Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7](=O)[CH2:6][CH:5]=[CH:4][C:3]1=2.[OH:16][C:17]1[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([OH:28])[C:18]=1[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([C:37](C)=[O:38])C>>[OH:16][C:17]1[CH:26]=[C:25]([O:27][CH2:35][C:37]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:38])[CH:24]=[C:23]([OH:28])[C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1c(O)cc(O)cc1O
Reactant: CC1(C)CCC(C)(C)C2=C1C=CCC2=O
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(O)cc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O

Procedure:
3.1 g (10 mmol) of 2-(2'-bromoaceto)-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthone, 1.8 g (10 mmol) of methyl 2,4,6-trihydroxybenzoate, 1.4 g (10 mmol) of potassium carbonate and 100 ml of methyl ethyl ketone are introduced into a flask. The mixture is heated under reflux for 1 hour and evaporated to dryness. The residue is taken up with water and dichloromethane, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (50:50). After evaporation of the solvents, 2.2 g (53%) of the expected product of melting point 169°-170° C. are collected.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[NH:35]1[CH2:40][CH2:39][CH:38]([CH2:41]CO)[CH2:37][CH2:36]1.C(=O)([O-])[O-:45].[K+].[K+].O>CN(C)C=O>[OH:45][CH2:41][CH:38]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([O:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=4[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:26])=[CH:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:33][CH3:34])[CH2:40][CH2:39]1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Reactant: OCCC1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCN1CCC(CO)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), 4-piperidine ethanol (45 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (32 mg, yield 41%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8](#[N:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>ClCCl.C(N(CC)CC)C.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>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][C:8]#[N:14])[CH:3]=1
Reactant: C#CCCCC#N
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCCC#Cc1cccnc1
Yield: 79 %

Procedure:
Argon was passed through a solution of 45 ml of 3-bromopyridine and 49.61 g of 5-hexynenitrile in 500 ml of dichloromethane and 150 ml of dry triethylamine for 15 minutes and 3.0 g of bis(triphenylphosphine)palladium dichloride and 0.45 g of cuprous iodide were added. The reaction flask was evacuated and refilled with argon and was heated to reflux for 12 hours. The resulting mixture was diluted with 1 L of dichloromethane and washed with 2×300 ml of water, 1×300 ml brine, dried over potassium carbonate and concentrated. The residue was distilled to afford 62.82 g (79%) of 6-(3-pyridinyl)-5-hexynenitrile as a yellow oil, bp 140°-170° C./0.2 mm., suitable for use in the next step. A portion was purified by chromatography over silica gel eluting with 1:1 ethyl acetate-hexane containing 1% triethylamine and was redistilled to give an analytical sample of 6-(3-pyridinyl)-5-hexynenitrile.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([O:18][Si](C(C)C)(C(C)C)C(C)C)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][CH2:32][CH2:33]C[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:52]CC1.O>C1COCC1>[CH:32]([O:52][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][CH:5]=1)[CH2:1][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)([CH3:33])[CH3:31]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CCN(Cc1ccccc1)C2
Agent: [F-]
Solvent: O
Product: COc1cc2c(cc1O)CCN(Cc1cccc(OC(C)C)c1)C2

Procedure:
A solution of 2-benzyl-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline (1 mmol) in THF (20 mL) was stirred with a 1M solution of TBAF/THF (1.1 mmol) for 60 minutes at RT. After addition of water, the organics were extracted with ethyl acetate (80 mL) and the organic layer washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residual oil/solid was purified by flash chromatography (hexane/ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1.[C:22]1([CH:28]([N:35]=[C:36]=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:28]([NH:35][C:36]([N:19]1[CH2:18][CH2:17][N:16]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH3:9])[CH2:21][CH2:20]1)=[O:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CN1CCC(C(C)(c2ccccc2)N2CCNCC2)CC1
Solvent: ClCCl
Product: CN1CCC(C(C)(c2ccccc2)N2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 1-[1-(1-methylpiperidin-4-yl)-1-phenylethyl]piperazine 0.1 g (0.348 mmol) dissolved in methylene chloride (20 ml) was added diphenylmethyl isocyanate 0.073 g (0.348 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.15 g of desired product in 87% yield.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][Cl:43])[CH3:39].[CH:46]([N:49]([CH2:53][CH3:54])[CH:50](C)[CH3:51])(C)[CH3:47]>CN(C=O)C>[ClH:43].[ClH:43].[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][O:2][C:1](=[O:3])[CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:11]=1)[CH2:6][C:7]([O:9][CH2:47][CH2:46][N:49]([CH2:53][CH3:54])[CH2:50][CH3:51])=[O:8])[CH3:39]
Reactant: CCN(CC)CCCl
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OCCN(CC)CC)CC(=O)OCCN(CC)CC)c1
Product: Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.8 %

Procedure:
A mixture of 0.50 g (0.96 mmol) of N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine, 1.3 g (9.6 mmol) of 2-diethylaminoethyl chloride and 1.34 ml (7.7 mmol) of N,N-diisopropyl ethylamine in 15 ml of DMF was stirred at room temperature for 48 hours. The reaction mixture was concentrated on the oil pump and the residue was treated with NaHCO3 solution. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to an oil which was purified by chromatography on 25 g of 230-400 mesh silica gel using methylene chloride(90):methanol(10):concentrated ammonium hydroxide(0.1). The resultant pure free base (0.51 g) was convened to the dihydrochloride salt by treatment of a methylene chloride solution with 0.95 ml of 3N HCl in ethanol. After concentration, the product was dissolved in ether and stored at -18° until crystals formed. Filtration gave 0.28 g, mp 132°-135° of N-[3,5-bis(decyloxy)phenyl]-N-[ 2-[2-(diethylamino)ethoxy]-2-oxoethyl]glycine 2-(diethylamino)ethyl ester dihydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and 4-chlorobenzenesulfonyl chloride following the method described in Example 3, Step B with a reaction time of 96 h. MS 584 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25]#[N:26]>CC(=O)CC.O>[CH3:14][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[C:9]([O:13][CH2:24][C:25]#[N:26])[C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: N#CCCl
Reactant: Cc1ccc2c(Cl)cc(Cl)c(O)c2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc2c(Cl)cc(Cl)c(OCC#N)c2n1
Temperature: 25 °C

Procedure:
10.7 g of 5,7-dichloro-8-hydroxyquinaldine are dissolved at elevated temperature in 150 ml of 2-butanone; 10.4 g of potassium carbonate are then added portionwise, and the mixture is refluxed for one hour. After the addition of 1 g of potassium iodide, there are added dropwise, with stirring and refluxing, 7.1 g of chloroacetonitrile in 30 ml of 2-butanone, and the mixture is subsequently heated for 3 hours at an internal temperature of 75° C. To the resulting reaction mixture, after cooling to room temperature, is added 1 liter of water, and the whole is filtered; the residue is washed with water, dried, and recrystallised from chloroform/petroleum ether (40°-60° C.) to thus obtain 2-methyl-5,7-dichloro-8-(cyanomethoxy)-quinoline, m.p. 157°-158° C.
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.[NH2:33][CH:34]([CH3:44])[CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][OH:43])[CH:39]=[CH:40][CH:41]=1>>[OH:43][CH2:42][C:38]1[CH:37]=[C:36]([CH2:35][CH:34]([NH:33][C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][CH2:19][N:18]4[C:22](=[O:32])[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:25]=[C:17]34)[CH:13]=[CH:12][N:11]=2)[CH3:44])[CH:41]=[CH:40][CH:39]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Reactant: CC(N)Cc1cccc(CO)c1
Product: CC(Cc1cccc(CO)c1)Nc1nccc(N2CCCn3c2cc(-c2ccccc2)cc3=O)n1

Procedure:
Following the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl -1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.29 g, 0.83 mmol) was displaced with [3-(2-amino-propyl)-phenyl]-methanol (0.3 g, 1.66 mmol) to give the title compound as a light yellow solid. MS m/e 468 (M+H)+.
Reaction SMILES: [CH2:1](O)[CH3:2].[C:4]1([CH3:14])[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:4]1([CH3:14])[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:1][CH3:2])=[O:12])=[CH:8][CH:9]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cc1ccc(C)cc1
Yield: 94.7 %

Procedure:
Toluene (100 ml), ethanol (9.20 g, 199.77 mmol) and p-tolylacetic acid (25 g, 166.48 mmol) was added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (4.75 g, 24.97 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (4.21 g, 41.62 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl p-tolylacetate (28.09 g, 95%) was isolated in distillation.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([O:7][C:8]([NH:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([O:22]C)=[O:21])[NH:17]2)=[CH:13][CH:12]=1)=[O:9])([CH3:6])[CH3:5].C1COCC1.CO>O>[CH3:6][C:4]([O:7][C:8]([NH:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([OH:22])=[O:21])[NH:17]2)=[CH:13][CH:12]=1)=[O:9])([CH3:3])[CH3:5]
Reactant: COC(=O)c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
Lithium hydroxide (0.095 g, 3.96 mmol) was added to a solution of methyl 6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.115 g, 0.396 mmol) in a 3:1:1 mixture of THF:methanol:water (2 ml). The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was dissolved in water and acidified with 1N aqueous HCl. The resulting suspension was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and the solvent was evaporated to give the title compound (0.115 g, >99%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.18 (s, 1H), 9.21 (s, 1H), 7.70 (s, 1H), 7.37 (d, 1H), 6.93 (dd, 1H), 6.74 (s, 1H), 1.46 (s, 9H). MS: m/z 275 (M−1).
Reaction SMILES: O1CCCC1.[CH3:6][N:7]1[C@@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([C:19](=[O:36])[CH2:20][CH2:21][CH2:22][C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[C:8]1=[O:37].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56]>CN(P(N(C)C)(N(C)C)=O)C>[CH3:6][N:7]1[C@@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([C:19](=[O:36])[C@@H:20]([CH2:21][CH2:22][C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH:50]=[CH2:49])[C:8]1=[O:37]
Reactant: C=CCCCCCCBr
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Anhydrous tetrahydrofuran (10 ml) was added to (4S, 5R)-3,4-dimethyl-1-(5,5,6,6,7,7,8,8,8-nonafluoro-octanoyl)-5-phenylimidazolidin-2-one (1.20 g, 2.5 mmol) under nitrogen atmosphere, and the resulting mixture was cooled to −78° C. Lithium bis(trimethylsilyl)amide (2.75 ml, 1.0 M in tetrahydrofuran, 2.75 mmol) was added to the mixture, which was then stirred for 1 hour. After addition of 8-bromo-1-octene (714 mg, 3.0 mmol) and HMPA (1.25 ml) at −78° C., the reaction mixture was warmed with stirring up to −50° C. over 2 hours and up to 0° C. over 30 minutes, and then stirred for 12 hours at 0° C. The reaction mixture was quenched with saturated aqueous ammonium chloride at 0° C., and then extracted with a mixed solvent of ethyl acetate and n-hexane (3:7). The organic layer was washed sequentially with saturated aqueous potassium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure using an evaporator and the resulting residue was purified by silica gel column chromatography (Kanto Kagaku, silica gel 60 (spherical, neutral), 40-100 μm, eluent: ethyl acetate/n-hexane=1/5 3/7) to give (4S, 5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoyl]-5-phenylimidazolidin-2-one (1.37 g, Yield 93%).
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].C[N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=O.O.[NH2:19]N>C1COCC1>[CH:1]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[NH:7][N:19]=1)([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1n[nH]c(=O)c2ccccc12
Reaction time: 0.25 h

Procedure:
A solution of isopropylmagnesium bromide in THF (1M, 6.4 mL, 6.4 mmol) was added to a solution of 2-methylisoindoline-1,3-dione (0.793 g, 4.92 mmol) in THF (15 mL) at 0° C., stirred for 15 minutes, concentrated, dissolved in EtOH (12 mL) with a catalytic amount of concentrated HCl. Hydrazine hydrate (0.58 mL, 15 mmol) was added, and mixture was microwaved at 180° C. for 30 minutes, concentrated, and chromatographed on SiO2 (33% EtOAc/hexane) to give the title compound as a white solid (0.591 g, 3.14 mmol). 1H NMR (300 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.28 (dd, 1H), 8.06 (d, 1H), 7.94 (ddd, 1H), 7.85 (ddd, 1H), 3.57 (quin, 1H), 1.27 (d, 6H); LC/MS (APCI) M/Z 189.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].[CH3:14][C:15]1([OH:24])[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1>C1(C)C=CC=CC=1>[C:8]([O:24][C:15]1([CH3:14])[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(O)Cc2ccccc2C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1(C)Cc2ccccc2C1

Procedure:
With stirring and ice cooling, 111 g of triethylamine was added to a mixture of 120 g of methacrylic acid chloride, 200 g of 2-methyl-2-hydroxyindane, and 1500 g of toluene. The mixture was stirred at room temperature for 16 hours. By standard aqueous work-up and solvent distillation, a crude product was obtained. It was purified by column chromatography, yielding the target compound, 2-methylindan-2-yl methacrylate, designated Monomer 1.
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si](C(C)(C)C)(C)C)[C:22]=4[Cl:35])[CH3:20])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1>>[Cl:35][C:22]1[C:23]([OH:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C@H:19]([O:18][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:36]=[CH:37][C:2]([C:43]4[CH:42]=[CH:41][N:40]=[C:39]([CH3:38])[CH:44]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[S:13][C:12]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:20]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[C@H](C)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Product: COC(=O)c1sc(-n2cnc3cc(-c4ccnc(C)c4)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Yield: 37.9 %

Procedure:
Methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 8, 400 mg, 0.64 mmol) and (2-methyl-4-pyridinyl)boronic acid (105 mg, 0.77 mmol) were coupled using a procedure analogous to Intermediate 9 to give the title compound (126 mg, 38%). 1H NMR (400 MHz, d6-DMSO) δ 8.54 (s, 1H), 8.09 (s, 1H), 7.62-7.22 (m, 8H), 7.03 (dd, J=6.9, 2.5 Hz, 1H), 6.69 (s, 1H) 5.77 (q, J=6.4 Hz, 1H), 3.93 (s, 3H), 2.64 (s, 3H), 1.77 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].C(N(CC)CC)C.O>O1CCOCC1>[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([NH:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)CN
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.1 %

Procedure:
To a stirred solution of neopentylamine (0.86 g ml, 9.93 mmol) in dioxane (25 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol) and triethylamine (1.38 ml, 9.93 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization from ethyl acetate/hexane to yield 3-nitro-N-(2,2-dimethyl-propyl)-benzenesulfonamide (2.14 g, 87%) as a white solid. MS (ISP) 271.1 [(M−H)−]; mp 117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][C:21]([C:23](OC)=[O:24])=[CH:22][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:28][NH2:29]>CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][C:21]([C:23]([NH:28][NH2:29])=[O:24])=[CH:22][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1cccc(Cl)c1)c1ccncc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: NNC(=O)c1ccc2c(c1)nc(Nc1cccc(Cl)c1)c1ccncc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methyl 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylate (47 mg, 0129 mmol) was suspended in a mixture of methanol (1 ml) and hydrazine hydrate (1 ml). 3 drops of DMF were added and the mixture stirred at 60-70° C. for 2 hours. The volatiles were removed in vacuo. The resulting material was suspended in AcOEt/Hexanes, filtered and dried to afford 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carbohydrazide as solid (47 mg, 100% yield). LCMS (ES): 95% pure, m/z 364 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(O)=O.O.[CH:20]([NH2:22])=O>>[OH:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:20][NH:22][C:4]2=[O:5]
Reactant: NC=O
Reactant: COC(=O)c1cc(O)c(OC)cc1N
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2nc[nH]c(=O)c2cc1O
Temperature: 140 °C
Yield: 89 %

Procedure:
A mixture of methyl 2-amino-5-hydroxy-4-methoxybenzoate (3.1 g, 15.7 mmol) and AcOH (7.1 mL) in formamide (15.5 mL) was heated at 140° C. overnight. To it was added water (20 mL) and filtered to afford 6-hydroxy-7-methoxyquinazoline-4(3H)-one as a solid (2.7 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 7.1 (s, 1H), 3.9 (s, 3H).