Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.Cl>C(#N)C.O>[OH:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:15]([CH3:16])[N:22]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30])[C:4]2=[O:6]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Reactant: c1c[nH]cn1
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: O
Solvent: CC#N
Product: Cc1nc2c(O)cccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
To a stirred mixture of 2-amino-3-hydroxybenzoic acid (2.0 g, 13.1 mmol) and imidazole (2.0 g, 29.4 mmol) in acetonitrile (30 mL), was added acetyl chloride (2.0 mL, 28.7 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.2 g, 13.1 mmol), imidazole (2.0 g, 29.4 mmol) and triphenyl phosphite (4.11 mL, 15.7 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL) and cone HCl until pH 1. The solvent was removed in vacuo. To the residue, was added water (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). To the aqueous layer, was added sodium hydrogen carbonate (1.8 g) to pH=7-8, and the mixture was stirred at room temperature to give a suspension. The suspension was filtered to give 3-(8-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (0.6 g, 16% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CF3CN/0.1% H3PO4, 3.03 min (99.3%); mp: 266-268° C.; 1H NMR (DMSO-d6) δ 2.10-2.22 (m, 1H, CHH), 2.57-2.72 (m, 5H, CH3, 2CHH), 2.78-2.92 (m, 1H, CHH), 5.25 (dd, J=5, 11 Hz, 1H, NCH), 7.19 (dd, J=1, 8 Hz, 1H, Ar), 7.30 (t, J=8 Hz, 1H, Ar), 7.45 (dd, J=1, 8 Hz, 1H, Ar), 9.65 (s, 1H, OH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.92, 23.37, 30.59, 56.45, 115.62, 118.51, 121.19, 127.05, 135.91, 152.34, 153.09, 160.45, 169.52, 172.62; LCMS: MH=288; Anal Calcd for C14H13N3O4+1H2O: C, 55.08; H, 4.95; N, 13.76. Found: C, 54.88; H, 4.97; N, 13.77.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:18])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:19]1([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15](=[O:16])[N:14]3[C:9]=2[C:10]([CH3:18])=[C:11]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:12]=[CH:13]3)[CH2:21][CH2:20]1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 62.2 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 4-chloro-phenyl boronic acid (75 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl, acetate 2:3) to afford the title compound as a yellow solid (95 mg, 62%). ESI-MS m/z: 382 (M+H)+.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[OH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:17]1.C[O:30][C:31](=O)[C:32]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[N:41](COCC[Si](C)(C)C)[CH:40]=[CH:39]2)=O.Cl>CN(C=O)C.CCOC(C)=O>[OH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[C:26](=[O:27])[NH:28][C:31](=[O:30])[C:32]=2[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:42]=2[NH:41][CH:40]=[CH:39]3)=[CH:17]1
Reactant: COC(=O)C(=O)c1cccc2ccn(COCC[Si](C)(C)C)c12
Reactant: NC(=O)Cc1cn(CCCO)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2cccc3cc[nH]c23)=C1c1cn(CCCO)c2ccccc12
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A 1.0 M solution of KOtBu in THF (8.1 mL, 8.1 mmol) was added to a solution of 2-(1-3-hydroxypropyl-1H-indol-3-yl)-acetamide (586 mg, 2.52 mmol) and {1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-7-yl}-oxo-acetic acid methyl ester (770 mg, 2.31 mmol) in DMF (30 mL). The initially clear orange-red solution turned deep red over 15 min, and was then heated to 65 C. for 18 h. 1N HCl was added, the mixture stirred 8 h and then the volume was reduced to ˜20 mL. The residue was poured into EtOAc/0.1 N HCl and the aqueous layer was separated and extracted with EtOAc. The EtOAc solutions were combined and washed with water, saturated aq NaHCO3 and brine (3×), dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography (8:2 EtOAc:hexanes) afforded a red solid that was dried at 75° C. for overnight giving the title compound (454 mg, 51%) as a bright red solid. 1H NMR (400 MHz, DMSO-d6) 11.04 (s, 1H), 10.71 (s, 1H), 8.03 (s, 1H), 7.56–7.62 (m, 1H), 7.41 (d, J=8 Hz, 1H), 7.20 (dd, J=3, 3 Hz, 1H), 6.94–7.0 (m, 3H), 6.45 (dd, J=8, 8 Hz, 1H), 6.40–6.43 (m, 1H), 6.11 (d, J=8 Hz, 1H), 4.64 (t, J=5 Hz, 1H), 4.29 (t, J=7 Hz, 2H), 3.38 (s, 2H), 1.88 (m, 2H). MS (electrospray, m/z) 386.2 (M++1), 384.2 (M−−1). HRMS 386.1504 (M++1, calcd for C23H20N3O3 386.1505)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:11].Br.C1(S[C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[NH:21])C=CC=CC=1>CCOCC>[NH2:11][C:2]1[S:1][C:5]2[CH:6]=[C:7]([NH:10][C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[NH:21])[CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: N=C(Sc1ccccc1)c1cccs1
Reactant: Nc1ccc2nc(N)sc2c1
Agent: Br
Solvent: CCOCC
Product: N=C(Nc1ccc2nc(N)sc2c1)c1cccs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94 %

Procedure:
A mixture of benzothiazole-2,6-diamine (Example 1, 50 mg, 0.3 mmol) and thiophene-2-carboximidothioic acid phenyl ester hydrobromide (91 mg, 0.3 mmol) was stirred at room temperature for 17 hours. After this time a precipitate formed. The mixture was diluted with 4 mL of Et2O and filtered to give the title compound. Yield: 94%, 1H-NMR (DMSO-d6): δ 11.30 (br s, 1H); 9.71 (s, 1H); 8.80 (s, 1H); 8.18 (m, 2H); 7.74 (m, 3H); 7.29 (m, 3H).
Reaction SMILES: C(=O)([O-])N.[C:5](Cl)(=O)[C:6](Cl)=[O:7].Cl.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23](=[NH:28])[O:24]C(C)C)=[CH:14]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[C:23](=[O:28])[NH:24][C:6](=[O:7])[CH:5]=2)=[CH:14]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Agent: Cl
Agent: NC(=O)[O-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cn1cc(C2=CC(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 3.0 g (9.57 mmol) of tert.butyl[1(R or S)-(6,7,8,9-tetrahydropyrido[1,2-a]indol-8(R or S)-yl)ethyl]carbamate in 150 ml of dichloromethane was treated dropwise at 0° C. with 1.28 g (10.3 mmol) of oxalyl chloride. After 5 minutes, the solvent was removed under reduced pressure and the residue was dissolved in 150 ml of dichloromethane and treated with 2.94 g (11 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 4.38 g (43 mmol) of triethylamine at 0° C. under nitrogen. After warming to room temperature, the solution was stirred for 24 hours, washed with water and dried over magnesium sulfate. The solvent was removed by evaporation and the residue was dissolved in 30 ml of pyridine. The resulting solution was cooled to ice bath temperature and treated dropwise with 1.5 ml (10.8 mmol) of trifluoroacetic anhydride. After 15 minutes, the solvent was removed under reduced pressure and the residue was partitioned between 200 ml of ethyl acetate and 200 ml of 0.2M hydrochloric acid. The organic layer was washed with 50 ml of sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 1.35 g of 3-[8(R or S)-[1(R or S)-tert.butoxyformamidoethyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereomer A) in the form of a red solid of melting point 255°-7° C. Further elution gave 1.38 g of diastereomer B as a red solid of melting point 230°-233° C.
Reaction SMILES: COC1C=CC(N2C=CN=C2C=[N:15][S@@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[CH:34]=O)=[CH:25][CH:24]=1.CC([S@@](N)=O)(C)C>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2/[CH:34]=[N:15]/[S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=[CH:25][CH:24]=1
Reactant: COc1ccc(-n2ccnc2C=N[S@](=O)C(C)(C)C)cc1
Reactant: O=Cc1ncoc1-c1ccc(Cl)cc1
Agent: CC(C)(C)[S@@](N)=O
Product: CC(C)(C)S(=O)/N=C/c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5B of Example 5 utilizing 33D and (S)-2-methylpropane-2-sulfinamide. MS (m/z) 311.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][NH:9][C:10]2[C:15]([NH:16][C:17]([NH:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)=S)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1)[CH3:2]>[Hg]=O.C(O)C>[CH2:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[N:16]=[C:17]2[NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cccnc2NCc2ccc(CC)o2)CC1
Agent: O=[Hg]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2ccc(CC)o2)CC1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of 50 parts of ethyl 4-[[[[2-[[(5-ethyl-2-furanyl)methyl]amino]-3-pyridinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate, 32.4 parts of mercury(II) oxide and 480 parts of ethanol was stirred for 1 hour at reflux temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was stirred in 1,1'-oxybisethane. The crystallized product was filtered off and dried, yielding 38 parts (83.1%) of ethyl 4-[[3-[(5-ethyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate; mp. 111.1° C. (int. 14). In a similar manner there were also prepared:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(OCC)C>[C:7]1([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Brc1cccs1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(-c2cccs2)cc1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 0.7 gram (catalyst) of bis(1,3-diphenylphosphino)propanenickel (II) chloride in 200 mL of dry diethyl ether was stirred, and 40 grams (0.245 mole) of 2-bromothiophene was added. The mixture was cooled to 0° C., and 113 mL (0.328 mole) of phenylmagnesium bromide (3M in diethyl ether) was added during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature and then was heated under reflux for 16 hours. The reaction mixture was poured with shaking into 500 mL of an aqueous 10% hydrochloric acid solution. The organic layer was separated and washed with distilled water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was distilled under vacuum to yield 36 grams of 2-phenylthiophene; b.p. 140° C./3 mm, as a low melting solid.
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[C:10]#[N:11].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH:2]1[CH2:5][CH2:4][CH2:3]1)[C:10]#[N:11]
Reactant: BrC1CCC1
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC2CCC2)c(Br)c1
Yield: 86 %

Procedure:
Bromocyclobutane (2.7 g, 20.2 mmol), 3-bromo-4-hydroxybenzonitrile (2.0 g, 10.1 mmol), and K2CO3 (2.8 g, 20.2 mmol) were mixed in 5 mL of dimethylformamide and reacted at 60° C. for 72 hours. The mixture was diluted with ethyl acetate, washed with water, brine, dried with MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed (SiO2) using a gradient from hexane to 30% ethyl acetate in hexane over 500 mL to afford the title compound. (2.2 g, 8.7 mmol, 86% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.69-1.82 (m, 1H), 1.87-2.00 (m, 1H), 2.21-2.35 (m, 2H), 2.45-2.57 (m, 2H), 4.69-4.79 (m, 1H), 6.76 (d, J=8.48 Hz, 1H), 7.53 (dd, J=8.48, 2.03 Hz, 1H), 7.82 (d, J=2.03 Hz, 1H). MS (DCI/NH3) m/z 251.9 (M+H)+.
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)C=O.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH2:1]([S:13]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([Cl:33])=[O:19])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccccc1C(=O)Cl
Temperature: 25 °C

Procedure:
The o-dodecanesulfonylbenzoic acid (30.0 g, 0.084 mol) was dissolved in 100 ml of methylene chloride, then 0.5 ml of N,N-dimethylformamide was added, and they were stirred at room temperature. Then 12 ml of oxalyl chloride was added dropwise over 15 min, and after the addition the reaction mixture was stirred for 1 hour. The reaction solution was concentrated, to obtain o-dodecanesulfonylbenzoyl chloride.
Reaction SMILES: C([C@@H]1COC(=O)[N:9]1[C:14](=[O:40])[C@H:15]([CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([F:38])=[C:33]([CH3:39])[CH:32]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=1)C1C=CC=CC=1.[C-]#N.[K+].Cl.C1C[O:48]CC1.CO>>[OH:48][NH:9][C:14](=[O:40])[C@H:15]([CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([F:38])=[C:33]([CH3:39])[CH:32]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=1
Reactant: C1CCOC1
Reactant: Cc1cc(CCCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: Cc1cc(CCCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)NO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (R)-4-Benzyl-3-[(S)-2-(4-fluoro-3,5-dimethyl-benzyl)-8-(4-fluoro-3-methyl-phenyl)-octanoyl]-oxazolidin-2-one (0.036 g, 0.0657 mmol) in 2.5 mL of THF/MeOH/50% NH2OH—H2O (2:2:1), was added KCN (0.001 g, 0.007 mmol). After stirring at room temperature for overnight, the reaction mixture was acidified with concentrated HCl to pH=2 and filtered. The product was isolated by RP-HPLC eluting with 20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the title compound as an off-white solid (0.005 g, 18% yield). LC-MS: tR=11.1 min, m/z 404 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 1.21-1.33 (m, 6H), 1.34-1.48 (m, 2H), 1.49-1.66 (m, 2H), 2.18 (s, 6H), 2.21 (s, 3H), 2.23-2.32 (m, 1H), 2.51 (t, J=7.32 Hz, 2H), 2.56-2.62 (m, 1H), 2.67-2.78 (m, 1H), 6.81 (d, J=6.74 Hz, 2H), 6.88 (t, J=9.37 Hz, 1H), 6.91-6.97 (m, 1H), 7.00 (d, J=7.03 Hz, 1H).
Reaction SMILES: [OH-].[K+].[C:3]([N:5]=[C:6]([NH2:8])[NH2:7])#[N:4].CC(C)=O.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O.C(O)(=O)C>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:7][C:6]([NH:5][C:3]#[N:4])=[NH:8])=[O:19])=[CH:16][CH:15]=1
Reactant: N#CN=C(N)N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: N#CNC(=N)NC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Potassium hydroxide, 13.02 g (0.2 mole) is dissolved in 40 ml of water and 10.51 g (0.125 mole) of dicyanodiamide is added, followed by the addition of 50 ml of acetone. The mixture is cooled to 0° C. and the 4-fluorobenzoyl chloride from Step 1A, above, is added dropwise. The mixture is stirred at 0° C. for 1 hour and placed in the refrigerator overnight. The mixture is poured into 500 ml of water and the water is then acidified with an excess of acetic acid. The product forms a precipitate which is filtered, washed with water followed by ether and air dried to give 10.1 g of 1-(4'-fluorobenzoyl)-3-cyanoguanidine, m.p. 322° C. dec.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[O:4].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reaction time: 8 h
Yield: 84 %

Procedure:
500 mg (2.27 mmole) 6-Nitro-1H-indole-2-carboxylic acid methyl ester was dissolved in 4 mL neat N1,N1-dimethyl-ethane-1,2-diamine, was kept at 55° C. overnight and was evaporated. The oily residue was triturated with n-hexane to give 528 mg (84%) yellow solid which was no further purified. MS: 277.13 (calcd for M+H+:277.13)
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[C:1]1([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Yield: 448.4 %

Procedure:
The product of Example 118 (400 mg, 0.094 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (200 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])OCCCl)=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.O.[O:34]1CC[CH2:36][CH2:35]1>>[NH2:1][C:2]1[N:3]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:5]=[C:6]2[C:7]=1[N:8]([CH2:36][CH2:35][OH:34])[C:9](=[O:14])[NH:15]2
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1NC(=O)OCCCl
Reactant: C1CCOC1
Solvent: O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(CCO)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
350 mg (0.833 mmol) of the compound obtained in example 6A were initially charged in 12 ml of tetrahydrofuran at 0° C. Then 1.665 ml of a 1M solution of bis(trimethylsilyl)sodium amide in tetrahydrofuran were added dropwise and the mixture was stirred at 0° C. for a further 10 min. The mixture was then stirred at RT overnight. Subsequently, 2 ml of water were added to the mixture, which was concentrated to dryness. The residue was purified by means of preparative HPLC (acetonitrile/water (+0.05% formic acid) gradient). 188 mg of the title compound were obtained (53% of theory).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=2)=[N:4][N:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(NS(C1C=NC=C(C2C3C(=C(C4C=CC=CC=4)C=CC=3)C(NCC3C=CC=CN=3)=NN=2)C=1)(=O)=O)(C)(C)C>>[NH2:24][C:20]1[CH:19]=[C:18]([C:5]2[C:6]3[C:11](=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=[CH:8][CH:7]=3)[C:2]([NH:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:3][N:4]=2)[CH:23]=[N:22][CH:21]=1
Reactant: Nc1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Reactant: NCc1ccccc1
Agent: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Product: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Yield: 31 %

Procedure:
4-(5-Aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (0.300 g, 30.9% yield, white solid) was prepared from 5-(4-chloro-5-phenylphthalazin-1-yl)pyridin-3-amine (0.800 g, 2.40 mmol) and benzylamine (10.0 mL, 92.0 mmol) by the methods described for the preparation of N-(tert-butyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridine-3-sulfonamide in Example 1. The residue was purified by combiflash (REDISEP®, silica gel, 12 g, 8% MeOH/CHCl3). The resulting residue was further purified by preparative HPLC (Condition 21 as described in general methods). LCMS (Condition 5): retention time 2.03 min, [M+1]=404.6. HPLC (Condition 28): retention time=5.47 min, purity 97.63%. 1H NMR (400 MHz, DMSO-d6) δ 4.49 (d, J=5.2 Hz, 2 H), 4.99 (t, J=5.2 Hz, 1 H), 5.52 (s, 2 H), 7.01-7.03 (m, 2 H), 7.15-7.28 (m, 4 H), 7.43-7.50 (m, 5 H), 7.66 (dd, J=2.0 Hz, J=6.4 Hz, 1 H), 7.85-7.90 (m, 2 H), 7.94 (d, J=2.0 Hz, 1 H), 8.09 (d, J=2.0 Hz, 1 H).
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[CH2:19]([N:23](CCCC)CCCC)[CH2:20]CC.C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:23][CH2:19][CH3:20])=[O:4]
Reactant: CCCCN(CCCC)CCCC
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: CCN
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 66.7 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone and 5.7 g (31 mmol) of tri-n-butylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 3.6 g of theanine (yield: 66.7%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([F:24])[CH:17]=[C:18]3[C:23]=2[O:22][CH2:21][CH2:20][CH2:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:24][C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=1)[O:22][CH2:21][CH2:20][CH2:19]2
Reactant: Fc1cc2c(c(N3CCN(Cc4ccccc4)CC3)c1)OCCC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Fc1cc2c(c(N3CCNCC3)c1)OCCC2
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 1-benzyl-4-(6-fluoro-chroman-8-yl)-piperazine (1.64 g, 5 mmol), 10% palladium on carbon (0.4 g) and ammonium formate (0.64 g, 10 mmol) in ethanol (20 ml) was allowed to refux for 2 hours. The catalyst was filtered off and the solvent removed under vacuum. Chromatography (10-20% methanol-methylene chloride plus ammonium hydroxide) afforded 1.0 g (84%) of product as a yellow oil; MS EI m/e 296 (M+).