Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1N=C(N(CC2C=C(OCC)C=C(OC(C)C)C=2F)C2C=CC(C#N)=CC=2)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.[Br:50][C:51]1[N:52]=[CH:53][N:54]([C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:55]=1.[Si:75]([O:82][C:83]1[C:84]([F:101])=[C:85]([CH:96]=[C:97]([CH2:99][CH3:100])[CH:98]=1)/[CH:86]=[N:87]/[C:88]1[CH:95]=[CH:94][C:91]([C:92]#[N:93])=[CH:90][CH:89]=1)([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76]>>[Br:50][C:51]1[N:52]=[C:53]([N:87]([CH2:86][C:85]2[CH:96]=[C:97]([CH2:99][CH3:100])[CH:98]=[C:83]([O:82][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76])[C:84]=2[F:101])[C:88]2[CH:89]=[CH:90][C:91]([C:92]#[N:93])=[CH:94][CH:95]=2)[N:54]([C:56]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:55]=1
Reactant: CCc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Product: CCc1cc(CN(c2ccc(C#N)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Yield: 65.6 %

Procedure:
According to the procedure for the preparation of Intermediate 28.1, reaction of 4-bromo-1-triphenylmethyl-imidazole (100 mg) with Intermediate 188.4 (102 mg) afforded 130 mg of Intermediate 188.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[O:17]=[C:5]1[C:4]2[C:14](=[CH:15][CH:16]=[C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:18]#[N:19])[CH:3]=2)[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1CC2(CCOCC2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCOCC2)O3)c1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 43.8 %

Procedure:
A mixture of 6-bromo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-one (300 mg, 1 mmol), 3-cyanophenylboronic acid (298 mg, 2 mmol), Cs2CO3 (2 M, 4 mL) and Pd(PPh3)2Cl2 (80 mg) in 1,4-dioxane (10 mL) under Ar was stirred under microwave at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified bypreparative TLC to give 3-(4-oxo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-6-yl)benzonitrile (140 mg, 43%). 1H-NMR (CDCl3): 1.81-1.85 (m, 2H), 2.00-2.04 (d, 2H), 2.80 (s, 2H), 3.78-3.87 (m, 4H), 7.14 (d, 1H), 7.52-7.56 (t, 1H), 7.61-7.64 (d, 1H), 7.71-7.74 (d, 1H), 7.78 (d, 1H), 7.80 (s, 1H), 8.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:19])[F:20])=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1cc(Cl)ccc1OC(F)F
Reaction time: 1 h

Procedure:
To a solution of (E)-tert-butyl 3-(5-chloro-2-(difluoromethoxy)phenyl)acrylate (458 mg, 1.503 mmol) in DCM (4 mL) was added TFA (2.0 mL, 26.0 mmol). After 1 h, the solvent was removed to give Intermediate 15 as a white solid. MS (ESI) m/z: 249.0 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16]2>ClCCl>[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N+:19]([O-:9])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16]2
Reactant: Cc1ccc2ncc([N+](=O)[O-])cc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc2c(c1)cc([N+](=O)[O-])c[n+]2[O-]
Reaction time: 70 h
Yield: 43.2 %

Procedure:
A solution of 46 g of m-chloroperbenzoic acid in 19 ml of dichloromethane is added dropwise to a solution of 17.6 g of 6-methyl-3-nitroquinoline (compound E2) in 400 ml of dichloromethane. The reaction mixture is stirred for 70 h, diluted with 20 ml of dichloromethane and extracted two times each with 800 ml of halfsaturated aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 98:2). 8.25 g of the title compound are obtained as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH2:10][NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:4][N:3]=1.C(N(CC)CC)C.ClC(Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:42])[N:11]([C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:10][C:5]2=[CH:4][N:3]=1
Reactant: CNc1nc(Cl)ncc1CNc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1Cc2cnc(Cl)nc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 185.6 %

Procedure:
To a stirred solution of N-{3-[(2-chloro-4-methylaminopyrimidin-5-ylmethyl)amino]-4-methylphenyl}-3-trifluoromethylbenzamide (559 mg, 1.24 mmol) and triethylamine (693 μL, 4.97 mmol) in THF (15 mL) is added triphosgene (147 mg, 0.49 mmol) in THF (5 mL) at 0° C., and the mixture is stirred for 30 minutes at room temperature. The precipitate is filtered off and the filtrate is stirred for 3 hours at 110° C. The reaction mixture is then diluted with EtOAc and washed with saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated under reduced pressure to give crude oil which is purified by flash column chromatography (SiO2, EtOAc/hexane=1/2) to give N-[3-(7-chloro-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-trifluoromethylbenzamide (420 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH3:14][C:15]([CH3:19])([CH3:18])[CH:16]=O>C1COCC1>[CH2:6]([C@@H:4]1[NH:5][C@H:16]([C:15]([CH3:19])([CH3:18])[CH3:14])[N:2]([CH3:1])[C:3]1=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)C=O
Reactant: CNC(=O)[C@@H](N)Cc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 23.4 %

Procedure:
Hydrochloride salt of (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (1): To a solution of ethanolic MeNH2 (8.0 M, 50 ml) was added (S)-phenylalanine methyl ester (23.0 g, 130 mmol). The resulting solution was stirred at room temperature until the amino ester was judged to be consumed by TLC analysis. The resulting solution was then concentrated to provide (S)-phenylalanine N-methyl amide (18 g, 82% yield) as a white solid. To a flask containing (S)-phenylalanine N-methyl amide (8.9 g, 50 mmol) was added THF (100 ml), trimethylacetaldehyde (5.4 g, 50 mmol), FeCl3 (1.7 g, 10 mmol) and 4 Å MS (5.0 g). The resulting mixture was stirred at room temperature for 36 h, then washed with H2O (3×100 mL). The combined organics were concentrated and the resulting residue was treated with HCl (27 mL, 1N in ether). The resulting heterogeneous mixture was filtered to removed the undesired trans isomer.HCl salt and the resulting solution was concentrated. The residue was recrystallized (9:1 pentane/CH2Cl2) to provide the product (1) as a crystalline solid (2.88 g, 23% yield, >99% ee). IR (film) 3343, 2958, 1605, 1028 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.31-7.17 (m, 5H, ArH), 4.04 (s, 1H, NCHN), 3.72-3.65 (m, 1H, CHCH2), 3.13 (dd, J=4.1, 13.7 Hz, 1H, CH2), 2.92 (dd, J=7.7, 13.7 Hz, 1H, CH2), 2.90 (s, 3H, NCH3), 0.82 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 175.3, 138.0, 129.8, 128.7, 126.8, 82.7, 77.8, 77.4, 76.9, 59.7, 38.6, 35.4, 31.0, 25.7; [α]D=−39.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC using a Chiralpak OD-H and OD guard column (3.0% i-PrOH/hexanes, 1 mL/min); (5S) isomer tr=16.7 min, (5R) isomer tr=20.1 min.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[C:14](O)(=O)[CH2:15][OH:16]>Cl>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:14]([CH2:15][OH:16])=[N:1][C:2]=2[CH:8]=1
Reactant: O=C(O)CO
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Product: NS(=O)(=O)c1cc2[nH]c(CO)nc2cc1Cl
Yield: 23.1 %

Procedure:
To 11.0 g of 2-amino-4-chloro-5-sulfamylaniline in 50 ml of 4 N hydrochloric acid was added 5.6 g of glycolic acid. After refluxing for 6 hours, the resulting solid was collected by filtration and then added with stirring to 200 ml of 38% ammonium hydroxide; the pink precipitate was then collected and suspended in water with stirring at 60° for 20 minutes. Recrystallization of the solid from methanol provided 3.0 g of colorless crystals, m.p. 247°-250°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH:22]=[C:21]([C:23]([OH:25])=O)[C:20]3[N:19]=[C:18]4[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:17]4=[CH:16][C:15]=3[C:14]2=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:32]1[N:36]=[CH:35][N:34]([C:37](N2C=NC=C2)=O)[CH:33]=1>C(#N)C>[CH3:35][N:34]([CH3:37])[CH2:33][CH2:32][NH:36][C:23]([C:21]1[C:20]2[N:19]=[C:18]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:17]3=[CH:16][C:15]=2[C:14](=[O:31])[N:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=1)=[O:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CCn2cc(C(=O)O)c3nc4c(C)cccc4cc3c2=O)cc1OC
Solvent: CC#N
Product: COc1ccc(CCn2cc(C(=O)NCCN(C)C)c3nc4c(C)cccc4cc3c2=O)cc1OC
Yield: 81 %

Procedure:
From acid 18s with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h, and obtained as a yellow solid (81%), mp 113-114° C. (from acetonitrile). 1H NMR (CDCl3): δ 2.26 [s, 6H, N(CH3)2], 2.58 (t, J=6.5 Hz, 2H, CH2CH2NMe2), 2.77 (s, 3H, ArCH3), 3.01 (m, 2H, CH2CH2Ph), 3.67 (q, J=6.1 Hz, 2H, CH2CH2NMe2), 3.79 (s, 6H, 2×OCH3), 4.22 (m, 2H, CH2CH2Ph), 6.72-6.75 (m, 3H, H-2′, H-5′ and H-6′), 7.41 (t, J=7.6 Hz, 1H, H-8), 7.64 (d, J=6.8 Hz, 1H, H-7), 7.77 (d, J=8.2 Hz, 1H, H-9), 8.51 (s, 1H, H-3), 9.15 (s, 1H, H-10), 10.83 (br t, J=5.3 Hz, 1H, CONH).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)=O)=[C:8]([CH3:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].O>N1C=CC=CC=1>[OH:3][C:1]1[C:4]2[C:9](=[C:8]([CH3:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=2)[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH:2]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C(C)C)n2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(O)cc(-c3cccc(C(C)C)n3)nc2c1C
Temperature: 133 °C
Yield: 94 %

Procedure:
To a solution of 6-isopropylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methyl-phenyl)amide (107, 0.70 g, 2.14 mmol) in pyridine (5 mL) were added 2.5 equivalents of freshly grounded KOH along with water (50 μL). The mixture was heated by microwave irradiation at 133° C. for 55 min, then 80-85% of the pyridine was evaporated under reduced pressure. The residue was poured on ice and neutralized with acetic acid. The precipitate was filtered off, then dried to give 0.62 g (95%) of the title compound 108 (1.8 g, 95%): m/z=309 (M+H)+.
Reaction SMILES: [C:1]([O-])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>CN(C=O)C>[OH:3][C@@H:2]([CH3:4])[C:1]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[O:5]
Reactant: CC(O)C(=O)[O-]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of sodium lactate (1.7 g, 15.0 mmole), diphenyl phosphorylazide (3.6 ml, 16.5 mmole) and dry DMF (30 ml) at 0° C. (ice bath) in an argon atmosphere was treated with triethyl amine (2.1 ml, 15.2 mmole) and L-proline, phenylmethyl ester, hydrochloride salt (3.6 g, 15.0 mmole). After 24 hours, the reaction mixture was partitioned between EtOAc and H2O. The aqueous phase was back extracted, the organic extracts combined, washed with 5% KHSO4, brine, and evaporated. The residue (5.0 g) was chromatographed on silica (130 g) eluting with EtOAc/Hexane (1:1) to give the title compound (2.5 g, 9.0 mmole, 60% yield) as a white crystalline solid after evaporation, m.p. 86°-88° C.
Reaction SMILES: Cl[CH:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][NH:3]1.[CH3:20][O-:21].[Na+]>CO>[CH:11]1([N:10]2[C:6]3[C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][NH:3][CH:2]([O:21][CH3:20])[C:7]=3[CH:8]=[CH:9]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[O-]
Reactant: COC(=O)C1=CNC(Cl)c2ccn(C3CCCC3)c21
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CNC(OC)c2ccn(C3CCCC3)c21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-chloro-1-cyclopentyl-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (1.37 g) in methanol (5 mL) was added sodium methoxide (28% methanol solution, 5 mL), and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (879 mg).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:22]Br)[CH:18]=2)[N:13]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:10]([CH2:22][C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]=[C:12]([CH3:11])[CH:21]=[CH:20]4)[C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[CH:18]=2)[N:13]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Cc1ccc2cc(CBr)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc2cc(CN(Cc3ccc4nc(C)ccc4c3)c3ccc4[nH]cnc4c3)ccc2n1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), (2-methylquinolin-6-yl)methylbromide (519 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.067 g (15.1%); MS m/z: 444.5 [M+H]+, 222.8 [M+2H]2+; 1H-NMR (500 MHz, DMSO d6): δ 2.60 (s, 6H); 4.92 (s, 4H); 6.77-6.82 (m, 2H); 7.33-7.35 (m, 3H); 7.67 (dd, 2H, 4J=2.1 Hz, 3J=8.5 Hz); 7.77 (br s, 2H); 7.85-7.87 (m, 3H); 8.14 (d, 2H, 3J=8.5 Hz); 11.81 (br s, 1H); HPLC (METHOD [A]): doublepeak rt 6.61 min (61.2%), 6.84 min (38.8%)
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: O=[N+]([O-])c1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1
Yield: 50.6 %

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was refluxed in 400 ml of toluene containing morpholine (3.5 g) and 4-nitrobenzaldehyde (3.78 g). After forty-eight (48) hours an additional 3.78 g of aldehyde was added and reflux was continued for an additional twenty-four (24) hours. At the end of this time the reaction mixture was concentrated and purified by flash chromatography. Fractions containing the product were concentrated and recrystallized from CH2Cl2 /pentane to give 3.38 g of product, m.p. 237°-238° C.
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][C:42](=O)[CH2:43][O:44][CH3:45]>CC(C)=O>[CH3:45][O:44][CH2:43][C:42]1[CH2:41][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: COCC(=O)CCl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(NC=S)P(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N=CSC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of p-nitrobenzyl α-thioformamidodiphenylphosphonoacetate (2.43 g), powdered anhydrous potassium carbonate (2.07 g), 1-chloro-3-methoxy-2-propanone (0.67 g), and acetone (25 ml) is stirred under a nitrogen atmosphere at room temperature for 16 hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is dissolved in methylene chloride, washed twice with water and saturated brine, dried over MgSO4, filtered, and evaporated in vacuo to yield crude p-nitrobenzyl 5-methoxymethyl-6H-1,3-thiazine-4-carboxylate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>C(O)C>[NH2:9][C:7]1[NH:8][C:21]([C:20]2[CH:25]=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:22][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)[nH]c1N

Procedure:
Analogously to Step 8.1, 1.67 g (10 mmol) of 2-amidino-acetic acid ethyl ester hydro-chloride in 20 ml of abs. ethanol are reacted with 716 mg (10 mmol) of sodium ethanolate and 1.145 g (5.0 mmol) of 4-methoxy-phenacyl bromide (Fluka; Buchs/Switzerland) to form the title compound; m.p. 141-142° C.; TLC-Rf =0.4 (hexane/ethyl acetate [1:1]); FAB-MS: (M+H)+ =261.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH2:5][C:6]([OH:8])=O.[OH:10][PH:11]([OH:13])=[O:12].P(Cl)(Cl)Cl>O>[CH3:1][N:2]1[C:3]([P:11]([OH:13])(=[O:10])[OH:12])([P:11]([OH:13])(=[O:10])[OH:12])[CH2:4][CH2:5][C:6]1=[O:8]
Reactant: CNC(=O)CCC(=O)O
Reactant: O=[PH](O)O
Solvent: O
Solvent: ClP(Cl)Cl
Product: CN1C(=O)CCC1(P(=O)(O)O)P(=O)(O)O
Reaction time: 5 h

Procedure:
28.5 gm of succinic acid monomethylamide (0.216 mol) were melted with 35.4 gm of H3PO3 (0.432 mol) at 70° C. and then slowly mixed with 37.8 ml of PCl3 (0.432 mol). After an additional 5 hours at 70° C., the product was hydrolyzed with 300 ml of H2O. Filtration with activated carbon at the boiling point yielded a clear solution from which the N-methyl-pyrrolidone-5,5-diphosphonic acid was precipitated with ethanol and acetone. Crude yield 4.2 gm (7% of the theory).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2].[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:3]1[CH:8]=[C:7]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1cc(Br)cc(C=O)c1O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCCCCCCCC#Cc1cc(C=O)c(O)c(C=O)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
2,6-Diformyl-4-bromophenol (2.50 g, 10.9 mmol), 1-dodecyne (2.00 g, 12.0 mmol), Cul (65 mg, 0.33 mmol), and bis(triphenylphosphine)palladium)II)dichloride were suspended in degassed acetonitrile (MeCN) (5 mL) and degassed benzene (1 mL). The yellow suspension was sparged with argon for 30 min and degassed Et3N (1 mL) was added. The resulting brown suspension was sealed in a pressure vial, warmed to 80° C. and held there for 12 h. The mixture was then partitioned between EtOAc and KHSO4 solution. The organic layer was separated, washed with brine, dried MgSO4) and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% Et2O in hexanes) to give 1.56 g (46%) of the title compound.
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([OH:22])[CH2:15]2>>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([O:22][C:12](=[O:13])[NH:11][C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)[CH2:15]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C=Nc1cccc2ccccc12
Product: O=C(Nc1cccc2ccccc12)OC1CN2CCC1CC2

Procedure:
1-Naphthylisocyanate and 3-quinuclidinol were used. The title compound was isolated as a white solid (34%): mp 186-188° C.; FAB LRMS m /z 297 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH:19]1([C:17]([N:14]2[CH2:13][CH2:12][CH:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:22])=[O:2])=[CH:9][CH:8]=3)[CH2:16][CH2:15]2)=[O:18])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)C3CC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC2CCN(C(=O)C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-benzoic acid methyl ester (0.75 g, 2.472 mmol), methanol (25 mL) and 1 N NaOH (10 mL) was stirred at room temperature for 16 hrs. The volatiles were evaporated in vacuo and the residue was redissolved in water (10 mL) and washed with EtOAc (2×5 mL). The aqueous phase was acidified to pH ˜1 with 1N HCl and extracted with EtOAc (2×10 mL), dried (MgSO4), filtered and evaporated affording 0.6 g 84%) of 4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-benzoic acid as a solid. 1H-NMR (400 MHz, CDCl3) δ 0.73-0.84 (m, 2H), 0.97-1.07 (m, 2H), 1.72-2.11 (m, 5H), 3.63-3.74 (m, 2H), 3.75-4.00 (m, 2H), 4.64-4.75 (m, 1H), 6.96 (d, 2H), 8.06 (d, 2H).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH2:35][O:36][CH3:37])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:40](O)C>O1CCCC1.ClCCl>[CH2:37]([O:36][CH2:35][CH2:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]([CH3:23])[CH3:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH3:40]
Reactant: CCO
Reactant: COCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 34 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-{1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-1H-pyrrolo[2,3-b]pyridine (0.6 g, 1.1 mmol) in ethanol (8 mL), tetrahydrofuran (15 mL) and an aqueous sodium hydroxide solution (10%, 10 mL) was heated at 45° C. for 16 h. The mixture was diluted with dichloromethane (150 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 2-{1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (160 mg, 34%): LC/MS m/e calcd for C22H25FN2O3S [M+H]+ 417.52, observed 416.8.