Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:41][C:5]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester and 5N NaOH (0.7 mL) in ethanol (6 mL) is refluxed for 1 h, cooled to ambient temperature, and concentrated. The residue is diluted with CH2Cl2, washed, dried, and concentrated to provide the title compound (0.186 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 2H, J=8.3 Hz), 7.35 (d, 2H, J=8.3 Hz), 7.24-7.17 (m, 4H), 7.00 (t, 1H, J=7.4 Hz), 6.89 (d, 2H, J=7.4 Hz), 6.73 (d, 2H, J=8.3 Hz), 4.45, 4.37 (ABq, 2H, J=15.7 Hz), 3.96 (t, 2H, J=5.5 Hz), 3.68-3.62 (m, 1H), 3.38 (t, 1H, J=8.3 Hz), 3.32, 3.10 (ABq, 2H, J=12.9 Hz), 3.00 (t, 1H, J=8.3 Hz), 2.84 (s, 3H), 2.27-2.19 (m, 1H), 1.92-1.85 (m, 1H), 1.39 (s, 3H). MS [EI+] 557 (M+H)+, [EI−] 555 (M−H)+.
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[CH2:16][C@@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:5](Cl)[N:4]=1>CO>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[CH2:16][C@@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:5]([NH2:1])[N:4]=1
Reactant: N
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C=C[C@H](CO)C3)c2n1
Solvent: CO
Product: Nc1nc(N)c2ncn([C@@H]3C=C[C@H](CO)C3)c2n1
Temperature: 75 °C
Yield: 80 %

Procedure:
Liquid ammonia is passed into a solution of cis-(±)-2-amino-6-chloro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purine (0.265 g, 1 mmol) in methanol (10 mL) at -80° C. in a bomb. The bomb is sealed and heated at 75° C. for 48 hours. The bomb is cooled to room temperature and the ammonia and methanol are evaporated. The residue is purified by silica gel chromatography using 15:1 chloroform methanol as eluent to give cis-(±)-2,6-diamino-9-[4-(hydroxymethyl)-2-cyclo-penten-1-yl]-9H-purine (0.196 g, 80%). M.pt. 152°-155° C. MS (30 ev, 200° C.): m/e 246 (M+), 229 (M+-17), 216 (M+-30).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.CS([Cl:28])(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:28])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(CO)ccc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CCl)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine methyl 2-methoxy-5-hydroxymethylbenzoate (1.34 g, 6.8 mmol) and N,N-diisopropylethylamine (1.4 mL) in dichloromethane (25 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.56 mL). After 30 minutes, warm to ambient temperature. After 2 hours, dilute with dichloromethane and extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give methyl 2-methoxy-5-chloromethylbenzoate: Rf=0.64 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH3:15])=O.COC1C=CC(/C=[C:31]2/[C:32]([NH:34][C:35]([S:37]/2)=[NH:36])=[O:33])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:36][C:35]1[S:37]/[C:31](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH3:15])/[C:32](=[O:33])[N:34]=1
Reactant: Cc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-methyl-quinoline-3-carbonitrile (example 73c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-methyl-quinoline-3-carbonitrile. LC-MS m/e 295 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[C:8]1[C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)=[O:19].C(OCC)(=O)C.[ClH:52]>C(OCC)(=O)C>[ClH:52].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[C:8]1[C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])[CH2:24][NH:23][CH2:22]1)=[O:19]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)ccc1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)ccc1-c1ccccc1
Reaction time: 1 h

Procedure:
tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (150 mg) was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate(5 ml) was added and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure to give the object product (110 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[I-].[K+].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: ClCc1nnc(-c2ccc(I)cc2)o1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Product: Ic1ccc(-c2nnc(CN3CCCCC3)o2)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
2-Chloromethyl-5-(4-iodophenyl)-[1,3,4]oxadiazole (Intermediate 7) (48 mg, 0.15 mmol) and potassium iodide (25 mg, 0.15 mmol) were dissolved in piperidine (2 ml) and stirred for 18 hours at 20° C. The amine was then removed in vacuo and the product was purified on a 10 g silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetate:cyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC=CC=1>[CH:1]1([NH:7][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)NC1CCCCC1

Procedure:
5.26 g (0.02 mole) of(2-methyl 1-phenyloxy 2-hydroxy propyl)-cyclohexylamine is dissolved in 300 ml of benzene. 2.38 g (0.02 mole) of phenylisocyanate were added. Slight heating was observed as well as the appearance of a solid. It was heated under reflux for 1 hour. After cooling, it was filtered and the product was recrystallized in ethanol. Melting point 164° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=[O:17].BrCC1C=CC=[C:22]([O:26]C)C=1>>[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:26][CH3:22])[CH:12]=2)[C:4]1=[O:17]
Reactant: COc1cccc(CBr)c1
Reactant: N[C@H]1CCCCN(Cc2ccccc2)C1=O
Agent: Cl
Product: COc1cccc(CN2CCCC[C@H](N)C2=O)c1

Procedure:
(S)-3-Amino-1-(3-methoxybenzyl)azepan-2-one (175 mg, 0.705 mmol) was synthesized as described for the preparation of Intermediate 42 using 1-(bromomethyl)-3-methoxybenzene in step A. Anal. Calcd. for C14H20N2O2 m/z 248.3. found: 249.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:6][NH:5][C@H:4]([CH2:7][C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CO>[F:14][C:2]1([F:1])[CH2:6][N:5]2[C@H:4]([CH2:7][C:8](=[O:13])[CH2:9][C:10]2([CH3:11])[CH3:12])[CH2:3]1
Reactant: CC(C)=CC(=O)C[C@@H]1CC(F)(F)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C)CC(=O)C[C@@H]2CC(F)(F)CN21
Yield: 69 %

Procedure:
A MeOH (350 ml) solution of 1-((R)-4,4-difluoropyrrolidin-2-yl)-4-methylpent-3-en-2-one and K2CO3 (2.5 g, 18 mmol) was stirred at 40° C. for 15 hours, the reaction went to completion as monitored by LC-MS. Solvent was removed in vacuo, remaining material was suspended in CH2Cl2, solid was filtered off, filtrate was collected and solvent was removed in vacuo. Product was purified by silica gel chromatography (Hexane/EtOAc, linear gradient from 100:0 to 80:20). Compound (R)-2,2-difluoro-hexahydro-5,5-dimethylindolizin-7(1H)-one was obtained as a light yellow solid: 637.4 mg (69% yield over 3 steps).
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([CH3:17])=O)=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].BrC1C(O)=C(Br)C=CC=1C(OCC)=O.ClCC(=O)C.C([O-])([O-])=O.[Na+].[Na+].Cl.[CH2:45]([O:47][NH2:48])[CH3:46]>CO.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15](=[N:48][O:47][CH2:45][CH3:46])[CH3:17])=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCON
Reactant: CCOC(=O)c1ccc(Br)c(OCC(C)=O)c1Br
Agent: CC(=O)CCl
Agent: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: Cl
Solvent: CO
Solvent: O
Product: CCON=C(C)COc1c(Br)ccc(C(=O)OCC)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.00 g (2.60 mmol) of ethyl 2,4-dibromo-3-(methylcarbonylmethoxy)benzoate (prepared from ethyl 2,4-dibromo-3-hydroxybenzoate and chloroacetone analogously to preparation a), step 1, above) and 0.614 g (5.80 mmol) of Na2CO3 were initially charged in 10 ml of methanol. 0.529 g (5.30 mmol) of O-ethyl hydroxylamine hydrochloride, dissolved in 12 ml of water, was added dropwise and the mixture was stirred at RT for 2 h. The mixture was then poured into water and extracted with diethyl ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated to dryness. Drying under oil pump vacuum gave ethyl 2,4-dibromo-3-(2-ethoxyiminopropyloxy)benzoate as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:30])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[C:9]([O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]=2)=[O:4].[C:31]1([Mg]Cl)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[C:9]([O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:8]=2)=[O:4]
Reactant: Cl[Mg]c1ccccc1
Reactant: COC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1(O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile (350 mg, 0.878 mmol) obtained in Step 1 was dissolved in THF, and phenylmagnesium chloride (0.483 mL, 0.966 mmol) was added thereto, followed by stirring for 3 hrs at 0° C. Upon the completion of the reaction, the mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 378 mg of the titled compound (yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].CO[CH:25]1[CH:29]([CH3:30])[CH2:28][CH:27](OC)[O:26]1>C(O)(=O)C>[CH3:30][C:29]1[CH2:28][C:27](=[O:26])[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]3=[O:22])[CH:25]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Reactant: COC1CC(C)C(OC)O1
Solvent: CC(=O)O
Product: CC1=CN(c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)C(=O)C1

Procedure:
To a solution of 60 mg (0.18 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide in 5 ml of acetic acid are added 26 mg (0.18 mmol) of 2,5-dimethoxy-3-methyl-tetrahydro-furan (prepared according to: Markwell, Roger Edward; Hadley, Michael Stewart; Blaney, Frank Edward. Azabicycloalkane derivatives and medicaments containing them. Eur. Pat. Appl. (1983) EP 95262 A1). The reaction mixture is stirred at reflux for 10 hours. Subsequently the solvents are evaporated and the crude product is purified by flash-master chromatography (cyclohexane/ethyl acetate, from 100/0 to 20/80) to yield N-[6-(4-methyl-2-oxo-2,3-dihydro-pyrrol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl] methanesulfonamide. 1H-NMR ; DMSO-d6 (400 MHz, ppm):; 8.06 (s, 1H, aromatic); 7.60 (s, 1H , aromatic); 7.13 (m, 1H, N-CH═C(CH3)); 4.24 CO—CH2-C(s, 2CO—CH2-C(CH3)); 3.16 (s, 3H, S02-CH3); 1.84 (d, 3H, CH3) [M−H]-; Agilent LC/MSD 1100 Series, LC-MS method: Column: SunFireC18, 4.6*50 mm, 3.5 μm; negative MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>ClCCl>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C(=O)c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane is added triethylamine (0.24 ml). Subsequently, thereto is added benzoyl chloride (0.2 ml) under ice-cooling, and the temperature thereof is raised to room temperature, and the mixture is stirred overnight. Water is added to the reaction solution and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 5-(N-methyl-N-benzoylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.64 g) as colorless needles, m.p. 248-249° C.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][N:23]=1>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:29][CH2:28][C:25]3[CH:24]=[N:23][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:27][CH:26]=3)[C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CC2CCCN2C1
Reaction time: 16 h

Procedure:
A solution of 3-methyl-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (100 mg, 0.44 mmol) and powdered KOH (172.6 mg, 3.038 mmol) in NMP (2 mL) was stirred at RT for 5 min. 2-(Trifluoromethyl)-5-vinylpyridine (152 mg, 0.881 mmol) was added into the reaction mixture and stirring continued for 16 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 3-methyl-11-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Cl:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.F[B-](F)(F)F.[NH4+].[N:21]([O-])=O.[Na+].C1OCCOCCOCCOCCOCCOC1.C([O-])(=O)C.[K+]>O>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]2[C:3](=[CH:13][NH:21][N:1]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(Cl)ccc(N)c1C
Reactant: O=N[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: COC(=O)c1c(Cl)ccc2n[nH]cc12
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
To a solution of methyl 3-amino-6-chloro-2-methylbenzoate (25.0 g, 125 mmol) in water (139 mL) were added concentrated hydrochloric acid (26.1 mL, 313 mmol), ammonium tetrafluoroborate (17.1 g, 163 mmol) and sodium nitrite (8.64 g, 125 mmol) at 0° C., and the mixture was stirred for 30 min. The reaction solution was diluted with water, and washed with ethyl acetate. The water of the obtained aqueous layer was evaporated under reduced pressure, and the residue was dissolved in chloroform (287 mL). 18-Crown-6 (993 mg, 3.76 mmol) and potassium acetate (13.5 g, 138 mmol) were added. The reaction mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (4.10 g, yield 20%).
Reaction SMILES: [OH:1][P:2]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:4][C@@H:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])=[O:3].[Ca]>>[C:15]1([CH2:14][O:12][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C@@H:5]([O:4][P:2]([O:1][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:3])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CCNC(=O)[C@H](Cc1ccccc1)OP(=O)(O)OCc1ccccc1
Agent: [Ca]
Product: O=C(CCNC(=O)[C@H](Cc1ccccc1)OP(=O)(OCc1ccccc1)OCc1ccccc1)OCc1ccccc1

Procedure:
N-[(S)2-[[hydroxy(phenylmethoxy)phosphinyl]oxy]-1-oxo-3-phenylpropyl]β-alanine, calcium salt thereof;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:17])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C(Cl)(Cl)Cl.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>[CH3:17][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][C:12]=2[S:13][C:14]2[C:5]1=[CH:4][CH:3]=[C:2]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:14][CH:15]=1)[CH:15]=2
Reactant: OB(O)c1ccccc1
Reactant: CN1c2ccc(Br)cc2Sc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: COCCOC
Product: CN1c2ccc(-c3ccccc3)cc2Sc2cc(-c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g (6.7 mmol) of 3,7-dibromo-10-methylphenothiazine (C. Bodea and M. Terdic, Acad. Rep. Rom. 1962, 13, 81-87), 1.85 g (14.9 mmol) of 98% phenylboronic acid, 0.11 g (0.14 mmol) of bis(triphenylphosphine)palladium dichloride and 1.03 g (7.4 mmol) of potassium carbonate were heated to boiling (75° C.) under reflux under nitrogen for 5 hours in 55 ml of dimethoxyethane and 28 ml of water. The reaction mixture was cooled to room temperature and stirred further overnight. The precipitate was filtered off with suction, washed successively with 125 ml of ethanol and hot water and dried at 70° C. under reduced pressure. The crude product (2.30 g) was heated to boiling under reflux in cyclohexane for two hours. After the hot suspension had been filtered, the residue was dried, dissolved in 40 ml of methylene chloride and filtered through a silica-gel-filled glass fit. After the solvent had been removed, 1.05 g (43% of theory) of light yellow, analytically pure solid having a melting point of 239-241° C. were obtained, whose solution in chloroform fluoresced at λ=464 nm.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.O.NN.Cl>C(O)C.ClCCl>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccc(Br)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: NCCCCOc1ccc(Br)cc1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
N(4-(4-bromophenoxy)butyl)phthalimide (6.01 g, 16.1 mmol) is dissolved in ethanol (200 mL) under nitrogen, followed by the addition of hydrazine monohydrate (7.8 mL, 161 mmol). The reaction was refluxed at 80° C. for 2 hours. Once reaction completed (solids formed at the top layer), cooled reaction to room temperature and neutralized with 1M HCl (50 mL). The mixture is allowed to stir until all solids are completely dissolved and diluted with dichloromethane (150 mL). The solution was extracted with two portions of saturated NaHCO3 (2×). The organic layers were combined, washed with brine and water, then dried over MgSO4, and filtered. Removal of solvent yields a yellow oil (2.93 g, 75%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:20])[CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:4][C:3]=2[O:2]1.O>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][CH:12]([OH:20])[CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)CN1CCOCC1
Solvent: CO
Solvent: O
Product: OC(C=Cc1ccc2c(c1)OCO2)CN1CCOCC1
Reaction time: 8 h

Procedure:
27.5 g of the ketone (0.1 M) obtained in Example 1 is dissolved in 300 cm3 of methanol and an aqueous solution of KBH4 is added dropwise. The reaction mixture is left overnight and decomposed with water. The product obtained is filtered and recrystallised in ethanol.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][C:22]3[C:28](=[O:29])[NH:27][C:26]4[CH:30]=[C:31]([CH2:34][C:35]([N:37]5[CH2:41][CH2:40][CH:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38]5)=[O:36])[CH:32]=[CH:33][C:25]=4[NH:24][C:23]=3[CH:50]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]>C(Cl)Cl>[NH2:42][CH:39]1[CH2:40][CH2:41][N:37]([C:35](=[O:36])[CH2:34][C:31]2[CH:32]=[CH:33][C:25]3[NH:24][C:23]4[CH:50]=[C:19]([C:12]5[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([O:9][CH3:8])[CH:11]=5)[CH:20]=[CH:21][C:22]=4[C:28](=[O:29])[NH:27][C:26]=3[CH:30]=2)[CH2:38]1
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CC(=O)N4CCC(NC(=O)OC(C)(C)C)C4)cc2NC3=O)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CC(=O)N4CCC(N)C4)cc2NC3=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.5 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of Example 365 (35 mg, 0.06 mmol) in CH2Cl2 (3 mL) and stirred at room temperature for 5 hours. Concentrated under vacuum. Residue was purified by preparative HPLC to provide 25 mg (70%) of the desired product as the trifluoroacetate salt. MS (DCI) m/e 488 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.87 (s, 1H), 7.99-8.08 (m, 4H), 7.95 (s, 1H), 7.80 (d, J=8.42 Hz, 1H), 7.52 (s, 1H), 7.36 (s, 1H), 7.34 (dd, J=8.42, 1.56 Hz, 1H), 7.30 (dd, J=8.11, 1.25 Hz, 1H), 6.82-6.97 (m, 2H), 4.03 (s, 3H), 3.83 (m, 1H), 3.64-3.74 (m, 2H), 3.38-3.57 (m, 4H), 2.19 (m, 1H), 1.95 (m, 1H).