromomethyl]benzoate according to the method of example 1 step (viii).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.C(S[C:18]1[O:19][C:20]([C:23]2[O:24][C:25]([Br:28])=[CH:26][CH:27]=2)=[N:21][N:22]=1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C>[OH-].[Na+]>[Br:28][C:25]1[O:24][C:23]([C:20]2[O:19][C:18]([N:4]3[CH:5]4[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]4)[CH2:2][CH2:3]3)=[N:22][N:21]=2)=[CH:27][CH:26]=1
Reactant: C1CN2CCC(CC2)N1
Reactant: Brc1ccc(-c2nnc(SCc3ccccc3)o2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(-c2nnc(N3CCN4CCC3CC4)o2)o1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1,4-diazabicyclo[3.2.2]nonane (4.05 g, 32.1 mmol), 2-benzylsulfanyl-5-(5-bromo-furan-2-yl)-[1,3,4]oxadiazole (10.3 g, 30.5 mmol) and N,N-diisopropylethylamine (8.29 g, 64.1 mmol) was stirred at 100° C. for 4 hours. Aqueous sodium hydroxide (30 ml, 1 M) was added followed by extraction with chloroform (3×30 ml). The organic phase was dried and evaporated. The crude solid mixture was solved in hot ethyl acetate (100 ml), some red, glue-like impurities where removed by filtration. The filtrate was evaporated and finally the crystalline product was triturated with diethylether. Yield 3.43 g (33%). LC-ESI-HRMS of [M+H]+ shows 339.0453 Da. Calc. 339.045664 Da, dev. −1.1 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O>CN(C)C=O>[CH2:33]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 40.8 %

Procedure:
To a solution of 15.0 g of 4-aminophenol dissolved in 300 ml of N,N-dimethylformamide, was added 28.5 g of anhydrous potassium carbonate. Subsequently, 46.0 g of 1-bromooctadecane was added thereto at 80° C., and the mixture was stirred for 3.5 hours at 80° C. Water was added to the reaction mixture, and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane—ethyl acetate—chloroform=5:1:1 to 1:1:1), followed by recrystallization from chloroform—methanol, to yield 20.28 g of 4-octadecyloxyaniline (melting point: 95-97° C.) (Reaction Scheme (58) described below).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 112 %

Procedure:
A slurry of 4-cyanophenol (1.24 g, 10.4 mmol), potassium carbonate (3.3 g, 23.9 mmol), and 4-fluoro benzaldehyde (1.0 g, 8 mmol) in dry DMF (50 mL) was stirred at 100° C. overnight under nitrogen atmosphere. After the reaction is completed it was cooled to room temperature and poured in to ice cold water. The mixture was extracted with ethyl acetate (100 mL×2), the combined organic layers were washed with water (50 mL×2), and brine, then dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound (2 g, 86%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCc3ccccc32)cc1
Yield: 73.1 %

Procedure:
To a stirred refluxing mixture of 119 g (1 mole) of indoline, 800 ml of toluene (other solvents, e.g. isopropyl alcohol, are satisfactory), and 207 g (1.5 mole) of pulverized, anhydrous potassium carbonate is added dropwise 126.5 g (1 mole) of benzyl chloride. When addition is complete, refluxing is continued until evolution of gas ceases as evidenced by a gas meter (about three hours). The mixture is allowed to cool, and the solids are removed by filtration. The filtrate is evaporated, and the residue is distilled to give 153 g (73%) of 1-benzylindoline, b.p. 162°-165° (4.5 mm).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:19]=1)[CH3:10]>C(#N)C>[CH2:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:19]=1[I:1])[CH3:10]
Reactant: CCc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
As shown in FIG. 8, N-iodosuccinimide (8.37 g, 57.25 mmol) was added to a solution of 2-ethyl-imidazo[1,2-α]pyridine 70 (Example 27) (12.88 g, 57.25 mmol) in dry acetonitrile (100 mL) at 0° C. The reaction was warmed to room temperature and then stirred for 12 hours. The mixture was then concentrated and purified on silica gel (CombiFlash, Heptane/EtOAc elution) to afford 2-ethyl-3-iodo-imidazo[1,2-α]pyridine 72, as photosensitive yellow crystals with a yield of 5.6 g, 35%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.[C:41]1([CH3:65])[CH:46]=[CH:45][C:44]([S:47]([O:50][CH2:51][CH2:52][CH2:53]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:49])=[O:48])=[CH:43][CH:42]=1>>[CH3:39][O:38][CH2:37][CH2:36][CH2:35][N:31]1[C:30]2[CH:40]=[C:26]([CH2:25][O:24][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:53][CH2:52][CH2:51][O:50][S:47]([C:44]5[CH:43]=[CH:42][C:41]([CH3:65])=[CH:46][CH:45]=5)(=[O:48])=[O:49])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:10]3)[CH:27]=[CH:28][C:29]=2[O:34][CH2:33][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21

Procedure:
Analogously to Method I, 0.204 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.514 g of 1,3-propanediyl di-p-toluenesulphonate are reacted. The title compound is obtained as an orange oil. Rf=0.37 (2:1 EtOAc-heptane); Rt=5.72.
Reaction SMILES: O.C([O:9][C:10]1[C:11]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[CH:12][C:13]([CH2:40][CH3:41])=[C:14]([CH:39]=1)[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21]([CH2:36][CH2:37][CH3:38])=[C:22]([NH:26][C:27](=[O:35])[CH2:28][C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:40]([C:13]1[CH:12]=[C:11]([C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[C:10]([OH:9])=[CH:39][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21]([CH2:36][CH2:37][CH3:38])=[C:22]([NH:26][C:27](=[O:35])[CH2:28][C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31])[CH:23]=[CH:24][CH:25]=1)[CH3:41]
Reactant: [H][H]
Reactant: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(O)c(-c2ccc(F)cc2)cc1CC
Yield: 112.3 %

Procedure:
Hydrogenate a slurry of 10% palladium on charcoal, 50% wet (with water by weight) (13 g) and 4-[[3-[3-[5-benzyloxy-2-ethyl-4-(4-fluorophenyl)phenoxy]propoxy]-2-propyl-phenyl]amino]-2,2-dimethyl-4-oxo-butanoic acid (260 g, 405 mmol)) in THF (1560 mL) starting at a hydrogen pressure of 900 psi. Continue the hydrogenation 20 h while not adding additional hydrogen. Hydrogenate two additional days maintaining hydrogen pressure of 200 psi. Filter the mixture through diatomaceous earth and concentrate the filtrate in vacuo to yield the title compound (251 g, quantitative) as a solid. Excess weight is due to the presence of THF. ES/MS m/z 552 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:7]1([C:6]2[NH:5][N:4]=[C:3]([C:13]([F:16])([F:15])[F:14])[C:2]=2[NH:1][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.0 g of 4-amino-5-phenyl-3-trifluoromethyl-1H-pyrazole in 30 mL of dichloromethane was treated with 1.1 mL of pyridine followed by 0.57 mL of benzoyl chloride. The reaction mixture was stirred at RT for 5 hours and then concentrated. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by MPLC, eluting with 2/3 ethyl acetate/heptane, to give the title compound as a white solid, melting point 229–230° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][N:11]2[C:18]([NH2:19])=[C:17]([NH2:20])[C:15](=[O:16])[NH:14][C:12]2=[S:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:26](O)=O>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][N:11]2[C:18]3[N:19]=[CH:26][NH:20][C:17]=3[C:15](=[O:16])[NH:14][C:12]2=[S:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OC1CCCC1
Reactant: O=CO
Product: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)cc1OC1CCCC1

Procedure:
14.62 g (40 mmoles) of 1-(3-cyclopentyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil were dissolved in 200 ml of formic acid. The solution was concentrated in vacuo at room temperature to remove the water. 50 ml of formic acid were added and the procedure repeated. After a total of 1 hour the formic acid solution was concentrated to 30 ml at 25° and diluted with 300 ml of water. The crystals were collected, washed, and dried: 13.48 g (86.3%) of crude 5-formamide (mp 210-30° C.), which was refluxed in 86 ml of 1N NaOH for 15 min. The turbid solution was treated twice with 0.6 g of charcoal, filtered, acidified with 5N HCl to pH 2, and neutralized to pH 6.5. The amorphous solid was collected, washed, and dried at 60° C.: 11.93 g (80.1%) of crude 2-thioxanthine, which was dissolved in 150 ml of THF, treated with charcoal (5%), filtered, concentrated to 40 ml, and diluted with 250 ml of ethanol. After concentration to 120 ml the formed solid is collected, washed, and dried: 9.21 g (61.9%) of 2-thioxanthine with mp 254-65° C.