Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].[OH-].[Na+].C.[H][H]>C(Cl)Cl.C(OCC)(=O)C>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 45 g (0.35 mole) of 5-amino-2-chloropyridine and 42.4 g (0.42 mole) of triethylamine in 300 ml of CH2Cl2 was added, dropwise, a solution of 44.3 g (0.368 moles) of trimethyl acetyl chloride in 60 ml of dichloromethane over a period of 1.5 hours. This mixture was stirred at room temperature for 2 hours, poured into 5% aqueous NaOH and the dichloromethane layer separated. The organic layer was washed with 5% aqueous NaOH, dried over Na2SO4 and evaporated to leave a brown oil which solidified on standing. This solid was taken up in hot ethyl acetate, treated with charcoal, filtered and diluted with hexane. Cooling this solution resulted in the precipitation of 58.7 g (79% of theoretical) of white crystals having a melting point of 120°-123° C. Carbon, hydrogen and nitrogen content calculated for C10H13ClN2O is C, 56.47; H, 6.16; and N, 13.17 percent by weight which compared to that actually found of C, 56.31; H, 6.14; and N, 13.02 percent by weight.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1.I[CH2:24][CH3:25]>>[CH2:24]([N:13]([CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:21])[F:22])=[CH:6][CH:7]=1)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH3:25]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Reactant: CCI
Product: CCN(C(=O)OC(C)(C)C)C(C)c1ccc(OCC(F)(F)F)nc1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (0.24 g, colorless oil) from tert-butyl (1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamate (0.22 g, 0.69 mmol, Step-1 of Amine-3) and iodoethane instead of iodomethane by the similar manner in Step-2 of Amine-3.
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([CH2:10]P(=O)(OCC)OCC)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][O:22][CH2:23][O:24][C:25]1[C:29]([CH:30]=O)=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.O>O1CCCC1>[C:1]([C:5]1[O:6][CH:7]=[C:8](/[CH:10]=[CH:30]\[C:29]2[C:25]([O:24][CH2:23][O:22][CH3:21])=[N:26][N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(Cc1coc(C(C)(C)C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C\c1coc(C(C)(C)C)n1
Reaction time: 0.5 h
Yield: 0.7 %

Procedure:
To a solution of diethyl [(2-tert-butyl-1,3-oxazol-4-yl)methyl]phosphonate (2.32 g) in tetrahydrofuran (30 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (3.30 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:20-1:3, v/v) to give 2-tert-butyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.02 g, yield 0.6%).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1)[CH3:8])=[O:5])C.O.[OH-].[Na+].[ClH:27]>CO.O1CCCC1>[ClH:27].[C:4]([CH2:6][CH:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1)[CH3:8])([OH:5])=[O:3]
Reactant: CCOC(=O)CC(C)c1cn(-c2cccnc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(CC(=O)O)c1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 2.66 g of 3-(3-ethoxycarbonyl-2-propyl)-N-(3-pyridyl)indole in 15 ml of methanol and 15 ml of water containing 0.7 g of sodium hydroxide is stirred at room temperature for 18 hours, refluxed for 15 minutes, cooled and evaporated. The residue is redissolved in 25 ml of water, neutralized to pH 6 with 1.44 ml of concentrated hydrochloric acid. The resulting oil is extracted into methylene chloride and the extract is dried over sodium sulfate. Filtration and evaporation gives an oil which is redissolved in 5 ml of tetrahydrofuran and treated with 0.55 ml of concentrated hydrochloric acid. The resulting semi-solid is crystallized from methanol-ether to yield 3-(3-carboxy-2-propyl)-N-(3-pyridyl)indole hydrochloride, m.p. 205°-207°.
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=O)[C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26]>N1C=CC=CC=1>[N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[S:26])[C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2ccccc2N(C(=O)CN2CCCC2)c2ncccc21
Solvent: c1ccncc1
Product: O=C(CN1CCCC1)N1c2ccccc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 6,11-dihydro-11-(pyrrolidinoacetyl)-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 6,11-dihydro-11-(pyrrolidinoacetyl)-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [CH:1]([NH2:3])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:5].Cl[CH2:19][C:20]([C:22]1[CH:49]=[CH:48][C:25]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:44]=[CH:43][C:34]3[CH2:35][CH2:36][CH:37]([C:39]([O:41][CH3:42])=[O:40])[O:38][C:33]=3[C:32]=2[CH2:45][CH2:46][CH3:47])=[C:24]([CH2:50][CH2:51][CH3:52])[C:23]=1[O:53][CH3:54])=O.C(=O)([O-])[O-].[Mg+2]>O1CCOCC1.C(OCC)C>[CH3:54][O:53][C:23]1[C:24]([CH2:50][CH2:51][CH3:52])=[C:25]([CH:48]=[CH:49][C:22]=1[C:20]1[N:3]=[CH:1][S:5][CH:19]=1)[O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:44]=[CH:43][C:34]2[CH2:35][CH2:36][CH:37]([C:39]([O:41][CH3:42])=[O:40])[O:38][C:33]=2[C:32]=1[CH2:45][CH2:46][CH3:47]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC=O
Reactant: CCCc1c(OCCCOc2ccc(C(=O)CCl)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCc1c(OCCCOc2ccc(-c3cscn3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Yield: 98.2 %

Procedure:
Formamide (24 mL, 0.69 mmol), phosphorus pentasulfide (54 mg, 0.123 mmol) and 4 mL of dioxane were refluxed for 30 min. Methyl 7-[3-[4-(2-chloro-1-oxoethyl)-3-methoxy-2-propylphenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate (30 mg, 0.056 mmol) in 0.5 mL dioxane was added along with 50 mg magnesium carbonate, and the mixture was refluxed for 18 hr. The reaction mixture was poured into ethyl ether/0.5 N sodium hydroxide, and the ether layer was washed with brine, dried over sodium sulfate, and concentrated. Flash chromatography of the concentrate using 10:1 hexane/ethyl acetate as eluant provided the product (30 mg, 0.055 mmol, 99% yield). High resolution mass spectrum, m/e 539.2335 (calculated for C30H37SO6N, 539.2341).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCCC1=O>C(OCC)(=O)C.[Cu]I>[C:11]1([S:17]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1cnccc1Br
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=Cc1cnccc1S(=O)(=O)c1ccccc1
Temperature: 60 °C
Yield: 158.8 %

Procedure:
A mixture of 4-bromopyridine-3-carbaldehyde (0.90 g), benzenesulfinic acid sodium salt (4.0 g), copper (I) iodide (4.6 g) and 1-methyl-2-pyrrolidinone (50 mL) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a yellow oil (1.9 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17](OC)=O)[N:12]3[C:21]=2[CH2:22][CH:23]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].[BH3-]C#N.[Na+].C[OH:42]>>[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][N:30]1[CH:11]2[N:12]3[C:21](=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[N:10]=[CH:17][C:13]3=[CH:14][CH2:15][C:16]1=[O:42])[CH2:22][CH2:23]2
Reactant: CO
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(CC=O)n12
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(CN2C(=O)CC=C3C=NC(c4ccc(C#N)cc4)=C4CCC2N34)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(4-cyanophenyl)-3-(2-oxoethyl)imidazo[1,2-a]pyridine-5-carboxylate in MeOH (0.2 M), 2,4-dimethoxybenzylamine (1.2 eq.) was added and the reaction mixture was stirred at RT for 2 h. Then, NaBH3CN (1.5 eq.) was added and stirring was continued for 12 h. The solvent was reduced in vacuo and the residue partitioned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column on silica using a gradient of EtOAc/Petroleum ether from 30:70 to 50:50 to yield (55% over two steps) the title compound. 1H NMR (600 MHz, DMSO-d6, 330K) δ 7.96 (2H, d, J=8.4 Hz), 7.93 (2H, d, J=8.4 Hz), 7.85 (1H, d, J=8.8 Hz), 7.80 (1H, d, J=7.0 Hz), 7.45 (1H; dd, J=9.0, 7.0 Hz), 7.22 (1H, d, J=8.0 Hz), 6.62 (1H, d, J=2 Hz), 6.53 (1H; dd, J=8.4, 2.0 Hz), 4.73 (2H; s), 3.84 (3H, s), 3.77 (3H, s), 3.72-3.68 (2H, m), 3.46-3.42 (2H, m). MS (ES+C26H22N4O3 requires: 438, found: 439 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:33][C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29](=[O:31])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: C1CCNC1
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N1CCCC1
Yield: 60.5 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with pyrrolidine (0.36 ml, 4.3 mmol) to give the title compound as a solid (130 mg, 60%), except that the mixture was heated at 45° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM). NMR Spectrum 1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.38 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.79 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.51 (s, 1H), 7.77-7.71 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.53 (m, 2H), 9.04 (s, 1H), 11.07 (br s, 1H); Mass spectrum MH+ 500.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]12O[CH:7]1[CH:8]=[CH:9][C:10]1CC=[CH:13][CH2:14][C:15]=12)=O.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:31]([OH:33])[CH3:32]>>[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][C@@H:13]([N:28]1[CH2:27][CH2:26][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]1)[C@H:31]([OH:33])[CH2:32]2
Reactant: O=C(NC12OC1C=CC1=C2CC=CC1)C(F)(F)F
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CCO
Product: Nc1cccc2c1C[C@@H](N1CCC(c3ccccc3)CC1)[C@H](O)C2
Temperature: 45 °C
Yield: 33 %

Procedure:
N-(Trifluoroacetyl)-1-amino-5,8-dihydronaphthalene oxide (1.9 g, 7.4 mmol) was dissolved in 25 ml of absolute ethanol to which was added 4-phenylpiperidine (3.0 g, 19 mmol). The solution was maintained at 45° C. for 17 hours and then refluxed for 3 hours. After cooling to 23° C. for 7 hours, a crystalline solid was collected by filtration and washed with ethanol and carbon tetrachloride. A polar isomer, (±)-trans-8-amino-3-hydroxy-2-(4-phenylpiperidino)tetralin, results from deacylation during the reaction (0.78 g, 33% yield). The mother liquor was evaporated to an oil which was dissolved in carbon tetrachloride. This process was repeated in order to remove most of the ethanol. When the oil was again dissolved in carbon tetrachloride, crystallization commenced and yielded 0.7 g of 4-phenyl-piperidinium trifluoroacetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.C(N(CC)CC)C>C(Cl)Cl.CC#N.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of trans (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) in DCM and CH3CN (1:1, 0.14 M) was added BOC2O (1.0 equiv.), triethylamine (1.5 equiv.), and DMAP (catalytic amount). The reaction was stirred at room temperature for 15 h, upon which time the solution was concentrated and purified via silica gel column chromatography eluting with EtOAc and hexanes (1:6) to give the desired product as a white foam. LCMS (m/z): 451.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-chloropyridine (10.0 g, 0.078 mol) (Aldrich) and triethylamine (12 mL, 0.086 mol) in methylene chloride (200 mL), at 0° C, was added dropwise trimethylacetyl chloride in methylene chloride (15 mL). The reaction was allowed to warm to room temperature while stirring overnight. The resulting mixture was washed with water, brine, and was dried over MgSO4 and filtered. Concentration of the filtrate in vacuo provided a colorless oil (19.2 g). The oil was dissolved in hexanes and cooled causing the precipitation of a solid. The solid was collected by filtration affording the amide as a white solid (14.96 g, 90%): mp 51.4–53.4° C. 1H NMR (CDCl3/300 MHz) 8.25–8.15 (m, 2H), 8.00 (br s, 1H), 7.68–7.60 (m, 1H), 1.28 (s, 9H). Anal. Calc'd for C10H13N2OCl: C, 56.47; H, 6.16; N, 13.17 Found: C, 56.72; H, 6.34; N, 12.88.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[CH2:30]([C:32]1[CH:49]=[C:35]2[C:36](OS(C(F)(F)F)(=O)=O)=[CH:37][C:38]([F:40])=[CH:39][N:34]2[N:33]=1)[CH3:31].CN(C=[O:54])C>C(OC=CC)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([C:32]1[CH:49]=[C:35]2[C:36]([C:2](=[O:54])[CH2:1][CH3:6])=[CH:37][C:38]([F:40])=[CH:39][N:34]2[N:33]=1)[CH3:31]
Reactant: CN(C)C=O
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: CCc1cc2c(OS(=O)(=O)C(F)(F)F)cc(F)cn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC=COCC
Solvent: CCN(CC)CC
Product: CCC(=O)c1cc(F)cn2nc(CC)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Palladium acetate (101.8 mg) was dissolved in DMF (25 mL) in an argon atmosphere. To this solution, 1,3-bis(diphenylphosphino)propane (373.9 mg) was added and the mixture was stirred at room temperature for 15 min. Subsequently, the compound of Example 67 (4.25 g) in DMF (65 mL), ethyl-1-propenyl ether (15.0 mL) and triethylamine (3.8 mL) were added and the mixture was stirred at 80° C. for 20 hours. The reaction was terminated by adding water and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, followed by evaporation of the solvent under reduced pressure. THF (50 mL) and 3 mol/L hydrochloric acid (50 mL) were added and the mixture was stirred at room temperature for 16 hours. Subsequently, the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=6:1) afforded the title compound as a yellow powder (670 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][C:11]([CH3:13])=[CH:12][C:5]=12.[CH3:14]I>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:5]=12
Reactant: CI
Reactant: Cc1cc2c(Br)ccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(Br)ccnc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
NaH (60% in oil dispersion) (1.228 g, 30.7 mmol) was suspended in THF (60 mL) and the mixture cooled to 0° C. A solution of 4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (D24) (3.24 g, 15.35 mmol) in THF (30.0 ml) was added dropwise to the mixture and allowed to stir at that temperature for 15 mins, after which MeI (1.440 mL, 23.03 mmol) was added dropwise. The final mixture was stirred at 0° C. for 15 min and then at RT for ca. 3 hours. The reaction mixture was quenched with NH4Cl solution (ca. 100 mL), extracted with ethyl acetate (50 mL×3). The combined organics were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane. The corresponding fractions were combined to give the title compound (2.18 g, approx. 47% purity) which was used without further purification in the next stage. LCMS (A): m/z (M+H)+ 225/227, C9H9BrN2 requires 224/226 (acidic).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13]([F:16])([F:15])[F:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:20][CH:19]=1)([O-:3])=[O:2].S(OC)(O[CH3:35])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13]([F:16])([F:15])[F:14])[C:5]=1[N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])=[CH:20][CH:19]=1)([O-:3])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccc(OC(F)(F)C(F)F)cc2)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(c1ccc(OC(F)(F)C(F)F)cc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
Following the procedure of Example 18, N-(2,4-dinitro-6-trifluoromethylphenyl)-4-(1,1,2,2-tetrafluoroethoxy)benzenamine was reacted with dimethyl sulfate and sodium carbonate in acetone to provide N-(2,4-dinitro-6-trifluoromethylphenyl)-N-methyl-4-(1,1,2,2-tetrafluoroethoxy)benzenamine.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=1)O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(#N)C>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CC#N
Product: CSc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
In a nitrogen stream, triethylsilane (1.23 mL, 7.72 mmol) and a boron trifluoride-diethyl ether complex (0.88 mL, 5.48 mmol) were added to a solution of (2-benzyloxy-phenyl)-(4-methylsulfanylphenyl)-methanol (2.13 g, 6.3 mmol) in acetonitrile (15 mL) at −40° C. and the mixture solution was stirred at the same temperature for 1.5 hours and further at 0° C. for 30 minutes, and then water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (1.9 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>C(C(C)=O)C.O>[CH2:22]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCn1cc(C#N)c2ccc(O)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOc1ccc2c(C#N)cn(CC)c2c1
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution 6-hydoxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodoethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100%) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.