Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:24])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22]O)[CH:14]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:46][CH:45]=1>C(#N)CC>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:24])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22][N:53]2[CH2:52][CH2:51][N:50]([C:47]4[CH:46]=[CH:45][C:44]([Cl:43])=[CH:49][CH:48]=4)[CH2:55][CH2:54]2)[CH:14]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncc(CO)cc3NC(=O)C2C1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
7-Hydroxymethyl-10-oxo-1,3,4,9,10,10a-hexahydro-2,4-a,5,9-tetraaza-phenanthrene-2-carboxylic acid tert-butyl ester (22.0 mg, 0.598 mmol) was suspended in propionitrile (1.5 mL) and (cyanomethyl)trimethylphosphonium iodide (174.0 mg, 0.718 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (313 ul, 1.794 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (139 mg, 0.598 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and purified on silica column (24 g, 25% THF in ethyl acetate). The fractions were combined and concentrated to afford 250.9 mg (82%) of the title compound as a brown solid in 80% purity. [M+H] calc'd for C26H33ClN6O3, 513; found, 513.
Reaction SMILES: NC1N=C(NCCC(C)C)C=C(Cl)N=1.[NH2:15][C:16]1[N:21]=[C:20]([NH:22][CH:23]2[CH2:27]CC[CH2:24]2)[CH:19]=[C:18]([Cl:28])[N:17]=1>>[NH2:15][C:16]1[N:21]=[C:20]([NH:22][CH:23]([CH3:24])[CH3:27])[CH:19]=[C:18]([Cl:28])[N:17]=1
Reactant: Nc1nc(Cl)cc(NC2CCCC2)n1
Agent: CC(C)CCNc1cc(Cl)nc(N)n1
Product: CC(C)Nc1cc(Cl)nc(N)n1

Procedure:
In analogous manner to that described in Example 1, 2-amino-4-iso-pentylamino-6-chloro-pyrimidine and 2-amino-4-cyclopentylamino-6-chloro-pyrimidine may be produced. Isolation and purification may be effected in conventional manner.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CCO>[CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(F)cc1
Yield: 77.1 %

Procedure:
Ethyl ester (168) (0.25 g, 0.53 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.18 g (79%) of the title compound (169) as a white solid. mp 169-170° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.78 (t, J=7.3 Hz, 3H), 1.15-1.28 (m, 2H), 1.40-1.50 (m, 2H), 2.60 (t, J=7.9 Hz, 2H), 6.27 (d, J=16.0 Hz, 1H), 6.56 (d, J=8.6 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H), 7.12-7.22 (m, 2H), 7.32-7.42 (m, 3H), 7.46-7.56 (m, 2H), 7.70-7.80 (m, 2H), 7.90 (d, J=8.2 Hz, 1H). LCMS (ESI): m/z 441 (M+H)+, m/z 439 (M−H)−. Anal. Calc for C29H25FO3.0.1H2O: C, 78.75; H, 5.74. Found: C, 78.85; H, 5.64.
Reaction SMILES: N([O-])=[O:2].[Na+].[CH3:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:7]=1[CH2:8]N.C(O)(=O)C.[OH-].[Na+]>O.CO>[CH3:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:7]=1[CH2:8][OH:2]
Reactant: O=N[O-]
Reactant: Cc1ccc([N+](=O)[O-])c(CN)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(CO)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
Sodium nitrite (36.5 g, 0.53 mole) in water (125 ml) was added dropwise to a stirred mixture of 2,3-dimethyl-6-nitrobenzylamine (63.5 g, 0.35 mole), acetic acid (165 mL) and water (165 mL) cooled in an ice bath. After completing the addition, the mixture was stirred for 10 minutes, warmed to room temperature and stirred to a further 10 minutes before being diluted with water (1000 mL). The mixture was extracted with dichloromethane (3×500 mL), the combined extracts dried over magnesium sulfate and concentrated to afford an oil which was dissolved in methanol (400 mL). 1N Sodium hydroxide solution (400 mL) was added dropwise over 20 minutes. The methanol was removed under reduced pressure, and the residue diluted with water (1200 mL) and extracted with dichloromethane (3×700 mL). The combined extracts were dried over magnesium sulfate and the solvent evaporated to afford 2,3-dimethyl-6-nitrobenzyl alcohol (59.3 g, 93%) as brown solid used in Step 3 below without further purification. An analytical sample was prepared by crystallization from hexane/diethyl ether, m.p. 48°-51° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]2[O:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH:20]2[O:21][CH2:22][CH2:23][CH2:24][O:25]2)[CH2:16][CH2:17]1
Reactant: CCOc1ccc(C2CCC(=CCC3OCCCO3)CC2)c(F)c1F
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc([C@H]2CC[C@H](CCC3OCCCO3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The 2-(2-(4-(2,3-difluoro-4-ethoxyphenyl)cyclohexylidene)-ethyl)-1,3-dioxane (36.9 mmol) obtained by the reaction of Step 3 was dissolved in 100 ml of a mixed solvent of toluene/ethanol (1/1), 4.0 g of 5-wt %-palladium/carbon catalyst was added, and the solution was stirred for 7 hours at room temperature under a hydrogen pressure of 1–2 kg/cm2. After the catalyst was filtered off, the solvent was distilled off from the filtrate under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: a mixed solvent of ethyl acetate/toluene=3/7), the solvent was distilled off under reduced pressure, and the product was re-crystallized from ethanol to form 2-(2-(trans-4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexyl)-ethyl)-1,3-dioxane (36.9 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([OH:12])=O.[CH2:34]([N:36](CC)[CH2:37]C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CNC>ClCCl.C(#N)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:32]2)[C:14]1=[O:33])[C:10]([N:36]([CH3:37])[CH3:34])=[O:12]
Reactant: CCN(CC)CC
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1ccc(F)cc1F
Agent: CNC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc(F)cc1F
Reaction time: 16 h

Procedure:
The acid (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoic acid (0.747 g) prepared as described above was dried over P4O10 in vacuo for five hours to give 0.724 g drier material; this was dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated with triethylamine (0.223 ml) and BOP—Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated with triethylamine (0.223 ml) and BOP—Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, 0.450 g) and the mixture was sonicated for ca. 1 min to give a gelatinous mass. After 10 minutes at room temperature a solution of dimethylamine in tetrahydrofuran (10 ml of 2M solution) was added to give a clear solution; this was left for 16 hours at room temperature. The solvents were removed under reduced pressure and the mixture was partitioned between dichloromethane and 0.1M hydrochloric acid. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The crude product was purified by flash column chromatography (12 g Biotage™ silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1) to give the (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide as a colourless solid 0.285 g.
Reaction SMILES: NCCCCCC([C:9]1[C:18](N)=[CH:17][CH:16]=[C:11]([C:12]([NH:14][OH:15])=[O:13])[C:10]=1[O:20]C)=O>C([O-])(O)=O.[Na+]>[C:12]([NH:14][OH:15])(=[O:13])[C:11]1[C:10](=[CH:9][CH:18]=[CH:17][CH:16]=1)[OH:20]
Reactant: COc1c(C(=O)NO)ccc(N)c1C(=O)CCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NO)c1ccccc1O

Procedure:
SHA-Sepharose 4B was prepared by mixing 130 mg of (6-aminohexanoyl)-4-amino-methylsalicylhydroxamic acid (SHA-Z-NH2), dissolved in 30 mL 0.2M NaHCO3, with. 6.5 g HCl washed CNBr activatedSepharose 4B (Pharmacia) overnight at room temperature. After the coupling reaction, 2 mL 0.5M Tris, pH 8.5 were added and the gel slurry mixed at room temperature for 1 hour, and washed with water, 0.5M NaCl, and water again. The resulting SHA-Sepharose 4B was suspended in 30 mL of 20% ethanol, and stored at 4° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:7])=[O:4].[C:15](O)(C)([CH3:17])[CH3:16].CC(C)([O-])C.[K+].C(Br)C#C>CC#N.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]([F:13])([F:14])[C:3]([N:5]([CH2:17][C:15]#[CH:16])[C@@H:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:7])=[O:4]
Reactant: CCCCCC(C)NC(=O)C(F)(F)F
Reactant: CC(C)(C)O
Agent: C#CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: CC#N
Product: C#CCN(C(=O)C(F)(F)F)[C@H](C)CCCCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-trifluoroacetyl-N-2-heptylamine(6.33 g, 30 mmol) in CH3CN (75 ml)/t-butanol(0.5 ml) was added 18-crown-6(300 mg) and powdered potassium t-butoxide (3.36 g, 30 mmol). After stirring for 15 min most of the solids had dissolved and propargyl bromide (80% in toluene) (3.5 ml, 31.5 mmol) was then added dropwise. The solution was stirred at 80-85° C. (oil bath temperature) for 24 h during which time the solution became brown in color and a white solid precipitated. After the reaction mixture had cooled to room temperature, dichloromethane (75 ml) was added and the solids were filtered with suction and washed with dichloromethane. The weight of the solids (KBr) was 3.6 g (theoretical: 3.57 g). The combined filtrates were rotary evaporated to give 7.3 g of a dark brown liquid (theoretical yield=7.47 g). The product was not purified but used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].I[CH3:13]>C1COCC1.C(OCC)C>[CH3:13][O:8][CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC[C@H]1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (9.8 g, 74.2 mmol) in anhydrous THF (150 mL) at 0° C. was added sodium hydride (60% in mineral oil) (3.26 g, 82 mmol) in 4 portions over 5 min (caution: gas evolution). The reaction was stirred for an additional 15 min at 0° C., then iodomethane (5.09 mL, 82 mmol) was added and the reaction was warmed to rt. After approximately 1 h at rt, the reaction was diluted with diethyl ether (100 mL), filtered and concentrated to 15-20 mL under vacuum. The yellow liquid was used in the next step without purification.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:8]=[C:7]([CH3:9])[S:6][C:5]=1[C:10]([O:12][CH3:13])=[O:11]>C(O)(=O)C>[Br:1][C:8]1[C:4]([OH:3])=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=1[CH3:9]
Reactant: COC(=O)c1sc(C)cc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1sc(C)c(Br)c1O
Temperature: 0 °C
Yield: 56.3 %

Procedure:
Bromine (4.6 g, 29 mmoles) is added dropwise at room temperature to a stirred solution of methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (5.0 g, 29 mmoles) in acetic acid (25 mL). After 16 hours the mixture is stirred into ice water (200 mL), and the precipitate is filtered off, rinsed with water, with aqueous sodium thiosulfate, again with water and dried. Recrystallization from methyl t-butyl ether gave the pure product (4.1 g); mp 96°-97° C.
Reaction SMILES: C([O-])(=O)C.[CH3:5][P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8].P(=O)([O-])[O-].C([Li])CCC.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][C:27](OC)=[O:28]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:28]=[C:27]([CH2:26][C:22]1[S:21][CH:25]=[CH:24][CH:23]=1)[CH2:5][P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)Cc1cccs1
Agent: CC(=O)[O-]
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)Cc1cccs1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 37.2 g (0.3 -thienyl)acetate mole) dimethyl methylphosphonate (Aldrich) in 400 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 194 ml of 1.6 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 23.4 g (0.15 mole) methyl 2-(2 -thienyl)acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water the aqueous phase extracted with 100 ml portions of chloroform (3a) the combined organic extracts were backwashed (50 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150-52° (<0.5 mm) to give 4.8 g dimethyl 2-oxo-3-(2-thienyl)propylphosphonate (2a).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[C:27]1([CH:33]([N:37]2[CH2:42][CH2:41][S:40][CH2:39][CH2:38]2)[C:34]([OH:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[C:27]1([CH:33]([N:37]2[CH2:38][CH2:39][S:40][CH2:41][CH2:42]2)[C:34]([O:36][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)C(c1ccccc1)N1CCSCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCSCC1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
PS-DCC (loading: 1.25 mmol/g; 0.73 g, 0.91 mmol) was suspended in dry THF (9 ml). HOBT (0.14 g, 0.91 mmol), 2-phenyl-2-thiomorpholinoacetic acid hydrochloride (0.12 g, 0.46 mmol) and (R)-quinuclidin-3-ol (0.17 g, 1.37 mmol) were sequentially added. The mixture was shaken overnight. PS-DCC was filtered off and washed with EtOAc and THF. The solution was evaporated and the residue was portioned between EtOAc and water. The organic phase was washed with sat. NaHCO3, dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 85/15) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-thiomorpholinoacetate (70 mg, 44.2% yield) as a colorless oil.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:21]([O:23][C:24](=[O:36])[CH2:25][NH:26][S:27]([C:30]1[S:31][C:32](Br)=[CH:33][CH:34]=1)(=[O:29])=[O:28])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl>[CH2:21]([O:23][C:24](=[O:36])[CH2:25][NH:26][S:27]([C:30]1[S:31][C:32]([C:19]#[C:18][C:16]2[CH:15]=[N:14][C:12]3[N:13]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[N:9]=[C:10]([OH:20])[C:11]=3[CH:17]=2)=[CH:33][CH:34]=1)(=[O:29])=[O:28])[CH3:22]
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)s1
Yield: 93.2 %

Procedure:
A mixture of 436 mg (1.27 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 415 mg of N-(5-bromothien-2-ylsulfonyl)glycine ethyl ester, 20 mg of palladium chloride, 54 mg of triphenylphosphine, 10 mg of cuprous iodide, and 0.4 mL of triethylamine in 7 mL of acetonitrile was heated to reflux under nitrogen for 1 hour. The resulting reaction mixture was then concentrated in vacuo and the residue flash chromatographed with 4% CH3 OH/chloroform to give 610 mg of N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)thien-2-ylsulfonyl]glycine ethyl ester as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ1.13 (t, J=7 Hz, 3H), 1.25, (s, 9H), 3.79 (d, J=5.8 Hz, 2H), 3.99 (q, J=7 Hz, 2H), 7.48 (d, J=3.6 Hz, 1H), 7.56 (d, J=3.6 Hz, 1H), 8.51 (s, 1H), 8.65 (t, J=5.8 Hz, 1H), 8.99 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([C:26](OCC)=[O:27])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:26]([OH:27])[C:13]1=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(C(=O)OCC)cc2cc(OCc3ccccc3)ccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)c2cc3cc(OCc4ccccc4)ccc3n2CC1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of ethyl 5-(benzyloxy)-1-(4-ethoxy-4-oxobutyl)-1H-indole-2-carboxylate (1 g, 2.442 mmol) in THF was added a 1 M solution of KOtBu in THF (3.17 mL, 3.17 mmol) at 0° C. The reaction mixture was stirred at that temperature for 2 h, poured into 1 N HCl aqueous solution, extracted with ethyl acetate. The combined organics were washed with water, dried over Na2SO4, and concentrated to give the title compound (850 mg) without further purification. LCMS m/z=364.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[CH:8]=2)[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:25]([O:27]C)Cl.O>C(Cl)Cl.[N+](C)([O-])=O>[C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[CH:25]=[O:27])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc3ccc4cnccc4c3[nH]2)cc1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline XIXA (2.75 mmol) in DCM (13 mL) and nitromethane (13 mL), cooled to 0° C., aluminum chloride (8.25 mmol) and dichloromethylmethylether (5.5 mmol) were added dropwise. The mixture was kept at 4° C. overnight and poured dropwise into stirred ice-cooled water. The solid product was filtered and the layers were separated. The aqueous layer was extracted with DCM and AcOEt. The combined organic layers, washed with water, dried (Na2SO4) and concentrated, were joined to the previously described solid affording the title compound in 51% yield. ESI (+) MS: m/z 273 (MH+). 1H NMR: 7.66-7.71 (m, 3H), 7.91-7.96 (m, 2H), 8.19 (d, J=8.79, 1H), 8.71 (d, J=8.55, 1H), 8.79 (d, J=6.35, 1H), 8.93 (d, J=6.35, 1H), 9.77 (s, 1H), 10.12 (s, 1H), 13.80 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]3[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]3[CH2:40][CH2:41]3)=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (193 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (342 mg, 88%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([CH:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1)[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:9]([CH:11]1[CH2:16][CH2:15][CH:14]([O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=2)[CH2:13][CH2:12]1)[CH3:10]
Reactant: Oc1cccc(O)c1
Reactant: CCC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC1CCC(Oc2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27 %

Procedure:
In a four necked flask (2 L) sufficiently dried, substituted with nitrogen, and equipped with a dropping funnel, Dimroth condenser tube, thermometer and stirring blade, resorcinol (72 g, 0.65 mol), 4-ethylcyclohexanol (92 g, 0.72 mol) and triphenylphosphine (185 g, 0.70 mol) were dissolved in dried tetrahydrofuran (700 ml) under a nitrogen gas stream, and a mixed solution of diisopropyl azodicarboxylate (132 g, 0.65 mol) and dried tetrahydrofuran (180 ml) was dropped for 1 hour while cooling with an iced saline solution. Next, it was stirred at room temperature for 12 hours. After the reaction terminated, 30% hydrogen peroxide (140 ml) was dropped through the dropping funnel for 10 minutes, then the reaction solution was dissolved in 1 L toluene, and washed three times with 500 ml water. Toluene was distilled away by evaporation, and the residue was purified by column chromatography using hexane and ethyl acetate as developing solvents, to obtain a red brown objective product (hereinafter, referred to as R-3A) (38.5 g, 27% yield, 99% GC purity).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].CN(C)C(N(C)C)=N.Cl>C(#N)C.O>[CH2:18]([O:17][C:15]([C:3]1([CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])[CH2:4][CH2:5][N:6]2[C:14]3[C:9]([CH:8]=[C:7]2[C:2]1=[O:1])=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Reactant: C=CC(=O)OC
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(CCC(=O)OC)CCn2c(cc3ccccc32)C1=O
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 5 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate. 1.85 g of methyl acrylate and 250 mg of 1,1,3,3-tetramethylguanidine was dissolved in 250 ml of acetonitrile and the solution was stirred overnight, poured into 500 ml of water containing 20 ml of 2M hydrochloric acid and extracted with diethyl ether. The ethereal extracts were washed with water, dried and concentrated. There were obtained 6.33 g of methyl 8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-propionate.