Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]#[CH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[N:1]1([CH2:6][C:7]#[C:8][C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCN1CCCC1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(C#CCN2CCCC2)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(pyrrolidin-1-yl)-prop-2-yne (prepared by the method of Biel and DiPierro J. Am. Chem. Soc. 1958, 80, 4609) (0.545 g) in dry tetrahydrofuran (15 ml) was treated at -78° C. with a solution of n-butyl lithium in hexanes (2.5 M, 2.2 ml) and the mixture was allowed to stir at -78° C. for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78° C. this mixture was treated with a solution of cyclohexanone (0.61 g) in tetrahydrofuran (1 ml). The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by column chromatography over silica gel (5% methanol in dichloromethane was used as the eluant) to afford the product as a white solid. MS(+ES), m/z: 208 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:31]([CH3:33])[CH3:32])[C:3]1[C:4]([C:16]2[CH:20]=[CH:19][N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O-:15])=[O:14])=[CH:8][CH:7]=2.[CH3:34]CCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][N:2]([CH:31]([CH3:33])[CH3:32])[C:3]1[C:4]([C:16]2[CH:20]=[CH:19][NH:18][CH:17]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:34])=[O:14])=[CH:8][CH:7]=2
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)N(C)c1nc2cc(C(=O)[O-])ccc2nc1-c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3cc[nH]c3)c(N(C)C(C)C)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a solution of 3-[methyl(propan-2-yl)amino]-2-[1-[tris(propan-2-yl)silyl]-1H-pyrrol-3-yl]quinoxaline-6-carboxylate (130 mg, 0.27 mmol) in THF (10 mL) was added TBAF (71 mg, 0.27 mmol) with stirring for 10 min at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (30 mL), and extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solids were collected via filtration. The resulting mixture was concentrated under vacuum to give methyl 3-[methyl(propan-2-yl)amino]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylate (70 mg, 80%) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)OCc2ccccc2)C1

Procedure:
A solution of 3-aminomethylpiperidine-1-carboxylic acid tert-butyl ester (2.20 g, 10.3 mmol) in dichloromethane (40 mL) was treated with triethylamine (1.90 mL, 13.3 mmol) and stirred on an ice bath. A solution of benzyl chloroformate (1.90 mL, 13.3 mmol) in dichloromethane (10 mL) was added over 5 minutes. The mixture was stirred at room temperature for 70 hours. It was washed with 0.1 N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated under vacuum to provide a colorless gum (3.58 g, quantitative) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.37 (m, 5H), 5.11 (s, 2H), 3.75 (m, 2H), 3.18 (m, 1H), 3.05 (m, 2H), 2.83 (m, 1H), 1.9-1.6 (m, 4H), 1.46 (s, 9H), 1.27 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]1=[O:22])[CH2:5][CH2:6][CH3:7].O.[OH-].[Li+].O>O1CCCC1.O>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[O:13][C:11]1[CH2:12][N:8]([C@@H:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:23])=[O:2])[C:9](=[O:22])[CH:10]=1
Reactant: CCC[C@@H](C(=O)OC)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.108 g, 0.33 mol) in tetrahydrofuran:water (1:1, 8 mL) was added lithium hydroxide monohydrate (0.042 g 1.00 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and washed with diethyl ether and the diethyl ether layer discarded. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH <2), and extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to afford (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid, (0.086 g, 87%), as an off-white solid: LR-ES-MS m/z calculated for C15H15F2NO4 [M+H]+ 312, observed 312.
Reaction SMILES: C[O:2][C:3](=O)[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13].P(=O)(O)(O)O.O>C(OCC)(=O)C>[Br:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH2:5][NH:4][C:3]2=[O:2]
Reactant: COC(=O)NCCc1ccccc1Br
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NCCc2c(Br)cccc21
Yield: 8.8 %

Procedure:
1.36 g of methyl[2-(2-bromophenyl)ethyl]carbamate and 5.2 g of phosphoric acid are stirred under an inert atmosphere at a temperature close to 150° C. The reaction mixture is cooled to a temperature close to 20° C., then it is hydrolysed with a mixture of water and ethyl acetate using ultrasound treatment. After decanting, the organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, water, a saturated aqueous solution of sodium chloride, then concentrated using a rotary evaporator under reduced pressure (5 kPa). 0.105 g of 5-bromo-3,4-dihydroisoquinolin-1(2H)-one is obtained in the form of an amorphous beige solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2(O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:12]2([C:9]3[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=3)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:29][CH:28]=1
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
Solid aluminum trichloride (0.68 mL, 5.1 mmol) was added to a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (0.40 g, 1.3 mmol) in bromobenzene (5.4 mL, 51.3 mmol) at 0° C. under nitrogen. After being stirred at 0° C. for 4 hours, the mixture was quenched with ice and concentrated under reduced pressure. The mixture was dissolved in 1N LiOH (30 mL) and extracted with EtOAc (2×30 mL). The combined organics were dried with Na2SO4, filtered and concentrated. The crude product was directly taken up in EtOAc (4 mL) and aqueous Na2CO3 solution (2M, 4 mL). Di-tert-butyldicarbonate (0.851 g, 3.9 mmol) was added in one portion. The mixture was stirred at 23° C. overnight. The next day, two layers were separated, and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organics were dried over Na2SO4, concentrated, and purified by column chromatography (0-40% EtOAc/hexanes) to give tert-butyl 4-(4-bromophenyl)-4-(4-chlorophenyl)piperidine-1-carboxylate (0.302 g, 51% yield). 1H NMR (CDCl3, 400 MHz) δ 7.46 (d, J=7.2 Hz, 2H), 7.32 (d, J=6.9 Hz, 2H), 7.19 (d, J=7.0 Hz, 2H), 7.12 (d, J=7.3 Hz, 2H), 3.54 (br s, 2H), 2.35 (br s, 2H), 1.54 (br s, 2H), 1.43 (s, 11H). LCMS: M+1 452.2.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[CH:24].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[C:25]1([C:23]#[C:24][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc(-c2cnc3[nH]cc(I)c3n2)cc(OC)c1OC
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3[nH]cc(C#Cc4ccccc4)c3n2)cc(OC)c1OC
Temperature: 70 °C
Yield: 90.8 %

Procedure:
7-Iodo-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (500 mg, 1.22 mmol), PdCl2(PPh3)2 (43 mg, 0.061 mmol), and cuprous iodide (6 mg, 0.031 mmol) were added to a 20 ml microwave vial. The vial was capped and purged with nitrogen. Ethynyl benzene (0.4 ml, 3.6 mmol), triethylamine (5 ml) and N,N-dimethylformamide (5 ml) were added through the septum and the vial was purged again with nitrogen. The mixture was heated in a microwave reactor at 70° C. for 30 minutes. The crude mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water/brine. The organic layer was filtered through celite and concentrated. The residue was triturated with a mixture of ethyl acetate and hexanes and filtered, washed with hexanes, and dried to give 427 mg of 7-phenylethynyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine. MS: (M+H)+=386.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:5][CH:15]1[CH2:16][CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
Methanesulfonic anhydride (996 mg, 5.72 mmol) was added to a mixture of 3-hydroxy-N-t-butoxycarbonylpiperidine (959 mg, 4.76 mmol) and triethylamine (0.86 ml, 6.19 mmol) in methylene chloride (30 ml) at 0° C. After stirring for 1 h, the reaction mixture was washed with saturated NaHCO3 and dried (Na2SO4). Concentration gave the title compound. 1H NMR (CDCl3) d 1.46 (s, 9 H), 1.77-2.17 (m, 4 H), 3.05 (s, 3 H), 3.14-3.49 (m, 2 H), 3.62 (m, 2 H), 4.72 (br s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:18]=3[S:19][C:20]=2N(C)C)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[N:36]1([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47](Br)=[CH:46][C:45]=2[CH3:51])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:18]=3[S:19][C:20]=2[C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:42][CH2:41][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:45]([CH3:51])[CH:46]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: Cc1cc(Br)ccc1OCCN1CCCC1
Product: Cc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(C)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Yield: 59 %

Procedure:
The title compound was prepared from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methyl-4-[(1-pyrrolidinyl)methyl]phenyl ketone (Example 124, Part C) and 4-bromo-2-methylphenyl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 59% yield after PrepLC (SiO2; gradient of 85:10:5 to 75:20:5 hexanes-THF-TEA) by essentially following the procedure detailed in Example 123, Part A.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([F:19])[CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)c(F)c3)cccc2c1N
Yield: 78.5 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 3-fluoro-4-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (135 mg, 78% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.57 (br, 1H), 7.88-7.66 (m, 3H), 7.52-7.41 (m, 2H), 7.10(m, 1H), 3.96 (s, 3H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.76 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[C:15]([CH3:20])[C:14]=1[CH3:21]>CS(C)=O>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][C:13]2[CH:18]=[CH:17][N+:16]([O-:19])=[C:15]([CH3:20])[C:14]=2[CH3:21])[CH2:4][O:3]1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OC[C@@H]2COC(C)(C)O2)cc[n+]([O-])c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 135.9 %

Procedure:
To a dimethylsulfoxide (48 ml) solution of the ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (4.87 g, 39.7 mmol), sodium hydride, in oil (1.73 g, 39.6 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (4.8 g, 30.5 mmol) was added, the mixture was stirred at 60° C. for 2 hours. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (10.5 g, yield: 136%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:18])[C:12]#[C:13][C:14]([O:16]C)=[O:15])=[CH:5][CH:4]=1.[OH-].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11](=[O:18])[C:12]#[C:13][C:14]([OH:16])=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)C#CC(=O)/C=C/c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)C#CC(=O)O)cc1
Reaction time: 0.17 h

Procedure:
A solution of 5.3 g (21.7 mmol) of methyl (E)-6-(4-methoxyphenyl)-4-oxo-5-hexen-2-ynoate in 70 ml of tetrahydrofuran was treated at 0° within 15 minutes with 48.6 ml (26 mmol) of a 3% aqueous potassium hydroxide solution. The reaction mixture was stirred at 0° for 10 minutes, then diluted with 100 ml of water and extracted once with 100 ml of ether. The organic phase was discarded. The aqueous phase was adjusted to pH 1 by the careful addition of 1N hydrochloric acid and extracted twice with ether. The combined organic phases were washed with water, dried over sodium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded (E)-6-(4-methoxy-phenyl)-4-oxo-5-hexen-2-ynoic acid of melting point 98°-100°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[CH:14][N:13]=1>CN(C)C=O>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:13][CH:14]=1)=[O:29]
Reactant: COc1ccc(C(=O)c2ccc(Cl)nc2)cc1OC
Reactant: CNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(N(C)c3ccccc3)nc2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
In dimethylformamide (30 ml) was dissolved N-methylaniline (1.2 g). To the solution was added 60% sodium hydride (dispersion in praraffin) (150 mg), and the mixture was stirred for 30 minutes. Then there was added 2-chloro-5-(3,4-dimethoxybenzoyl)pyridine (500 mg). The mixture was stirred for 4 hours at 90° C. The reaction mixture was poured into ice-water, which was subjected to extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (eluent: n-hexane +ethyl acetate=2:1) to obtain 5-(3,4-dimethoxybenzo-yl)-2-(N-methylanilino)pyridine (200 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]#[N:19])[CH:7]=1.O.O.[Sn](Cl)[Cl:26].Cl>CCO>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]=[C:18]([NH2:19])[C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Temperature: 25 °C
Yield: 78.7 %

Procedure:
Combine 2-(5-fluoro-2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile (2.15 g, 6.87 mmol) and Tin(II) chloride, dihydrate (4.65 g, 20.6 mmol) in a mixed solvent of EtOH (25 mL) and 5.0 N HCl (25 mL), heat the suspension to reflux for 3 hours, cool to RT. Suction filtration obtains the title compound 1.73 g (yield 78%) as a yellow solid by. Mass spectrum: ACPI (m/e): 284((M+1-HCl); 1H NMR (300 MHz, DMSO-d6) δ 11.46 (br, 1H), 10.02 (br, 1H), 9.02 (br, 2H), 7.90-7.87 (m, 1H), 7.71-7.68 (m, 1H), 7.46-7.40 (m, 1H), 7.33-7.28 (m, 1H), 7.12-6.94 (m, 2H), 6.85-6.81(m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1.[SH2:12].[K]>>[SH:12][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)n2ccnc2n1
Reactant: S
Agent: [K]
Product: Cc1cc(S)n2ccnc2n1

Procedure:
In a similar way to Reference Example 1, using 5-chloro-7-methylimidazo[1,2-a]pyrimidine and potassium hydrogen sulfide, the title compound is obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:25]([F:26])=[CH:24][N:23]=[C:22]4[N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:28]=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1>C1COCC1>[F:26][C:25]1[C:20]([C:18]2[CH:17]=[N:16][N:15]([C:4]3([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]3)[CH:19]=2)=[C:21]2[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:37])[CH3:35])[C:22]2=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3c(F)cnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)c(F)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.7 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (3.05 g, 5.79 mmol) in THF (40 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (70 mL, 280 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 3.08 g (99.2%) of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] as a yellowish solid. LC/MS found: 427.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[CH2:6]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](F)=[CH:12][C:11]=1[F:20])[CH3:7].O>C1COCC1>[CH2:6]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[CH:12][C:11]=1[F:20])[CH3:7]
Reactant: NCC(F)F
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCC(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Difluoro-ethylamine (2.4 g, 29.8 mmol) in THF is added at 0° C. to ethyl-2,4-difluoro-5-nitro-benzoate (4.6 g, 20 mmol) and it is stirred overnight at rt. Water is added to the mixture and the mixture is concentrated. The precipitate is filtered, washed with water and dried with P2O5 in vacuo. Yield: 3.8 g (66%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[NH:18]1[CH2:21][CH2:20][CH2:19]1>CO>[N:18]1([C:4]2[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: C1CNC1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CO
Product: Clc1nc2c(c(N3CCC3)n1)CCC2c1ccccc1
Yield: 100.2 %

Procedure:
A solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg, 0.566 mmol) and excess azetidine (162 mg, 2.83 mmol) in methanol (1 mL) was stirred at rt for 30 min. The solvent was removed in vacuum to afford 4-(azetidin-1-yl)-2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (162 mg, 0.567 mmol, 100% yield). LC-MS (M+H)+=286.3.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:22])[N:6]3[CH3:21].Cl.C(O)(=O)C>O>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:22])[N:6]3[CH3:21]
Reactant: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CC(C)N2C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn(c23)N1C
Yield: 88.1 %

Procedure:
To 830 mg (2.7 mmol) of the compound (156) obtained in Example 34, 4 ml of concentrated hydrochloric acid and 16 ml of acetic acid were added and the solution was heated at reflux for 3 hours. 10 ml of water was added to the solution. Solids were filtered off and washed with ethanol and ether in this order to obtain 700 mg of the subject compound (157) in a 88% yield.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f15) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.