Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)#[CH:21]>O1CCOCC1.[Cu]I.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>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cnc(OCc2ccccc2)cc1I
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: COCOc1cnc(OCc2ccccc2)cc1C#Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (3.0 g, 8.08 mmol), copper (I) iodide (92 mg, 0.485 mmol), PdCl2(PPh3)2 (284 mg, 0.404 mmol), 1-ethynyl-4-fluorobenzene (1.07 g, 8.89 mmol) were combined in dioxane (40 mL) and TEA (40 mL), degassed and stirred at 80° C. for 1.5 hrs. The mixture was diluted with EtOAc and washed with sat NaCl and H2O. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(benzyloxy)-4-((4-fluorophenyl)ethynyl)-5-(methoxymethoxy)pyridine (2.52 g, 6.93 mmol, 86% yield) consistent by LCMS. LC-MS retention time: 2.71 min; m/z (MH+): 364. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9]N.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C(=O)([O-])O.[Na+]>C(O)C.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.ClCCl>[CH2:17]([O:16][C:11]([C:12]1[NH:9][C:3]2[C:4]([CH:14]=1)=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])=[O:15])[CH3:18]
Reactant: NNc1ccc(F)cc1Br
Reactant: CCOC(=O)C(C)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc2cc(F)cc(Br)c2[nH]1
Temperature: 0 °C
Reaction time: 15 h
Yield: 50.8 %

Procedure:
2-Bromo-4-fluoro-phenylhydrazine (20 g, 0.097 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (11.3 ml, 0.101 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield 24.4 g, 82%. The hydrazone mixture (22 g, 0.073 mol) was dissolved in Eaton's reagent (230 ml) and the mixture heated 3 h at 50° C. The mixture was cooled to room temperature, diluted with dichloromethane and added to saturated aqueous sodium hydrogen carbonate. The phases were separated and the aqueous phase extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated. The residue was taken up in diethyl ether, and hexane added whereupon part of the product precipitated. This was filtered and the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant) to afford the product as a light yellow solid (14.1 g, 68%). Mp: 125° C., EI MS: 285.0 (M+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH2:21][C:17]4([CH2:20][CH2:19][CH2:18]4)[O:16][N:15]=3)[CH:11]=[C:10]([C:22](O)=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[N:26]1[N:27]=[C:28]([C@@H:31]([NH2:33])[CH3:32])[NH:29][CH:30]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH2:21][C:17]4([CH2:20][CH2:19][CH2:18]4)[O:16][N:15]=3)[CH:11]=[C:10]([C:22]([NH:33][C@H:31]([C:28]3[NH:29][CH:30]=[N:26][N:27]=3)[CH3:32])=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1nnc[nH]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C3=NOC4(CCC4)C3)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)c3nnc[nH]3)cc(C3=NOC4(CCC4)C3)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 4′-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)biphenyl-3-carboxylic acid (0.15 g, 0.47 mmol) in N,N-dimethylformamide (3 mL) were added (1S)-1-(4H-1,2,4-triazol-3-yl)ethanamine hydrochloride salt (0.12 g, 0.65 mmol), EDC (0.13 g, 0.70 mmol), HOAT (0.06 g, 0.47 mmol) and triethylamine (0.39 mL, 2.80 mmol). The reaction mixture was heated to 50° C. After 1 h, the mixture was cooled to ambient temperature. Saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (188 mg). The title compound was dissolved in dichloromethane and HCl (2.0 M in ether) was added. The mixture was concentrated gave the hydrochloride salt of the title compound. HRMS 416.2083 (M+1). 1H NMR (400 MHz, CD3OD): δ 9.35 (s, 1H); 8.16 (t, J=1.7 Hz, 1H); 8.11 (t, J=1.6 Hz, 1H); 8.03 (t, J=1.7 Hz, 1H); 7.56 (d, J=7.9 Hz, 2H); 7.26 (d, J=7.8 Hz, 2H); 5.54-5.44 (m, 1H); 3.69-3.45 (m, 2H); 2.52-2.42 (m, 2H); 2.35 (s, 3H); 2.30-2.22 (m, 2H); 1.77 (d, J=7.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH2:18]([O:20][C:21](=[O:29])[CH:22](Br)[C:23](OCC)=[O:24])[CH3:19].Cl>C(O)C.O>[CH2:18]([O:20][C:21]([C:22]1[C:23](=[O:24])[NH:1][C:2]2[C:3](=[CH:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[N:4]=1)=[O:29])[CH3:19]
Reactant: COc1ccc(N)c(N)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
2-Amino-4-methoxy aniline (5.0 g, 36.2 mmol) was dissolved in 50 mL of ethanol and triethylamine (5.08 mL, 69.1 mmol) added. The mixture was cooled to 0° C. and diethylbromomalonate (8.02 mL, 47.0 mmol) in 8 mL of ethanol was added dropwise over 30 minutes. Mixture is stirred at 0° C. for 30 minutes and 16 h at room temperature. The resulting solid was isolated and stirred in 200 mL water and 50 mL 1N HCl for 1 h. The solid was filtered, suspended in toluene and evaporated to dryness to give the 6-methoxy-3-oxo-3,4-dihydro-quinoxaline-2-carboxylic acid ethyl ester as a solid (5.2 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.[CH2:10](O)[CH3:11]>S(=O)(=O)(O)O>[OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(O)CC1(CO)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g 2-[1-(hydroxymethyl)cyclopropyl]acetic acid (compound (13) was dissolved in 120 ml ethanol followed by addition of 6 drops of conc. sulfuric acid. The mixture was stirred at room temperature overnight. The mixture was concentrated partly to remove ˜40 ml ethanol and further stirred at room temperature (“rt”) for another day. The mixture was neutralized to pH˜7 (using ˜3 ml aq. saturated NaHCO3) and concentrated in vacuo. After re-dissolving in ethylacetate (200 ml), it was washed with brine (15 ml), dried and concentrated in vacuo to give a light-yellow oil (6.85 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:48]([CH3:49])[CH3:50])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN(C)C)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCN(C)C)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-3-[1-(2-dimethylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-[2-[7-(4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl)-3,4-dihydro-2H-quinolin-1-yl]-ethyl]-dimethyl-amine as a yellow oil; MS: 588 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C@H:27]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[CH2:35]([O:34][C:32]([NH:31][C@@H:27]([CH2:26][NH:25][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:28]([OH:30])=[O:29])=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 27 %

Procedure:
To mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (200 mg, 0.63 mmol) and 3-amino-2-(S)-benzyloxycarbonylamino-propionic acid (745 mg, 3.12 mmol) (Bachem) in 2-methoxyethanol (10 mL) was added NaOMe solid (135 mg, 2.5 mmol). The resultant mixture was refluxed overnight. Reaction mixture was concentrated. Residue was dissolved in water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. It was purified by silica gel chromatography, eluting with 10-100% EtOAc (with 0.075% acetic acid)/CH2Cl2 (with 0.01% acetic acid) to provide the title compound 91 mg (0.17 mmol) in 28% yield. LC-MS ESI−: 525.05 (M−1)−.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:7]([O:14][CH2:15][CH2:16][O:17][CH:18]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:26][CH:25]=3)[CH2:22][CH2:21][N:20]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:19]2)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:71](OC(=O)C)(=[O:73])[CH3:72]>O1CCCC1>[C:71]([NH:1][CH2:4][CH2:5][C:6]1[C:7]([O:14][CH2:15][CH2:16][O:17][CH:18]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:26][CH:25]=3)[CH2:22][CH2:21][N:20]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:19]2)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])(=[O:73])[CH3:72]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.13 g of tert-butyl 3-{2-[5-(2-azidoethyl)-6-chloro-2-methylpyrimidin-4-yloxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 25 ml of tetrahydrofuran is admixed at room temperature successively with 3.1 ml of water, 0.54 g of triphenylphosphine and 0.74 ml of acetic anhydride. The reaction mixture is stirred at room temperature over 16 hours and subsequently concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (3:1 EtOAc-heptane); Rt=5.49.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7](=[O:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[O:4].Cl.O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:15]([O:14][C:12]([C:11]1[CH:10]=[C:9]([NH:8][C:7](=[O:21])[NH:6][CH2:5][C:3]([OH:4])=[O:2])[CH:20]=[CH:19][CH:18]=1)=[O:13])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)O)c1
Reaction time: 2.5 h
Yield: 70.3 %

Procedure:
To a solution of allyl 3-(methoxycarbonylmethylureido)benzoate (5.27 g, 18.7 mmol) in THF (27 ml) is added 2N hydrochloric acid (37.4 ml), and the mixture is refluxed with stirring for 2.5 hours. After allowing to cool, water and an aqueous saturated sodium bicarbonate solution are added to the reaction solution to adjust the pH of the aqueous layer to 8, which is then extracted with ethyl acetate. Concentrated hydrochloric acid is added to the aqueous layer to adjust the pH to 1, followed by extraction with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is crystallized from toluene to obtain the objective compound (3.66 g). Yield 70%.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([N:4]1[C:5]2[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=2)[C:2]([I:1])=[N:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
3-Iodo-4-nitro-1H-indazole (0.50 g; 1.73 mmol) was dissolved with stirring in dimethylformamide (15 mL) under an atmosphere of nitrogen. Potassium carbonate (0.478 g; 3.46 mmol) was added followed by benzyl bromide (0.325 g; 1.90 mmol). The mixture was stirred for 16 hours at 25° C. The mixture was added to water (50 mL) and ethyl acetate (50 mL) with stirring. The mixture was transferred to a reparatory funnel and the phases were separated. The ethyl acetate phase was dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography, eluting with hexane/ethyl acetate (5:1). The fractions containing product were concentrated under vacuum to give the 1-benzyl-3-iodo-4-nitro-1H-indazole as a yellow oil (456 mg).
Reaction SMILES: C(O[CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:5]([C:11](OCC)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:9]([O:8][C:6]([C:5]1[C:11](=[O:12])[N:18]2[C:17]([CH:22]=[CH:21][CH:20]=[CH:19]2)=[CH:16][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)C(Cc1ccccn1)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1ccc2ccccn2c1=O
Temperature: 250 °C
Yield: 86.5 %

Procedure:
A mixture of ethyl 3-ethoxy-2-ethoxycarbonyl-4-(2-pyridyl)butyrate (18.9 g), diphenyl (48.85 g) and diphenyl ether (135.8 g) was heated to 250° C. for 40 minutes. The reaction mixture was cooled to ambient temperature and chromatographed on silica gel (Merck 70-230 mesh, 620 g) eluting with hexane and then a mixture of ethanol and chloroform (1:49) to give a crude oil, which was crystallized from a mixture of ether and hexane (1:1) to give 3-ethoxycarbonyl-4H-quinolizin-4-one (11.48 g) as yellow crystal.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1.Cl>ClCCCl>[C:21]([CH2:20][CH2:19][C:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:9]3[C:17](=[CH:5][C:6]([C:21](=[O:22])[CH2:20][CH2:19][C:18]([OH:23])=[O:24])=[CH:7][CH:8]=3)[CH2:16][C:15]=2[CH:14]=1)=[O:24])([OH:23])=[O:22]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCC(=O)O)ccc1-2
Reaction time: 16 h

Procedure:
In a dry agon-purged round bottom flask, anhydrous AlCl3 (98 g, 0.735 mol) was suspended in anhydrous 1,2-dichloroethane (140 mL). In a separate flask, fluorene (23 g, 0.138 mol) was dissolved in anh. 1,2-dichloroethane (125 mL) then added to the AlCl3 suspension. The reaction flask was placed in a room temperature bath and succinic anhydride (34.5 g, 0.345 mol) was carefully added. The reaction was stirred for 16 hours and then very carefully quenched by slow addition to cold 3 M HCl (Caution! The reaction can react violently when HCl is added too rapidly.) The final well mixed suspension was acidic and not reactive to additional HCl solution. The organic solvent was removed at reduced pressure then the product was filtered and washed well with water. The crude product was dissolved in warm NaOH solution (approximately <1M NaOH), filtered and precipitated with the addition of concentrated HCl. The product was filtered, washed with water and then dried at reduced pressure in the presence of P2O5. The product was a pale yellow solid (49.3 g, 97%). 1H-NMR (CD3OD): δ (ppm) 8.3 (s, 2H, Ar); 8.2 (m, 2H, Ar); 8.1 (m, 2H, Ar); 4.1 (s, 2H, CH2); 3.5 (t, 4H, CH2); 2.8 (t, 4H, CH2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:6]([C:8]1[N:13]([CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:12](=[O:20])[NH:11][C:10](=[O:21])[C:9]=1[CH:22]([CH3:24])[CH3:23])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1.[I-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:6]([C:8]1[N:13]([CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:12](=[O:20])[N:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:10](=[O:21])[C:9]=1[CH:22]([CH3:24])[CH3:23])=[O:7])#[N:2]
Reactant: CC(=O)OCCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(=O)c(C(C)C)c(C(=O)c3cc(C)cc(C#N)c3)n(CCOC(C)=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
Acetic acid 2-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-ethyl ester (Compound 8) (126 mg, 0.328 mmol, 1.0 eq.) was dissolved in 1.5 mL of DMF. Potassium carbonate (45 mg, 1 eq.) was added and the reaction mixture was stirred at room temperature for 10 minutes. 1-Bromomethyl-4-methoxy-benzene (47 μL, 0.328 mmol, 1 eq.) and lithium iodide (44 mg, 1 eq.) were added. The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give a white powder (88 mg, 0.175 mmol, 53%). LC-MS shows 504.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([NH:10][S:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([OH:19])[C@@:15]2([CH3:23])[C:20](O)=[O:21])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[OH:19][C@@H:16]1[CH2:17][CH2:18][N:14]2[C@:15]1([CH3:23])[C:20](=[O:21])[N:10]([C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:24])[S:11]2(=[O:13])=[O:12]
Reactant: Cc1c(NS(=O)(=O)N2CC[C@@H](O)[C@@]2(C)C(=O)O)ccc(C#N)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: Cc1c(N2C(=O)[C@]3(C)[C@H](O)CCN3S2(=O)=O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a suspension of 3D (70 mg, 0.187 mmol) in 4 mL of acetonitrile at rt was added. DCC (39 mg, 0.187 mmol) followed by p-nitrophenol (53 mg, 0.374 mmol). The suspension was refluxed for 1 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 50:50) to afford the title compound (48 mg) as a yellow foam. 1H NMR (CD3OD) δ 1.59, 1.64 (s, 3H), 2.14-2.18 (m, 1H), 2.33-2.39 (m, 4H), 3.62-3.68 (m, 1H), 3.98-4.07 (m, 1H), 4.29, 4.31 (d, J=3.3, 1H), 7.45, 7.52 (d, J=8.3, 1H), 7.81, 7.82 (d, J=8.3, 1H); 13C NMR (CD3OD) δ 16.11, 16.25, 22.94, 23.24, 34.60, 50.21, 50.67, 77.10, 77.26, 82.46, 82.66, 116.44, 116.55, 129.95, 131.05, 133.22, 133.35, 136.32, 138.82, 140.34, 141.02, 169.27; HPLC a) column: Phenominex LUNA C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.90 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.75 min retention time (98%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% Isopropanol/Hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 6.96 min retention time (98%); MS (ES) m/z 356 [M+H]+.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@@H:13]3[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[NH2:1][C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@@H:13]3[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: OC[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Reactant: N
Agent: O=C=O
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO)C1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
Gaseous ammonia (from a lecture bottle) was bubbled into a suspension of cis-[3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (406.8 mg, 1.12 mmol) in dioxane (10 mL) and iPrOH (10 mL) in a Parr bomb, cooled by dry ice/acetone, for 5 min, then the vessel was sealed and heated to 90° C. overnight. LC/MS after 17 h indicated incomplete conversion. More ammonia was bubbled into the mixture, and heating to 90° C. was continued. After 1d, conversion was complete. The solvents were evaporated, water was added to the residue, and the pale yellow solid was filtered off and dried in vacuo to give the title compound as a pale yellow solid. The compound was used in the next step without further purification. The aqueous filtrate was extracted with CH2Cl2 (3×20 mL), the combined extracts were dried over MgSO4, filtered and concentrated to give a yellow oil that slowly solidified. Purification by HPLC gave analytically pure material. 1H NMR (CDCl3, 400 MHz): δ=2.40-2.57 (m, 4H), 2.57-2.66 (m, 2H), 3.73 (d, J=4.4 Hz, 2H), 5.03 (quint, J=8.4 Hz, 1H), 5.62 (brs, 2H), 7.21 (s, 1H), 8.26 (s, 1H). 13C NMR (DMSO-d6, 100.6 MHz, DEPT135): δ=29.96 (+), 32.70 (2C, −), 44.42 (+), 50.25 (Cquart), 64.16 (−), 102.98 (Cquart), 126.94 (+), 149.41 (Cquart), 151.72 (+), 157.13 (Cquart). MS (ES+): m/z 345.0 (100) [MH+]. HPLC: tR=1.7 min (OpenLynx, polar—5 min). C11H13lIN4O.2/3H2O: C: calc. 37.10, found 36.92; H: calc. 4.06, found 3.88; N: calc. 15.73, found 16.07.