Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2[CH:39]=[CH:38][C:37](F)=[CH:36][CH:35]=2)[CH2:23][CH2:22]1.CC1(C)C(C)(C)OB(C2C=CC([C:54]([O:56][CH3:57])=[O:55])=CC=2)O1>>[NH2:33][C:29]1[C:28]([C:34]2[CH:39]=[CH:38][C:37]([C:54]([O:56][CH3:57])=[O:55])=[CH:36][CH:35]=2)=[C:27]([N:24]2[CH2:23][CH2:22][CH:21]([C:6]3[N:5]([CH2:4][CH2:3][N:2]([CH3:41])[CH3:1])[CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=4)[N:7]=3)[CH2:26][CH2:25]2)[N:32]=[CH:31][N:30]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: COC(=O)c1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN(C)C)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine using methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate instead of 4-fluorophenyl boronic acid. LC-MS: (M+1=612, obsd.=612).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].Cl[CH2:11][CH:12]=O>C(O)CCC>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]2[N:6]([CH:11]=[CH:12][N:8]=2)[N:7]=1
Reactant: O=CCCl
Reactant: Cc1cc(N)nnc1Cl
Solvent: CCCCO
Product: Cc1cc2nccn2nc1Cl
Yield: 33.4 %

Procedure:
6-chloro-5-methylpyridazin-3-amine 7 (0.6 g, 4.18 mmol) was dissolved in n-butanol (10 ml) and chloroacetaldehyde (0.328 g, 4.18 mmol) was added. The reaction was refluxed for 6 hrs and n-butanol was removed under reduced pressure. The crude product was purified by column chromatography (DCM/hexane, 70:30) to afford compound 8 (0.234 g, yield=33.4%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.[N:24]([O-])=O.[Na+]>C(O)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[C:10]([O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[C:11]2[N:12]=[N:24][NH:1][C:2]2=[CH:3][CH:4]=3)=[CH:21][CH:20]=1
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1oc2c(ccc3[nH]nnc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 7,8-diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (115 mg, 0.35 mmol) and 5% aqueous acetic acid (5 ml) is cooled to 0° C., and sodium nitrite (26 mg, 0.38 mmol) is added portionwise. The mixture is stirred for 18 h as it is allowed to warm to room temperature. The reaction is quenched with saturated aqueous sodium bicarbonate (50 ml), and the mixture is extracted with ethyl acetate (3×50 ml). The organic phases are combined, washed with saturated aqueous sodium bicarbonate (50 ml) and then with saturated brine (50 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue is purified by chromatography on silica gel using n-hexane/ethyl acetate (0-100% ethyl acetate) as eluant to give the product as a colourless solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH:28][C:29]1[N:37]=[C:36]([C:38]2[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[S:41][CH:42]=2)[N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:47]([CH3:49])[CH3:48])=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH:28][C:29]1[N:37]=[C:36]([C:38]2[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[S:41][CH:42]=2)[N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:47]([CH3:49])[CH3:48])=[O:15]
Reactant: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCNC(=O)OC(C)(C)C)cc34)nc(-c3csc4ccccc34)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCN)cc34)nc(-c3csc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-yl 6-(tert-butoxycarbonylamino)hexanoate (a) (80 mg, 0.117 mmol) in DCM (20 ml) was added TFA (5 ml). The reaction was stirred at rt for 3 hr. It was concentrated. Aqueous sodium carbonate solution was added and the mixture was extracted with DCM. The organic fractions were combined, dried over sodium sulfate, and concentrated to afford the product as an oil. MS m/z 582.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: C1COCCN1
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1

Procedure:
Prepared analogously to Example 1.1.c. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and morpholine. Yield: 0.3 g (39.4% of theory); C13H18N2O5 (M=282.29); calc.: molecular ion peak (M+H)+: 283; found: molecular ion peak (M+H)+: 283; Rf value: 0.6 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(OCC)=[O:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[CH:1]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)=[O:2]
Reactant: CCOC(=O)C1CCN(c2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=CC1CCN(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The product from Example 28, Step C is dissolved in THF and cooled to −78° C. under nitrogen. A solution of diisobutylaluminum hydride (1 eq.) in toluene is added dropwise. After 30 min, the reaction is quenched with saturated sodium potassium tartrate solution. The mixture is extracted with ethyl acetate, and the organic phase washed with saturated brine, and dried over MgSO4. Filtration and concentration provides the title compound
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=2)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN([C@@H]2CCCC[C@@H]2NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a mixture of benzaldehyde (0.061 mL, 0.6 mmol) and N-(2-{[(3R)-1-(cis-2-aminocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0.278 g, 0.60 mmol) in CH2Cl2 (10 mL) was added NaB(OAc)3H (0.128 g, 0.60 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (EtOAc to EtOAc:MeOH:Et3N=9:1:0.5) to give 0.21 g of the title compound. MS (EI) calcd: (M+H)+=503.3; found: 503.4.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2ccccn2)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
2-[(4-Nitrophenoxy)methyl]pyridine (2.30 g, 10 mmol) was dissolved in ethanol (160 mL) and water (40 mL). NH4Cl (5.30 g) was added to the above mixture and heated to 70-80° C. To this reaction mixture was added iron powder (5.50 g) in portion wise manner under a vigorous stirring and the stifling was continued for 2 h. The reaction mixture was filtered through a Celite pad when hot and washed the filter bed with MeOH. The filtrate was concentrated, diluted with water, extracted with CH2Cl2 (3×75 mL), dried and concentrated to provide 2-[(4-aminophenoxy)methyl]pyridine as brown solid (1.735 g) in 86% yield. 1H NMR (CDCl3): δ 8.56 (m, 1H), 7.67 (m, 1H), 7.49 (d, 1H, J=7.8 Hz), 7.18 (m, 1H), 6.80 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz), 5.12 (s, 2H), 3.43 (br s, 2H); LCMS (m/z): 201 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1>>[CH3:20][NH:19][C:17]([C:13]1[CH:12]=[C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[Cl:9])[CH:16]=[CH:15][N:14]=1)=[O:18]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)c(Cl)c1
Product: CNC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1

Procedure:
Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29]1>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([C:28](=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNc1ccccc12
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: O=C(O)CCC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (20 mg, 0.06 mmol) and succinic anhydride (12 mg, 0.12 mmol) in CH2Cl2 (5 mL) was added TEA. After stirred for 2 h at rt the solvent was removed to give 4-(1′-(2-adamantylcarbamoyl)spiro[indoline-3,4′-piperidine]-1-yl)-4-oxobutanoic acid (20 mg, 74%). LC-MS Method 5 tR=3.6 min, m/z=953.1; 1H NMR (CD3OD) δ=1.69 (d, 2H), 1.75 (d, 2H), 1.80-1.99 (m, 11H), 2.00-2.10 (m, 5H), 2.20 (s, 2H), 2.60-2.70 (m, 2H), 2.80-2.90 (m, 2H), 3.06-3.18 (m, 2H), 3.93 (s, 1H), 4.10-4.19 (m, 2H), 4.20 (s, 2H), 5.90 (d, 1H), 7.10 (m, 1H), 7.19-7.28 (m, 2H), 8.16 (d, 1H).
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(F)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
Trimethylaluminium (2M solution in toluene) (2.86 mL, 5.71 mmol) was added to 5-fluoropyridin-2-amine in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) in toluene (8 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 24 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq.) and then diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.32 g, 55%). 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 3.60-3.68 (m, 3H), 3.79-3.83 (m, 2H), 3.86 (d, 2H), 4.31-4.35 (m, 1H), 7.34-7.46 (m, 7H), 7.64-7.69 (m, 4H), 8.14 (d, 1H), 8.22-8.28 (m, 1H), 9.18 (s, 1H); m/z (ES+), (M+H)+=483.63; HPLC tR=3.08 min.
Reaction SMILES: O=P(Cl)(Cl)Cl.[S:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2O)[CH:8]=[CH:7]1.C(Cl)(=O)C([Cl:19])=O>ClCCCl>[Cl:19][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:8]=[CH:7][S:6][C:14]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2ccsc12
Reaction time: 2 h

Procedure:
To a stirred solution of POCl3 (28.6 mL, 313 mmol) in 1,2-dichloroethane (200 mL) was added commercially available thieno[3,2-b]pyridin-7-ol (94.7 g, 626 mmol) as a powder in one portion. The reaction was stirred for 2 hours at reflux under N2. The mixture was concentrated, using toluene (3×100 mL) to azeotrope. The dark residue was resuspended in CH2Cl2 (1 L), and a saturated aqueous solution of NaHCO3 (500 mL) was carefully added. The mixture was stirred for 30 minutes until bubbling had ceased. The biphase was separated, and the aqueous was re-extracted with CH2Cl2 (500 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated, to obtain a brown oil, which crystallized upon standing (38.4 g, 71%). 7-Chlorothieno[3,2-b]pyridine has also been prepared using oxalyl chloride (WO 99/24440). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=5 Hz, 1H), 7.80 (d, J=6 Hz, 1H), 7.60 (d, J=6 Hz, 1H), 7.29 (d, J=5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH:20]=[CH:21][C:22]3[CH:27]=CN=CN=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)CC.Cl.[Cl-].[Na+].O.[C:40]([CH3:50])(OCC)([O:44]CC)[O:41][CH2:42][CH3:43]>>[CH2:42]([O:41][C:40](=[O:44])[CH2:50][CH:21]([C:22]1[CH:27]=[N:14][CH:9]=[N:8][CH:7]=1)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[N:14]=1)[CH3:43]
Reactant: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3ccncn3)n2)cc1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cncnc1
Temperature: 25 °C

Procedure:
A solution of the allylic alcohol 6-9 (1.6 g, 3.37 mmol) in (EtO)3CMe (10 mL) was treated with 100 uL of a 1 mL solution of (EtO)3CMe containing 10 uL of propionic acid. The yellow solution was heated at 150° for 90 minutes. The solution was cooled to room temperature and poured into 1N HCl/brine. The mixture was extracted with CHCl3, dried, concentrated, and purified on silica gel (5%MeOH/CHCl3) to give 2.01 g of 6-10.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH3:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1>CN1C(=O)CCC1.CCOCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:4][CH3:5])[C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: CCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCC(C#N)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
A mixture of NaH (4.0 g, 99 mmol) in 50 mL NMP stirred at 0° C., was treated dropwise with a mixture of bromoethane (11 g, 99 mmol) and 2-(4-chlorophenyl)acetonitrile (15 g, 99 mmol) in 20 mL ether. The mixture was stirred at room temperature for 2 hours, cooled to 0° C., and quenched carefully with H2O. The resulting mixture was neutralized with 10% HCl to a pH of 5. The mixture was extracted with ether (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 5% EtOAc/hexane to give 9.1 g of the product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:22]([CH2:24][NH2:25])[OH:23].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[NH:25][CH2:24][CH2:22][OH:23]
Reactant: NCCO
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)c3c(NCCO)cc(-c4ccc[nH]4)c1c23
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
To a solution of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (396 mg, 1.0 mmol) in DMF (4.0 mL) and ethanolamine (Aldrich, 0.6 mL, 610 mg, 10.0 mmol) was added NaH (Aldrich, 95%, 270 mg, 10.0 mmol) in portions at 0° C. After stirring at the same temperature for 10 minutes, the reaction mixture was heated to 130° C. for 2 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 20% ethyl acetate in hexanes) to afford 6-fluoro-5-(2-hydroxy-ethylamino)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 25.0 mg, 8.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:12])[CH:4]=3)=[N:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Cl)c(F)c3)nc2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-chloro-3-fluorophenyl)acetic acid 168-1 (188 mg, 1.0 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (220 mg, 1.0 mmol) and HATU (400 mg, 1.05 mmol) in DMF (4 mL) was added DIEA (521 uL, 3.0 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4 and the solvent was evaporated. The residue was subject to silica gel flash chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-chloro-3-fluorophenyl)acetamide 168-2. MS m/z 391.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][CH:19]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([I:20])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc(C3CC3)n3nccc3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 91.6 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine (1.08 g, 4.0 mmol) and N-iodo-succinimide (0.90 g, 4.0 mmol) in N,N-dimethylformamide (8 mL) was stirred at 20° C. for 40 min. The heterogeneous mixture was partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give 5-(4-chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine (1.45 g, 92%) as a yellow solid. MS (ISP) 395.8 [(M+H)+]; mp 189-190° C.
Reaction SMILES: C(S([N:7]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:8]1=[O:30])=O)(C)(C)C.[ClH:31]>CO.O1CCOCC1>[ClH:31].[ClH:31].[C:12]1([CH:11]2[CH2:10][C:9]3([CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[C:8](=[O:30])[NH:7]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(c1ccccc1)N(S(=O)C(C)(C)C)C2=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1NC(c2ccccc2)CC12CCNCC2

Procedure:
To a solution of tert-butyl 2-(tert-butylsulfinyl)-1-oxo-3-phenyl-2,8-diazaspiro[4.5]decane-8-carboxylate (21 mg, 0.048 mmol) in methanol (4 mL) was added 4N HCl in dioxane (4 mL). After 24 h the reaction was concentrated give the title compound). MS: m/z=231.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:26]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:27][C:28]([CH3:30])=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[C:9]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:30][C:28](=[O:29])[CH2:27][C:26]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][CH:3]=1
Reactant: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Yield: 61.5 %

Procedure:
Following the general procedure of Example 8, 196 mg (0.58 mmole) of 5,5-bis(4-fluorophenyl)-4-(1 H-tetrazol-1-yl)-2,4-pentadienal was condensed with two equivalents (1.2 mmoles) of the dianion of ethyl acetoacetate. The product thereby produced was purified by silica gel chromatography using ethyl acetate-hexanes as eluent to yield 173.8 mg (61.5%) of the title compound.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C:1]([N:17]1[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CC1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCC(C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-methylpiperidine as starting raw materials, to produce an intended compound.