Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][CH2:32][C@@H:3]12.[Li+].[OH-]>O1CCOCC1>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][CH2:32][C@@H:3]12
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 85.8 %

Procedure:
(S)-ethyl 4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate (280 mg, 0.643 mmol) was suspended in 1,4-Dioxane (3.22 mL) and treated with 1N LiOH (3.215 mL, 3.22 mmol). The reaction mixture was stirred at room temperature for 23 h. The reaction mixture was concentrated in vacuo until most of the dioxane was gone and acidified with HCl (4.5 N) until a thick precipitate resulted. It was filtered off, washed with water and dried in vacuum to afford (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (225 mg, 0.552 mmol, 86% yield) as a brown solid. [M+H] calc'd for C22H25N5O3, 408; found, 408.
Reaction SMILES: C[C:2]1[C:10]2[C:6](=[N:7][NH:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:11][O-].[Na+]>>[Cl:11][N:9]1[C:10]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=[N:8]1
Reactant: Cc1cccc2n[nH]nc12
Reactant: [O-]Cl
Agent: [Na+]
Product: Cln1nnc2ccccc21

Procedure:
The Performance of Tolytriazole in the Presence of Sodium Hypochlorite Under Simulated Field Conditions, NACE Corrosion/83, Paper No.283, (1983).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[C@@H:9]([CH2:10]OS(C)(=O)=O)[O:8]1)(=O)=O.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:16][C:17]1[CH:18]=[C:19]([N:20]2[CH2:10][CH:9]3[O:8][CH:7]3[CH2:6]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)OC[C@@H]1O[C@@H]1COS(C)(=O)=O
Reactant: Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(N2CC3OC3C2)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 5.4 g of cis-2,3-bis(methanesulfonyloxymethyl)oxirane, 2 ml of 3-bromoaniline, 4.3 g of anhydrous potassium carbonate and 30 ml of N,N-dimethylformamide was stirred under nitrogen atmosphere at 60° C. for 2 hours and at 110° C. for 2 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography with 5–10% ethyl acetate/hexane, to give 420 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.O.[NH2:12][NH2:13]>C(O)CCC>[Br:1][C:2]1[CH:9]=[C:8]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2cc(Br)ccc12
Temperature: 25 °C

Procedure:
4-bromo-2-fluorobenzonitrile (67.8 g), hydrazine hydrate (32.8 ml) in n-butanol (410 ml) were heated to 112° C. for five hours. The reaction mixture was allowed to cool down to r.t. The precipitated crystalline solid was filtered off and washed three times with ethylacetate (100 ml each). The product was dried in vacuo at 40° C. mp. 222-225° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:22]1[S:23][C:24]([CH2:27][N:28]=[N+]=[N-])=[CH:25][CH:26]=1)#[N:21]>C1COCC1.O>[C:20]([C:22]1[S:23][C:24]([CH2:27][NH2:28])=[CH:25][CH:26]=1)#[N:21]
Reactant: N#Cc1ccc(CN=[N+]=[N-])s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CN)s1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Triphenylphosphine (Aldrich, 5.7 g) was added to a solution of 2-cyano-5-(azidomethyl)thiophene (compound 25, 2.5 g, 10 mmol) in THF (Aldrich, 40 ml) and water (10 ml) at 0° C. The resulting solution was allowed to warm to room temperature and stirred at ambient temperature for 10 hours. RP HPLC purification led to the title compound (2.3 g, 94%). MS (electrospray): 139 (M+1); 1HNMR (CDCl3): δ 4.01 (s, 2H), 4.75 (br s, 2H, NH2), 6.82 (d, 1H, J=3.5 Hz), 7.08 (d, 1H, J=3.5 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([F:14])[CH:8]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:17]=[O:19])=[C:9]([F:14])[CH:8]=1
Reactant: COC(=O)COc1ccc(N)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(N=C=O)c(F)c1

Procedure:
In analogy to the procedure described in example 9.1, (4-amino-3-fluoro-phenoxy)-acetic acid methyl ester hydrochloride (Kori, Masakuni; Mild, Takashi; Nishimoto, Tomoyuki; Tozawa, Ryuichi. PCT Int. Appl. (2001), WO 2001098282 A1) was reacted with triphosgene in the presence of Et3N (3.5 eq.) in CH2Cl2 under reflux conditions for 14 h to give the title compound as brown solid. MS: m/e=243.1 [M+NH4+].
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1.Cl>CN(C)C=O>[C:17]([C:15]1[CH:16]=[C:11]([CH2:10][N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[CH:12]=[CH:13][C:14]=1[OH:20])(=[O:19])[CH3:18]
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: O=C1CCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CN2CCCC2=O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20.0 mmol) in 15 mL dry dimethylformamide under argon, cooled in an ice-bath was added dropwise a solution of 2-pyrrolidinone (1.70 g, 20.0 mmol) in 5 mL dimethylformamide. The ice-bath was removed, the mixture was stirred 30 minutes, and a solution of 5'-(chloromethyl)-2'-hydroxyacetophenone (1.85 g, 10.0 mmol) in 5 mL dimethylformamide was added dropwise. The mixture was stirred four hours, poured into 75 mL ice water, acidified with 7 mL 3N hydrochloric acid, and extracted with methylene chloride (3×75 mL). The extract was washed with water (25 mL) and brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude product which was purified by flash chromatography on silica gel slutlug with 2:98 methanol:chloroform to give 1.92 g (82%) product as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[NH:9][C:8](=[O:15])[CH2:7][CH2:6]2.[CH3:16][C:17](C)([O-])C.[K+].C(I)C>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:16]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH:13]=[O:14])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:15])[CH3:17]
Reactant: CC(C)(C)[O-]
Reactant: COc1cc2c(cc1C=O)NC(=O)CC2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1C(=O)CCc2cc(OC)c(C=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde (preparation 3) 60 mg (0.293 mmol) was dissolved in 5 ml of anhydrous THF and the solution was cooled to 0° C. The reaction mixture was treated with 33 mg (0.293 mmol) of potassium t-butoxide whereupon it became yellow in color. After stirring for 30 minutes, the mixture was treated with 23 μl (0.293 mmol) ethyl iodide and slowly warmed to room temperature while stirring for 16 hours (h). The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to an oil. The residue was chromatographed on silica gel eluting with 6/4 ethyl acetate/hexane to afford 34 mg (40%) as a white solid. MS APCI m/e 234 (p+1)
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([CH:52]=[CH:53][CH:54]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:49]=[CH:50][CH:51]=2)[CH2:34][N:35]2[CH2:41][CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[N:35]1([CH2:34][C:33]2[CH:32]=[C:31]([CH:51]=[CH:50][CH:49]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:52]=[CH:53][CH:54]=[C:3]([C:2]([F:55])([F:56])[F:1])[CH:4]=2)=[O:9])=[O:30])[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CN3CCCNCC3)c2)c1
Temperature: 15 °C
Reaction time: 3 h
Yield: 149.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzyl)-1,4-diazepane-1-carboxylate (100 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (15 mL), and trifluoroacetic acid (147.9 mg, 1.30 mmol, 10.00 equiv). The resulting solution was stirred for 3 h at 15° C. The resulting mixture was concentrated under vacuum to yield 130 mg of crude product as a red solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].S(Cl)([Cl:14])(=O)=O>ClCCl>[CH3:9][O:8][C:6](=[O:7])[CH:5]([Cl:14])[C:4](=[O:10])[CH2:3][O:2][CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCC(=O)CC(=O)OC
Solvent: ClCCl
Product: COCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
46.0 g Methyl 4-methoxyacetoacetate were dissolved in 500 ml dichloromethane. 28.1 ml Sulfuryl chloride were added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the resulting residue was dissolved in 300 ml ethyl acetate and washed with 100 ml water and 100 ml brine. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate=5:1=>2:1 to obtain 45.0 g 2-chloro-4-methoxy-3-oxo-butyric acid methyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCN(C)CC4)c3)c2)n1
Temperature: 25 °C
Yield: 37 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess N-methylpiperazine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.085 g, 37%) as a white solid. MS (ISP) 552 8 [(M+H)+]; mp 180° C. (dec.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([O:11][CH2:12][C:13]([N:15]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[NH:25][C:26]([C:28]1[NH:32][C:31]2[C:33]([Cl:37])=[C:34]([Cl:36])[S:35][C:30]=2[CH:29]=1)=[O:27])=[O:14])(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([O:11][CH2:12][C:13]([N:15]([CH2:38][C:39]([OH:41])=[O:40])[C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[NH:25][C:26]([C:28]1[NH:32][C:31]2[C:33]([Cl:37])=[C:34]([Cl:36])[S:35][C:30]=2[CH:29]=1)=[O:27])=[O:14])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC(=O)N(CC(=O)OC(C)(C)C)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCC(=O)N(CC(=O)O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
TFA (3 mL) was added to a solution of 1,1-dimethylethyl [[(acetyloxy)acetyl]((1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetate (Method 20, 130 mg, 0.25 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 2 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (130 mg, 99%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[N:19]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCC1CCCCC1N(Cc1ccccc1)Cc1ccccc1
Product: O=[N+]([O-])c1ccc(NCC2CCCCC2N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 2, react 1-fluoro-4-nitrobenzene with N-[2-(aminomethyl)cyclohexyl]-N-(phenylmethyl)benzenemethanamine to obtain the title compound.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>CO>[OH:8][CH:9]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CN(CC(CN(C)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(CC(O)CN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
Di-tert-butyl 2-(tert-butyldimethylsilyloxy)propane-1,3-diylbis (methylcarbamate) (21 g, 48.6 mmol) was dissolved into 200 ml methanol at 0° C. Concentrated HCl (4 mL) was added dropwise and the reaction mixture was stirred at RT for 6 hrs. The mixture was placed over an ice water bath and 10 g of NaHCO3 was added slowly. Then the reaction mixture was dried with MgSO4, and then filtered. The filtrate was concentrated to yield 15.0 g of di-tert-butyl 2-hydroxypropane-1,3-diylbis(methylcarbamate) (97%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH:23]1([CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCCOCC1CCCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCC2CCCCC2)CC1
Yield: 48.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as starting compound and 5-(cyclohexylmethoxy)pentyl bromide (1.30 g) were reacted and treated in the same manner as in Example 168 to give 0.51 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(cyclohexylmethoxy)pentyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: CO[C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[Cl:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:19]>CO>[CH3:10][O:9][C:7]([C:6]1[NH:19][C:13]2[C:14]([C:3](=[O:4])[CH:5]=1)=[CH:15][C:16]1[C:3](=[O:4])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[NH:18][C:17]=1[C:12]=2[Cl:11])=[O:8]
Reactant: Nc1cccc(N)c1Cl
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1cc(=O)c2cc3c(=O)cc(C(=O)OC)[nH]c3c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.0 g. of dimethylacetylene dicarboxylate is added dropwise to a solution of 5.25 g. of 2-chloro-1,3-diaminobenzene in 100 ml. of methanol at room temperature. The mixture is stirred for 2 hours at room temperature and the resulting yellow solid is collected by filtration. The solid is washed with 20 to 50 ml. of methanol, dried under vacuum at 60° C., and recrystallized from acetone. The tetramethyl[2-chloro-m-phenylene-diamino]dimaleate melts at 202.5°-204.5°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:6]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:26](=[O:28])[CH3:27])[CH2:23][CH3:24])[CH:6]=1
Reactant: CCNCc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC
Reactant: CC(=O)Cl
Product: CCN(Cc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC)C(C)=O

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(4-bromo-2-ethylaminomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([C:23]3[CH:24]=[CH:25][C:26]4[O:39][CH2:38][N:29]5[C:30]6[CH:31]=[CH:32][CH:33]=[C:34]([F:37])[C:35]=6[CH:36]=[C:28]5[C:27]=4[N:40]=3)=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=O)[CH3:2].Cl.[CH3:42][O:43][NH2:44]>C(O)C.N1C=CC=CC=1>[F:37][C:34]1[C:35]2[CH:36]=[C:28]3[C:27]4[N:40]=[C:23]([C:14]5[C:15]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][C:6]6[O:5][C:4](/[C:1](=[N:44]/[O:43][CH3:42])/[CH3:2])=[C:8]([C:9]([NH:11][CH3:12])=[O:10])[C:7]=6[CH:13]=5)[CH:24]=[CH:25][C:26]=4[O:39][CH2:38][N:29]3[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CON
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CNC(=O)c1c(/C(C)=N/OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution compound 2-acetyl-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.088 mmol) in ethanol (1.5 mL) was added O-methylhydroxylamine hydrochloride (25 mg, 0.26 mmol) and 2 drops pyridine. The resulting mixture was stirred at 70° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the product of (E)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(1-(methoxyimino)ethyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 9.56 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.48 (dd, J=10 Hz, 2H), 7.18˜7.23 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.84 (t, J=8.0 Hz, 1H), 5.99 (s, 2H), 4.12 (s, 3H), 3.41 (s, 3H), 2.99 (d, J=4.8 Hz, 3H), 2.66 (s, 3H), 2.41 (s, 3H). MS (M+H)+: 592.
Reaction SMILES: [ClH:1].Cl.CN1C2CCCC1CC([NH:13][C:14]([C:16]1[CH:17]=[C:18]([NH2:31])[CH:19]=[C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][C:21]=13)=[O:15])C2.Cl>CO.C(OCC)C>[ClH:1].[ClH:1].[NH2:31][C:18]1[CH:19]=[C:20]2[O:24][C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:22][C:21]2=[C:16]([C:14]([NH2:13])=[O:15])[CH:17]=1
Reactant: CN1C2CCCC1CC(NC(=O)c1cc(N)cc3oc(-c4ccccc4)nc13)C2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC(=O)c1cc(N)cc2oc(-c3ccccc3)nc12
Yield: 106.8 %

Procedure:
To a solution of the amide from Step B (120 mg, 0.31 mmol) in methanol (1.0 mL) was added a solution of HCl in diethyl ether (1 N, 0.93 mL, 0.93 mmol) at room temperature slowly. The reaction mixture was diluted with diethyl ether. The resulting solid was filtered and washed with diethyl ether to afford N-(9-methyl-9-azabicyclo[3.3.1]non-6-amino-2-phenylbenzoxazole-4-carboxamide dihydrochloride (54 mg, 38%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 10.48 (br s, 0.4H), 9.69 (br s, 0.6H), 9.16 (d, J=5.8 Hz, 0.6H), 8.88 (d, J=6.9 Hz, 0.4H), 8.23-8.15 (m, 2H), 7.70-7.60 (m, 3H), 7.55-7.50 (m, 1H), 7.36 (s, 1H), 4.90-4.35 (m, 4H), 3.70-3.65 (m, 1.4H), 3.60-3.55 (m, 0.6H), 2.90-2.80 (m, 4H), 2.75-2.60 (m, 2H), 2.40-2.10 (m, 3H), 1.95-1.82 (m, 2H), 1.60-1.50 (m, 2H); MS (ESI+) m/z 391 (M+H); HPLC>99% (AUC), tR=11.49 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:20]=[C:19]([OH:21])[C:18]([OH:22])=[CH:17][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH:13]([CH3:15])[O:12][CH:11]([CH3:16])[CH2:10]1)=[O:8].[N+:23]([O-])([OH:25])=[O:24]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:20]=[C:19]([OH:21])[C:18]([OH:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH:11]([CH3:16])[O:12][CH:13]([CH3:15])[CH2:14]1)=[O:8]
Reactant: CC1CN(C(=O)c2sc3cc(O)c(O)cc3c2Cl)CC(C)O1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)c2sc3c([N+](=O)[O-])c(O)c(O)cc3c2Cl)CC(C)O1
Reaction time: 4 h

Procedure:
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morpholin-4-yl)-methanone (0.20 g) was dissolved in ethyl acetate and 1 N HNO3 solution in dichloromethane (0.64 ml) was added. Stirring was continued for 4 hours. The mixture was concentrated to smaller volume and the precipitate filtered and washed with water. The crude product was recrystallized from N,N-dimethylformamide/ethanol (25:75).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.O1CCCC1.B.Cl>O1CCCC1>[ClH:1].[Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[CH2:4][NH2:6]
Reactant: NC(=O)c1ccc(F)c(F)c1Cl
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ccc(F)c(F)c1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
2-Chloro-3,4-difluorobenzamide (11.85 g, 62 mmol) was dissolved in tetrahydrofuran (200 ml) and treated with 1M borane tetrahydrofuran (247 ml, 247 mmol). The mixture was heated to 70° C. and stirred for 18 hrs. The mixture was then cooled in an ice-water bath and concentrated aqueous hydrogen chloride (150 ml) was added dropwise. Heating, with stirring, at 70° C. was then resumed for a further 2 hrs. The mixture was then allowed to cool and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml). The aqueous layer was separated and the pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide. The resulting cloudy suspension was extracted with ethyl acetate (4×200 ml) and the combined organic extracts were then passed through a hydrophobic frit and reduced in volume to ˜200 ml. The mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml) resulting in formation of a precipitate. The solvent was evaporated in vacuo to give a white solid. The solid was recrystallised from methylated spirit (60 ml) to give three crops of pure [(2-chloro-3,4-difluorophenyl)methyl]amine hydrochloride (combined mass=4.46 g) as a white solid.