Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].C[Si](C)(C)Cl.C(#N)C.[F:11][C:12]1[CH:13]=[CH:14][C:15]2=[C:16]([CH:44]=1)[O:17][CH2:18][C:19]1[CH:29]=[C:28]([CH:30](O)[C:31]3[N:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]4=[N:33][C:32]=3[CH2:40][O:41][CH3:42])[CH:27]=[CH:26][C:20]=1/[C:21]/2=[C:22](/[CH3:25])\[C:23]#[N:24]>O.CCCCCC>[F:11][C:12]1[CH:13]=[CH:14][C:15]2=[C:16]([CH:44]=1)[O:17][CH2:18][C:19]1[CH:29]=[C:28]([CH2:30][C:31]3[N:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]4=[N:33][C:32]=3[CH2:40][O:41][CH3:42])[CH:27]=[CH:26][C:20]=1/[C:21]/2=[C:22](/[CH3:25])\[C:23]#[N:24]
Reactant: COCc1nc2ccccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: O
Product: COCc1nc2ccccn2c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
[step 5] To sodium iodide (197 mg, 1.32 mmol) were added trimethylchlorosilane (165 mL, 1.32 mmol) and acetonitrile (69 mL, 1.3 mmol), and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added hexane (0.22 mL). Furthermore, (E)-2-(3-fluoro8-{hydroxy[2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (100 mg, 0.22 mmol) obtained in step 4 was added, and the mixture was stirred for 1 hr. The reaction was discontinued with water, and the mixture was extracted with chloroform, the extract was washed with saturated sodium thiosulfate aqueous solution, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained reaction residue was purified by silica gel column chromatography (chloroform/methanol=10/1 v/v) to give the title compound (60 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1.[CH3:43][O:44][CH2:45][CH2:46][C:47](Cl)=[O:48]>>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][O:23][CH2:22][CH2:21][CH2:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]2[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:8][CH:7]2[O:6][CH2:5][C:4]2[CH:40]=[CH:41][CH:42]=[C:2]([NH:1][C:47](=[O:48])[CH2:46][CH2:45][O:44][CH3:43])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: COCCC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(N)c2)cc1
Product: COCCC(=O)Nc1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Example 116b, 0.610 g of tert-butyl 3-(3-aminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.270 g of 3-methoxypropionyl chloride are reacted. The title compound is obtained as a beige oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.56.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C(O)(C)C>[Cl:1][C:2]1[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccc1
Reactant: Nc1ccnc(Cl)c1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Nc1ccnc(Cl)c1Sc1ccccc1
Reaction time: 24 h
Yield: 91 %

Procedure:
To a 250 mL round flask was added 2-chloro-3-iodo-4-aminopyridine (5.0 g, 19.6 mmol), thiophenol (2.16 g, 19.6 mmol), CuI (0.187 g, 0.98 mmol), ethylene glycol (2.5 g, 39 mmol), potassium carbonate (5.4 g, 39 mmol), and 150 mL of isopropanol. The reaction was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the mixture was purified by a silica gel column. Yield (91%) of 2-chloro-3-phenylthio-4-aminopyridine was 4.2 g.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
A mixture of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (21.5 g, 107 mmol) and triethylamine (30 mL, 214 mmol) in dichloromethane (250 mL) was cooled to 0° C. Methanesulfonyl chloride (12.5 mL, 160.5 mmol) was added dropwise via an addition funnel and the resulting mixture was stirred at 0° C. then gradually warmed to room temperature over 3 h. A 10% aqueous citric acid solution was added and the two layers were separated. The organic layer was washed with 10% aqueous citric acid, sat'd aqueous NaHCO3, and brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator to afford 30 g of (R)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate as an orange oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 4.17 (m, 2H), 3.33 (m, 2H), 3.20 (m, 1H), 3.18 (s, 3H), 3.00 (m, 1H), 2.55 (m, 1H), 2.01 (m, 1H), 1.53 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[N:15][NH:14][C:13](=[O:27])[CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O>O1CCCC1>[C:17]1([CH:16]([NH:15][C:5]2[N:10]=[C:9]([C@H:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=4)=[N:15][NH:14][C:13](=[O:27])[CH2:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1nccc(C2CC(=O)NN=C2c2cccc(C(F)(F)F)c2)n1
Solvent: C1CCOC1
Product: CC(Nc1nccc([C@@H]2CC(=O)NN=C2c2cccc(C(F)(F)F)c2)n1)c1ccccc1

Procedure:
Compound 7 (5.00 g, 13.1 mmol), s-(−)-α-methylbenzylamine (3.37 mL, 26.2 mmol) and tetrahydrofuran (100 mL) were heated to reflux under argon for 24 h. The solvent was removed in vacuo. Purification by flash column chromatography (methylene chloride:methanol: ammonium hydroxide 98:2:0.2) gave Compound 8 as a foam: 5.0 g (9.6 mmol, 73%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>O1CCCC1>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:38](=[O:40])[CH3:39])[CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-2-(piperidin-4-ylmethyl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (49 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.03 ml) and acetic anhydride (0.05 ml) and the mixture was stirred at room temperature for 16 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to give the title compound (18 mg, 36%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][C:18]=1[F:24].BrC1C=CC(OC[C@@H]2CC[C@H](OC3CCCCO3)CC2)=CC=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:15][CH2:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:9][CH2:10]2)=[CH:19][C:18]=1[F:24]
Reactant: OC[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: Oc1ccc(Br)c(F)c1
Agent: Brc1ccc(OC[C@H]2CC[C@@H](OC3CCCCO3)CC2)cc1
Product: Fc1cc(OC[C@H]2CC[C@H](OC3CCCCO3)CC2)ccc1Br

Procedure:
The title compound (885 mg, 81.6%) was prepared from (+/−)-[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (600 mg, 2.80 mmol) and 4-bromo-3-fluorophenol (588 mg, 3.08 mmol) by a procedure analogous to that described for (+/−)-2-({cis-4-[(4-bromophenoxy)methyl]cyclohexyl}oxy)tetrahydro-2H-pyran in Example 8, Step C. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03-1.21 (m, 2H) 1.21-1.36 (m, 1H) 1.35-1.50 (m, 1H) 1.49-1.66 (m, 4H) 1.65-1.99 (m, 5H) 2.03-2.17 (m, 2H) 3.44-3.55 (m, 1H) 3.60 (tt, J=10.98, 4.24 Hz, 1H) 3.72 (d, J=6.24 Hz, 2H) 3.86-4.00 (m, 1H) 4.70-4.80 (m, 1H) 6.59 (ddd, J=8.88, 2.83, 0.98 Hz, 1H) 6.68 (dd, J=10.54, 2.73 Hz, 1H) 7.35-7.44 (m, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH:17]C(=O)C)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1.[ClH:22]>CO>[ClH:22].[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1
Reactant: CC(=O)Nc1n[nH]c2cc(-c3cc(C)nc(N)n3)ccc12
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
In a 100 mL flask under argon was dissolved N-[6-(2-amino-6-methyl-4-pyrimidinyl)-1H-indazol-3-yl]acetamide (0.021 g, 0.074 mmol) in CH3OH (5 mL). HCl (2.26 μl, 0.074 mmol) was added and the solution was stirred for 8 hours at 60° C. The reaction was cooled to room temperature. The resulting precipitate was filtered and washed with minimal CH3OH to afford an HCl salt of the title compound (6 mg, 26%) as a white solid. LC-MS (ES) m/z=241 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.51 (s, 3H {assumed to be hidden beneath DMSO peak}), 7.59 (s, 1H), 7.81 (dd, J=8.6, 1.3 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 8.21 (s, 1H), 12.72 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([O:35][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2ccc3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
reacting the product of step f) with 2-bromomethyl-naphthalene and sodium hydride to yield (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([C:6]1[O:7][C:8]2[C:9](=[C:11]([C:17]([OH:19])=[O:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=1)(=[O:5])=[O:4].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:18][C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:8]3[O:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[CH3:20])=[CH:10][C:9]=23)=[O:19])=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2cc(S(=O)(=O)N(C)C)oc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(S(=O)(=O)N(C)C)oc12
Yield: 86.9 %

Procedure:
Prepared from 2-dimethylsulfamyl-7-methoxybenzofuran-4-carboxylic acid (0.5 g), 4-nitrophenol (270 mg), 4-dimethylaminopyridine (11 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (370 mg) in dichloromethane (30 ml). Trituration from ethyl acetate and hexane afforded the desired product as a cream solid (0.61 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Product: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Ethyl N-(3-nitroquinolin-4-yl)-β-alaninate (50.0 g, 173 mmol) was hydrogenated in the presence of 5% platinum on carbon (1.0 g) according to the method described in Part C of Example 1. The reaction was allowed to proceed overnight under hydrogen pressure (40 psi, 2.8×105 Pa) and then subjected to the work-up procedure to provide 42.3 g of ethyl N-(3-aminoquinolin-4-yl)-β-alaninate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[C:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)(=[O:11])[CH3:10].C([Li])CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)([OH:11])[CH3:10])=[N:6][CH:7]=1
Reactant: Clc1cnc(I)nc1
Reactant: COC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(Cl)cn2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-2-iodopyrimidine (0.2 g, 0.83 mmol) and methyl trans-4-acetylcyclohexanecarboxylate (0.15 g, 0.83 mmol) in THF (4 mL) was added n-butyllithium (2.5 M in hexanes, 0.33 mL, 0.83 mmol) dropwise under a nitrogen atmosphere at −78° C. The mixture was stirred at −78° C. for 2 hours, and then quenched with saturate aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to afford methyl trans-4-[1-(5-chloropyrimidin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI calc'd for C14H20ClN2O3 [M+H]+ 299. found 299. 1H NMR: (400 MHz, CDCl3) δ 8.67 (s, 2H), 3.63 (s, 3H), 2.22-2.16 (m, 1H), 2.07-1.97 (m, 2H), 1.86-1.83 (m, 2H), 1.52 (s, 3H), 1.46-1.19 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]([NH2:18])=[N:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH2:19]=O.Cl>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:13]([NH2:18])=[N:14][N+:15]([O-:17])=[O:16])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: NC(=N[N+](=O)[O-])NCCNCc1ccc(Cl)nc1
Reactant: C=O
Agent: Cl
Solvent: O
Product: NC(=N[N+](=O)[O-])N1CCN(Cc2ccc(Cl)nc2)C1

Procedure:
A mixture consisting of 1-{2-(6-chloro-3-pyridylmethylamino)ethyl}-2-nitroguanidine (1 g), a 37% aqueous solution of formalin (0.35 g), catalytic amount of hydrochloric acid, and water (20 ml) was stirred at 50° C. for one hour. After cooling, the solvent was removed from the reaction mixture under reduced pressure, leaving crystals that were then washed with chloroform to obtain the 1-(6-chloro-3-pyridylmethyl)-3-{1-(nitroimino)-aminomethyl}-imidazolidine. mp 170°-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][NH:15][C:16](=[O:17])[C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.[H-].[Na+].[Br-].[Li+].I[CH2:31][CH3:32]>COCCOC.CN(C)C=O.O>[CH2:31]([N:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:4]=3)=[CH:9][N:10]=[C:11]2[C:16]1=[O:17])[CH3:32]
Reactant: CCI
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3c(=O)[nH]ccn23)ccc1F
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: CCn1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.2 %

Procedure:
A suspension of 2′-fluoro-5′-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile (50.0 mg, 0.51 mmol) in 1,2-dimethoxyethane (2 ml) and N,N-dimethylformamide (0.5 ml) was treated with sodium hydride (6.4 mg of a 60% dispersion in mineral oil, 0.16 mmol). After stirring at ambient temperature for 10 min, lithium bromide (26.3 mg, 0.30 mmol) was added, and stirring continued for 15 min. Iodoethane (24.2 μl, 0.30 mmol) was added and the solution heated at 65° C. for 18 h. Water (15 ml) was added and the resulting mixture was extracted with dichloromethane (3×10 ml). The combined organic layers were washed with water (10 ml), saturated sodium chloride solution (10 ml), dried over anhydrous magnesium sulphate then concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 2% methanol in dichloromethane. Crystallisation from methanol afforded the title compound as a white solid (23.9 mg, 44%): δH (500 MHz, CDCl3) 1.38 (3H, t, J 7.2), 4.06 (2H, q, J 7.2), 6.72 (1H, d, J 5.9), 7.39 (1H, t, J 9.3), 7.44 (1H, d, J 5.9), 7.53-7.61 (5H, m), 7.69-7.73 (1H, m), 7.84 (1H, d, J 7.3); m/z (ES+) 359 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]([N:26]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:27])=[O:25])=[CH:11][N:10]=1)(C)(C)C.Cl>CCOC(C)=O>[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24](=[O:25])[N:26]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:27])=[CH:11][N:10]=1
Reactant: COc1cc2c(NC(=O)N(C)Cc3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(NC(=O)N(C)Cc3ccccc3)cnc(CN)c2cc1OC
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of the Boc protected amine, [4-(3-benzyl-3-methyl-ureido)-6,7-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester, (155 mg) was taken up in 5 mL of EtOAc, then 600 μL of HCl in EtOAc was added and the reaction was allowed to stir overnight. Solvent was removed in vacuo, and the resulting white solid was washed with ether to give 109 mg (89%) of the desired product as the hydrochloride salt. H1-NMR (CDCl3): δ 8.31 (s, 1H), 7.3-7.4 (m, 5H), 7.17 (s, 1H), 6.82 (s, 1H), 6.51 (s, 1H), 4.66 (s, 2H), 4.29 (s, 2H), 3.99 (s, 3H), 3.83 (s, 3H), 3.16 (s, 3H), 2.83 (br s, 1H). MS: APCI (M+H) calc'd for C26H32N4O5+H 481.6; found 481.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[O:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(C2CCOCC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 8.9 g of 4-(p-hydroxyphenyl)-tetrahydropyran in 50 ml of ethanol was added to a mixture of 1.15 g of sodium in 100 ml of ethanol and the mixture was stirred for 2 hours at room temperature and was then cooled to 0° C. 7.82 ml of ethyl 2-bromo-propanoate were added to the mixture which was then allowed to return to room temperature and the mixture was refluxed for 5 hours. The mixture was evaporated to dryness and the residue was dissolved in a mixture of 100 ml of ether, 45 ml of water and 5 ml of 2N hydrochloric acid. The aqueous phase was removed by decanting and the organic phase was washed with 2N sodium hydroxide, was dried and evaporated to dryness under reduced pressure to obtain 7.9 g of ethyl 2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoate with a boiling point of 138°-140° C at 0.05 mm Hg.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Li]C[CH2:12][CH2:13][CH3:14].C1(C(Cl)=O)CC1.O>C1COCC1>[CH:12]1([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:13][CH2:14]1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: [Li]CCCC
Agent: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)C1CC1
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 36.6 %

Procedure:
To a cooled (-70° C.) solution of monoethyl malonate (33.97 g, 257.10 mmol) in THF (639 mL) was added n-BuLi (1.6M in hexanes, 319 mL, 514.19 mmol) and the mixture was stirred under an argon atmosphere for 15 min. The resulting solution was cooled to -65° C. and cyclopropanecarbonyl chloride (15.55 g, 148.77 mmol) was added. The reaction mixture was stirred for 1 h and then allowed to warm up to room temperature. Some drops of water were added and THF was removed. The residue was taken up in 1N HCl/Et2O and extracted with Et2O. The organic phase was washed with saturated NaHCO3, dried and concentrated to a residue. This was purified by chromatography on silica gel (hexane-EtOAc mixtures of increasing polarity) to afford the title compound as a yellow oil (14.7 g, 63%).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[N:8]3[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1.[CH3:27][C:28]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:29]=1[C:30](Cl)=[O:31].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:27][C:28]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:29]=1[C:30]([C:17]1[CH:16]=[C:15]2[C:7]([N:8]([C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:26])[CH3:25])=[CH:22][CH:23]=3)[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=12)=[O:31]
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3ccc4ccccc4c32)cc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2c3ccccc3c3cc(C(=O)c4c(C)cc(C)cc4C)c4ccccc4c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1-(4-benzo[a]carbazol-11-yl-phenyl)-ethanone (649 mg, 1.93 mmol) in CH2Cl2 (10 mL) are added 2,4,6-trimethylbenzoyl chloride (369 mg, 2.02 mmol) and AlCl3 (1.50 g, 11.24 mmol) at 0° C. After stirring for 0.5 hour, the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into ice-water, and the crude product is extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with a mixed solvent of n-hexane and CH2Cl2 (1:1) to obtain an off-white solid (383 mg; 41%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 2.22 (s), 2.41 (s), 2.77 (s), 6.97 (s), 7.15 (d), 7.30-7.34 (m), 7.39 (t), 7.51 (d), 7.63 (d), 7.65 (d), 8.01 (d), 8.28 (d), 8.28 (d), 8.39 (s), 9.53 (d).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:15][CH:16]=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[CH3:16][NH:15][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=CNCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCc1ccccc1

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of LiAlH4 (868 mg, 22.84 mmol, 1.50 equiv) in tetrahydrofuran (70 mL). This was followed by the addition of a solution of N-phenethylformamide (2.27 g, 15.23 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) dropwise with stirring while the resulting solution maintained reflux. The resulting solution was stirred overnight at reflux in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100:1). This resulted in 1.36 g (34%) of N-methyl-2-phenylethanamine as yellow oil.