Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.ClCCl>[C:29]([NH:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc(N(C)c2nc(N)nc3ccccc23)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(NC(C)=O)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-amino-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (20 mg, 0.07 mmol), triethylamine (0.02 ml, 0.14 mmol), acetyl chloride (0.01 ml, 0.14 mmol) and DMAP (1 mg) in 2 ml of dichloromethane similar to example 28 to give 3 mg (13.6%) of white solids. 1H NMR (CDCl3): 7.88 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.52-7.47 (m, 1H), 7.15-7.12 (m, 2H), 6.95-6.86 (m, 4H), 3.85 (s, 3H), 3.55 (s, 3H), 2.68 (s, 3H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C@@H:8]1[CH2:14][CH2:13][C@@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[O:16]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][NH:5][C:6]([C@@H:8]1[CH2:14][CH2:13][C@@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[OH:16])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 96 %

Procedure:
A mixture of (2S,5R)-N′-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 174 (0.14 g, 0.43 mmol) and Pd/C (0.070 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 175 (0.10 g, 95%) as a white foam.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH:9]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2]
Reactant: CCCc1c(OC(CCCCC(=O)OCC)c2ccc(Cc3ccccc3)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OC(CCCCC(=O)O)c2ccc(Cc3ccccc3)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 2.5 g. of ethyl 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-6-(4-benzylphenyl)hexanoate in 40 ml. of 1N sodium hydroxide and 20 ml. of ethanol was stirred for 24 hours. The reaction was diluted with 100 ml. of water, and was extracted with hexane and ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate, and evaporated in vacuo yielding 1.83 g. of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].[CH3:29][C:30]([CH3:35])([CH3:34])[CH2:31][CH:32]=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:32][CH2:31][C:30]([CH3:35])([CH3:34])[CH3:29])[CH2:27][CH2:28]1)=[O:22]
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCNCC2)c2cc(Cl)ccc21
Reactant: CC(C)(C)CC=O
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c2cc(Cl)ccc21

Procedure:
Prepared from 1-{3-[5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indol-3-yl]-1-oxopropyl}piperazine (Description 31) and 3,3-dimethylbutanal according to the method of Example 145. 1NMR (360 MHz, CDCl3) δ7.58 (1H, d, J 1.7 Hz), 7.48 (2H, d, J 6.5 Hz), 7.31 (2H, d, J 6.5 Hz), 7.24 (1H, d, J 8.6 Hz), 7.20 (1H, dd, J 8.6, 1.7 Hz), 3.58 (2H, m), 3.54 (3H, s), 3.23 (2H, m), 2.98 (2H, m), 2.50 (2H, m), 2.33 (2H, m), 2.28 (2H, m), 2.20 (2H, m), 1.37 (2H, m), and 0.90 (9H, s). m/z (ES+) 500, 502 (M+1).
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]([CH3:12])[CH2:7][C:8]([CH3:11])=[CH:9][CH3:10])[CH:3]=O.NC1C=CC=CC=1.S([O-])([O-])(=O)=[O:21].[Na+].[Na+].[OH-].[K+]>CCOCC>[CH3:12][CH:6]1[CH2:5][C:2]([CH3:3])([CH3:1])[C:9]([CH:10]=[O:21])=[C:8]([CH3:11])[CH2:7]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC=C(C)CC(C)C=C(C)C=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: CCOCC
Product: CC1=C(C=O)C(C)(C)CC(C)C1
Reaction time: 1 h

Procedure:
A mixture of the two isomeric aldehydes obtained according to paragraph (d) (36.5 g.), aniline (21.4 g.) and anhydrous sodium sulphate (20 g.) in 55 ml. of ether was left at 20° under stirring during one night. After having filtered washed and concentrated to the initial volume the solution was poured with vigorous stirring into 221 ml. of conc. H2SO4 and 22.1 g. of ice. The temperature was kept between -20 and -25° during 1 h., and the mixture was then added to 300 g. of ice and immediately distilled by means of steam distillation. The distillate was saturated with NaCl, extracted with ether and treated as usual. 36 g. of a mixture of crude α- and β-cyclocitral were thus obtained. The subsequent isomerisation was carried out at -10° in 120 ml. of a 8.5% Chanolic KOH solution (80% ethanol). The mixture was allowed to react during 3 h. in an atmosphere of argon, diluted then with pet.-ether (30°-50°), poured into 400 ml. of a NaCl saturated aqueous solution and finally extracted with pet.-ether. By distillation 4-methyl-β-cyclocitral was obtained:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].CC1C2C=C3C4([C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[NH:37]C4=O)COC3=CC=2ON=1.Br.BrCC1C=CC=CN=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:39][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:37]=1)[C:12]4=[O:20]
Reactant: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Br
Agent: BrCc1ccccn1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 2-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one was obtained (38%) as a colorless solid: mp 249-250° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ8.63-8.59 (m, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.85-7.70 (m, 2H), 7.38-7.31 (m, 1H), 7.27-7.1 (m, 3H), 7.02-6.95 (m, 1H), 6.85 (d, J=7.8 Hz, 1H), 5.31 (d, J=16.9 Hz, 1H), 4.96-4.84 (m, 3H), 2.67 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 170.2, 160.2, 155.7, 149.3, 148.5, 142.3, 137.0, 131.9, 128.8, 128.1, 123.4, 123.1, 122.7, 120.7, 119.5, 109.3, 108.4, 81.0, 57.4, 45.6, 20.1; MS (ES+) m/z 400.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].C([O-])(O)=O.[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH4-].[Na+]>CO>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])=[CH:16][CH:15]=1
Reactant: CC(=O)NCCN
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCCNCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-amino-ethyl)-acetamide (1.2 eq.) in MeOH were added NaHCO3 (1.5 eq.) and 4-chlorobenzaldehyde (1 eq.). The reaction was refluxed for 4 h, then cooled to 0° C. NaBH4 (1.2 eq.) was added portionwise. The reaction was stirred for 1 h at 0° C., then 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and DCM. The aqueous layer was then extracted twice with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 0/1) to afford N-[2-(4-chloro-benzylamino)-ethyl]-acetamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9]
Reactant: Oc1cc(F)ccc1Br
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cc(F)ccc1-c1cccs1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
2-Bromo-5-fluoro-phenol (0.87 ml, 7.9 mmol) and 2-thiopheneboronic acid (2.02 g, 15.8 mmol) are dissolved in 100 ml dioxane. The resultingsolution is flushed with argon before tetrakis(triphenylphosphine)palladium (456 mg, 0.395 mmol) and 2 ml of aqueous 2M sodium carbonate solution (20 mmol) are added. After flushing again with argon the mixture is refluxed for 15 hours at 100° C. The solution is allowed to cool to room temperature and the mixture is filtered. The filtrate is evaporated and the residue is taken up in dichloromethane and extracted with water. The organic layer is dried with sodium sulfate then concentrated. The residue is purified by chromatography (CH2Cl2/EtOH gradient 100:0 to 98:2) to yield 1.13 g of 2-(thien-2-yl)-5-fluorophenol (74%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([OH:10])[N:7]=[C:6]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1)[CH3:2].[OH-].[K+].COCCOCCOC.Cl[CH:27]([F:29])[F:28]>O>[F:28][CH:27]([F:29])[O:10][C:8]1[N:9]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[C:6]([NH:11][CH:12]([CH3:13])[CH3:14])[N:7]=1
Reactant: FC(F)Cl
Reactant: CCNc1nc(O)nc(NC(C)C)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: CCNc1nc(NC(C)C)nc(OC(F)F)n1
Temperature: 90 °C

Procedure:
A mixture of 200 g (1.02 moles) of 2-ethylamino-4-hydroxy-6-isopropylamino-1,3,5-triazine, 454 g (8.11 moles) of potassium hydroxide, 1150 ml of diethylene glycol dimethyl ether and 1150 ml of water was vigorously stirred, and heated to 90° C. Chlorodifluoromethane gas was blown into the reaction mixture until 2-ethylamino-4-hydroxy-6-isopropylamino-1,3,5-triazine was no longer detected by thin-layer chromatography. After the reaction, the reaction mixture was cooled to room temperature, extracted with methylene chloride. The methylene chloride layer was washed with water twice or thrice, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column. The column was eluted with n-hexane/ethyl acetate (5:1) to give 58.9 g of 2-difluoromethoxy-4-ethylamino-6-isopropylamino-1,3,5-triazine.
Reaction SMILES: [F:1][C@@H:2]1[CH2:19][C@@:18]2([CH3:20])[C:5]([C:6](=[O:22])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:21])=[CH:4][C:3]1=[O:23].[Na+].[I-].Cl.C([O-])(O)=O.[Na+]>CC(C)=O.CCOCC>[F:1][C@@H:2]1[CH2:19][C@@:18]2([CH3:20])[CH:5]([C:6](=[O:22])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:21])[CH2:4][C:3]1=[O:23]
Reactant: C[C@]12CC[C@H]3[C@@H](CC(=O)C4=CC(=O)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)C4CC(=O)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of 2α-fluoro-17β-hydroxyandrost-4-en-3,6-dione (510 mg) in acetone (76 ml), NaI (950 mg) and conc. HCl (0.51 ml) were added. The mixture was then stirred at RT for 5 min. NaHCO3 was added until neutrality. The organic layer was diluted with Et2O and washed with Na2S2O3 till the brown colour disappeared. The organic phase was washed with H2O and brine, dried over Na2SO4 and was evaporated to dryness. The crude reaction mixture was purified by flash chromatography (SiO2, n-hexane/DCM/acetone 5/3/2) to give the title compound in 72% yield.
Reaction SMILES: [Br:1]Br.[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[C:12](=[O:14])[CH3:13]>CCOCC>[Br:1][CH2:13][C:12]([CH:4]1[CH2:3][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[O:14]
Reactant: CC(=O)C1Cc2ccccc2C1
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)C1Cc2ccccc2C1

Procedure:
Bromine (6.8 g) is slowly added to a stirred solution of 1-(2,3-dihydro-1H-inden-2-yl)ethanone (6.8 g) in 200 ml of dry ether, while keeping the temperature at +10° C. The rate of the addition of bromine is controlled so that the colour due to one added portion of bromine has been discharged before another portion is added. When the addition is complete, the ethereal solution is washed four times with 3M sodium carbonate solution, and is then washed three times with water. The ethereal solution is dried with anhydrous magnesium sulphate. After removal of the solvent the solid 2-bromo-1-(2,3-dihydro-1H-inden-2-yl)ethanone is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:23]1([CH3:26])[CH:24]=[CH:25][C:20]([O:19][CH:16]2[CH2:15][CH2:14][N:13]([CH2:11][CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:18][CH2:17]2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(OC2CCN(C(=O)C(=O)c3c[nH]c4ccccc34)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1
Reaction time: 24 h

Procedure:
A suspension of 4.0 g of 1-(indol-3-ylglyoxyloyl)-4-(p-tolyloxy)piperidine in 40 ml. of tetrahydrofuran is added dropwise to a stirred suspension of 2.1 g of lithium aluminum hydride in 60 ml. of tetrahydrofuran. After addition is complete the mixture is stirred and refluxed for 3 hours under nitrogen. After cooling, the excess hydride is carefully destroyed with water. The mixture is filtered, the filter cake is washed with tetrahydrofuran, and the filtrate is concentrated to a colorless oil under reduced pressure. The oil is kept under vacuum for 24 hours and then permitted to stand for several days. The oil slowly solidifies to a white solid. The solid is collected, washed with petroleum ether (b.p. 30°-60°) and recrystallized from an ethanol and water mixture to give white needles of 3-{2-[4-(p-tolyloxy)piperidyl]ethyl}indole, m.p. 115°-117° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:11])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[NH:12]1[C:20]2[C:15](=[CH:16][C:17](B(O)O)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C([O-])(=O)C.N1C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:11])=[N:8][N:9]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][CH:13]=[CH:14]3)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1C
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(-c2ccc3[nH]ccc3c2)nc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
3-Methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.43 g, 9.27 mmol) and 1H-indol-5-ylboronic acid (1.50 g, 9.29 mmol) were dissolved in N,N-dimethylformamide (93 mL). Cupper (II) acetate (1.27 g, 6.98 mmol) and pyridine (1.50 mL, 18.5 mmol) were added, and the mixture was stirred for 3 days at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give the title compound (1.2433 g, 4.62 mmol, 50% Yield).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:21])[CH2:13][CH2:12]2)=[N:3]1.[BH4-].[Na+].[OH-].[Na+]>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[OH:21])[CH2:13][CH2:12]2)=[N:3]1
Reactant: O=C(CCCN1CCN(c2noc3ccccc23)CC1)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCCN1CCN(c2noc3ccccc23)CC1)c1ccc(F)cc1

Procedure:
Reduction of 4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone hydrochloride (2.0 g., 0.005 mole) with sodium borohydride (0.57 g., 0.015 mole) in 200 ml. of absolute ethanol is carried out according to the procedure of Example 13. Residual material remaining after concentration of the acidified mixture is basified with sodium hydroxide and extracted with chloroform. The combined extracts are dried over magnesium sulfate, concentrated in vacuo and triturated with ether to give 1.2 g. of the free base product. Crystallization of this material from ethanol affords analytically pure α-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]propyl]-4-fluorobenzenemethanol, m.p. 142.5°-143.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (0.46 g, 3.3 mmol) and methyl 4-amino-benzoate (0.5 g, 3.3 mmol) was cooled in an ice-bath, treated dropwise with a solution of potassium tert-butoxide (0.5 g, 4.9 mmol) in DMSO, stirred at room temperature overnight, quenched with water at 0° C. and extracted with ethyl acetate. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound in 56% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 9.5 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.46 (d, J=4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 6.91 (m, 1H), 3.92 (s, 3H). LCMS (ESI+) 272 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:30]2[CH:35]=[N:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C(F)(F)F)nc3)ncc2Cl)CC1
Temperature: 120 °C
Yield: 30.1 %

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (A14) (150 mg, 446 μmol), Cs2CO3 (436 mg, 1.34 mmol) and 5-amino-2-trifluoromethylpyridine (145 mg, 892 μmol) in 1,4-dioxane (3 mL) was sonicated for 10 minutes. Xantphos (10.3 mg, 17.8 μmol) and Pd(OAc)2 (2.00 mg, 8.92 μmol) were added and the resulting mixture was heated under microwave irradiation for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-40% MeOH in EtOAc). The purified solid was dissolved in acetone (0.2 mL) and petroleum benzene 40-60° C. (30 mL) added. The precipitate was collected by vacuum filtration and the filter cake dried under high vacuum to yield the title compound 9 as a tan solid (62 mg, 30%); 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=2.6 Hz, 1H), 8.43-8.34 (m, 2H), 7.69 (d, J=8.7 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.36 (dd, J=7.8, 3.1 Hz, 2H), 7.30 (d, J=4.9 Hz, 1H), 5.39 (d, J=8.9 Hz, 2H), 3.35-3.17 (m, 4H), 1.78 (s, 2H), 1.16 (s, 2H). LCMS-A: rt 4.816 min; m/z 462 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([CH:21]([F:23])[F:22])[C:18]([C:24]#[N:25])=[C:17](Cl)[N:16]=2)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[SH:28][CH2:29][C:30]([NH2:32])=[O:31]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[C:17]3[S:28][C:29]([C:30](=[O:31])[NH2:32])=[C:24]([NH2:25])[C:18]3=[C:19]([CH:21]([F:23])[F:22])[CH:20]=2)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2cc(C(F)F)c(C#N)c(Cl)n2)CC1
Reactant: NC(=O)CS
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2cc(C(F)F)c3c(N)c(C(N)=O)sc3n2)CC1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
A suspension of (6′-chloro-5′-cyano-4′-difluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methyl-carbamic acid tert-butyl ester (1.1 g, 2.74 mmol) potassium carbonate (1.9 g, 13.7 mmol) in DMF (15 mL) was treated with 2-mercaptoacetamide (solution of 1 g, 11 mmol in 10 mL of methanol), and the reaction mixture was heated in a sealed tube at 80° C. overnight. The reaction mixture was then cooled to room temperature and filtered. The filtrate was treated with water (50 mL) and the resulting precipitate was collected by filtration to provide 1.03 g (82.4%) of [1-(3-amino-2-carbamoyl-4-difluoromethyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-yl]-methyl-carbamic acid tert-butyl ester as a tan solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Yield: 76.8 %

Procedure:
A flask was charged with 300 mg (0.98 mmol) of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 223 mg (1.47 mmol, 1.50 equiv.) of 4-methoxyphenylboronic acid, 80.3 mg (0.098 mmol, 0.100 equiv.) of [1,1′-bis (diphenylphosphino)-ferrocene}dichloropalladiuin (II) complex with dichloromethane (Aldrich), 1.04 g (4.90 mmol, 4.98 equiv.) of powdered potassium phosphate (K3PO4), and 4.90 mL of anhydrous 1,2-dimethoxyethane (DME). The mixture was refluxed under nitrogen for 19 h. The mixture was diluted with CH2Cl2, washed with 2× sat. aq. NaHCO3, and dried (Na2SO4). The crude material was purified by silica gel chromatography using 20-30% EtOAc in hexanes affording the title compound (251 mg, 77% yield): ES-MS (m/z) 334 [M+1]+.