Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:21]1([CH2:20][N:17]2[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][NH:11][C:2]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][N:3]=3)[CH2:15][CH2:16]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Reactant: Clc1noc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(CN2CCC(CCNc3noc4ccccc34)CC2)cc1
Yield: 15.5 %

Procedure:
The procedure described in Example 21 was followed with 3-chloro-1,2-benzisoxazole (0.682 g, 4.44 mmol), 4-aminoethyl-1-phenylmethyl piperidine (0.970 g, 4.44 mmol), and K2CO3 (0.614 g, 4.44 mmol) in DMSO (30 mL). After purification, the title compound (0.231 g, 15%) was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:20])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])=[C:4]([F:23])[CH:3]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BT) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 98.6%, 497.0254 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[Si:35]([O:42][CH2:43][CH2:44][C:45]([CH3:48])([NH2:47])[CH3:46])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:35]([O:42][CH2:43][CH2:44][C:45]([NH:47][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[NH:18][CH:19]=1)=[O:23])([CH3:48])[CH3:46])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(N)CCO[Si](C)(C)C(C)(C)C
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCO[Si](C)(C)C(C)(C)C)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 42.8 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 6 mL of DMF were added EDCI (123 mg, 0.64 mmol), 4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-amine (139 mg, 0.64 mmol) and DMAP (78 mg, 0.64 mmol) in one portion at room temperature and stirred for 16 hours. The reaction mixture was poured into 35 mL of water filtered and the solid obtained was passed through a pad of silica gel (200-300 mesh, eluting with a mixture of methanol and ethyl acetate (1:20, v/v) to give N-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 42.8%) as a pale yellow solid which was used for the next step without further purification. MS: (M+H)+=511.2.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[O:13][C@H:5]1[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[C:38]([C@@:15]1([OH:25])[C@@H:14]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[O:13][C@@H:5]([S:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:4]([N:1]=[N+:2]=[N-:3])[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=N[C@@H]1[C@@H](OCc2ccccc2)[C@H](O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@H]1Sc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)[C@]1(O)[C@H](OCc2ccccc2)[C@@H](N=[N+]=[N-])[C@H](Sc2ccccc2)O[C@@H]1CN1C(=O)c2ccccc2C1=O
Reaction time: 72 h
Yield: 597.5 %

Procedure:
Under an argon atmosphere, 19 (5.28 g, 10.2 mmol) was dissolved in pyridine (100 ml), and the solution was added with acetic anhydride (1.5 ml, 1.59 mmol, 1.56 equiv) with stirring. After three days, stirring was terminated, and the solvent was evaporated. The residue was dissolved in chloroform, and the solution was washed three times with saturated aqueous sodium hydrogencarbonate in a separating funnel. The organic layer was dried over anhydrous sodium sulfate, then recrystallization was performed by using ethanol (50 ml), and primary crystals were collected to obtain 20 as colorless solid (5.29 g, 9.5 mmol, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=C)=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=[O:26])=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(s1)n(Cc1ccc(OC)cc1)c(=O)n1ncnc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)sc32)cc1
Reaction time: 4 h
Yield: 63.5 %

Procedure:
6-(4-Methoxybenzyl)-8-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (2.85 g; 8.42 mmol) was suspended in tetrahydrofuran (40 ml) and heated with a heat gun to effect dissolution. Similarly sodium periodate (4.14 g; 19.4 mmol) was heated in water (20 ml) to effect dissolution. The above solutions were combined with vigorous stifling. While the stirred mixture was still about 40° C., osmium(VIII) oxide (2.06 ml, 2.50% w/w, 0.21 mmol) was added and the mixture was stirred vigorously for 4 hours. The crude mixture was diluted with water (300 mL) and extracted with DCM (4×100). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified over silica gel (120 g) eluting with 0-30% IPA in ethyl acetate over 25 minutes. Product fractions were combined and concentrated to yield the aldehyde as a brown solid (1.82 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3H), 5.40 (s, 2H), 6.94 (d, J=8.66 Hz, 2H), 7.45 (d, J=8.53 Hz, 2H), 8.58 (d, J=4.77 Hz, 2H), 9.95 (s, 1H). LCMS (MH+, 341.2).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1([OH:19])[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH:7]=[C:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][O:21][CH2:22][C:23]([CH2:32][O:33][CH3:34])([CH3:31])[C:24]([NH:26][CH2:27][CH2:28][CH:29]=O)=[O:25].C([BH3-])#N.[Na+]>C(Cl)Cl.CC(O)=O>[OH:19][C@@:5]1([CH2:4][CH2:3][N:2]([CH3:1])[CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[C:23]([CH2:32][O:33][CH3:34])([CH3:31])[CH2:22][O:21][CH3:20])[CH2:10][C@H:9]2[CH2:11][CH2:12][C@@H:6]1[CH:7]=[C:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCCC1(O)CC2CCC1C=C2c1ccccc1
Reactant: COCC(C)(COC)C(=O)NCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCC(C)(COC)C(=O)NCCCN(C)CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
50 mg of rac-(1R*,2R*,4R*)-2-(2-methylamino-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol were dissolved in DCM/AcOH. 46 mg of 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide and 50 mg of sodium cyanoborohydride were added. The reaction mixture was stirred for 3 days at room temperature, quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using EtOAc/MeOH/NEt3 90/10/1 as eluant to yield 49 mg of rac-N-(3-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-amino}-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellow oil.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.CS(O[CH2:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][C:4]1[S:3][C:2]([S:1][CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:6][C:5]=12)[CH3:21]
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.80 g, 5.60 mmol) in N,N-dimethylformamide (15 mL) was added 2,2-diphenylethyl methanesulfonate (1.80 g, 6.20 mmol) followed by addition of potassium carbonate (857 mg, 6.20 mmol), and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 2.70 g of ethyl[[2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound (2.00 g, 3.99 mmol) in ethanol (8 mL)-water (2 mL) was added sodium periodate (4.30 g, 19.9 mmol) and the mixture was refluxed for 14 hours. This reaction mixture was diluted with ethyl acetate and water and, after phase separation, the aqueous layer was extracted with ethyl acetate. The pooled organic solution was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. To a solution of the above concentration residue in tetrahydrofuran (16 mL)-methanol (4 mL) was added 1N-aqueous sodium hydroxide solution (2 mL) dropwise, and the mixture was stirred at room temperature for 10 minutes. The solvent was then distilled off under reduced pressure. To the residue was added 1N-hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to provide 0.72 g of the title compound. Yield 41%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].O.Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.3 g (80.21 mmol) of 4,4-dimethyl thiochroman (from Example 2) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150° C., 0.7 mm) to give the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][CH2:28][O:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C>>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([O:29][CH2:28][CH2:27][N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:31][CH:32]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Cl)n2)cn1
Solvent: CC(=O)O
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(OCCN4CCCC4)cc3)n2)cn1

Procedure:
A mixture of 3-[4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopentylpropanenitrile (prepared according to the procedure described in Example 33, Step 2; 0.030 g, 0.000099 mol) and 4-(2-pyrrolidin-1-ylethoxy)aniline (0.0308 g, 0.000149 mol) in acetic acid (0.7 mL, 0.01 mol) was refluxed overnight. After being evaporated to dryness, the residue was diluted with EtOAc, washed with aqueous sodium bicarbonate, brine, dried, and concentrated. The residue was applied on RP-HPLC to obtain the desired product as a racemic mixture (free base). LCMS (M+H) 472.4.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:28]([C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[O:25][CH2:24][CH2:23][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccccc1OCCN1CCOCC1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3OCCN3CCOCC3)nc(=O)c1-2
Temperature: 120 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.95 g, 4.28 mmol), 2-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.51 g) and xylenes (15 ml) was heated to 120° C. for 1 hour, then to 160° C. until the reaction was complete. The reaction mixture was then cooled to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography eluting with ethyl acetate (100%), followed by ethanol/ethyl acetate (1/1) to afford 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one (Example 11 (b)), as an oil. The free base was then converted into its hydrochloride salt, which was recrystallized from ethanol and dried at 110° C. under high vacuum to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one monohydrochloride, as an off-white powder, m.p. 235-237° C., labelled as Example 11 (c).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2.[OH:27]O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2)=[O:27]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSc3nc4ccccc4s3)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)c3nc4ccccc4s3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(2-benzthiazolyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].N1C=CC=CC=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([N:4]1[C:5](=[O:6])[C:7]([CH3:8])=[CH:9][NH:1][C:2]1=[O:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of thymine (1) in THF was added pyridine and the reaction was cooled to 0° C. Benzoyl chloride was added carefully at 0° C. and the reaction was stirred overnight at room temperature. The reaction mass was evaporated to give the crude solid which was purified by SiO2 flash chromatography to give the N3-benzoyl thymine (4) as a white solid. NMR (600 MHz, CD3OD): δ 7.94 (m, 2H), 7.71 (t, 1H, J=7.3 Hz), 7.57 (m, 2H), 7.38 (s, 1H), 1.90 (s, 3H); Mass (ESI-MS): 231.22 (M+H); m.p: 178-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)c1

Procedure:
6-Bromo-N-(3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and m-anisidine (94 mg, 0.76 mmol) in a similar manner as described above to give 37 mg (26%) of a white solid; 1H-NMR (DMSO-d6): δ 11.04 (s, 1H), 7.55 (s, 1H), 7.23 (d, 1H), 7.12 (dd, 1H), 6.97 (t, 1H), 6.32-6.27 (m, 2H), 6.13 (dd, 1H), 5.96 (d, 1H), 4.76-4.72 (m, 1H), 3.65 (s, 3H), 2.68-2.52 (m, 2H), 2.00-1.87 (m, 2H), 1.82-1.74 (m, 2H); MS m/z (M−1) 369, 371.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=2)[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.28 g--see Preparation 3), 4-methylphenethyl bromide (0.2 g), anhydrous potassium carbonate (0.28 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.19 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH:15][C:16](=O)[CH3:17])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.C([O-])(O)=O.[Na+].C(Cl)Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH:15][C:16](=[S:28])[CH3:17])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=S)NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1

Procedure:
To a suspension of N-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-ylmethyl]-acetamide (1.1 g, 3.7 mmol) in 1,2 dimethoxyethane (11 ml) was added Lawesson's reagent (0.82 g, 2.0 mmol) and the mixture refluxed for 90 min. After addition of saturated NaHCO3 solution (50 ml) and extraction with CH2Cl2 (3×100 ml) the combined organic phases were dried (Na2SO4), concentrated and the obtained crude product was chromatographed [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH=9:1)]. The title compound was obtained as a brown crystalline material (0.75 g, 68%). Mp. 166-170° C. (MeOH/CH2Cl2), MS: m/e=299 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[I:11]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]=1[I:11]
Reactant: Nc1ccc(CCO)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(CCO)cc1I
Reaction time: 1.5 h
Yield: 32.6 %

Procedure:
4-Aminophenethyl alcohol (9.60 g, 70 mmol, 1.0 eq) was added to a mixture of iodine (17.78 g, 70 mmol, 1.0 eq) and silver sulfate (21.83 g, 70 mmol, 1.0 eq) in anhydrous ethanol (200 mL) at room temperature. The reaction mixture was stirred under nitrogen for 1.5 hours. After stirring was stopped, the solid was removed by filtration. The filtrate was concentrated, and the residue was dissolved in dichloromethane (200 mL), and then washed with aqueous 5% NaOH solution (2×150 mL) and water (150 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a crude oil which was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 6.0 g of the desired ortho-iodo aniline as orange gel-like solid (32.4% yield).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[CH:6][N:5]=1.C(O)C.[H][H]>[Pd].CCCCCC>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1
Reactant: FC(F)Oc1cc(OCc2ccccc2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Product: Oc1ccnc(OC(F)F)c1
Yield: 87.3 %

Procedure:
2-Difluoromethoxy-4-benzyloxypyridine (219.75 g, 0.875 mol), ethanol (500 mL) and palladium on carbon (7.8 g, 5 mol %, 50% by weight water) were shaken on a Parr hydrogenator at 5393 kPa of hydrogen at RT for 2.5 h. The mixture was then filtered through celite and the solvent was evaporated in-vacuo. 2-Difluoromethoxy-4-hydroxypyridine (123 g, 87% yield) was obtained as a white solid after trituration with hexane, mp=88.6° C. -89.8° C. Anal. Calcd. for C6H5NO2F2 : C,44.73; H,3.13; N,8.69 Found: C,44.82; H,3.13; N,8.76.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23].CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:19]([C:18]([F:17])([F:32])[F:33])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
The method of example 3.1 was used with 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1 mmol) and 3,5-bis(trifluoromethyl)-benzoyl chloride (1 mmol) to obtain a residue. Chromatography of the residue on silica gel eluting sequentially with 1% methanol in dichloromethane and then 6% methanol in dichloromethane gave the title compound.