Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[Br:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35].C(Cl)Cl>C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([C:2]([CH3:1])([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)(=[O:5])=[O:6])[CH3:3])[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2Br)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a 10 ml vial was loaded 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (60 mg, 0.179 mmol), diisoprpoylethylamine (0.093 ml, 0.54 mmol), 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (87 mg, 0.27 mmol), N,N-dimethylaminopyridine (4.4 mg, 0.036 mmol) and 1 ml methylene chloride. The resulting reaction solution was stirred at room temperature for one hour. It was diluted with 20 ml ethyl acetate, washed sequentially with 20 ml 1N HCl, 20 ml 10% KOH and 20 ml brine. Organics were dried over sodium sulfate, filtered and concentrated to give 91 mg white solid. A fraction of this crude product (20 mg) was further purified on a reverse phase column eluted with water/acetonitrile gradient solvent to give 16 mg desired product as fluffy white solid after lyophilizing.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[S:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[S:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccc(C#N)s1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccc(C#N)s1
Yield: 94.1 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and 3-(5-cyano-thiophen-2-yl)-3-oxo-propionic acid tert.-butyl ester (Example H17) (276 mg, 1.1 mmol) according to the general procedure K. Obtained as a yellow solid (451 mg).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10](Cl)=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:15][NH2:16])=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OCc1ccc(Cl)nc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OCc1ccc(NN)nc1

Procedure:
7.9 g (39.6 mmol) 5-(tert-butoxymethyl)-2-chloropyridine together with 19.8 g (395.6 mmol) hydrazine hydrate are divided into three portions of equal size and 15 ml ethanol are added to each portion. Each portion is reacted in a single mode microwave (CEM Explorer) at 170° C. for in each case 4 h. Thereafter, the three mixtures are combined and the solvent is removed. The residue is taken up in ethyl acetate and the mixture is washed once with saturated sodium bicarbonate solution. The aqueous phase is extracted once with ethyl acetate. The two ethyl acetate phases are combined and washed once with saturated sodium chloride solution. The mixture is dried over magnesium sulfate and the solvent is removed. The residue obtained is stirred in petroleum ether and the solid is filtered off.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CCCCCC.C(O[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[C:7]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(O)c1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)ethanol (10.2 mmol, 1660 mg, commercial) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 mol/L) in hexane (2.4 equiv., 24.4 mmol, 9.8 mL) dropwise. The mixture was stirred at −78° C. for 2 hours. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.50 equiv., 25.4 mmol, 5.29 mL) was added, and the reaction mixture was stirred over night allowing to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3(aq.) And extracted with etoac. The organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrated was concentrated to afford the desired product which was used without further purification.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCOCCCCCCCCCC(O)=O.[CH:42]1([N:48]=[C:49]=[N:50][CH:51]2[CH2:56][CH2:55][CH2:54]CC2)CCCCC1>O1CCCC1>[CH3:1][N:48]([C:49]1[CH:54]=[CH:55][CH:56]=[CH:51][N:50]=1)[CH3:42]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: COCOCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 865 mg of 10-(methoxymethoxy)decanoic acid, 7 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 543 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43]N>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:38](=[C:37]([CH3:36])[CH:42]=[CH:41][CH:40]=4)[NH:43][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(C(F)(F)F)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 562.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:14](O)=O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:13]2[C:12]([N:11]=[C:3]3[C:4]=1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]3[CH3:1])=[CH:20][CH:19]=[C:18]([O:21][CH3:22])[CH:17]=2
Reactant: COc1ccc(Nc2cc([N+](=O)[O-])ccc2C)c(C(=O)O)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc3c(C)ccc([N+](=O)[O-])c3c(Cl)c2c1
Yield: 68 %

Procedure:
N-(2′-methyl-5′-nitrophenyl)-5-methoxyanthranilic acid (7.2 g) is heated in phosphorous oxychloride (60 ml) at 120° C. for 1 hour. Excess phosphorous oxychloride is distilled off under reduced pressure, and the residue poured slowly into a stirred mixture of chloroform, concentrated ammonium hydroxide and ice. The separated chloroformic layer is washed with water and dried using magnesium sulfate. Chloroform is evaporated to dryness, and the residue is crystallized from benzene to give 9-chloro-7-methoxy-4-methyl-1-nitroacridine (6.1 g, 68% yield), m.p. 227-228° C. 1H NMR (d6 DMSO): δ8.23 (d, 1 H, J=9.3 Hz), 8.13 (d, 1 H, J=7.3 Hz), 7.79 (bd, 1 H, J=8.3 Hz), 7.71 (dd, 1H, J1=9.3 Hz, J2=2.9 Hz), 7.58 (d, 1 H, J=2.9 Hz), 4.02 (s, 3 H), 2.85 (s, 3 H).
Reaction SMILES: [C:1]([C:4]1[C:5](F)=[C:6]([F:22])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[N-:24]=[N+]=[N-].[Na+]>CC(C)=O.O>[F:22][C:6]1[C:5]2=[N:24][O:3][C:1]([CH3:2])=[C:4]2[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1F
Temperature: 65 °C
Yield: 88.7 %

Procedure:
To a solution of methyl 5-acetyl-3,4-difluoro-2-(2-fluorophenylamino)benzoate (example 3, step D) (1.50 g, 4.64 mmol) in a mixture of acetone (36 ml) and H2O (12 ml) was added NaN3 (452 mg, 6.96 mmol). The reaction was heated at 65° C. for 16 h and cooled to room temperature. Acetone was concentrated and the resulting mixture was extracted with EtOAc (2×50 ml). The combined organic solution was washed with brine (50 ml), dried over MgSO4 and concentrated to give a yellow solid. To the solid was added H2O (24 ml) and the reaction was heated at reflux for 3 h. The reaction was cooled to room temperature, filtered, and washed with H2O. The resulting solid was dried under high vacuum with P2O5 at 65° C. for 24 h to give 1.31 g (89%) of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:15][C:14]3([CH2:18][CH:17]([NH:19][C:20]([O:22][CH2:23][C:24]4[O:28][N:27]=[C:26]([C:29](OCC)=[O:30])[CH:25]=4)=[O:21])[CH2:16]3)[CH2:13]1)[CH:6]=[CH:5]2.[CH3:34][NH2:35]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][C:14]3([CH2:16][CH:17]([NH:19][C:20](=[O:21])[O:22][CH2:23][C:24]4[O:28][N:27]=[C:26]([C:29](=[O:30])[NH:35][CH3:34])[CH:25]=4)[CH2:18]3)[CH2:15]1)[CH:6]=[CH:5]2
Reactant: CN
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(C2)CN(c2ccc4cc(F)ccc4n2)C3)on1
Solvent: CCO
Product: CNC(=O)c1cc(COC(=O)NC2CC3(C2)CN(c2ccc4cc(F)ccc4n2)C3)on1

Procedure:
In a sealed tube, a solution of 0.130 g (0.28 mmol) of ethyl 5-[2-(6-fluoroquinolin-2-yl)-2-azaspiro[3.3]hept-6-ylcarbamoyloxymethyl]isoxazole-3-carboxylate, prepared in step 11.9., in 4.13 mL (28.01 mmol) of a solution (8M) of methylamine in ethanol, is stirred at room temperature for 5 hours. The mixture is evaporated to dryness. The residue obtained is crystallized from hot ether. The precipitate thus formed is filtered off and rinsed thoroughly with ether. After drying under vacuum at about 60° C., 0.05 g of pure product is obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]([CH3:13])[N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH2:9][CH:8]([CH3:13])[N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC1CC(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC1CC(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.28 g (0.001 mole) of (rac)-2-chloro-9-cyclopentyl-8-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 2 mL of N,N-dimethylacetamide and 0.093 mL (0.0015 mole) of iodomethane at 0 degrees was added 0.06 g (0.0015 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 10 mL of water was added. The precipitate collected by filtration to give 0.278 g of (rac)-2-chloro-9-cyclopentyl-5,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-3) as an yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].Cl[CH2:22][CH2:23][S:24][CH3:25].O>CN(C)C=O>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:3]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22][CH2:23][S:24][CH3:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Reactant: CSCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
Sodium hydride (0.96 g, 50% suspension in mineral oil) was added to a stirred solution of t-butyl benzyl malonate (5 g) in dry dimethylformamide (50 ml), maintained at 0° C. under an atmosphere of nitrogen. After stirring for 15 minutes, 2-chloroethyl-methyl sulphide (2.21 g) in dimethylformamide (10 ml) was added dropwise, while the temperature of the reaction was maintained below 10° C. The reaction was allowed to warm to room temperature and stirred for 15 hours when water was cautiously added. The reaction mixture was extracted with ethyl acetate (2×100 ml), the ethyl acetate extracts were washed with water (4×), dried (Na2SO4) and evaporated to give 4-methylthio-2-t-butyloxycarbonyl-butanoic acid benzyl ester as an oil (6.4 g). This product was dissolved in trifluoroacetic acid (50 ml) with vigorous stirring at 0° C. under nitrogen. After stirring for 45 minutes, the trifluoroacetic acid was evaporated under reduced pressure at below 35° C. Final traces of trifuoroacetic acid were removed by azeotroping with carbon tetrachloride (3×20 ml), to leave an oily residue, which was dissolved in pyridine (20 ml). To this solution were added piperidine (0.44 ml) and paraformaldehyde (1.47 g), and the mixture heated at 60° C. under nitrogen for 2 hours. The reaction mixture was cautiously poured onto iced water, and the pH adjusted to 1 using concentrated suphuric acid. The mixture was extracted with ether (2×100 ml), and the ether extracts dried (Na2SO4) and evaporated under reduced pressure to yield the crude product (5.4 g) as an oil. This was chromatographed over silica gel, eluting with a mixture of hexane and ethyl acetate, to yield the title ester as a colourless oil (1.22 g). Found: C,64.69; H,6.55. C13H16O2S (0.25 H2O) requires C,64.85; H,6.91%.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][SiH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:3]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH2:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>[Cu]I.C1COCC1>[CH2:8]([Si@H:5]1[CH2:6][CH2:7][C@H:2]([CH2:26][CH2:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:3][CH2:4]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Fc1ccc(-c2ccc([C@H]3CC[C@H](CCBr)CC3)cc2)cc1
Reactant: CCCCC[SiH]1CCC(Br)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)cc3)CC2)CC1

Procedure:
24.9 g (0.1 mol) of 1-bromo-4-n-pentyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 36.1 g (0.1 mol) of 4-(trans-4-(2-bromoethyl)cyclohexyl)-4'-fluorobiphenyl. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-fluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 30.5 g (yield 67.6%) of the trans isomer.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.CN(C)C=O.[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([Br:26])[CH:21]=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18].[OH-].[Na+]>[Cl-].[Na+].O.O>[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([Br:26])[C:21]([I:1])=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1c(Br)cc(C)c(C(=O)O)c1N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(N)c(C(=O)O)c(C)c(I)c1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
N-Iodosuccinimide (104 mg, 461 μmol) was put into an N,N-dimethylformamide (2.0 ml) solution of 2-amino-4-bromo-3-methoxy-6-methylbenzoic acid (I-3) (100 mg, 384 μmol), followed by stirring at room temperature for 40 minutes. The reaction liquid was put into water (30 ml), followed by controlling at pH of 4 with aqueous 2 N sodium hydroxide solution, then saturated brine (30 ml) was added, the product was extracted with ethyl acetate (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=1:0→100:3) to obtain the entitled compound (84.9 mg, 57%) as a yellow white solid.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:118])[C:82]2[CH:81]=[C:80]([C:83]3[CH:84]=[CH:85][C:86]4[N:90]=[C:89]([C@@H:91]5[CH2:95][CH2:94][CH2:93][N:92]5[C:96](=[O:106])[C@@H:97]([NH:101][C:102](=[O:105])[O:103][CH3:104])[CH:98]([CH3:100])[CH3:99])[NH:88][C:87]=4[CH:107]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:108]1[NH:112][C:111]([C@@H:113]3[CH2:117][CH2:116][CH2:115][NH:114]3)=[N:110][CH:109]=1)=[CH:74][CH:75]=2>>[CH3:104][O:103][C:102](=[O:105])[NH:101][C@@H:97]([CH:98]([CH3:100])[CH3:99])[C:96]([N:92]1[CH2:93][CH2:94][CH2:95][C@H:91]1[C:89]1[NH:88][C:87]2[CH:107]=[C:83]([C:80]3[CH:79]=[CH:78][C:77]4[C:76]5[C:71](=[CH:72][C:73]([C:108]6[NH:112][C:111]([C@@H:113]7[CH2:117][CH2:116][CH2:115][N:114]7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=[N:110][CH:109]=6)=[CH:74][CH:75]=5)[C:70]([F:69])([F:118])[C:82]=4[CH:81]=3)[CH:84]=[CH:85][C:86]=2[N:90]=1)=[O:106]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc3-4)cc2[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-1-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 871.95 [M+H]+. (174 mg, 53%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1C=CC(N)=CC=1)C>C(O)(=O)C>[CH2:24]([C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1)[CH3:25]
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CCc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CCc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 60 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.42 ml), 4-ethylaniline (0.05 ml, 0.39 mmol), and acetic acid (0.05 ml) were used to give 59.5 mg (0.18 mmol, 60% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C:6]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].CC(C)=O>CCCCCC>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C:6]=2[CH:18]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Oc1ccc2c(c1)CC(CCc1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CC(CCc1ccccc1)O2
Yield: 82 %

Procedure:
A mixture 5-hydroxy-2-(2-phenylethyl)-2,3-dihydrobenzoruan, E5, (50 gm; 208 mmoles), potassium carbonate (55 gm; 400 mmoles), allyl bromide (48 gm; 400 mmoles) and acetone (500 mL) was refluxed for 18 hours. The mixture was cooled, diluted with hexane (250 mL) and filtered through celite. The filtrate was concentrated in vacuo and the residue chromatographed in silica gel using 10% ethylacetate in hexane as eluent to obtain 47.8 gm (82%) of 5-allyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran E6 as an oil.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][CH2:6][OH:7].Br[C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=2[S:11][C:10]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26].O>O1CCCC1>[OH:7][CH2:6][CH2:5][CH2:4][S:3][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=2[S:11][C:10]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]
Reactant: OCCCS
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(=O)c3cccnc3)sc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(C(=O)c3cccnc3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
To a suspension of sodium hydride (0.068 g) in dry tetrahydrofuran (25 ml) was added dropwise a solution of 3-mercaptopropanol (0.14 g) in dry tetrahydrofuran (5 ml). After 15 minutes, a solution of 5-bromo-3-methyl-1-(2-methylpropyl)-6-[(pyridin-3-yl)carbonyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.60 g, Example 39 step c) in dry tetrahydrofuran (20 ml) was added dropwise and the reaction was stirred for 3 hours at room temperature. The solution was poured into water and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a cream solid (0.35 g).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.C1(O)CCCCC1.[H][H]>[Ni]>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: OC1CCCCC1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Yield: 82.8 %

Procedure:
To a mixture of 12.8 grams of 5-nitrotetrahydroanthraquinone and 170 grams of cyclohexanol was added 0.3 gram of a Raney-nickel catalyst. Then, hydrogen was fed into the mixture while agitating at 100° C. for hydrogenation. After hydrogen was absorbed in an amount of 2 mols per mol of the nitro compound, the catalyst was separated by filtration. To the resultant filtrate was added 10 grams of a 20% aqueous sodium hydroxide solution, followed by agitating at 100° C. for 1 hour. Then, the reaction solution was cooled to 10° C. to precipitate crystals which were separated by filtration, washed with water and dried to obtain 9.2 grams of 1-aminoanthraquinone having a purity of 98%.