Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.C(N(CC)CC)C.[Cl:23][C:24]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][S:26][C:25]=1[C:33](Cl)=[O:34]>C(Cl)Cl.CC#N>[Cl:23][C:24]1[C:28]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][S:26][C:25]=1[C:33]([NH:14][C:12]1[CH:11]=[N:10][N:9]([CH2:8][C:7]2[C:3]([CH3:2])=[N:4][O:5][C:6]=2[CH3:15])[CH:13]=1)=[O:34]
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: CS(=O)(=O)c1csc(C(=O)Cl)c1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2scc(S(C)(=O)=O)c2Cl)cn1
Temperature: 0 °C
Yield: 45.2 %

Procedure:
To a stirring mixture of ((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (500 mg, 2 mmol) in DCM (20 mL), cooled to 0° C. via an ice water bath, was added triethylamine (600 mg, 6 mmol). The mixture was stirred until all solids were in solution (˜10 minutes). 3-Chloro-4-(methylsulfonyl)thiophene-2-carbonyl chloride (543 mg, 2.1 mmol), in 2 mL CH3CN, was added via syringe to the free amine at 0° C. The ice bath was removed and the mixture was stirred for 2 hours. The reaction was diluted with dichloromethane (100 mL) and the organic phase was washed with H2O (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid was triturated with ethyl acetate/hexanes (1/5) to afford 3-chloro-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-4 (methylsulfonyl)thiophene-2-carboxamide (375 mg, 45%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 2.20 (s, 3H), 2.43 (s, 4H), 3.22 (s, 3H), 5.05 (s, 2H), 7.57 (s, 1H), 7.94 (s, 1H), 8.41 (s, 1H), 8.59 (bs, 1H). LC/MS; [M+H] 415.5. Melting point: 202-204° C.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:27]([NH:28][C:3](=[O:4])[CH2:2][F:1])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:20][CH2:21]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CF
Reactant: Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(CF)Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Following the general procedure of PREPARATION 101 and making non-critical variations but starting with fluoroacetyl chloride (0.94 g), 1-benzyloxycarbonyl-4-[3-amino-2-pyridinyl]piperazine (PREPARATION 100, 3.0 g), the title compound is obtained, NMR (300 MHz, CDCl3) 8.83, 8.65, 8.14, 7.38-7.32, 7.12, 5.17, 4.96, 3.70 and 3.07 δ.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:29]=O>C1(C)C=CC=CC=1.C(OCC)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[O:21]=[C:20]1[O:22][CH2:29][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[C@H:19]1[CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: O=C(N[C@@H](Cc1cscn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: C=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C1OCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]1Cc1cscn1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77.5 %

Procedure:
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(thiazol-4-yl)propanoic acid (Fmoc-Ala(4-Thz)-OH, Compound SP818) (50 g, 127 mmol), camphorsulfonic acid (2.10 g, 9.04 mmol) and paraformaldehyde (110 g, 3.66 mol) were dissolved in toluene (2 l) under a nitrogen atmosphere, and the mixture was stirred at 80° C. for two days. The reaction solution was diluted with diethyl ether and sequentially washed with an aqueous sodium bicarbonate solution and brine. The resulting organic extract was dried over sodium sulfate and then concentrated under reduced pressure to afford (S)-(9H-fluoren-9-yl)methyl 5-oxo-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (Compound SP817) (40.0 g, 98%) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[ClH:12].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[CH2:22]2)[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:12])=[CH:4][C:3]=1[S:8]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[CH2:22]2)[CH2:18][CH2:19]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1cc2c(cc1OC)CN(CC1CCNCC1)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)CN(CC1CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
2-Chlorobenzene-1-sulfonyl chloride (301.9 mg, 1.43 mmol) was added to a solution of 2-(piperidin-4-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (472 mg, 1.3 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol) in CH2Cl2 (25 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×30 mL), dried over Na2SO4, and evaporated to dryness. The free base was dissolved in ethyl acetate (2 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.6 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (406 mg, 63%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1cccc(N)c1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cccc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 65 %

Procedure:
4-Hydroxy-2-methyl-N-(3-tolyl)- 2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and m-toluidine. Yield: 65% of theroy; m.p. 240-242° C (decomp.; from xylene).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([CH2:14][N:15](CC2C=CC=CC=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[OH:13])=[CH:4][C:3]=1[Cl:38].CCCCCC>C(O)C.Cl.C(O)C.[Pd]=O>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH:12]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[OH:13])=[CH:4][C:3]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCc2ccccn2)Cc2ccccc2)cc1C(F)(F)F
Agent: O=[Pd]
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccccn2)cc1C(F)(F)F
Yield: 69.4 %

Procedure:
A solution of 4-amino-3-chloro-α-[[(phenylmethyl)[6-(2-pyridinylethoxy)hexyl]amino]methyl]-5-(trifluoromethyl)benzenemethanol (1.50 g) in absolute ethanol (10 ml) and conc. hydrochloric acid/ethanol (1:9 v/v, 2.48 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (50% aqueous, 300 mg) in absolute ethanol (10 ml). The mixture was filtered through hyflo and evaporated in vacuo to give an oil. Purification by FCC eluting with toluene-ethanol- triethylamine (95:5:1) gave a pink oil. Trituration with hexane afforded the title compound as a pale orange solid (0.87 g), m.p. 51.5°-53°.
Reaction SMILES: C[C:2]1C=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].BrC1C=CC=C2C=1C=C[N:27]2S(C1C=NC=CC=1)(=O)=O.C([Sn](CCCC)(CCCC)C=C)CCC.CO>CC#N.C(Cl)Cl>[N:27]1[CH:6]=[CH:5][CH:4]=[C:3]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:2]=1
Reactant: O=S(=O)(c1cccnc1)n1ccc2c(Br)cccc21
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1C
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccnc1
Yield: 80 %

Procedure:
The experimental for Intermediate 15 was followed using 4-bromo-1-(pyridin-3-ylsulfonyl)-1H-indole (285 mg, 0.85 mmol; Intermediate 24) in dry MeCN (5 mL, one vial), tributyl(vinyl)stannane (0.494 mL, 1.69 mmol) and Pd(PPh3)2OAc2 (32 mg, 0.042 mmol). Flash chromatography (1% MeOH in DCM) afforded the title compound (208 mg, 80%) as a yellow sticky oil. MS (ESI+) for C15H12N2O2S m/z 285 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[NH:18]([CH3:20])[CH3:19]>C1COCC1>[CH3:19][N:18]([CH3:20])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.673 mmol) and aqueous Me2NH (4 mL) in THF (10 mL) was stirred at room temperature overnight. It was then concentrated under reduced pressure to give the title compound. MS (m/z): 262 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:15]=[CH:14][C:9]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][C:6]1=[O:7].[N-:16]=[N+:17]=[N-:18].[Na+]>C(#N)C>[N:16]([CH2:2][CH2:3][CH2:4][N:5]1[CH:15]=[CH:14][C:9]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][C:6]1=[O:7])=[N+:17]=[N-:18]
Reactant: CC(=O)Nc1ccn(CCCCl)c(=O)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1ccn(CCCN=[N+]=[N-])c(=O)n1
Temperature: 25 °C

Procedure:
A mixture of 1-(3-chloropropyl)-N4-acetylcytosine and sodium azide in acetonitrile was refluxed for 24 hours, cooled to room temperature, and filtered. The crude product was purified by silica gel column chromatography and gave 1-(3-azidopropyl)-N4-acetylcytosine as a white solid.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][N:11]([CH3:25])[C:12]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH:1]1([NH:9][CH:15]2[CH2:14][CH2:13][C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([N:11]([CH3:25])[CH3:10])[CH2:17][CH2:16]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NC1CCCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(NC2CCCCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.5 %

Procedure:
254 mg Cyclooctylamine and 434 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry tetrahydrofuran (15 ml) and 1,2-dichloroethane (5 ml) under argon. Glacial acetic acid (120 mg) and 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 18 hours at RT. For working up, the reaction mixture was concentrated and the residue was washed with one molar hydrochloric acid (20 ml) and with ether (2×30 ml). The aqueous phase was rendered alkaline with five molar sodium hydroxide solution and extracted with ether (3×30 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product (515 mg) was chromatographed over silica gel with methanol. 108 mg N′-cyclooctyl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a colorless oil, from which the corresponding dihydrochloride was precipitated with 3.3 M ethanolic hydrochloric acid (0.25 ml) in 2-butanone (2 ml) (102 mg; m.p. 247-249° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=4)[C@@H:26]([NH2:28])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:30]=[CH:31][C:32]([S:35][CH3:36])=[CH:33][CH:34]=4)[C@@H:26]([NH:28][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1
Reactant: COCC(=O)Cl
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methoxyacetyl chloride (10 μL, 0.11 mmol) was added to a suspension of (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine hydrochloride (40 mg, 0.09 mmol) and triethylamine (42 μL, 0.3 mmol) in THF (1 mL). The reaction was stirred at r.t. for 30 min and then quenched by adding water, the mixture was diluted with a small volume of MeCN so that a solution was obtained. This crude mixture was purified by semi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow 10 mL/min, 20 min gradient of 20%-90% MeCN in water followed by isocratic final concentration until product had eluted. UV=254 nm was used for detection. Fractions with product was combined and lyophilized to afford the title compound as a colourless solid. Yield 30 mg (69%).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN(C)C=O>[CH:36]1([CH2:39][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:4][CH2:3][C:2]([F:1])([F:33])[CH2:7][CH2:6]2)=[O:9])[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCC(N2CCOCC2)CC1
Yield: 16 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a white solid (16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][CH:16]=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C.ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]([OH:43])[C:16]([NH:15][CH2:14][CH2:13][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[CH:12])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:17])=[CH:40][CH:39]=1
Reactant: C#CCOc1ccc(CCNC=O)cc1OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide (34 g, 0.14 mol) and triethylamine (34 g, 0.34 mol) are dissolved in dichloromethane (120 ml). Bis(trichloromethyl)carbonate (triphosgene, 16 g, 55 mmol) in dichloromethane (80 ml) is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of titanium tetrachloride (28 g, 0.15 mol) in dichloromethane (150 ml) is added and the mixture is stirred for 2 hours at −40° C. 4-Chlorobenzaldehyde (20 g, 0.14 mol) in dichloromethane (70 ml) is added dropwise and the mixture is stirred for 17 h at room temperature. The mixture is hydrolyzed with 5N HCl (80 ml), stirred 30 minutes at room temperature and washed with water. After evaporation of the organic layer the residue is submitted to flash-chromatography (ethyl acetate/hexane) to give 2-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 2.54 (t, 1H, C≡CH), 2.72 (t, 2H, CH2CH2), 3.53 (t, 2H, CH2CH2), 3.84 (s, 3H, OCH3), 4.78 (m, 2H, OCH2), 4.98 (s, 1H, CHOH), 6.07 (bs, 1H, NH), 6.53-7.38 (m, 7H, CH arom.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[CH:7]=[CH:6][C:5]=1[Cl:12].C[Si]([N:18]=[N+:19]=[N-:20])(C)C>C(O)CCC>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:20][NH:19][N:18]=2)[CH:7]=[CH:6][C:5]=1[Cl:12]
Reactant: C#Cc1ccc(Cl)c(C(=O)OC)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCCCO
Product: COC(=O)c1cc(-c2cn[nH]n2)ccc1Cl
Yield: 43.5 %

Procedure:
A mixture of 2-chloro-5-ethynyl-benzoic acid methyl ester (0.18 g, 0.92 mmol) and trimethylsilyl azide (0.16 g, 1.39 mmol) in n-butanol was heated to reflux for 16 h. A second portion of trimethylsilyl azide (0.16 g, 1.39 mmol) was added and the mixture was refluxed for a further 16 h. A third portion of trimethylsilyl azide (0.16 g, 1.39 mmol) was added and the mixture was refluxed for a further 16 h. Silica gel was added and the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (2:1 hexanes-ethyl acetate) to afford the title compound (0.095 g).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:8]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19](Cl)=[C:20]([NH:25][CH2:26][CH:27]([F:29])[F:28])[N:21]=2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[F:32][C:33]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:34]=1[O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:39]3[CH2:38][CH2:37][CH:36]([O:35][C:34]4[CH:42]=[CH:43][C:44]([F:46])=[CH:45][C:33]=4[F:32])[CH2:41][CH2:40]3)=[C:20]([NH:25][CH2:26][CH:27]([F:29])[F:28])[N:21]=2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCNCC2)c(F)c1
Reactant: FC(F)CNc1nc2c(nc1Cl)CN(Cc1ccccc1)CC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCN(Cc3ccccc3)C4)CC2)c(F)c1

Procedure:
A solution of 6-benzyl-3-chloro-N-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (150 mg, 0.331 mmol), 4-(2,4-difluorophenoxyl)piperidine hydrochloride (99 mg, 0.398 mmol), Pd2(dba)3 (15.2 mg, 0.017 mmol), BINAP (20.63 mg, 0.033 mmol), and sodium tert-butoxide (96 mg, 0.994 mmol), in toluene (1104 μL) was stirred at 90° C. overnight. The solvent was removed and the crude product diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give 6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine as a TFA salt (152 mg).
Reaction SMILES: [CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.Br[CH2:23][CH:24]=[CH2:25].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[CH2:25]([CH:3]1[CH2:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[N:10]([C:12]5[CH:21]=[CH:20][N:19]=[CH:18][C:13]=5[C:14]=4[CH2:15][CH2:16][CH:17]=3)[C:11]=2[CH2:1][CH2:2]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC1CCC2=C(C=CC3=CCCc4c3n2c2ccncc42)C1

Procedure:
A mixture of 3.3 g. of the product of Example 1, 1.45 g. of freshly distilled 3-bromopropene and 1.7 g. of sodium bicarbonate is stirred at room temperature, for 24 hours, in 50 ml. dimethylformamide. At the end of this period, the mixture is poured into water, extracted with ether, and the combined extracts are dried and stripped down. The residue is dissolved in benzene, and the resulting solution chromatographed through a column of neutral alumina. The oily residue obtained on stripping down the eluate is recrystallized from isopropyl alcohol to yield 3-allyl-1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine m.p. 112°-113°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17]=C)[N:14]([C:19](=[C:24]([CH3:26])[CH3:25])[C:20]([O:22][CH3:23])=[O:21])[C:13]1=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl([O-])(=O)=[O:29].[Na+].I([O-])(=O)(=O)=O.[Na+]>O.O1CCCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17]=[O:29])[N:14]([C:19](=[C:24]([CH3:26])[CH3:25])[C:20]([O:22][CH3:23])=[O:21])[C:13]1=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H]1[C@@H](NC(=O)OCc2ccccc2)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: [O-][Cl+2]([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](NC(=O)OCc2ccccc2)[C@H]1CC=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 84 %

Procedure:
A solution of osmium tetroxide (0.61 mg) in water (0.05 ml) was added to a solution of methyl 2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)azetidin-1-yl]-3-methylbut-2-enoate (58 mg) and sodium chlorate (50 mg) in a mixture of tetrahydrofuran (1 ml) and water (1 ml) and the mixture was stirred for 17 hours at ambient temperature. Sodium periodate (60 mg) was then added and stirring was continued for 30 minutes. The resulting mixture was diluted with brine and extracted with ethyl acetate. The extract was washed successively with brine, brine containing sodium bicarbonate, and brine. The mixture was dried over magnesium sulfate and concentrated under reduced pressure to give an oil, which was chromatographed on silica gel (1.5 g, eluting with 2.5% methanol in dichloromethane) to give 49 mg of methyl 2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(2-oxoethyl)azetidin-1-yl]-3-methylbut-2-enoate.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1.[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[C:3]2([CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1)[O:13][CH2:12][CH2:11][O:10]2
Reactant: OCCO
Reactant: CC1(C)C=C(I)C(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C=C(I)C2(CC1)OCCO2
Yield: 90.1 %

Procedure:
A solution of 2-iodo-4,4-dimethylcyclohex-2-en-1-one (Synlett, 2005, 1263-1266; 5.46 g, 21.8 mmol), ethylene glycol (3.00 g, 48.3 mmol), p-toluenesulfonic acid hydrate (100 mg) in benzene (100 mL) was stirred for 7 hours under reflux, and the solvent was subjected to azeotropic distillation with water. After allowing to cool, a saturated aqueous solution of sodium hydrogencarbonate (100 mL) was added to the reaction solution, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=95:5) to yield the title compound (5.78 g, 90%) as a colorless oil.