Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)[CH:25]=[C:26]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:27]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>>[C:44]([CH2:43][CH2:42][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)[CH:25]=[C:26]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])([OH:46])=[O:45]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC3CCCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(OCC3CCCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Yield: 98.8 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(5-cyclopentylmethoxy-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (104 mg, 0.15 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-cyclopentylmethoxy-3′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (92 mg, 97%) as a off-white waxy solid: ES(+)-HRMS m/e calcd for C37H45FO7 (M+H)+ 621.3222. found 621.3222.
Reaction SMILES: [NH2-].[Na+].[Cl:3][C:4]1[C:9]2[C:10](=[O:21])[N:11]([CH3:20])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[CH:18]=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1.O1CCC[CH2:23]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:3][C:4]1[C:9]2[C:10](=[O:21])[N:11]([CH3:20])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[CH:18]=[CH2:23])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Product: C=Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 1 h

Procedure:
6.25 g of an equimolar mixture of methyltriphenylphosphonium bromide and sodium amide was stirred for 15 minutes in 40 ml of tetrahydrofuran. 4.13 g (15 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde was then added to the yellow suspension, whereby the temperature rose to 43° and the suspension decolorized. The mixture was stirred for a further 1 hour, filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1) and recrystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-5-methyl-3-vinyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 205°-207°.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:35])[CH2:31][CH2:32][CH2:33][CH2:34]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 4 h
Yield: 64.5 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.15 mL) was added to a solution of [5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 94-(2); 24.9 mg, 0.0488 mmol) in methanol (1.0 mL), and the mixture was stirred for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (5% methanol/dichloromethane) to give the title compound (15.6 mg, 64%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[O:14][CH2:13][CH:12]([OH:15])[CH2:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16]I>C1COCC1.O>[CH3:16][O:15][CH:12]1[CH2:13][O:14][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH2:11]1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1COC(c2ccccc2)OC1
Temperature: 0 °C

Procedure:
Sodium hydride (0.7 g, 18 mmol) was added in three portions to a solution of 2-phenyl-1,3-dioxan-5-ol. (3.0 g, 17 mmol) in THF (50 mL) at −10° C. The reaction mixture was stirred at 0° C. until no gas was generated. MeI (3.5 g, 25 mmol) was then added at room temperature, and reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with water (50 mL). The solvent was removed; the residue was extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown crude oil which was recrystallized from THF/hexane to afford 5-methoxy-2-phenyl-1,3-dioxane as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.51-7.48 (m, 2H), 7.41-7.37 (m, 3H), 5.56 (s, 1H), 4.25-4.19 (m, 2H), 4.07-4.03 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36]>CO>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: N
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 90 °C

Procedure:
Add N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (196 mg, 0.364 mmol) and 7M methanol solution of ammonia (8 ml, 56 mmol) into a 25 mL autoclave, heat to 90° C. and react for 24 h; when the TLC shows the raw material is completely reacted, cool the above reaction system to room temperature, filter to get N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (i.e. Dabrafenib). 1H-NMR (400 MHz, DMSO-d6) δppm 10.83 (s, 1H), 7.93 (d, J=5.2 Hz, 1H), 7.55-7.70 (m, 1H), 7.35-7.43 (m, 1H), 7.31 (t, J=6.3 Hz, 1H), 7.14-7.27 (m, 3H), 6.70 (s, 2H), 5.79 (d, J=5.13 Hz, 1H), 1.35 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[N:24]=[N:25][NH:26][N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:44][CH2:45][N:46]1[C:50](=[O:51])[C:49]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:48]2[C:47]1=[O:56].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:44][CH2:45][N:46]3[C:47](=[O:56])[C:48]4[C:49](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:51])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN3C(=O)c4ccccc4C3=O)n2)c2cc3c(cc21)COC3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (Example 72, Step 6) (0.84 mmol) and N-(2-Hydroxyethyl)phthalimide (2.51 mmol) in dichloromethane (10 mL), add triphenylphosphine (2.51 mmol) followed by dropwise addition of diethylazodicarboxylate (2.51 mmol). After stirring at room temperature for 14 h, remove the solvent under vacuum. Chromatograph over silica gel eluting with ethyl acetate/hexane (5-50%) to provide the title compound as a colorless foam. MS (ES+): 772 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:15])[C:6]2=[C:16]([CH3:19])[CH:17]=[CH:18][N:5]2[N:4]=1.[Br:20][C:21]1[C:22]([NH2:28])=[N:23][CH:24]=[N:25][C:26]=1Cl.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:28][C:22]1[N:23]=[CH:24][N:25]=[C:26]([NH:1][CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7](=[O:15])[C:6]3=[C:16]([CH3:19])[CH:17]=[CH:18][N:5]3[N:4]=2)[C:21]=1[Br:20]
Reactant: Nc1ncnc(Cl)c1Br
Reactant: Cc1ccn2nc(CN)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc(CNc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Yield: 95 %

Procedure:
2-(Aminomethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (420 mg, 0.97 mmol) was treated with 5-bromo-6-chloropyrimidin-4-amine (304 mg, 1.46 mmol), cesium fluoride (222 mg, 1.46 mmol) and N,N-diisopropylethylamine (0.508 mL, 2.92 mol) according to Preparation 13. The residue was purified using SP1® Purification System (0% to 10%, dichloromethane-methanol) to give 394 m g (95% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([OH:13])[CH3:12].[OH-].[Na+].O>CN1CCCC1=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:13][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])cc1

Procedure:
(a.) bringing p-nitrochlorobenzene, ethanol and 40-40-60% aqueous solution of sodium hydroxide into reactive contact at an elevated temperature in a cosolvent liquid system comprising the solvents of ethanol, water and N-methylpyrrolidone to ethoxylate the p-nitrochlorobenzene to produce p-nitrophenetole, the mol ratio of ethanol to p-nitrochlorobenzene being about 5:1 to 1:1 and the mol ratio of N-methylpyrrolidone to p-nitrochlorobenzene being about 4:1 to 1:1,
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]([CH3:18])([CH3:17])[CH3:16].O>[N+](C)([O-])=O.[Cl-].[Zn+2].[Cl-]>[C:15]([C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][C:8]([C:5]([CH3:6])([CH3:13])[CH3:4])=[CH:9][CH:10]=3)([CH3:18])([CH3:17])[CH3:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)(C)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)c1ccc2[nH]c3ccc(C(C)(C)C)cc3c2c1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a solution of carbazole (6.6 g, 39.5 mmol) and zinc (II) chloride (16.2 g, 118.8 mmol) in nitromethane (100.0 ml) was added dropwise 2-chloro-2-methylpropane (11.1 g, 120.0 mmol) under nitrogen atmosphere and stirring. The addition of 2-chloro-2-methylpropane was carried out over a 15 minute period. The mixture was stirred at room temperature for 24 hours. Water (100.0 ml) was then added. The product was extracted with dichloromethane (3×60.0 ml). The organic layer was washed with water (3×100.0 ml), and then dried with MgSO4, and dichloromethane was evaporated under vacuum. The product was purified by recrystallization from hot hexane to afford a white product crystal in the amount of 5.0 g (in 45.0% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH:26]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH2:26])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCCOCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a solution of 663 mg (S)-4-[6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-piperazine-1-carboxylic acid ethyl ester in 4.9 ml DMF were added at room temperature 0.97 ml morpholine. After stirring for 2 h the reaction mixture was evaporated and the crude product thus obtained used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.Cl.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].[NH4+].[OH-]>>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([O:9][CH3:10])[CH:3]=1)[N:6]=[C:14]([CH3:15])[CH:13]=[CH:12]2
Reactant: COc1cc(F)ccc1N
Reactant: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(F)cc2ccc(C)nc12
Yield: 99.8 %

Procedure:
To 4-fluoro-2-methoxyaniline (370 mg, 2.62 mmol) in refluxing 6N HCl (5 mL) was added dropwise (E)-but-2-enal (367 mg, 5.24 mmol). The reaction was heated to reflux for 2 hours then cooled and neutralized with NH4OH. The aqueous phase was extracted with DCM, and the combined organic phases dried over MgSO4 and concentrated to yield 6-fluoro-8-methoxy-2-methylquinoline (500 mg, 99.8% yield) as a brown solid.
Reaction SMILES: [C:1](=[S:3])=S.[S-2].[Na+].[Na+].[CH:7]1([NH:13][C:14](=[O:17])[CH:15]=C)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>CO.O>[CH:7]1([NH:13][C:14](=[O:17])[CH2:15][CH2:1][SH:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=CC(=O)NC1CCCCC1
Reactant: S=C=S
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: O=C(CCS)NC1CCCCC1
Yield: 100.3 %

Procedure:
Carbon disulfide (76 g) was added to a mixture of sodium sulfide (55 g) in methanol (80 g) and water (80 g) and kept at 20° C. To this was slowly added N-cyclohexylacrylamide (100 g) maintaining the pot temperature at 20°-30° C. The resulting solution was stirred for an additional 2-3 hour and neutralized with concentrated hydrochloric acid. The organic layer was separated, washed with water and evaporated to dryness to afford 122.6 g of N-cyclohexyl-3-mercaptopropionamide (90.5% yield).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH3:24])=[CH:12][C:11]=2[CH3:17])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)cc2C)c1C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as outline in Example 63; 56 mg, 0.20 mmol) in 2 mL of dry DMF was added bromoethane (100 μL) and K2CO3 powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 314 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].CO.[BH4-].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([F:12])=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)c(F)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CO)c(F)c1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 56.7 %

Procedure:
In a 100 mL round bottomed flask equipped with a stir bar was placed 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30, 1.67 g, 7.17 mmol), methanol (12 mL), dichloromethane (12 mL) and sodium borohydride. The reaction mixture was allowed to stir at room temperature for 17 hours, quenched with water (10 mL) and 1M HCl (5 mL) and extracted with dichloromethane (2×30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material was triturated with hexanes (15 mL) to produce 955 mg (57%) of (3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:15]([N:14]([CH:18]([CH3:20])[CH3:19])[CH2:13][CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)=[O:28])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)([CH3:16])[CH3:17]
Reactant: CC(C)N(CCN1CCCc2ccc(N)cc21)C(C)C
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N(CCN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21)C(C)C

Procedure:
7-Amino-1-(2-diisopropylaminoethyl)-1,2,3,4-tetrahydroquinoline (D15) (100 mg, 0.36 mmol), 4-biphenylcarbonyl chloride (258 mg, 1.11 mmol) and pyridine (0.5 ml, 6.2 mmol) in DCM (5 ml) were stirred at room temperatue for 4 hours. 10% Potassium carbonate solution was then added and the mixture extracted with DCM which was dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by flash column chromatography eluting with 0-5% methanol/DCM gave the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, 2H), 7.71 (d, 2H), 7.63 (m, 3H), 7.47 (t, 2H), 7.41 (t, 1H), 6.99 (br, 1H), 6.90 (d, 1H), 6.74 (d, 1H), 3.37 (m, 2H), 3.30 (m, 2H), 3.05 (sp, 2H), 2.72 (t, 2H), 2.66 (m, 2H), 1.93 (m, 2H), 1.05 (d, 12H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:19]=[CH:20][C:21](O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)cc1Br
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(Br)c3)nc2n(CC)c1=O
Yield: 17.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.00 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.72 g (10.6 mmol) of 3-bromo-4-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 726 mg (yield 17%) of Compound 118 as pale brown needles.
Reaction SMILES: [N+:1](C1C=C([N+]([O-])=O)C=CC=1)([O-:3])=[O:2].C(N1CCNCC1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=2[N+]([O-])=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O>[C:32]([O:36][C:37]([N:39]1[CH2:40][CH2:41][N:42]([C:45]2[CH:46]=[CH:47][C:48]([N+:1]([O-:3])=[O:2])=[C:49]([F:51])[CH:50]=2)[CH2:43][CH2:44]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2,4-dinitrobenzene (1.2 g), N-Boc-piperazine (1.4 g) and potassium carbonate (1.2 g) were dissolved in dimethylformamide (5 mL) and stirred at 50° C. overnight. Then, the mixture was distilled under reduced pressure to remove dimethylformamide, added with water, and extracted with ethyl acetate. The thus obtained organic layer was washed with brine, and water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The mixture was purified by column chromatography (silica gel) to obtain target compounds (Rf=0.3, hexane:ethyl acetate=2:1) and (tert-butyl-4-(5-fluoro-2-nitrophenyl)piperazin-1-carboxylate (Rf=0.6, hexane:ethyl acetate=2:1).
Reaction SMILES: [Cl:1][C:2]1[N:3](/[N:13]=C/C2C=CC(Cl)=CC=2)[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.O.NN>COCCO>[Cl:1][C:2]1[N:3]([NH2:13])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Clc1ccc(/C=N/n2cc(-c3cccnc3)nc2Cl)cc1
Agent: NN
Solvent: COCCO
Solvent: O
Product: Nn1cc(-c2cccnc2)nc1Cl
Temperature: 130 °C
Yield: 77.9 %

Procedure:
To a solution of E-2-Chloro-N-(4-chlorobenzylidene)-4-(pyridin-3-yl)-1H-imidazol-1-amine (210 mg, 0.66 mmol) in 2-methoxyethanol (5 mL) was added 80% hydrazine hydrate (0.5 mL). The reaction mixture was heated to 130° C. for 1 hour and then the reaction mixture was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (100 mg, 78%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.50-8.49 (m, 1H), 8.06-8.03 (m, 1H), 7.43 (s, 1H), 7.34-7.30 (m, 1H), 4.87 (br, 2H); ESIMS m/z 195 [(M+H)]+.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[N:10][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:8][C:7]=2O)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH3:35]>C(#N)C>[CH:1]1([C:6]2[N:11]=[N:10][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:8][C:7]=2[NH2:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C1CCCC1
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
730 mg (1.870 mmol) of 6-cyclopentyl-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazin-5-ol were admixed with 9 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 130 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the acetonitrile was removed on a rotary evaporator, the precipitate was filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 508 mg (70% of theory) of the target compound.