Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (40 mg, 0.1020 mmol), 4-dimethylaminopyridine (6.2 mg, 0.0508 mmol) and morpholine (18 mg, 0.2068 mmol) were dissolved in methylene chloride (5 ml), then WSC-HCl (59 mg, 0.3077 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (13 mg, 0.0281 mmol, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:45])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39](O)=[C:38]([CH3:43])[C:37]=1[CH3:44])([CH3:34])[CH3:33])[CH3:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:28]([O:30][C:31](=[O:45])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:38]([CH3:43])[C:37]=1[CH3:44])([CH3:33])[CH3:34])[CH3:29]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)c(C)c1C
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C)c1C

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), 2-(4-hydroxy-2,3-dimethyl-phenoxy)-2-methyl-propionic acid ethyl ester (CAS RN: 851508-28-6), tri-n-butylphosphin and N,N,N′,N′-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Colorless oil (11%). MS (Turbo Spray): m/z=625.5 [M+H].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
1-Fluoro-4-nitro-benzene (1.00 g, 7.09 mmol) is dissolved in DMF (20 mL), and to this solution, is added 1-methyl-piperazine (0.944 mL, 8.51 mmol) followed by K2CO3 (1.47 g, 10.6 mmol). After stirring the mixture at rt for 18 h, the solvent is removed via high vacuum. The resulting residue is dissolved in EtOAc (100 mL) and washed with H2O (10 mL) and brine (10 mL) and then dried (Na2SO4). The solvent is taken off via high vacuum to afford the product as a solid (1.50 g, 96%); 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37-2.42 (m, 4H), 3.39-3.43 (m, 4H), 6.98 (d, J=9.6 Hz, 2H), 8.00 (d, J=9.5 Hz, 2H); mass spectrum [(+) ESI], m/z 222 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]2[C:8]([CH:9]=[C:10]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:11]=[N:12]2)=[C:7]([I:31])[N:6]=1)=[O:4].O1CCCC1.[OH-].[Na+].Cl>CO>[CH2:16]([O:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([I:31])=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[CH:9]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above Compound 8 (20.0 g, 37.86 mmol) was added tetrahydrofuran (100 ml) and methanol (100 ml) to give suspension, followed by addition of 2N sodium hydroxide aqueous solution (24.6 ml, 49.2 mmol) under stirring at room temperature and stirring was continued. After 4 hours, 2N hydrochloric acid (24.6 ml, 49.2 mmol) was added, and the reaction solution was concentrated under reduced pressure and added with chloroform (150 ml) and water (150 ml). Then the solution was shaken for separation, washed with saturated sodium hydrogen carbonate and dried over sodium sulfate, followed by distillation under reduced pressure. The residue (20.8 g) was added with diisopropyl ether (80 ml) and n-hexane (80 ml), warmed on a water bath for crystallization, and then the crystals were collected by filtering and washed with diisopropyl ether:n-hexane (1:1), to give 8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylic acid 9 in a yield of (19.41 g, 99.7%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C@:15]2([CH2:22][CH:23]3[O:27][CH2:26][CH2:25][O:24]3)[CH2:20][NH:19][C:18](=[O:21])[CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14].F[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>COCCOC>[Cl:7][C:8]1[CH:9]=[C:10]([C@:15]2([CH2:22][CH:23]3[O:27][CH2:26][CH2:25][O:24]3)[CH2:20][N:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18](=[O:21])[CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Fc1ccccn1
Reactant: O=C1CC[C@](CC2OCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C1CC[C@](CC2OCCO2)(c2ccc(Cl)c(Cl)c2)CN1c1ccccn1

Procedure:
Potassium tert-butoxide (68 g, 0.606 mol) was added to a suspension of (5S)-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidinone (WO 9807722) (200 g, 0.606 mol) in 1,2-dimethoxyethane (700 ml), and the mixture heated under reflux for 1 hour. 2-Fluoropyridine (59 g, 0.606 mol) was then added and the mixture stirred under reflux for 1 hour. Additional potassium tert-butoxide (34 g, 0.303 mol) and 2-fluoropyridine (30 g, 0.303 mol) were added and the reaction mixture stirred under reflux for a further hour. The cooled mixture was partitioned with water (500 ml), and the aqueous layer then extracted with ethyl acetate (2×500 ml). The combined organic extracts were dried (MgSO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (20:80 to 100:0) to afford the title compound as a clear gum, 129 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]1[C:17]([C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)=[N:18][C:19]([NH:22][CH2:23][CH2:24][NH:25]C2C=CC(C(F)(F)F)=CN=2)=[N:20][CH:21]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:25][CH2:24][CH2:23][NH:22][C:19]2[N:18]=[C:17]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[C:16]([C:12]3[NH:11][CH:15]=[CH:14][N:13]=3)=[CH:21][N:20]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)cc1
Reactant: N#Cc1cnc(Cl)nc1N
Product: N#Cc1ccc(-c2nc(NCCNc3ncc(C#N)c(N)n3)ncc2-c2ncc[nH]2)cc1

Procedure:
4-amino-2-[(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]pyrimidine-5-carbonitrile was prepared from 4-amino-2-chloropyrimidine-5-carbonitrile using the general method for 4-{5-imidazolyl-2-[(2-{[5-(trifluoromethyl) (2-pyridyl)]amino}ethyl)amino]pyrimidin-4-yl}benzenecarbonitrile.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].FC1C=CC(C=O)=CC=1[C:25]#[N:26]>>[C:25]([C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9])#[N:26]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: N#Cc1cc(C=O)ccc1F
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C#N)c2)s1

Procedure:
The titled compound was prepared by an identical procedure to N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) replacing 3,4-difluorobenzaldehyde in this procedure with 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[K+].Cl.[CH2:9]([C:16]([NH2:18])=[NH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.ClCCCl>[CH3:5][O:4][C:2]([NH:18][C:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[NH:17])=[O:3]
Reactant: N=C(N)Cc1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)NC(=N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
137.2 parts of methyl chloroformate and a solution of 162.7 parts of potassium hydroxide in 180 parts of water are added via two inlets to a mixture of 246 parts of benzylmethanamidine hydrochloride in 530 parts of 1,2-dichloroethane and 85 parts of water, at from 10° to 15° C., in the course of 35 minutes. The mixture is stirred at 25° C. for 20 minutes, the organic phase is separated off and the aqueous phase is extracted twice more with 1,2- dichloroethane. The organic extracts are concentrated to give 259.8 parts (93% of theory) of N-methoxycarbonylbenzylmethanamidine of nD25 1.5247.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].C([S+](CC)CC)C.[F:15][C:16]1[CH:21]=[CH:20][C:19](C(=O)C)=[CH:18][CH:17]=1.[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:27]2([CH3:26])[CH:29]([CH3:25])[O:28]2)=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC[S+](CC)CC
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: CC1OC1(C)c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Triethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-fluorophenyl) ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-n2cccn2)ccn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(-n2cccn2)ccn1
Temperature: 25 °C
Yield: 24.6 %

Procedure:
To a stirred solution of 2-methyl-4-(1H-pyrazol-1-yl)pyridine (300 mg, 1.9 mmol) in CCl4 (25 mL), N-bromo succinimide (304 mg, 1.71 mmol) and benzoyl peroxide (23 mg, 0.09 mmol) were added and heated to reflux for 16 h. The reaction mixture was cooled to rt and precipitated succinimide was filtered. The filtrate was absorbed on silicagel and concentrated under reduced pressure. The crude product was purified flash column chromatography (eluent: 5% ethyl acetate in hexane) to yield the title compound (100 mg, 45%). [TLC Rf=0.34 (ethyl acetate/hexane 30:70)].
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:12]2=[O:23])=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[H-].[Na+].CO.C(Cl)Cl>CN(C=O)C.C(Cl)(Cl)Cl>[O:6]1[C:2]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])=[CH:7][C:3]=2[CH:4]=[N:5]1
Reactant: Cc1ccncc1N1CCN(c2ccc(F)c(C=NO)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccncc1N1CCN(c2ccc3oncc3c2)C1=O
Temperature: 25 °C
Reaction time: 70 h
Yield: 70.1 %

Procedure:
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde oxime (I-113b:160 mg, 0.509 mmol) in dry DMF (2 mL) was added dropwise to a stirred mixture of NaH (72 mg, 1.52 mmol) in DMF (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 70 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The aqueous layer was distilled to afford the solid residue which was dissolved 1:1 DCM:MeOH. The crude product was purified by column chromatography on silica gel (4-5% MeOH in CHCl3). The residue was washed with hexane and dried to afford 105 mg of the product (70.4% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](=[O:30])[CH2:28]Br)=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](=[O:30])[CH2:28][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH2:15])=[N:12][O:13][N:14]=2)=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.228 g, 1.14 mmol), potassium carbonate (0.40 g, 2.85 mmol) and 4-chloro-3-nitrophenacyl bromide (0.35 g, 1.25 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a solid, m.p. 198-200° C. (This compound is also listed as Example 66 in Table 1.)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].F[C:24](F)(F)C(O)=O.C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCCC1.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:24][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: COc1nc2nc(OC3CCCC3)[nH]c(N)c-2n1
Agent: ClCCCCBr
Product: COc1nc2c(N)nc(OC3CCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclopentyloxy)-8-(methyloxy) -1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: C([N:20]1[C:24]([CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:29]=2)=[CH:23][N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(O)(=O)C>CO>[NH:20]1[C:24]([CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH:29]=2)=[CH:23][N:22]=[CH:21]1
Reactant: COC(=O)c1ccc(/C=C/Cc2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(/C=C/Cc2cnc[nH]2)cc1-c1ccc(F)cc1
Yield: 20 %

Procedure:
A solution of methyl 4-[(E)-3-(1-tritylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (7.8 g; 10 mmol), 12N HCl (7.5 ml) and acetic acid (7.5 ml) in methanol (150 ml) was refluxed for 1 hour 30 minutes. After evaporation to dryness and neutralisation with an aqueous solution of ammonium hydroxide, the residue was extracted with dichloromethane and purified by flash chromatography, eluting with a gradient 2-5% ethanol/dichloromethane to give methyl 4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate. Yield: 20%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][C:44]([CH3:58])([O:47][Si](C(C)C)(C(C)C)C(C)C)[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].N>C1COCC1.CO.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][C:44]([OH:47])([CH3:58])[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(C)(O[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(C)(O)CC5)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a solution of Intermediate 79f (210 mg, 0.260 mmol) in THF (4 mL) at −30° C. was added TBAF (1M in THF, 390 μL, 0.390 mmol) and the mixture was allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, and then recrystallisation from boiling EtOAc (˜40 mL) gave the title compound as a white powder (67 mg, 40%). LCMS (Method 5): Rt 4.31 min, m/z 649.1 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.30 (3H, s), 1.33 (9H, s), 1.71-1.77 (2H, m), 1.84-1.93 (2H, m), 1.95-2.17 (3H, m), 2.25-2.32 (1H, m), 2.41 (3H, s), 3.20-3.28 (2H, m), 3.36-3.45 (2H, m), 4.72-4.92 (1H, m), 5.47 (1H, t, J 4.4), 6.36 (1H, s), 6.88 (1H, d, J 9.3), 7.21-7.40 (8H, m), 7.58 (1H, d, J 9.7), 7.62 (1H, d, J 1.7).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClC1C=CC=CC=1Cl>[CH2:9]1[C:8]2=[CH:7][C:1]3[C:6]([C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[CH2:11][CH2:10]1)=[CH:5][CH:4]=[CH:3][CH:2]=3
Reactant: COC(=O)C#CCCC/C=C/c1ccccc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1c2c(cc3ccccc13)CCC2
Temperature: 225 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a 10-20 mL microwave irradiation vial equipped with a stir bar was added enyne 5k (0.150 g, 0.66 mmol) in o-dichlorobenzene (11 mL). The reaction was irradiated with stirring at 225° C. for 90 min until complete by TLC. The reaction turned golden in color. The reaction was then transferred to a vial and concentrated under high vacuum to yield naphthalene 6k as a black oil (0.144 g, 97%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:12][N:11]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(COCC2CC2)cn1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(COCC2CC2)cn1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.089 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.142 g) as a light yellow gum (0.152 g). MS (ESI−): 365.0 ([M−H]−)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]([C@@H:16]([CH3:27])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH2:24][CH2:23][C:22]=3[CH:26]=2)[CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5].C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[O:25]1[C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:16]([N:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:7][CH2:8]3)[CH2:14][CH3:15])[CH3:27])=[CH:26][C:22]=2[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC1CCN(C(=O)CCN)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC1CCN(C(=O)CCNS(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To (S)-3-amino-1-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}-methyl)piperidin-1-yl]propan-1-one (0.4 grams, 1.07 mmol) and diisopropylethylamine (0.21 grams, 1.62 mmole) in dichloromethane (10 ml) at 0° C. was added methanesulfonyl chloride (0.16 grams, 1.39 mmole). The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with water, dried over potassium carbonate and concentrated to give a residue which was purified by flash chromatography on silica gel using 3% methanol in dichloromethane containing 0.1% ammonium hydroxide. Appropriate fractions were combined and evaporated to give (S)-N-{3-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}methyl)piperidin-1-yl]-3-oxopropyl}methanesulfonamide as an oil (0.32 grams, 66%), M+H 452. Analysis % of the hydrochloride salt: Found: C, 51.83; H, 7.38; N, 7.87. Requires: C, 51.82; H, 7.56; N, 7.88.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29].O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)#[N:29]
Reactant: N#Cc1ccccc1CCC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Yield: 97 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(2-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (991 mg, 2.51 mmol, prepared in Synthetic Example 11) in DMF (25 ml) was added hydrazine monohydrate (80%, 371 μl, 9.26 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-[2-(2-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (953 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:13]([C@@H:15]1[O:17][CH2:16]1)[Cl:14]>CCO.O>[Cl:14][CH2:13][C@H:15]([OH:17])[CH2:16][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: ClC[C@H]1CO1
Solvent: CCO
Solvent: O
Product: O=C1CSc2ccc(NC[C@@H](O)CCl)cc2N1
Yield: 81 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (18.39 g, 102 mmol; commercial) and (R)-epichlorohydrin (8.0 mL, 1 eq.) in EtOH/H2O (9:1; 450 mL) was heated at 80° C. overnight. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/EA followed by filtration. The filtrate containing the product was concentrated under reduced pressure to afford the title intermediate as a beige solid (22.52 g, 81% yield) which was used as such in the next step.