Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+].C([Mg]Cl)(C)C.[Cl-].[Li+].C([Mg]Cl)(C)C>O.O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC(C)Oc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc([C@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-iodo-4-isopropoxybenzene. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride-complex in tetrahydrofurane is used instead of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([NH2:8])[N:7]=1.[F:13]F.[He]>F>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([F:13])=[C:6]([NH2:8])[N:7]=1
Reactant: FF
Reactant: COC(=O)c1ncc(N)nc1N
Agent: F
Agent: [He]
Product: COC(=O)c1nc(F)c(N)nc1N
Temperature: -78 °C

Procedure:
In a Kel-FR reactor cooled to -78° C in an acetone-dry ice bath is placed methyl 3,5-diaminopyrazinoate (6g.) and liquid hydrogen fluoride (70 ml.). A stream of fluorine-helium mixture (1:4 v/v) is passed through the solution for 51/2 hours at -78° C. followed by a vigorous stream of nitrogen to remove the solvent. The reaction residue is treated with conc. hydrochloric acid (60 ml.), evaporated to dryness, dissolved in water (75 ml.) and neutralized with aqueous sodium hydroxide to give methyl 3,5-diamino-6-fluoropyrazinoate (5 g.) which is purified by sublimation (140°-50° C., 0.05 mm Hg.) and recrystallization from 2-propanol.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[Cl:31][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3cc(Cl)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.027 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.165 g, 0.34 mmol) and methylamine (0.107 g, 3.4 mmol). mp 193-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.CN([C:45]([O:49][N:50]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CO[NH3+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:28])[NH:50][O:49][CH3:45])([CH2:25][CH3:26])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CO[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-ethyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.084 mmol) prepared in Example 18, HATU (65 mg, 0.17 mmol) and DIPEA (66 mg, 0.54 mmol) in THF (1 mL) was added o-methylhydroxylamine hydrochloride (22 mg, 0.25 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (12 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([NH:12][NH2:13])(=O)[CH3:10]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:9]([CH3:10])=[N:12][N:13]=2)[N:3]=1
Reactant: CC(=O)NN
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: Cc1nnc2ccc(Cl)nn12
Temperature: 25 °C

Procedure:
To a stirred solution of 1.0 g (6.7 mmol) of 3,6-dichloropyridazine in 5 mL of butanol was added 500 mg (6.7 mmol) of acetic hydrazide and the resulting solution was stirred under nitrogen at reflux for 24 h. The reaction mixture was then cooled to ambient temperature, filtered, and the resulting precipitate washed with ethyl acetate and methanol. The combined filtrate and washings were concentrated and dissolved in 250 mL of 10:1 chloroform/methanol then washed with saturated aqueous brine (2×100 mL). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a yellow solid. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 80% ethyl acetate/hexanes gradient) to give the title compound as a brown crystalline solid. LC/MS 169.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH2:18][N:19]2[CH2:22][C:21]3([CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:20]2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:20]1[C:21]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:22][N:19]1[CH2:18][C:17]1[CH:16]=[N:15][N:5]2[CH:6]=[C:7]([C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=12
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(CN3CC4(CCN(C(=O)OC(C)(C)C)CC4)C3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnn(C)c2)cn2ncc(CN3CC4(CCNCC4)C3)c12
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]methyl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (47 mg, 0.10 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.008 mL, 0.1 mmol). After 30 minutes, the reaction mixture was concentrated. The residue was dissolved in methanol and eluted through a bicarbonate resin cartridge (StratoSpheres SPE, PL-HCO3 MP SPE) to give 3-(2,7-diazaspiro[3.5]non-2-ylmethyl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a solid. 1H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H); 8.24 (s, 1H); 7.97 (s, 1H); 7.12 (s, 1H); 6.77 (s, 1H); 3.95 (s, 3H); 3.85 (s, 3H); 3.79 (s, 2H); 2.89 (s, 4H); 2.50-2.54 (m, 4H); 1.47-1.50 (m, 4H). LRMS (ESI) calculated for C20H27N6O [M+H]+, 367.3; found 367.1.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([OH:17])=O)[N:6]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[NH:23][C:24]([C:26]1[C:34]2[NH:33][C:32]([NH2:35])=[N:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:20]1[CH:21]=[CH:22][N:18]=[C:19]1[NH:23][C:24]([C:26]1[C:34]2[N:33]=[C:32]([NH:35][C:15]([C:7]3[N:6]=[C:5]([CH2:4][CH2:3][S:2][CH3:1])[C:14]4[C:9]([CH:8]=3)=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:17])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: CSCCc1nc(C(=O)O)cc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSCCc1nc(C(=O)Nc2nc3c(C(=O)Nc4ncc[nH]4)cccc3[nH]2)cc2ccccc12
Yield: 67.1 %

Procedure:
42.4 mg (0.171 mmol) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid was reacted with 34 mg (0.14 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 114 mg (0.3 mmol) of HBTU and 0.106 mL (0.6 mmol) of DIEA in 0.8 mL of DMF stirring at 85° C. for 3 h according to the general procedure A. 44.3 mg (55%) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS: 472 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([CH:30]=[O:31])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Product: CCOC(=O)c1c(CN(C)C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with 4-nitrophenyl formate as described in Example 77.1. to give 5-fluoro-3-[(formyl-methyl-amino)-methyl]-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 389.5 ([M−H]−).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH3:26][NH2:27]>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:27][CH3:26])[S:8]1(=[O:25])=[O:24]
Reactant: CN
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Solvent: CO
Product: CNCCOCCN1c2ccccc2N(c2c(F)cccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with 8N methylamine in methanol to give 2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N-methylethanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.24 g, 25%). HRMS: calcd for C17H19F2N3O3S+H+, 384.11879; found (ESI, [M+H]+Obs'd), 384.1184.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[O:13][CH:14]1[CH2:19][CH2:18][N:17](C(OC=C)=O)[CH2:16][CH2:15]1.[ClH:25]>CO>[ClH:25].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C=COC(=O)N1CCC(Oc2cccc3c(OC)cccc23)CC1
Agent: Cl
Solvent: CO
Product: COc1cccc2c(OC3CCNCC3)cccc12

Procedure:
The thus obtained 4-(5-methoxy-1-naphthalenyloxy)-1-(vinyloxycarbonyl)piperidine is stirred for 2 hours with 2 N HCl in methanol to yield 4-(5-methoxy-1-naphthalenyloxy)piperidine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Cl>C1(C)C=CC=CC=1.Cl[Ni](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>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:3]1[CH:2]=[CH:11][CH:10]=[CH:9][C:4]=1[CH3:5]
Reactant: Brc1ccc2ccccc2c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc2ccccc2c1
Yield: 172 %

Procedure:
The Grignard solution was subsequently added dropwise to a solution of 120 g (0.57 mol) of 2-bromonaphthalene and 3.5 g of bis(triphenylphosphine)nickel dichloride in 800 cm3 of toluene at such a rate that the internal temperature did not exceed 50° C. The mixture was subsequently refluxed for a further 3 hours, 500 ml of 10% strength aqueous HCl were added, the phases were separated, and the organic phase was freed from solvents in vacuo. Filtration through silica gel (hexane) gave 107 g (87%) of 25 as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:69])([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[C:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:20]([CH2:24]Cl)[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:70].[Na+].C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([C:8]([CH3:69])([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[C:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:20]([CH2:24][I:70])[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
The compound obtained in (A) was dissolved in 200 ml of acetone, and 3.38 g (22.5 mmol) of sodium iodide was added. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 600 ml of ethyl acetate and 200 ml of a 10% sodium thiosulfate aqueous solution were added for extraction. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by slica gel flush column chromatography (ethyl acetate/n-hexane=1/2), and concentrated under reduced pressure. Then, diisopropyl ether was added thereto, and 7.0 g (yield: 63.0%) of a powder of the above-identified compound was collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[OH:7])=[CH2:5].[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([O:7][C:16](=[O:18])[CH3:17])[C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[CH2:5]
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)nc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C(=O)OC)C(OC(C)=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a solution of 2-[(6-chloro-pyridin-3-yl)-hydroxymethyl]acrylic acid methyl ester (4.788 mmol, 1 eq) in dichloromethane (10 ml), molecular sievies 4 Å and 4-DMAP (1.915 mmol, 0.4 eq) were added. Reaction mixture was cooled to 0° C. and acetic anhydride (7.182 mmol, 1.5 eq) was added. Mixture allowed to reach room temperature and stirred for 2 hours. The reaction mixture was poured in 50 ml NaHCO3 (sat.) and extraction with DCM (3×100 ml) followed. Organic layers were combined and evaporated to give crude product which was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of EtOAc in Cyclohexan: 10-45% in 15 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-(acetoxy-(6-chloro-pyridin-3-yl)-methyl]-acrylic acid methyl ester (2.099 mmol, yield=44%, purity=100%). [M+H]+=270.19 1H NMR (300 MHz, CDCl3) δ/ppm 2.10 (s, 3H), 3.69 (s, 3H), 5.97 (d, J=0.9 Hz, 1H), 6.44 (s, 1H), 6.62 (s, 1H), 7.19-7.33 (m, 1H), 7.58-7.70 (m, 1H), 8.35-8.44 (m, 1H)
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)=[O:4].[CH3:12][Li]>C1COCC1>[NH2:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH3:12])[CH:10]=[CH:9][N:8]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1ccnc(N)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
To a stirred solution of methyl-2-aminopyridine-4-carboxylate (20) (1.00 g, 6.57 mmol) in THF (100 mL), at −78° C. under nitrogen, was added methyllithium (1.6 M in diethyl ether, 16.43 ml, 26.3 mmol), over 10 min. After a further 30 min at −78° C., the viscous reaction mixture was warmed to 0° C. After a further 3 hr, the reaction was quenched at 0° C. by the cautious addition of iso-propanol (8.0 mL). The mixture was warmed to RT, brine (200 mL) and EtOAc (150 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL×3), and the combined organic extracts were dried and the solvents removed under reduced pressure. The crude residue was purified by column chromatography (80 g) eluting with 0 to 8% MeOH in EtOAc, to give 1-(2-aminopyridin-4-yl)ethanone (21) (176 mg, 20%) as a yellow powder: m/z 137 (M+H)+ (ES+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][CH2:6][C@H:5]([OH:8])[CH2:4]1.Br[CH2:10][CH2:11][CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:8][C@H:5]1[CH2:6][N:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C@@H:3]([CH2:2][OH:1])[CH2:4]1
Reactant: OC[C@H]1C[C@@H](O)CN1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCN1C[C@H](O)C[C@@H]1CO

Procedure:
(3R,5R)-5-Hydroxymethylpyrrolidin-3-ol and 4-bromobutyronitrile are reacted in the presence of potassium carbonate in N,N-dimethylformamide to give 4-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]butyronitrile. In the same manner as in Example 1b (e) and using 4-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]butyronitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{3-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[C:18]([F:26])[CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>C(O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([NH:28][NH2:29])=[O:21])=[C:18]([F:26])[CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Nc2nc(C)cc(Cc3ccccc3)n2)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(C(=O)NN)c(F)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of methyl 4-(4-benzyl-6-methyl-pyrimidin-2-ylamino)-2-fluoro-benzoate (420 mg, 1.20 mmol) and hydrazine monohydrate (1.4 mL, 28.8 mmol) in ethanol (9 mL) was stirred at 90° C. for 6 h. After cooling to 20° C., a white precipitate was formed which was isolated by filtration to afford the title compound (345 mg, 82%) as white solid. Mp 191-193° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:8]>>[C:5]1(=[O:8])[C:6]2=[C:6]3[C:5](=[CH:3][CH:2]=[CH:1]2)[CH:4]=[CH:3][CH:2]=[C:1]3[CH2:7]1
Reactant: Cc1ccccc1
Reactant: O
Product: O=C1Cc2cccc3cccc1c23
Reaction time: 0.08 h

Procedure:
With respect to 1 kg of the reaction solution generated in synthesis example 1, 1 L of toluene and 2 L of water were added. These components were stirred for 5 minutes and extraction was conducted. Then, the resultant substance was kept still for 15 to 20 minutes to be separated, and the upper toluene layer was recovered. The above-extracted solution and the same amount of 4% aqueous solution of sodium hydroxide were put into a separatory funnel, shaken and kept still. Then, the lower black liquid was removed. The remaining liquid was washed with water of the same amount as that of the remaining liquid. Then, the lower layer was removed. Water was added, 2 mL of hydrochloric acid was added, and these components were shaken. The lower layer was removed, and the remaining substance was washed with water again. The oil layer was washed with an alkaline substance and concentrated to remove the solvent. The concentrate was distilled at a pressure of 1 to 2 mmHg. As a result, 16 g of acenaphthene-1-one was obtained at a distillation temperature of 120° C.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:27])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16](OCC[Si](C)(C)C)[C:17](C)=[CH:18][C:11]=23)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].CO.[NH4+].[OH-]>>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[C:1]([C:5]1[N:6]([CH3:27])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][CH:17]=[CH:18][C:11]=23)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(-c3cn(C)c(C(C)(C)C)n3)ccnc2n1OCC[Si](C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccnc3[nH]ccc23)nc1C(C)(C)C
Yield: 94 %

Procedure:
A solution of 4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)-ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine (0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2 hours. Then the excess TFA was evaporated and the residue was stirred in methanol (3 mL, 0.07 mol) and NH4OH (1 mL) for 16 hours. The solvents were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine, trifluoroacetate salt (9 mg, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25]([CH:31]=O)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:31][C:25]2[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=2)[CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(C2CCN(C(=O)OC(C)(C)C)CC2)C(C)c2ccccn2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-(1-Pyridin-2-yl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(1-pyridin-2-yl-ethyl)-amine as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:23]
Reactant: O=C(Cl)c1cccnc1
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: CN(C)CCN(C(=O)c1cccnc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and nicotinic acid chloride