Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][C:27]=1[CH3:34]>C(OCC)(=O)C.CCCCCC>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])=[CH:28][C:27]=1[CH3:34]
Reactant: Cc1cc(CN)ccc1F
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCN3C(C)C)ccc1F
Yield: 93.7 %

Procedure:
Coupling of 6-(benzyloxy) 1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluoro-3-methylbenzylamine (0.133 g, 0.95 mmol) as described for the synthesis of intermediate 3 gave 0.384 g (93% yield) of the title amide as white crystals (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.6 Hz, 2×CH3), 2.25 (3H, broad d, J=1.8 Hz, CH3), 3.67 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.41 (1H, m, CH), 4.46 (2H, d, J=5.8 Hz, NCH2), 5.08 (2H, s, OCH2), 6.94 (1H, m, aromatic), 7.04-7.08 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.3-7.36 (3H, m, aromatics), 7.42-7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). HRMS (ESI+) calculated for C25H28FN4O3 [M+H+]: 451.2145. found: 451.2141.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[Br:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[C:25]([CH2:33]Br)[CH:24]=1.C(N(CC)C(C)C)(C)C.C(O)CCC>>[Br:22][C:23]1[CH:24]=[C:25]2[C:26](=[CH:31][CH:32]=1)[C:27](=[O:28])[N:1]([C@@H:2]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][N:4]1[C:5](=[O:14])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]1=[O:13])[CH2:33]2
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C1c2ccccc2C(=O)N1C[C@H](CC1CCCCC1)N1Cc2cc(Br)ccc2C1=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (914.3 mg, 3.193 mmol), methyl 4-bromo-2-(bromomethyl)benzoate (960.0 mg, 3.117 mmol) and N,N-diisopropylethylamine (0.6 mL, 3 mmol) in 1-butanol (4 mL, 40 mmol) was stirred at 140° C. for 2 h under microwave irradiation. Direct purification by combi-flash chromatography afforded 810 mg (54% yield) of the desired product. LC-MS found: 481.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][S:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:21])[F:22])=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH2:3][CH2:4]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N[C@H]1CC[C@H](O)CC1
Product: O=S(=O)(N[C@H]1CC[C@H](O)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.9, trans-4-amino-cyclohexanol and 4-(trifluoromethyl)-benzenesulfonyl chloride were converted to yield trans-N-(4-Hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide as white solid, 176.2° C., MS 322 (M-H).
Reaction SMILES: [C:1]([C:4]1[S:5]C=C[CH:8]=1)(=O)[CH3:2].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([CH2:16][C:17]#[N:18])=[O:15].N1CCOCC1.[S]>CC(=O)CC>[NH2:18][C:17]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:16]=1[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1cccs1
Reactant: N#CCC(=O)c1cccs1
Agent: [S]
Solvent: C1COCCN1
Solvent: CCC(C)=O
Product: Cc1sc(N)c(C(=O)c2cccs2)c1C
Yield: 44 %

Procedure:
The procedure of Example 1 was followed except that 2-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(thiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 44%; IR (KBr) cm−1: 3390, 3269, 1552, 1429, 1272, 852, 772; 1H NMR (CDCl3):δ 1.86 (s, 3H), 2.17 (s, 3H), 5.78(bs, 2H), 7.07 (dd, 1H, J=3.8 and 4.8 Hz), 7.56 (dd, 1H, J=2.8 and 0.8 Hz), 7.58 (dd, 1H, J=5.0 and 0.8 Hz); orange solid, mp: 117–118° C. (petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:12]([F:21])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=2)=[C:12]([F:21])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 27a (4.99 g, 17.51 mmol) is dissolved in N,N-dimethylformamide (275 mL). N-bromosuccinimide (3.15 g, 17.70 mmol) is added as a solid and the reaction mixture is stirred at room temperature under N2. After 30 minutes, the reaction mixture is quenched by the addition of aqueous saturated sodium bisulfite solution. The reaction mixture is then poured into a separatory funnel, diluted with water and ethyl acetate and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed three times with water, once with brine and then are dried (Na2SO4) and concentrated under reduced pressure to yield 6.38 g (100%) of the pure desired product as a tan solid. MS ESI (+) m/z 364, 366 (M+Br pattern) detected.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][NH:31][CH3:32].O>CN(C)C=O>[CH3:30][N:31]([CH3:32])[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[CH:7]=1
Reactant: CNC
Reactant: Cc1cc(C#Cc2cn(-c3cncc(F)c3)c(C)n2)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#Cc2cn(-c3cncc(N(C)C)c3)c(C)n2)ccn1

Procedure:
3-Fluoro-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyridine (48) (100 mg, 0.34 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (189 mg, 1.38 mmol) and dimethylamine hydrochloride (42 mg, 0.52 mmol) were added and the reaction mixture was refluxed overnight. The reaction mixture was poured into 60 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient) and the desired compound was obtained as an off-white solid (22 mg, 20%), MS: m/e=318.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=O)C.C(O)(=O)C.[CH:30](N)=[NH:31]>C(OCCO)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:7]=[C:6]3[C:4]([OH:3])=[N:31][CH:30]=[N:11][C:10]=23)=[CH:17][CH:16]=1
Reactant: N=CN
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Solvent: CC(=O)O
Solvent: CCOCCO
Product: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A mixture of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-2A-1a (19.27 g, 51.2 mmol) and formamidine acetate (15.99 g, 153.6 mmol) in 100 ml of 2-ethoxyethanol was refluxed for 3.5 hours under nitrogen. The reaction mixture was then cooled to room temperature and poured into ice-cold water. The yellow precipitate that formed was collected by filtration and washed with water. The solid was stirred in 45 ml methyl tert-butyl ether for 30 minutes. Cyclohexane (90 ml) was added, and the stirring was continued for another 45 minutes. The pale yellow solid was collected by filtration and dried to give 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol I-2A-1b (17.55 g, 87%): MS 357.1 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[CH2:37]([C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1)[CH3:38]
Reactant: CCc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl ]butyl]phenol (260 mg) in DMF (4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(4-ethylphenyl)ethenyl]oxazole (272 mg) was added under ice cooling. After stirring overnight at room temperature, water was added under ice cooling. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in ethyl acetate and dried (magnesium sulfate), after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (297 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][CH:39]=4)=[CH:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc(-c2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4′-formyl-biphenyl-4-carboxylic acid according to the procedure of Example 66. MS (ES) m/z 600.9.
Reaction SMILES: C([N:8]1[CH2:35][C:10]2([CH2:15][N:14]3[N:16]=[C:17]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)[C:18]([C:19]([NH2:21])=[O:20])=[C:13]3[NH:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1>C(Cl)Cl.CO.[Pd]>[O:28]([C:25]1[CH:24]=[CH:23][C:22]([C:17]2[C:18]([C:19]([NH2:21])=[O:20])=[C:13]3[NH:12][CH2:11][C:10]4([CH2:9][NH:8][CH2:35]4)[CH2:15][N:14]3[N:16]=2)=[CH:27][CH:26]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CN(Cc3ccccc3)C1)C2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CNC1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
To a solution of 1-benzyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide (200 mg, 0.43 mmol) in 10 mL of DCM and 10 mL of CH3OH was added 10% w/w Pd/C (100 mg). After stirring at RT under H2 for 16 hr, the mixture was filtered and concentrated. The residue was purified by pre-HPLC eluting from 25% to 90% CH3CN in 0.1% TFA in H2O. Fractions containing the desired product were combined and lyophilized overnight to afford 30 mg (19%) of desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (br s, 1H), 8.84 (br s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.46-7.38 (m, 2H), 7.18 (t, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.81 (br s, 1 H), 4.23 (s, 2 H), 3.90-4.00 (m, 2 H), 3.78-3.87 (m, 2 H) and 3.47 (s, 2H). MS (ESI) m/e [M+1]+ 375.9.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:13])[CH3:12]>CO>[CH2:11]([NH:13][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCN
Reactant: NC(=O)c1ccc(Cl)nn1
Solvent: CO
Product: CCNc1ccc(C(N)=O)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-chloropyridazine-3-carboxamide (28.5 g, 0.18 mol) in methanol (200 ml) was treated with aqueous ethylamine (70% solution, 77 ml). The reaction was heated at reflux for 3½ hours. The reaction was allowed to cool to ambient temperature and stand overnight. The precipitate was filtered and washed with a small volume of water and dried to give 6-(ethylamino)pyridazine-3-carboxamide as pink solid (8.9 g). [The filtrates were evaporated to a small volume diluted with cold water (100 ml) and more of the desired solid was filtered-off, washed with water and dried (12.8 g). Total yield (21.7 g, 72%)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14]>N1CCCCC1.CO>[C:13]([C:15](=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1ccc(OC)c(OC)c1

Procedure:
A mixture of 3,4-dimethoxybenzaldehyde 4.15 g, 0.025 mol), methyl cyanoacetate (2.48 g, 0.025 mol), methanol (100 mL) and piperidine (10 drops) is heated at reflux for 2 hours. The reaction mixture is then cooled and the product collected by filtration, washed with methanol and dried in air (yield--6.0 g, 97%). The following structure is supported by mass spectrometry: ##STR20## The compound has an absorption maximum at 361 nm in methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCCN(C(=O)OC(C)(C)C)c1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Methyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate (3.0 g), 4-methoxybutyl methanesulfonate (2.0 g) and potassium carbonate (2.1 g) were dissolved in DMF (30 ml), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated, aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10→8:2) was concentrated under reduced pressure to give the object product (2.9 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCc2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC(C(=O)O)(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4(4methoxy-benzenesulfonyl)-1-[2-(4methoxyphenyl)-ethyl]-piperidine-4carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.8 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83.
Reaction SMILES: S[C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.[Cl:13][C:14]1[CH:45]=[CH:44][C:17]([C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Si:38]([CH3:41])([CH3:40])[CH3:39])[C:33]=2[C:42]#[CH:43])=[O:19])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:19])([C:4]2[N:3]([CH3:7])[CH:2]=[N:6][CH:5]=2)[C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:33]=[CH:42][CH:43]=[C:36]([C:35]#[C:34][Si:38]([CH3:41])([CH3:39])[CH3:40])[CH:37]=2)=[CH:44][CH:45]=1
Reactant: C#Cc1c(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)cccc1[Si](C)(C)C
Reactant: Cn1ccnc1S
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C#C[Si](C)(C)C)c1)cc(=O)n2C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
2-Mercapto-1-methylimidazole (2.08 g, 18.2 mMol) was dissolved in anhydrous THF (200 mL) under an atmosphere of dry N2. The solution was cooled to −78° C. and a solution of tert-butyl lithium (1.7 M in pentane, 22 mL, 37 mMol) was added. The solution was then warmed to 0° C. After a yellow precipitate formed, the solution was cooled to −78° C. and a solution of 6-(4chloro-benzoyl)-1-methyl-4-(3-trimethylsilanyl ethynyl-phenyl)-1H-quinolin-2-one (8.55 g, 18.2 mMol) in anhydrous THF (25 mL) was added. After 30 minutes, the solution was warmed to 0° C. and stirred at this temperature for 1 hour. The reaction mixture was then warmed to ambient temperature and stirred overnight. The reaction was quenched with 20 mL of saturated aqueous ammonium chloride (NH4Cl) and then partitioned between DCM and water. The DCM layer was dried over sodium sulfate (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed on flash silica gel eluting with a gradient from DCM to MeOH/DCM (3:97) to give 5.0 g of the titled compound as a solid.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:34][C:35]1[C:36]([F:45])=[C:37]2[C:43]([NH2:44])=[CH:42][NH:41][C:38]2=[N:39][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:34][C:35]1[C:36]([F:45])=[C:37]2[C:43]([NH:44][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:11])=[CH:42][NH:41][C:38]2=[N:39][CH:40]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
2-Phenylpropanoic acid (653 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 (50 mL) was added. The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylpropanamide (384 mg, 48.8% yield) was obtained as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[O:36]>>[CH2:38]([O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36])[CH:39]([CH3:41])[CH3:40]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isobutyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with isobutyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, 6H, J=6.7 Hz), 1.86-2.09 (m, 6H), 3.04-3.16 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.82-3.84 (m, 2H), 4.12-4.16 (m, 2H), 5.02-5.08 (m, 1H), 7.62-7.64 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=474.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2cc(N)ccc2n1
Solvent: c1ccncc1
Product: Cc1ccc2cc(NS(C)(=O)=O)ccc2n1
Reaction time: 17 h

Procedure:
Methanesulphonyl chloride (6.2 ml) was added dropwise to a stirred solution of 6-amino-2-methylquinoline (12.5 g) in pyridine (100 ml) cooled to 5°. Stirring was continued for 17 hours at room temperature. The pyridine was then removed by evaporation in vacuo, the residue diluted with aqueous sodium bicarbonate, and extracted three times with methylene chloride. The combined organic extracts were combined, dried (MgSO4) and evaporated in vacuo to give the title compound, yield 13.0 g, m.p. 151°-153°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH2:12])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=NO)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1C(N)CC2
Reaction time: 16 h
Yield: 64 %

Procedure:
A mixture of 7-methoxy-indan-1-one oxime (CAS no: 908108-58-7, (E)-oxime 179899-16-2) (4.59 g, 25.9 mmol) in ethanol (500 mL) with 10% palladium on carbon (4.59 g) was hydrogenated at 23° C. and atmospheric pressure for 16 h. Filtered the catalyst off, washed with ethanol, evaporated the filtrate totally and dried in high vacuum to give the title compound as a brown oil (2.7 g, 64%); MS: m/e=164.2 (M+H+).