Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[C:4]([C:12]#[N:13])=[C:5]([C:10]#[N:11])[C:6](=[O:9])[C:7]=1[Cl:8].C1(C)C=CC=CC=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[C:5]([C:10]#[N:11])=[C:4]([C:12]#[N:13])[C:3]=1[OH:14]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N

Procedure:
The ⟦2,3-dihydroxanthotoxin⟧ 4',5'-dihydroxanthotoxin thus obtained is then dehydrogenated. This advantageously is effected by heating the ⟦2,3-dihydroxanthotoxin⟧ 4',5'-dihydroxanthotoxin with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a substantially inert solvent, for example, toluene or chlorobenzene, advantageously at reflux, until substantial dehydrogenation is obtained. The 2,3-dichloro-5,6-dicyano-hydroquinone formed and any residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are removed and the product taken up in chloroform and recovered therefrom. If substantial amounts of the residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are present, it is desirable to convert this to the corresponding hydroquinone with sodium dithionite, dissolve the hydroquinone in aqueous sodium bicarbonate, and extract the sodium bicarbonate solution with chloroform to recover the 8-methoxypsoralen which can be recovered by drying over sodium sulphate and concentrating to dryness. The resulting product can then be recrystallized from benzene or any suitable inert solvent in which 8-methoxypsoralen has limited solubility. If there is little residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, the reaction mixture can be cooled and the precipitated hydroquinone filtered off and the reaction mixture, i.e., the filtrate, then extracted with chloroform. If desired, the filter cake can be extracted with benzene or like solvents such as chlorobenzene, toluene, and the like, for example, by refluxing the filter cake in the solvent and then adding the extract to the reaction mixture filtrate prior to the chloroform extraction. The chloroform solution is then washed successively with dilute sodium bisulfite solution, dilute sodiium bicarbonate solution, and water and dried over sodium sulfate. The resulting chloroform solution is then concentrated by distillation until the product precipitates and an inert non-solvent such as hexane or like aliphatic or cycloaliphatic hydrocarbon is added to cause further precipitation of the product and the product is filtered. If desired, the product can be further purified by redissolving it in chloroform, or chloroform containing a minor amount of ethyl acetate, passing the solution over an alumina column concentrating the effluent until crystallization takes place, adding hexane or like solvent further to cause precipitation of the product, and filtering the solution.
Reaction SMILES: F[B-](F)(F)F.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7].[F:15]C1C=C([N+]([O-])=O)C=CC=1.FC1C=CC=CC=1[N+]([O-])=O>ClC1C=CC=CC=1.C1C=CC=CC=1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: O=[N+]([O-])c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])c1ccccc1F
Solvent: Clc1ccccc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(F)cc1
Temperature: 90 °C

Procedure:
A homogeneous reaction mixture was obtained in this experiment, whereas in the aforementioned fluorinations of benzene and chlorobenzene, the reaction mixtures contained suspended [(ClCN)3F]+BF4−. In order to drive the fluorination of nitrobenzene to completion, the reaction mixture was heated at 90° C. for 2 hours before it was tested with KI solution and gave a negative result. G.C. analysis revealed the presence of only 3-fluoronitrobenzene and 2-fluoronitrobenzene with no marked change in ratio (about 2:1 ratio). Despite the presence of the 2-fluoro derivative, no evidence were obtained for the presence of 4-fluoronitrobenzene. The absence of 4-fluoronitrobenzene may have resulted from loss of this isomer during the reaction or subsequent handling operations via nucleophilic displacement of the highly mobile fluorine. In this connection, the reaction vessel became etched during the reaction.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1)=[O:3].Cl>CO>[C:28]1([C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)[N:12]=[CH:11][N:10]=[C:9]3[NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c(C(N)=O)cc(-c4ccccc4)cc23)C1
Agent: Cl
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)cc2c(N[C@H]3CCCNC3)ncnc12

Procedure:
Dissolved tert-butyl (3S)-3-{[8-(aminocarbonyl)-6-phenylquinazolin-4-yl]amino}piperidine-1-carboxylate (30.00 mg; 0.07 mmol; 1.00 eq.) in methanol (3.00 ml) and then added hydrogen chloride (2.00 ml) (2.0 M in diethyl ether) with stirring. Stirred reaction at room temperature for 18 hours. LCMS: M+1=348 major peak.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.FC(F)(F)S(O[C:37]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49]([O:51][CH3:52])=[O:50])[CH:38]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.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>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:37]2[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49]([O:51][CH3:52])=[O:50])[CH:38]=2)=[CH:6][C:7]=1[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])=[C:10]([F:21])[CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)cnc2N)cc1F
Reactant: COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1C=C(c2cnc(N)c(-c3ccc(C(=O)OC(C)(C)C)c(F)c3)c2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 95 %

Procedure:
A mixture of tert-butyl 4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2-fluorobenzoate (400 mg, 0.966 mmol), (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (1.087 g, 2.90 mmol, Pd(PPh3)4 (112 mg, 0.097 mmol) and cesium carbonate (1.258 g, 3.86 mmol) in THF (10 mL) and water (2 mL) was degassed, then microwave heated to 90° C. for 10 min. At completion, the reaction was diluted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate and concentrated. The crude mixture was purified by flash chromatography over silica gel (20-90% ethyl acetate/heptane) to provide (S)-1-tert-butyl 2-methyl 4-(6-amino-5-(4-(tert-butoxycarbonyl)-3-fluorophenyl)pyridin-3-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (470 mg, 95%). LCMS (m/z): 514.3 (MH+), 0.92 min.
Reaction SMILES: [OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=O)[C:24](=[O:30])[C:25]=3[O:26]C(C)C)[CH:9]=2)[O:4][C:3]1([CH3:33])[CH3:32].CC#[N:36]>>[NH2:36][C:23]1[C:24](=[O:30])[C:25](=[O:26])[C:22]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[O:4][C:3]([CH3:32])([CH3:33])[C@@H:2]([OH:1])[C@@H:11]2[N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21]
Reactant: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Reactant: CC#N
Product: CC1(C)Oc2ccc(-c3c(N)c(=O)c3=O)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Reaction time: 16 h

Procedure:
To a solution of 154 mg (0.344 mmol) of 3-[trans-3-hydroxy-2,2-dimethyl-4-(1-oxo-1,3-dihydroisoindol-2-yl)-chroman-6-yl]-4-isopropoxy-cyclobut-3-ene-1,2-dione as prepared in Example 3 in CH3CN was bubbled ammonia gas for 30 min. The reaction mixture was then sealed and stirred for 16 h. The reaction mixture was concentrated. Flash chromatography (CH2Cl2 : MeOH: NH4OH (94.75/3.5/1.75)) followed by crystallization from THF and petroleum ether gave 136 mg of the title compound as a white solid, mp>250° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ8.90 (br s, 1 H), 8.76 (br s, 1 H), 7.7-7.8 (m, 3 H), 7.51-7.63 (m, 3 H), 6.98 (d, 1 H), 1.48 (s, 3 H), and 1.27 ppm (s, 3 H); IR (KBr) 1780, 1730, 1670, and 1640 cm-1 ; mass spectrum (+CI), m/e 405. Anal. Calcd. for C23H20N2OS: C, 68.31; H, 4.98; N, 6.93 Found.: C, 67.91; H, 5.12; N, 6.78.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a stirred solution of 5-chloro-2-methyl-3-nitrobenzoic acid (6.75 g, 31.25 mmol) in DMF (33 mL), sodium carbonate (13.23 g, 125.18 mmol) and methyl iodide (17.77 g, 125.2 mmol) were added. Resulting reaction mass was heated at 60° C. for 4 h. On completion, water was added to the reaction mass and extraction was carried out using DCM. Combined organic layers were dried, concentrated under reduced pressure and purified by column chromatography over silica (60-120 mesh size) giving desired compound (6 g, 84%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([N:25]1[C:29]([O:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([OH:39])[CH3:38])=[CH:33][CH:32]=2)=[CH:28][C:27]([C:40]2[CH:41]=[C:42]([C:46]([NH:49][S:50]([CH2:53][C:54]([F:57])([F:56])[F:55])(=[O:52])=[O:51])([CH3:48])[CH3:47])[CH:43]=[CH:44][CH:45]=2)=[N:26]1)[CH3:24].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][C:29]2[N:25]([CH2:23][CH3:24])[N:26]=[C:27]([C:40]3[CH:41]=[C:42]([C:46]([NH:49][S:50]([CH2:53][C:54]([F:55])([F:56])[F:57])(=[O:51])=[O:52])([CH3:47])[CH3:48])[CH:43]=[CH:44][CH:45]=3)[CH:28]=2)=[CH:36][CH:35]=1)(=[O:39])[CH3:38]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(C)O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(C)=O)cc1
Reaction time: 2 h
Yield: 55.8 %

Procedure:
Dess-Martin periodinane (415 mg, 0.977 mmol, 2.00 equiv) was added to a solution of N-[1-(3-{1-ethyl-5-[4-(1-hydroxyethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (250 mg, 0.489 mmol, 1 equiv) in dichloromethane (4.9 mL) at 22° C. The reaction mixture was stirred for 2 hours, and then saturated aqueous sodium thiosulfate solution (3 mL) and saturated aqueous sodium bicarbonate solution (3 mL) were added. The biphasic mixture was stirred for 15 minutes, then was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 90% ethyl acetate-hexanes) to afford N-(1-{3-[5-(4-acetylphenoxy)-1-ethyl-1H-pyrazol-3-yl]phenyl}-1-methylethyl)-2,2,2-trifluoroethanesulfonamide (139 mg, 56%) Calcd (M+1)+: 510.2. Found: 510.1.
Reaction SMILES: [N:1]#[N:2].[C:3]1([CH2:9][C:10]([C@@:12]2([N:20]3[C:30]4[N:29]=[C:27]([NH2:28])[NH:26][C:24](=[O:25])[C:23]=4[N:22]=[CH:21]3)[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[CH2:13]2)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:31][O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37](Cl)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1>N1C=CC=CC=1>[N:1]#[N:2].[C:3]1([CH2:9][C:10]([C@@:12]2([N:20]3[C:30]4[N:29]=[C:27]([NH2:28])[NH:26][C:24](=[O:25])[C:23]=4[N:22]=[CH:21]3)[O:19][C@H:16]([CH2:17][O:18][C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:54][CH:53]=3)[C@@H:14]([OH:15])[CH2:13]2)=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc2c(ncn2[C@@]2(C(=O)Cc3ccccc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N#N
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@](C(=O)Cc3ccccc3)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
N2 -(Phenylacetyl)-2'-deoxyguanosine (2a) (23.12 g, 60 mmoles) was dried by coevaporation with dry pyridine (2×100 ml), dissolved in 600 ml of dry pyridine and ice cooled. To this solution, 4,4'-dimethoxytrityl chloride (25.5 g, 72 mmoles) was added. The reaction mixture was stirred at 5° C. for 20 hours. After removing the pyridine under reduced pressure, the resulting residue was taken up in 600 ml of methylene chloride, washed successively with 2×400 ml of 5% NaHCO3 and 1×400 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated to near dryness. The product was purified on a silica gel column (6×50 cm) by gradient elution with 1L 0-6% methylene chloride-methanol. The desired fractions were collected, concentrated to about 100 ml and added dropwise to 1.5L cooled hexane (0° C.) to precipitate the product. The precipitated product was filtered, washed with hexane and air dried to yield 24 g (58%) of tritylated product (3a), as confirmed by spectroscopic and elemental analysis.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:11]([Cl:17])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:11]([Cl:17])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2nc(Cl)c(CC(=O)O)n2Cc2ccccc2)c1
Agent: Br
Product: O=C(O)Cc1c(Cl)nc(-c2cccc(O)c2)n1Cc1ccccc1
Yield: 83.3 %

Procedure:
1 g of 1-benzyl-4-chloro-2-(3-methoxyphenyl)imidazole-5-acetic acid was boiled in 14 ml of 48% hydrobromic acid for 2 hours. The reaction solution was evaporated to dryness and, when water was added to the residue, there separated out white powder. The powder was dissolved in 10 ml of hot ethanol, and water was added to the solution until turbidity was developed. After allowing it to stand, there was obtained 0.8 g of 1-benzyl-4-chloro-2-(3-hydroxyphenyl)imidazole-5-acetic acid as colorless, prism-formed crystals, m.p. 220°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl.[O:14]=[C:15]1[N:19]([CH2:20][CH2:21][C:22]#[N:23])[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[N:16]1[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.C1C=CC=CC=1>CO>[C:22]([CH2:21][CH2:20][N:19]1[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[N:16]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH2:30][CH2:29]2)[C:15]1=[O:14])#[N:23]
Reactant: O=C(c1ccc(F)cc1)N1CC1
Reactant: N#CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CCCn1c(=O)n(C2CCN(CCNC(=O)c3ccc(F)cc3)CC2)c2ccccc21

Procedure:
A mixture of 1.68 parts of 1-(4-fluorobenzoyl)aziridine, 3.07 parts of 2,3-dihydro-2-oxo-3-(4-piperidinyl)-1H-benzimidazole-1-propanenitrile hydrochloride, 1.65 parts of N,N-diethylethanamine, 10.8 parts of benzene and 1.6 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and poured onto water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered off and recrystallized from 2-propanol, yielding 1part of N-[2-{4-[3-(2-cyanoethyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-1-piperidinyl}ethyl]-4-fluorobenzamide; mp. 172.2° C.
Reaction SMILES: BrC1C=C2C(=CC=1[Cl:12])C=NC=C2.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH:18]=[CH:17]2>>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[Cl:12])[C:20](=[O:24])[N:19]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[CH:18]=[CH:17]2
Reactant: Clc1cc2cnccc2cc1Br
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Product: COc1ccc(Cn2ccc3cc(Br)c(Cl)cc3c2=O)cc1

Procedure:
Starting from 6-Bromo-7-chloro-isoquinoline (263), the title compound was prepared by the method described for 6-Bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (13). Rt=1.66 min (Method C). Detected mass: 318.3 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1>C(#N)C.[Pd]>[N:19]1([CH2:18][CH2:17][CH:14]2[CH2:15][CH2:16][N:11]([C:2]3[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH2:13]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CCN(CCC2CCNCC2)CC1
Agent: [Pd]
Solvent: CC#N
Product: Nc1cccnc1N1CCC(CCN2CCCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 0.317 g (2.00 mmol) of 2-chloro-3-nitro-pyridine in acetonitrile (10 mL) is added 0.393 g (2.00 mmol) of 1-(2-piperdin-4-yl-ethyl)-piperidine. The mixture is heated to 80° C. and stirred overnight. The mixture is cooled to room temperature and concentrated under reduced pressure. The crude residue is dissolved in ethanol (10 mL) and treated with 0.050 g (0.05 mmol) of 10% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture is concentrated under reduced pressure to provide 0.577 g (quant.) of 4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[Cl:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[Cl:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:1]([C:4]12[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:10][CH2:11]2)=[O:3]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccc(N)c(Cl)c1
Product: Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)c(Cl)c1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-chloro-4-methylaniline (41.8 μL) were used to obtain (2S,4S)-1-[[N-[4-[N-(2-chloro-4-methylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (22.6 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:11](I)=[N:10]2)=[N:6][CH:7]=1.[B-](F)(F)(F)[CH:23]=[CH2:24].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(O)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:23]=[CH2:24])=[N:10]2)=[N:6][CH:7]=1
Reactant: C=C[B-](F)(F)F
Reactant: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccc(F)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=Cc1nn(Cc2ccc(F)cn2)c2cccc([N+](=O)[O-])c12
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A suspension of 1-((5-fluoropyridin-2-yl)methyl)-3-iodo-4-nitro-1H-indazole (0.968 g, 2.43 mmol) in 4:1 IPA/THF (10 mL) was degassed under argon. To the suspension was added TEA (0.678 mL, 4.86 mmol), potassium trifluoro(vinyl)borate (0.651 g, 4.86 mmol) and PdCl2(dppf)*dcm (0.199 g, 0.243 mmol). The mixture was then heated with stirring at 90° C. for 16 hours under argon. The mixture was allowed to cool, filtered through GF/F paper and concentrated under reduced pressure. The residue was dissolved in DCM and purified by chromatography on silica using a Biotage system, eluting with 1-10% Et2O in DCM. This gave 1-((5-fluoropyridin-2-yl)methyl)-4-nitro-3-vinyl-1H-indazole (229 mg).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([O:25]C)=[O:24])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CCO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([OH:25])=[O:24])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
1M NaOH (2 mL; 2 mmol; 6.63 eq.) was added to a solution of 4-(2-methoxycarbonyl-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (100 mg; 0.30 mmol; 1 eq.) in EtOH (2 mL) and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was partitioned between DCM and 1M HCl and the two phases separated. The aqueous layer was extracted with DCM and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford the title compound (90 mg, 94%) as a white solid. HPLC (max plot) 98.9%; Rt 4.37 min. UPLC/MS: (MS−) 316.4 ([M−H]−).
Reaction SMILES: [C@H:1]1([CH2:9][OH:10])[CH2:6][CH2:5][C@H:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.CN1CCOCC1.P(Cl)(Cl)(=O)OCCCCCC>C(Cl)Cl>[CH2:3]1[CH:4]([CH2:7][OH:8])[CH2:5][CH2:6][CH:1]([CH2:9][OH:10])[CH2:2]1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Agent: CCCCCCOP(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: OCC1CCC(CO)CC1
Temperature: -40 °C

Procedure:
Under an argon stream, 10 g of trans-1,4-cyclohexane dimethanol (CHDM), 15.25 mL (14.03 g) of N-methyl morpholine (NMM), and 50 mL of methylene chloride were transferred into a 250 mL flash equipped with a funnel. The solution in the flask was cooled down to −40° C. with stirring. A solution of 15.19 g of hexyl phosphoro-dichloridate (HOP) in 20 mL of methylene chloride was added through the funnel, and an additional 10 mL of methylene chloride was used to flush through the funnel. The mixture was then brought up to room temperature gradually and kept stirring for four hours.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])=[CH:19][CH:18]=1>>[Cl:33][C:31]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:28]=[CH:27][C:20]([C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:32]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Product: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product from Example 128b (192 mg, 0.62 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (50.9 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.72 (s, 3H) 3.19 (s, 3H) 3.42 (s, 3 H) 6.71 (d, J=6.99 Hz, 1 H) 6.94 (d, J=8.82 Hz, 2 H) 7.36 (d, J=8.82 Hz, 1 H) 7.50 (d, J=8.82 Hz, 2 H) 7.63 (dd, J=8.82, 2.57 Hz, 1 H) 7.72 (d, J=8.82 Hz, 1 H) 7.75 (d, J=2.57 Hz, 1 H) 8.53 (d, J=6.99 Hz, 1 H) 8.81 (d, J=8.46 Hz, 1 H) 10.88 (s, 1 H) 14.46 (s, 1 H); MS (ESI+) m/z 449 (M+H−TFA)+.