Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:21]1([C:27]2[NH:31][N:30]=[C:29]([C:32]([OH:34])=O)[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:32]([C:29]2[CH:28]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:31][N:30]=2)=[O:34])[CH2:52][CH2:53]1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
HOBt (38 mg, 0.28 mmol) and DIPEA (145 mg, 1.12 mmol) were added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid hydrochloride (51 mg, 0.22 mmol) in DMF (1.0 mL). The reaction mass was cooled to 10° C., and EDCI.HCl (54 mg, 0.28 mmol) was added, followed by the addition of 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (100 mg, 0.22 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and the resulting precipitate was filtered and dried under reduced pressure to afford 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 26.8% yield, LC-MS purity: 96.054%, 1H NMR (DMSO): δ 8.1 (s, 1H), 7.95 (s, 1H), 7.8 (d, 2H), 7.56 (m, 2H), 7.5 (t, 2H), 7.4 (m, 1H), 7.1 (s, 1H) 4.2 (m, 2H), 3.75 (m, 1H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H), 3.1 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl-].[CH3:11]N(C=NC=[N+](C)C)C>O1CCOCC1>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH:11]=[N:1][C:2]=2[CH:7]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: CN(C)C=NC=[N+](C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ccc2ocnc2c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Combine 2-amino-4-methyl-phenol (1.0 g, 8.12 mmol), [(dimethylaminomethylene-aminomethylene)dimethylammonium chloride (Gold's reagent) (1.6 g, 9.91 mmol), anhydrous 1,4-dioxane (25 mL) and reflux for 17 h. Cool the reaction mixture to ambient temperature, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a yellow oil (0.7 g, 65%).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH3:20])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19].C(N(C(C)C)C(C)C)C.F[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH3:3][C:4]1([CH3:20])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]2[CH2:18][CH2:17][N:16]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:15][CH2:14]2)[C:5]1=[O:19]
Reactant: Fc1ccccn1
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2ncccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)N(C2CCN(c3ccccn3)CC2)c2ncccc21
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
A mixture of 3,3-dimethyl-1-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one dihydrochloride (intermediate 57, 0.1167 g, 0.367 mmol), N-ethyl-N-isopropylpropan-2-amine (0.192 ml, 1.100 mmol), and 2-fluoropyridine (0.189 ml, 2.200 mmol) was stirred at 150° C. for 90 minutes. The mixture was filtered and was purified by reverse phase HPLC (10-55% in 30 min, acetonitrile in water with 0.1% trifluoroacetic acid). The collected fractions were neutralized with solid sodium carbonate and extracted with dichloromethane three times. The organic phase was dried over sodium sulfate and concentrated in vacuo to give 3,3-dimethyl-1-(1-(pyridin-2-yl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.055 g, 0.171 mmol, 46.5% yield). M+1: 323.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 6 H) 1.72-1.84 (m, 2 H) 2.71-2.85 (m, 2 H) 2.95 (td, J=12.86, 1.86 Hz, 2 H) 4.43-4.65 (m, 3 H) 6.60 (dd, J=6.65, 5.28 Hz, 1 H) 6.71 (d, J=8.61 Hz, 1 H) 6.92 (dd, J=7.24, 5.28 Hz, 1 H) 7.41 (dd, J=7.24, 1.37 Hz, 1 H) 7.47 (ddd, J=8.71, 7.14, 1.96 Hz, 1 H) 8.12 (dd, J=5.18, 1.47 Hz, 1 H) 8.19 (dd, J=4.99, 1.08 Hz, 1 H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][N:12]=[C:13]([O:15][CH2:16][CH3:17])[CH3:14].[OH-].[Na+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][N:12]=[C:13]([O:15][CH2:16][CH3:17])[CH3:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(C)=NO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C)=NOc1ccc([N+](=O)[O-])cc1
Temperature: 17 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
4-Chloronitrobenzene, 136.2 g, and 111.4 g ethyl N-hydroxyacetimidate are dissolved in 216 ml DMF. The temperature is adjusted to 30° C. and 41.6 g solid NaOH is added in 8 portions keeping the temperature at 30-35° C. After one hour the temperature is adjusted to 40-45° C. and the mixture stirred for 1.5 hours. Cooling is applied and 520 ml water is fed at such a rate as to keep the temperature at ca 40° C. The slurry formed is cooled to 17° C. and filtered. The filter cake is washed with 175 ml ethanol/water 90/10 (V/V) followed by 175 ml water. Wet product, 214.5 g, corresponding to 192 g dry ethyl N-(4-nitrophenoxy)acetimidate is isolated. Yield 98.5%.
Reaction SMILES: [CH2:1](OC(N[C@](CC)(C(O)=O)CCC(O)=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:30][C:31]([NH:33][C@:34]([CH2:43][CH2:44][CH3:45])([C:40]([OH:42])=[O:41])[CH2:35][CH2:36][C:37](O)=[O:38])=O)C1C=CC=CC=1>>[CH2:1]([C:31]([NH:33][C@:34]1([CH2:43][CH3:44])[C:40](=[O:42])[O:41][C:37](=[O:38])[CH2:36][CH2:35]1)=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([C:31]([NH:33][C@:34]1([CH2:43][CH2:44][CH3:45])[C:40](=[O:42])[O:41][C:37](=[O:38])[CH2:36][CH2:35]1)=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@@](CCC(=O)O)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC[C@@](CCC(=O)O)(NC(=O)OCc1ccccc1)C(=O)O
Product: CCC[C@]1(NC(=O)Cc2ccccc2)CCC(=O)OC1=O
Product: CC[C@]1(NC(=O)Cc2ccccc2)CCC(=O)OC1=O

Procedure:
In a similar fashion from N-benzyloxycarbonyl-α-ethylglutamic acid and N-benzyloxycarbonyl-α-propylglutamic acid. there is obtained N-benzylcarbonyl-α-ethylglutamic anhydride and N-benzylcarbonyl-α-propylglutamic anhydride, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](=[C:13]([C:18](=[O:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[N-]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH:13]([C:18](=[O:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(=[N+]=[N-])C(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(Nc1ccc([N+](=O)[O-])cc1)C(C)=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Under an argon atmosphere, to a solution of 4-nitroaniline (3.84 g) in toluene (278 mL) were added methyl 2-diazo-3-oxobutanoate (5.13 g) and rhodium(II) acetate dimer (250 mg), and the mixture was stirred at 120° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=9:1→hexane:ethyl acetate=7:3 (volume ratio)] to give the title compound (4.63 g, yield 98%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([C:65]([F:67])([F:68])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a solution of 107 mg (0.5 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 161 mg of TBTU (0.5 mmol) in 6 ml DMF, were added 0.43 ml (2.51 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 200 mg (0.54 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 22 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; DCM/heptane 9:1) to give 182 mg off-white solid (54%). MS (EI) 564.2 (M)+.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Br:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Br:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2NC(N)=S)c1
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2Nc2nc(C)cs2)c1
Yield: 88.1 %

Procedure:
1-chloropropan-2-one (0.469 g, 5.07 mmol), ethyl 3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate (1.680 g, 3.39 mmol), triethylamine (0.671 g, 6.63 mmol), and ethanol (70 mL) were reacted according to the method of Example 10, Step E, to provide the title compound (1.40 g, 77% yield). 1H NMR (d6-DMSO) δ 8.26 (d, 1H), 7.78 (m, 2H), 7.50 (s, 1H), 7.46 (d, 1H), 6.59 (s, 1H), 4.29 (q, 2H), 2.23 (s, 3H), 1.28 (t, 3H); Mass spectrum (apci) m/z=470.1 (M+H).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCCCCCCCCCC.[NH2:20][C:21]1[N:22]=[N:23][N:24](CC2C=CC=CC=2)[N:25]=1>>[NH2:20][C:21]1[N:25]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:24]=[N:23][N:22]=1
Reactant: ClCc1ccccc1
Reactant: Nc1nnn(Cc2ccccc2)n1
Agent: CCCCCCCCCCBr
Product: Nc1nnnn1Cc1ccccc1

Procedure:
Following the general procedure of Example 2 only substituting an appropriate amount of benzyl chloride for 1-bromodecane, 5-amino-2-benzyltetrazole and 5-amino-1-benzyltetrazole were obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[BrH:8].[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: Brc1ncccn1
Reactant: C[C@H]1CNCCN1
Solvent: Cc1ccccc1C
Product: Br
Product: C[C@H]1CN(c2ncccn2)CCN1
Reaction time: 15 h
Yield: 38.6 %

Procedure:
To a solution of (S)-2-methyl piperazine (4.0 g, 40.0 mmol) in xylene (100 mL) at 140° C. under nitrogen was added 2-bromopyrimidine (6.36 g, 40.0 mmol) slowly over a period of 30 min. The heating was continued for additional 15 h and cooled. The solid precipitated was filtered and dried under suction to afford the title compound (4 g, 40%). TLC-Chloroform/MeOH (8/2); Rf: 0.15.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:13]
Reactant: Cc1cccnc1Cl
Reactant: NC(N)=O
Agent: OO
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
To a mixture of 2-chloro-3-methylpyridine (15 g, 118 mmol) and urea hydrogen peroxide (44.07 g, 468.5 mmol) in DCM (300 mL) was added trifluoroacetic anhydride (98.55 g, 469.2 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 20 h. The mixture was then poured into water (150 mL), and the layers were separated. The organic layer was washed with saturated aqueous Na2S2O3 (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH, 100:0 to 10:1) to afford the title compound (14.5 g, 86%) as a colorless solid.
Reaction SMILES: COC(=O)[CH2:4][CH2:5][NH:6][CH3:7].C1C2[C:12](=CC=CC=2)[CH2:11][C:10]1=[O:18].[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:7][N:6]1[C:10](=[O:18])[CH2:11][CH2:12][C:25]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:4][C:5]1=2
Reactant: Cc1ccccc1
Reactant: CNCCC(=O)OC
Reactant: O=C1Cc2ccccc2C1
Product: CN1C(=O)CCC2=C1Cc1ccccc12
Temperature: 25 °C
Yield: 28 %

Procedure:
3-Methylamino-propionic acid methyl ester (1.5 g, 13.64 mmol) is added to a solution of 2-indanone (1.7 g, 12.86 mmol) in toluene (20 mL) and the reaction is brought to reflux for 2.5 hours. Toluene is removed in vacuo and the residue is dissolved in ethylene glycol (17 mL) and the resulting solution is heated to reflux for 8 hours. The reaction is allowed to cool to ambient temperature, is poured over water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford the crude title compound as a brown oil. The crude product is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-100%) affording 720 mg (28% yield) of the title compound. 1H NMR (CDCl3) 2.70-2.80 (m, 4H), 3.23 (s, 3H), 3.5 (s, 7.07-7.15 (m, 2H), 7.24-7.33 (m, 1H), 7.38 (d, 1H, J=7.07). MS (m/z): 199.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:10])=[N:6][CH:7]=1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cc1cnc(C(=O)O)cn1
Product: CCOc1ccc(NC(=O)c2cnc(C)cn2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-methylpyrazine-5-carboxylic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 12.82 (s, 1H), 9.36 (s, 1H), 8.90 (d, J=9.6, 1H), 8.56 (d, J=1.0. 1H), 7.74 (d, J=2.7, 1H), 7.32-7.29 (m, 1H), 4.11 (q, J=6.9, 2H), 2.71 (s, 3H), 1.46 (t, J=6.9, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:7][C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(Cl)Cl.B(Br)(Br)Br>CO>[CH:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:14][C:15]=2[CH:16]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc2c(c1)Oc1ccccc1S2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)Oc1ccccc1S2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A stirred 3-methoxyphenoxathiin (3.00, 13.03 mmol) 25 ml CH2Cl2 was cooled to -70° C. under N2 and BBr3 (45.6 ml, 45.6 mmol, 1.0 M in CH2Cl2) was added dropwise over 1 h. The resulting bright, blue, heterogeneous mixture was allowed to warm to room temperature and stirred overnight. After 21 h the yellow homogeneous reaction is cooled to -60° C. and poured onto 300 mL MeOH at -60° C. After warming to room temperature the solution was concentrated in vacuo to a dark yellow oil which was purified by column chromatography (CH2Cl2 /hexane, gradient elution, 50:50 to 100:00) to give 2.59 g (91%) 3-phenoxathiinol as a white solid. TLC (CH2Cl2 /hexane 50:50) Rf =0.14; HPLC (Tr =14.2), 1H-NMR (CDCl3) δ 4.78 (s, 1H, --OH), δ 6.52 (d, J=8 Hz, 1H, C2 --H), δ 6.56 (s, 1H, C4 --H), δ 6.92-7.14 (m, 5H); MS m/z (relative intensity) 217 (MH+, 100).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=O.[NH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (64 mg, 0.14 mmol), glycine (3.42 g, 46 mmol) and NaOMe solution (69 mL, 35 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product obtained was further purified by silica gel chromatography (0-10% MeOH/EtOAc) to give 25 mg of the title compound. MS: (+) m/z 507.14 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:10][CH:11]1[NH:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCc2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a mixture of 5-benzylamino-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (10.2 g, 28.9 mmol) in toluene (110 mL) was added NaBH(OAc)3 (30 g, 141.5 mmol) and freshly activated 4A0 powder molecular sieve (24 g) with vigorous stirring. The reaction mixture was cooled to 0° C., then acetic acid (32.5 mL, 566 mmol) was added drop-wise in such a way that reaction mixture temperature remained below 5° C. After the addition of acetic acid was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was filtered and concentrated to remove most of the acetic acid. The crude residue was dissolved in ethyl acetate (125 mL) and saturated aqueous NaHCO3 solution (100 mL) was slowly added to neutralize the residual acid under stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure (11.25 g, crude). The residue was purified (FCC, SiO2, ethyl acetate/hexanes, gradient 0-40%) to yield the title compound (4.59 g, 45%). MS (ESI) mass calcd. for C20H30N2O2, 362.46; m/z found, 363.3 [M+H]+. 1H NMR (DMSO-d6): 7.53-6.76 (m, 5H), 4.10-3.96 (m, 3H), 3.89-3.87 (m, 1H), 3.66 3.54 (m, 1H), 3.05-2.60 (m, 4H), 1.80-1.65 (m, 2H), 1.60-1.45 (m, 1H), 1.40 (s, 9H), 1.14 (t, J=7.1, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1.[CH3:29][N:30](C)C(=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:29]#[N:30])[CH:11]=2)[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(Br)cc23)nc1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(C#N)cc23)nc1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (29 mg, 0.07 mmol, methyl ester of example 12-1), zinc cyanide (10 mg, 0.084 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.014 mmol) and N,N-dimethylacetamide (0.2 mL) was stirred at 150° C. for 24 hours under an argon atmosphere. The reaction mixture was diluted with water (5 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to give [6-cyano-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (17 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(c1)Nc1sc3ccccc3c1C(N1CCNCC1)=N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 136.4 %

Procedure:
8-Fluoro-12-(4-tert-butoxycarbonylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.6 g) was dissolved in trifluoroacetic acid (8 ml) and the mixture was stirred at room temperature for 3 hours. Trifluoroacetic acid was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was stirred at room temperature for 2 hours and the ethyl acetate layer was dried over magnesium sulfate. After natural filtration, the solvent was evaporated and the residue was separated and purified by silica gel column chromatography (chloroform:methanol=4:1) to give 8-fluoro-12-(piperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.7 g), which was treated with maleic acid to give 8-fluoro-12-(piperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.3/2 maleate.1/2 hydrate (347 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>>[ClH:1].[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[N:22]([C:2]2[N:11]=[C:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:21]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1CCNCC1
Product: Cc1cc(C)n(-c2nc(N3CCCCC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, piperidine and 3,5-dimethylpyrazole. Mp. 157° C.