Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[CH2:20]([O:23][CH2:24][CH2:25][NH2:26])[CH2:21][CH3:22].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:26][CH2:25][CH2:24][O:23][CH2:20][CH2:21][CH3:22])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CCCOCCN
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCNc1nc(NCCOCCC)nc2ccc([N+](=O)[O-])cc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
100 mg (0.38 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 1.5 ml of acetonitrile, and 124 mg (0.76 mmol) of 2-propoxyethylamine hydrochloride and 196 mg (1.94 mmol) of triethylamine were added thereto, followed by stirring at 80° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, washing brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 91 mg (72.3%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][OH:16])[C:3]#[C:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[BrH:17].C1(NC2CCCCC2)CCCCC1>ClCCCl.CCOC(C)=O.[Cu](Br)Br>[Br:17][C:4]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7](=[O:9])[O:8][C:3]=1[C@H:2]([OH:1])[CH2:15][OH:16]
Reactant: Br
Reactant: COC(=O)c1ccccc1C#C[C@H](O)CO
Agent: Br[Cu]Br
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=c1oc([C@H](O)CO)c(Br)c2ccccc12
Reaction time: 1.5 h
Yield: 309.3 %

Procedure:
A suspension of methyl 2-[(3S)-3,4-dihydroxy-1-butyn-1-yl]benzoate (500 mg, 2.270 mmol) in 1,2-Dichloroethane (DCE) (22 mL) was treated with dicyclohexylamine HBr (59.5 mg, 0.227 mmol) and then copper (II) bromide (1014 mg, 4.54 mmol) and stirred at 80° C. After 1.5 h, the reaction mixture was diluted with EtOAc, filtered through Celite and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-70%) to afford the title compound (200 mg, 0.702 mmol, 31% yield) as brown solid: Rt=0.46 min,
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[NH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:5]([NH:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][CH:12]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cccc(CN)n1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (1.29 ml) was added dropwise to a mixture of 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.10 g) in pyridine (21 ml). The solution was stirred for four hours at ambient temperature and evaporated in vacuo. The residue was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo to give 6-(acetylaminomethyl)-2-pyridinecarbonitrile (1.72 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].CI.[F:9][C:10]1[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=1[C:12]([C:14]1[N:15]([NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH:16]=[CH:17][CH:18]=1)=[O:13].O>CN(C=O)C>[F:9][C:10]1[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=1[C:12]([C:14]1[N:15]([N:19]([CH3:1])[C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH:16]=[CH:17][CH:18]=1)=[O:13]
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccccc1F
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.5 %

Procedure:
Sodium carbonate (22.4 g, 0.21 mol), methyl iodide (30 g, 0.21 mol), and [2-(2-fluorobenzoyl)-1H-pyrrol-1-yl]-carbamic acid, ethyl ester (25.4 g, 0.09 mol) were combined in 100 ml of dry DMF with stirring at ambient temperature. After 72 hours, the mixture was poured into 800 ml of H2O and extracted with three 250 ml portions of DCM. The combined extracts were washed with H2O and brine, dried (MgSO4), filtered and evaporated to an oil. This oil was purified by HPLC (silica, DCM) to give 26 g (97%) of crystals, m.p. 64°-66°.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[F:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].Cl>C(OCC)C>[ClH:25].[F:27][C:28]1[CH:29]=[C:30]([NH:31][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc(F)c1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCCCC3)c12
Agent: Cl
Solvent: CCOCC
Product: Cc1c[nH]c2c(Nc3cccc(F)c3)ncc(C(=O)N3CCCCC3)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-(1-piperidin-1-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (90 mg) and using 3-fluoroaniline (46 ul) instead of 3-bromoaniline and heating for 15 rather than 30 minutes. Isolated by MDAP rather than trituration with diethyl ether and then dissolved in diethyl ether (10 ml) and treated with a solution of 1M hydrochloric acid in diethyl ether (10 drops). The mixture was evaporated and dried at 40° C. under vacuum to afford the title compound (17 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C:10]2([CH3:26])[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cccc3C(F)(F)F)[C@H]2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(C(F)(F)F)cccc3C2(C)C1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (150 mg, 0.4 mmol) and methyl iodide (125 mg, 0.9 mmol) in dry DMF (6 mL) was added sodium hydride (15 mg, 0.6 mmol). The reaction was stirred for 3 h and then quenched with brine. The reactionwas extracted with EtOAc (3×10 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was purified by flash chromatography (silica gel, 0–50% EtOAc in hexanes) to yield 59 mg of the desired product as a white solid. MS (ESI) 371 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2)=[CH:5][C:4]=1[CH3:14].[Se](=O)=[O:16].C(Cl)Cl.[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:16])=[N:10]2)=[CH:5][C:4]=1[CH3:14]
Reactant: O=[Se]=O
Reactant: COc1cc2nc(C)ccc2cc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc2nc(C=O)ccc2cc1C

Procedure:
To 7-methoxy-2,6-dimethylquinoline (580 mg, 3.10 mmol) in dioxane/water (15/0.015 mL) was added selenium dioxide (447 mg, 4.03 mmol) and the reaction was heated to reflux for 5 hours. After cooling, DCM was added followed by MgSO4. After concentration, the residue was used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39]>CN(C=O)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (25.7 mg, 0.078 mmol) in DMF (0.1 mL) at room temperature was added sodium hydride (6 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour. 2-(Bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoromethyl)benzene (Enantiomer 1 from STEP D, 23.1 mg, 0.066 mmol) in DMF (0.2 mL) was added. The mixture was stirred at room temperature for 2 days. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-25% ethyl acetate in heptane) to afford the title compound (7.5 mg, 19%). 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.16 (m, 1H) 1.22-1.33 (m, 1H) 1.38-1.50 (m, 3H) 1.51-1.63 (m, 2H) 1.65-1.76 (m, 1H) 2.02-2.14 (m, 1H) 3.07 (s, 3H) 4.19 (d, J=7.88 Hz, 1H) 4.20-4.23 (m, 3H) 4.72 (d, J=2.49 Hz, 2H) 4.76 (d, J=16.18 Hz, 1H) 4.90 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.51-7.58 (m, 2H) 7.66 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1) To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (27.2 mg, 0.084 mmol) in DMF (0.1 mL) at room temperature was added sodium hydride (6 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour. 2-(Bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoromethyl)benzene (Enantiomer 2 from STEP D, 24.5 mg, 0.070 mmol) in DMF (0.2 mL) was added. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (18.6 mg, 45%). The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford a colorless oil (18.6 mg, 45%). 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.15 (m, 1H) 1.23-1.33 (m, 1H) 1.38-1.63 (m, 5H) 1.66-1.75 (m, 1H) 2.03-2.11 (m, 1H) 3.07 (s, 3H) 4.19 (d, J=7.88 Hz 1H) 4.21 (s, 3H) 4.72 (d, J=2.90 Hz, 2H) 4.76 (d, J=16.18 Hz, 1H) 4.90 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.51-7.58 (m, 2H) 7.66 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1).
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.[P:10](Cl)([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:11].Cl.C(N(CC)CC)C.ClCl>C1(C)C=CC=CC=1>[P:10]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O:2][CH3:1])=[O:11]
Reactant: CCCCCCCCCCCCOP(=O)(Cl)OCCCCCCCCCCCC
Reactant: CO
Agent: Cl
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOP(=O)(OC)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5 g. (0.15 mole) of methanol and 12.12 g. (0.12 mole) of triethylamine in 200 ml. of toluene was stirred at ambient temperature (22° C.) and a total of 45.25 g. (0.1 mole) of dilauryl chlorophosphate (prepared as described in Preparation 1) was added dropwise over a period of 13 minutes. After the addition was complete, the reaction mixture was stirred for a further 1.5 hour at ambient temperature before being filtered to remove triethylamine hydrochloride (7.85 g.). The filtrate was heated to 95° C. for a few minutes before being cooled to 5° C. and filtered. The solid so isolated was a further 2.82 g. of triethylamine hydrochloride. The filtrate was evaporated to dryness and the residue was triturated with 150 ml. of ether. The insoluble material (triethylamine hydrochloride; 0.33 g.; total triethylamine hydrochloride=11 g.=80 percent theoretical) was removed by filtration and the filtrate was evaporated to dryness to yield 44 g. of methyl dilaurylphosphate which was found to contain 0.09 percent of hydrolyzable chlorine corresponding to the presence of 1.15 percent of starting material (dilauryl chlorophosphate).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[N:14](C(OC(C)(C)C)=O)[C:13](=[O:22])[C@H:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11]1)(C(C)(C)C)(C)C>C(#N)C.O>[OH:8][CH2:9][C@H:10]1[NH:14][C:13](=[O:22])[C@H:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H](Cc2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CC#N
Solvent: O
Product: O=C1N[C@H](CO)C[C@H]1Cc1ccccc1

Procedure:
To 130 mg (0.34 mmol) of 5(S)-((t-butyl-dimethylsilyloxy)methyl)-3(R)-phenylmethyl-N-BOC-2-pyrrolidinone in 5 ml of acetonitrile was added 0.1 ml of a solution of 48% HF in water. After 3 hr at room temperature the reaction was concentrated to dryness and diluted with 30 ml of an aqueous 10% NaHCO3 solution. This was extracted with EtOAc (2×30 ml), dried filtered and concentrated to afford the crude product.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]3)=[O:28])=[CH:22][CH:21]=4)=[O:17])[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1>>[C:1]1([S:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[N:19]([C:43]4[CH:42]=[CH:41][N:40]=[C:39]([Cl:38])[CH:44]=4)[C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]3)=[O:28])=[CH:22][CH:21]=4)=[O:17])[CH2:14][CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)c5ccccc5)CC4)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)c4ccccc4)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 5, from (4-benzenesulfonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 13) and 2-chloropyridine-4-boronic acid to afford the desired product as a light brown solid (44%). MS (ISP): 635.3 (M+H)+.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:11][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To THF was added 3-methoxy-5-(trifluoromethyl)aniline (1.10 g, 5.7 mmol), potassium carbonate (2 equivalents), phenyl chloroformate (3 equivalents) and 4-dimethylaminopyridine (0.1 equivalent) and the reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc, filtered, concentrated in vacuo, and purified by silica gel column chromatography (5-15% EtOAc/hexanes) to give phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate (1.02 g, 3.28 mmol, 57%). 1H NMR (300 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.50-7.35 (m, 4H), 7.31-7.22 (m, 3H), 6.94 (s, 1H), 3.81 (s, 3H); LC-MS (ESI) m/z 312 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1.[Cl-].[Na+].O>[C:30]([O:29][C:27](=[O:28])[CH2:26][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC(=O)OC(C)(C)C)Cc2ccccc2C1
Reaction time: 0.25 h

Procedure:
To a solution of ethyl indane-2-carboxylate (Schaaf et al., J. Med. Chem. 1983, 26, 328-334) (2.00 g, 10.5 mmol) in THF at −78° C. was added sodium bis(trimethylsilyl)amide (15.8 mL of a 1.0 M solution in THF, 15.8 mmol) dropwise, over 10 min. The mixture was stirred for 15 min, then tert-butyl bromoacetate (3.08 g, 15.8 mmol) was added dropwise, over 30 min. The resulting mixture was stirred for 30 min at −78° C., then poured into brine (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give the title compound. MS: m/z=368 (M+Na+CH3CN).
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([NH:49][C:50]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[C:30]([F:36])[CH:31]=1)=[S:51])=[O:48]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>CC(N(C)C)=O>[C:31]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])=[CH:17][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:13]1)(=[O:33])[CH3:32]
Reactant: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCc2c(cc(NC(=O)C(C)C)cc2-c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
CO-AAW0003 (39 mgs, 0.12 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) followed by the addition of triethylamine (20 ul, 0.144 mmols) and acetyl chloride (10.3 ul, 0.144 mmoles). The reaction was then left stirring at room temperature for 1.5 hours. The reaction was purified by C18 reverse phase automated HPLC (21 mgs, 67% yield, 100% pure, CO-AAW00024).
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC1=2.[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[O:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53]CC)=[O:52])=[CH:49][CH:48]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[O:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([OH:53])=[O:52])=[CH:56][CH:57]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC1(C)CC=C(c2ccco2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-furyl)-2-naphthalenyl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 16.0 mg (0.38 mmol) of LiOH in H2O. PMR (d6-DMSO): δ 1.26 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.41 (1H, t, J=4.9 Hz), 6.60 (2H, m), 7.45-7.53 (3H, m), 7.64 (2H, d, J=8.3 Hz), 7.75 (1H, d, J=1.6 Hz), 7.93 (2H, d, J=8.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.Cl.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Sc2ccccc2)cc1N

Procedure:
3.5 G. of 2-amino-4-phenylthio-1-nitrobenzene in 8 ml. conc. hydrochloric acid is treated with a solution of 16 g. of stannous chloride in 8 ml. conc. hydrochloric acid. The mixture is heated for 1 hour on a steam bath, cooled and treated with potassium bicarbonate and chloroform. The mixture is filtered and the chloroform layer evaporated. The residue is triturated with hot cyclohexane yielding 1,2-diamino-4-phenylthiobenzene.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=[O:18].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:18])[CH3:12])=[C:7]([OH:11])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(C)oc2c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(C)=O)cc1O
Temperature: 25 °C

Procedure:
2-methyl-1,3-benzoxazol-6-yl acetate (8.1 g, 42.3 mmol) was dissolved in tetrahydrofuran (60 mL), and trifluoroacetic acid (4 mL, 53.2 mmol) was added. The light brown solution was stirred over night at room temperature. Sodium hydrogen carbonate (aq, sat) was added, and the solution was extracted twice with ethyl acetate. The combined organic layers were concentrated to the titled compound (8.0 g, 91%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:4][C:3]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cc(Cl)ccc1N
Product: Cc1cc(Cl)ccc1N=Cc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
2-Methyl-4-chloroaniline (0.25 mole) and 4-chlorobenzaldehyde (0.25 mole) are ground in a mortar. The mixture is heated, with stirring in a water bath for 1.5 hrs. Distillation at reduced pressure gives N-(p-Chlorobenzylidene)-2-methyl-4-chloroaniline. b.p. 139° C./0.020 mm.