Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]#[N:15].[CH2:16]([NH:18][C:19]1[C:24]([CH:25]=O)=[CH:23][N:22]=[C:21]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:20]=1)[CH3:17].O>C(OCCO)C>[CH2:16]([N:18]1[C:19]2[N:20]=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:22]=[CH:23][C:24]=2[CH:25]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[C:14]1=[NH:15])[CH3:17]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: CCn1c(=N)c(-c2ccc3ccccc3c2)cc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of 2-ethoxyethanol was added 2-naphthyl-acetonitrile (227 mg, 1.36 mmol). After stirring for 5 minutes at room temperature, 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.24 mmol) was added and the reaction heated at 110° C. for 1 hour, resulting in a dark brown solution. Upon cooling, the solution was poured into 30 mL of water which caused precipitation. The resulting precipitate was removed by filtration and washed with water. The crude product was purified by flash chromatography, eluting with 5% methanol/methylene chloride, followed by 10% methanol/methylene chloride. Concentration of product fractions yielded 400 mg (82%) of yellow solid, (8-ethyl-7-imino-6-naphthalen-2-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine; mp 236°-242° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9][N:8]3[CH:7]=1)=O.[Br:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH2:31][C:32]([NH2:34])=[O:33])=[CH:27][NH:28]2)=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH:31]3[CH:4]([C:6]4[C:16]5=[C:17]6[C:12](=[CH:13][CH:14]=[CH:15]5)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9][N:8]6[CH:7]=4)[C:3](=[O:2])[NH:34][C:32]3=[O:33])=[CH:27][NH:28]2)=[CH:24][CH:23]=1
Reactant: NC(=O)Cc1c[nH]c2cc(Br)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(CO)C2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)C1c1c[nH]c2cc(Br)ccc12

Procedure:
Beginning with (5-(hydroxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]oxoacetic acid methyl ester and (6-bromo-1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [N:1]1([C:7](=[S:11])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:12](OC(OCC)OCC)C.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:22]1([CH:12]=[C:8]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[S:11])[C:9]#[N:10])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: CCOC(OCC)OCC
Reactant: N#CCC(=S)N1CCOCC1
Product: N#CC(=CN1CCOCC1)C(=S)N1CCOCC1
Yield: 82.4 %

Procedure:
To a solution of 3-morpholin-4-yl-3-thioxopropanenitrile (0.1 g, 0.59 mmol) in triethylorthoformate (0.245 mL, 1.48 mmol) was added morpholine (0.064 mL, 0.73 mmol). The reaction mixture was subjected to microwave irradiation at 150° C. for 10 min. The reaction mixture was concentrated to small volume until the product precipitated. The precipitate was filtered off, washed with MeOH and hexane to give the title compound (0.13 g, 83%). LCMS: (AA) ES+ 268.2. 1H NMR (400 MHz, d6-DMSO) δ: 3.96 (m, 4H) and 3.67-3.78 (m, 12H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)#[CH:18]>>[F:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(F)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3cccc(F)c3)c2c2ccccc12
Yield: 71 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-ethynyl-3-fluoro-benzene (78 mg, 0.65 mmol) to provide 166 (96 mg, 70% yield) as a white solid. LC-MS (M+H=315, obsd.=315).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:35]([O:38][C:39](Cl)=[O:40])([CH3:37])[CH3:36]>C(Cl)Cl>[CH:35]([O:38][C:39](=[O:40])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:26][CH2:27][CH2:28]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=3)=[CH:4][CH:3]=1)([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)Cl
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(N3CCOCC3)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(N4CCOCC4)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
A solution of 2-(4-amino-phenyl)-1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (0.112 g, 0.3 mmol), pyridine (1.0 mL) in CH2Cl2 (2.0 mL) was treated with isopropylchloroformate (1.0 M in toluene, 0.6 mL, 0.6 mmol). The mixture was stirred at room temperature for 5 h and diluted with CH2Cl2 (5 mL). The organic layer was separated, washed with HCl (1.0 N, 3×2 mL), water (5 mL×2) and brine (5 mL), and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide [4-(3-cyano-1-cyclobutyl-6-morpholin-4-yl-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (0.12 g, 87%).
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[CH3:13][O:14][C:15]1[CH:16]=[C:17](C=[CH:27][C:28]=1[O:29][CH3:30])[CH2:18][CH:19]1[CH2:23][CH2:22][CH:21](OC)[O:20]1>C(Cl)Cl>[C:1]1([S:7]([CH:21]2[CH2:22][CH2:23][CH:19]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[C:28]([O:29][CH3:30])[CH:27]=3)[O:20]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O)c1ccccc1
Reactant: COc1ccc(CC2CCC(OC)O2)cc1OC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C2CCC(S(=O)(=O)c3ccccc3)O2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a solution of benzenesulphinic acid (8.68 g, 0.061 M) in DCM (120 ml) containing a suspension of CaCl2 (1.0 g) at room temperature was added a solution of 2-(3,4,dimethoxybenzyl)-5-methoxytetrahydrofuran (7.0 g, 0.029 M) in CH2Cl2 (80 ml). The mixture was stirred at room temperature for 4 h, quenched by washing with water (2×50 ml), dried (Na2SO4) and evaporated. Column chromatography (flash silica gel, hexane:ethyl acetate (3:2)) provided the product (Rf 0.3) as a clear oil which was crystallised from ethyl acetate/hexane to give 2-benzenesulphonyl-5-(3,4-dimethoxyphenyl)tetrahydrofuran (3.5 g, 35%).
Reaction SMILES: C1(S(O[C@H:11]2[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)(=O)=O)C=CC=CC=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)P(N(C)C)(N(C)C)=O.O>[N:19]([C@@H:11]1[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: COC(=O)[C@H]1C[C@H](OS(=O)(=O)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 105 °C
Reaction time: 2.75 h

Procedure:
A solution of trans 3-carbomethoxycyclobutyl benzenesulfonate* (6.1 g, 22.6 mmol) in hexamethylphosphoramide (35 ml) was treated with sodium azide (289 g, 44.5 mmol) and stirred at 105° C. for 2.75 h. The reaction mixture was cooled to 23° C., diluted with water (350 ml) and extracted with ether (4×125 ml). The organic extracts were combined, washed with water (2×15 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to a slightly yellow liquid which was distilled under high vacuum; bp 66°-7° C. (0.6 mm); 2.8 g; 80%; ir (neat) νmax : 2100 (N3) and 1735 cm-1 (C=O); Hmr (CDCl3) δ: 40.34 (m, H-1), 3.7 (s, methyl) and 2.9-2.1 ppm (5H, 2H-2, H-3 and 2H-4).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[CH:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:32](I)[CH2:33][CH2:34][CH2:35][CH3:36]>[Ag]=O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:27]([F:30])([F:28])[F:29])=[CH:20][N:19]=3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCI
Reactant: CCCCCc1ccc(-c2ccc(-c3ncc(OCC(O)C(F)(F)F)cn3)cc2)cc1
Agent: O=[Ag]
Product: CCCCCOC(COc1cnc(-c2ccc(-c3ccc(CCCCC)cc3)cc2)nc1)C(F)(F)F
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 2-(4'-pentylbiphenyl-4-yl)-5-(2-hydroxy-3,3,3-trifluoropropoxy)-pyrimidine (60 mg), pentyl iodide (30 mg) and silver oxide (40 mg) was stirred overnight, followed by filtering off insoluble substance, concentrating the mother liquid and recrystallizing from ethanol to obtain 2-(4'-pentylbiphenyl-4-yl)-5-(2-pentyloxy-3,3,3-trifluoropropoxy)-pyrimidine (30 mg).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C:15]([CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][NH2:31]>>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH:15]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:16][NH:31][O:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: C=C(CC1CCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1
Product: O=C1OCC(Cc2ccccc2)N1C(=O)C(CNOC1CCCCO1)CC1CCCC1
Temperature: 45 °C
Reaction time: 48 h
Yield: 68.8 %

Procedure:
4-Benzyl-3-(2-cyclopentylmethyl-acryloyl)-oxazolidin-2-one (22.90 g, 73.1 mmol) and O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (34.24 g, 292.3 mmol) is combined at stirred at 45° C. for 48 hours under nitrogen. The crude product is purified by flash chromatography (SiO2, 0→30% EtOAc in hexane), which gives 4-benzyl-3-[2-cyclopentylmethyl-3-(tetrahydro-pyran-2-yloxyamino)-propionyl]-oxazolidin-2-one (21.65 g, 69% yield) as an oil.
Reaction SMILES: C([O:9][C:10]1[CH:70]=[CH:69][C:13]([C:14]([O:16][C@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:36]C(=O)C4C=CC=CC=4)=[CH:23][C:24]=3[O:27]C(=O)C3C=CC=CC=3)[O:19][C@@H:18]2[C:45]2[CH:50]=[CH:49][C:48]([O:51]C(=O)C3C=CC=CC=3)=[C:47]([O:60]C(=O)C3C=CC=CC=3)[CH:46]=2)=[O:15])=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.C1COCC1.CO>[OH-].[OH-].[Pd+2].CO.C(Cl)Cl>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([OH:36])=[CH:23][C:24]=3[OH:27])[O:19][C@@H:18]2[C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([OH:60])[CH:46]=2)=[O:15])=[CH:69][CH:70]=1
Reactant: O=C(Oc1ccc(C(=O)O[C@H]2Cc3c(OC(=O)c4ccccc4)cc(OC(=O)c4ccccc4)cc3O[C@@H]2c2ccc(OC(=O)c3ccccc3)c(OC(=O)c3ccccc3)c2)cc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C(O[C@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1ccc(O)c(O)c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
Under an H2 atmosphere, Pd(OH)2/C (20%, 100 mg) was added to a solution of 102 (200 mg, 0.23 mmol) in a solvent mixture of THF/MeOH (1:1 v/v, 20 mL). The resulting reaction mixture was stirred at r.t. under H2 for 6 h, TLC showed that the reaction was completed. The reaction mixture was filtered to remove the catalyst. The filtrate was evaporated, and the residue was rapidly purified by flash chromatograph on silica gel (10% MeOH/CH2Cl2, then 20% MeOH/CH2Cl2) to afford 11 (82 mg, 87% yield): mp 220-222° C. (decomposed); [α]D=+87.2 (c=2.0, EtOH); 1H NMR (acetone-d6, 400 MHz): δ 7.98 (d, J=8.8 Hz, 2H), 7.13 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.99-6.96 (m, 2H), 6.27 (d, J=2.2 Hz, 1H), 6.19 (d, J=2.2 Hz, 1H), 5.62 (dd, J=11.8, 6.3 Hz, 1H), 5.34 (d, J=6.3 Hz), 3.15 (A of ABq, J=16.5, 5.2 Hz, 1H), 3.00 (B of ABq, J=16.5, 6.4 Hz, 1H); 13C NMR (acetone-d6, 400 MHz): δ 163.3, 160.0, 155.2, 154.5, 153.6, 143.1, 129.9, 128.7, 119.6, 116.6, 113.4, 113.3, 111.8, 111.7, 96.7, 93.8, 93.0, 76.2, 67.9, 21.9; HRMS (ESI) calcd for O22H18O8Na (M+Na) 433.0899. found 433.0909.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.[C:14]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][N:39]=2)[C:33]([O:35][CH3:36])=[O:34])[CH:19]=[CH:20][C:21]=1OS(C(F)(F)F)(=O)=O)#[N:15].[CH:40]([Si:43]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[N:44]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45]1)([CH3:42])[CH3:41]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:14]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][N:39]=2)[C:33]([O:35][CH3:36])=[O:34])[CH:19]=[CH:20][C:21]=1[C:46]1[CH:47]=[CH:48][N:44]([Si:43]([CH:52]([CH3:54])[CH3:53])([CH:55]([CH3:57])[CH3:56])[CH:40]([CH3:41])[CH3:42])[CH:45]=1)#[N:15]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: COC(=O)c1ccnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(C#N)c2)c1
Temperature: 130 °C
Yield: 5.2 %

Procedure:
58 mg of tetrakis(triphenylphosphine)palladium and 208 mg of potassium carbonate were added to a toluene (10 ml) solution of 386 mg of methyl 2-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)isonicotinate and 534 mg of 1-(triisopropylsilyl)pyrrole-3-boronic acid, then this was irradiated with microwaves and heated at 130° C. in a nitrogen atmosphere for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 70:30) to obtain 24 mg of methyl 2-{3-cyano-4-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]phenyl}isonicotinate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18](OCC)=[O:19])=[C:7]2[OH:23].Cl.[NH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])=[C:7]2[OH:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Temperature: 90 °C
Yield: 83.7 %

Procedure:
In a sealed flask was combined ethyl 8-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.8 g, 5.6 mmol), dioxane (75 mL), tert-butyl 2-aminoacetate hydrochloride (3.8 g, 22 mmol), and N-ethyl-N-isopropylpropan-2-amine (3.9 mL, 22 mmol). The flask was sealed and heated at 90° C. for 10 hours. After cooling to room temperature, the reaction was concentrated to give a solid that was purified by flash chromatography (20% EtOAc/hexane) to afford a white solid (1.9 g). MS m/e=406.1 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:35][CH:36](Cl)[CH3:37]>>[Cl:35][CH2:36][CH2:37][O:25][C:21]1[C:22]([I:24])=[CH:23][C:18]([O:17][C:13]2[C:14]([I:16])=[CH:15][C:10]([CH2:9][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:28])=[CH:11][C:12]=2[I:27])=[CH:19][C:20]=1[I:26]
Reactant: O=C(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC1CCCCC1
Reactant: CC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(Cc1cc(I)c(Oc2cc(I)c(OCCCl)c(I)c2)c(I)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 5 %

Procedure:
Compound 4 (2.0 g, 2.1 mmol, 1.0 eq.) was dissolved in anhydrous dichloroethane (30 mL) and then Cs2CO3 (1.7 g, 5.2 mmol, 2.5 eq.) was added. The reaction medium was then slowly heated to reflux. The mixture was stirred for 12 hrs. upon reflux then cooled to room temperature, filtered and the solvent was removed under vacuum. The residual oil then was purified by column chromatography (DCM/hexanes 80/20). The product was further recrystallized to give 2-(4-(4-(2-chloroethoxy)-3,5-diiodophenoxy)-3,5-diiodophenyl)-N-cyclohexylacetamide, compound 15, (94 mg, 0.1 mmol) as a powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)=[O:28])=[CH:23][CH:22]=1.[Li]CCCC.[ClH:40]>O1CCCC1>[Cl:40][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)[OH:28])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Reactant: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2ncc(-c3ccccc3)c(Cl)c2c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
In a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 6-bromo-4-chloro-3-phenylquinoline (460 mg, 1.44 mmol, Intermediate 3, step c), (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (266 mg, 1.21 mmol, Intermediate 18, step b) in tetrahydrofuran (20 mL). This solution was cooled to −78° C., followed by the addition of n-BuLi (0.624 mL, 1.56 mmol, 2.5M in hexane) dropwise. The mixture was gradually warmed to room temperature. After 4 hours stirring, 1.0 M HCl was added until pH 6-7. After removal of solvent under vacuum, the residue was purified by flash column chromatography (silica gel column, 100:0˜15:1 EtOAc/petroleum ether) to give the title compound as a white solid. 1H NMR (300 MHz, MeOH-d4) δ=8.83 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.88 (dd, J=1.9, 8.9 Hz, 1H), 7.75 (s, 1H), 7.46-7.62 (m, 5H), 7.41 (s, 4H), 6.35 (s, 1H), 3.51 (s, 3H); MS m/e 460 [M+H]+.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][CH2:26][C:27](=[S:29])[NH2:28])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO.CCOC(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([O:25][CH2:26][C:27]2[S:29][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=3)[N:28]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(CBr)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(N)=S)CC1
Agent: Br
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2nc(-c3ccncc3)cs2)CC1

Procedure:
A solution of 2-bromo-1-pyridin-4-yl-ethanone hydrobromide (35 mg, 1241 mol) and 4-thiocarbamoylmethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 18, 34 mg, 124 μmol) in methanol (2 ml) was heated at 60° C. for 1.5 h. The reaction mixture was diluted with EtOAc (60 ml), washed with saturated aqueous NaHCO3 (15 ml) and brine (15 ml) then dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (EtOAc) to afford the title compound: RT=2.95 ml, m/z (ES+)=376.1 [M+H]+.
Reaction SMILES: [CH2:1]([Mg:5]C(CC)C)CCC.[CH3:10][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13].[CH3:17][CH2:18][C:19]([O-])([CH3:21])[CH3:20].[K+]>CCCCCCC.C1CCCCC1>[CH3:10][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:12][O:13][CH2:20][CH:19]([CH3:21])[CH2:18][CH2:17][CH3:1].[Mg:5]
Reactant: CCC(C)(C)[O-]
Reactant: CCCC(C)CO
Reactant: CCCC[Mg]C(C)CC
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CCCCCCC
Product: CCCC(C)COCC(C)CCC
Product: [Mg]

Procedure:
To a volume of 10 ml of 1.156 Molar n-butyl-sec-butyl-magnesium (11.56 mmoles) there is added 1.43 ml (11.56 mmoles) of 2-methyl-1-pentanol, diluted to 5 ml with heptane. Then, 0.6 ml of 0.99 Molar (0.59 mmoles) of potassium tert-amylate in cyclohexane solution is added, followed by an additional 1.43 ml of 2-methyl-1-pentanol (11.56 mmoles). A pale yellow, clear, slightly viscous solution of magnesium 2-methyl-1-pentyloxide is obtained. No excess of 2-methyl-1-pentanol is added as in comparative Example I(a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[C:25]1([CH3:31])C=CC=C[CH:26]=1.ClC(Cl)([O:35][C:36](=O)[O:37]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)CC.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36](=[O:35])[O:37][CH2:26][CH2:25][CH3:31])=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCO
Product: CCCOC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 83 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-propanol (28 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (115 mg, yield 83%).
Reaction SMILES: [H][H].O.[C:4]([NH:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]([N+:17]([O-])=O)[C:11]([O:15][CH3:16])=[C:12]([Cl:14])[CH:13]=1)(=[O:6])[CH3:5]>[Fe].C(O)(=O)C>[C:4]([NH:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]([NH2:17])[C:11]([O:15][CH3:16])=[C:12]([Cl:14])[CH:13]=1)(=[O:6])[CH3:5]
Reactant: COc1c(Cl)cc(NC(C)=O)c(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)cc(NC(C)=O)c(OC)c1N
Temperature: 80 °C

Procedure:
253 g of powdered iron which had been reduced with hydrogen were added to 760 ml of water containing 13 ml of acetic acid and which had been previously heated to 80° C., and then 0.46 mole (126.5 g) of 5-acetamido-2,4-dimethoxy-3-nitrochlorobenzene prepared in the previous step was added gradually, with stirring. Upon completion of the additions, the reaction mixture was maintained in a boiling water bath for 15 minutes. After cooling, the reaction mixture was centrifuged. The iron slurries after being separated from the liquid phase were extracted with ethyl acetate. The ethyl acetate phase which was washed with water and then dried over sodium sulphate was diluted with 100 ml of a 7N hydrochloric acid solution in absolute ethanol. The expected product, which precipitated n the form of hydrochloride, was thoroughly drained. It was dissolved in the minimum amount of water. After neutralization, the expected product precipitated. Recrystallized from alcohol, it melted at 113° C.