Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:17])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
To a mixture of 4.97 g (0.0249 mol) 1-(3-bromo-phenyl)-ethanone and molecular sieves in 50 ml methanol, 23 g (0.298 mol) ammonium acetate and 1.75 g (0.0265 mol) sodium cyanoborohydride were added and the reaction mixture was stirred 2 d (HPLC control) at 50° C. After cooling to room temperature, the molecular sieves were filtered off and washed with methanol. The solvent of the combined filtrates was evaporated and ethyl acetate and water were added to the residue. While stirring the mixture was acidified with 6N aqueous HCl solution. The aqueous phase was separated and the organic phase was extracted two times with 1N aqueous HCl solution. Ethyl acetate was added to the combined aqueous phases and the mixture was basified with 6N NaOH. The organic phase was separated and the aqueous phase was extracted two more times with ethyl acetate. The organic combined organic phases were dried over MgSO4 and the solvent evaporated at reduced pressure to afford 2.96 g (0.0148 mol) 1-(3-bromo-phenyl)-ethylamine.
Reaction SMILES: [O:1]=[C:2]1[C:20]2=[CH:21][CH:22]=[C:23]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)[C:24](=[O:25])[N:19]2[C:4]2([CH2:8][CH2:7][N:6](C(OCC3C=CC=CC=3)=O)[CH2:5]2)[NH:3]1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[N:30]1[CH:31]=[CH:32][C:27]([NH:26][C:23]2[C:24](=[O:25])[N:19]3[C:4]4([NH:3][C:2](=[O:1])[C:20]3=[CH:21][CH:22]=2)[CH2:8][CH2:7][NH:6][CH2:5]4)=[N:28][CH:29]=1
Reactant: O=C1NC2(CCN(C(=O)OCc3ccccc3)C2)n2c1ccc(Nc1ccncn1)c2=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1NC2(CCNC2)n2c1ccc(Nc1ccncn1)c2=O
Reaction time: 4 h

Procedure:
To a stirred solution of benzyl 1,5-dioxo-6-(pyrimidin-4-ylamino)-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1′-carboxylate (5, 0.06 g, 0.138 mmol) in ethyl acetate:methanol (10:1, 33 mL), 20% palladium hydroxide (0.03 g) was added. The reaction mixture was hydrogenated under balloon pressure for 4 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC and repeated washing with ether to afford 6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1,5(2H)-dione (Cpd. No. 26) as a white solid. Yield: 0.025 g, 60%; MS (ESI) m/z 299.20 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.83-8.74 (m, 2H), 8.38 (d, J=5.9 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 3.67 (d, J=12.6 Hz, 1H), 3.19-3.03 (m, 2H), 2.95-2.75 (m, 2H), 2.05-1.88 (m, 1H).
Reaction SMILES: C(=O)(O)[O-:2].[Na+:5].O[C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18])[CH:10]=[CH:11][CH:12]=1>O>[OH:2][C:10]1[CH:11]=[CH:12][CH:7]=[CH:8][C:9]=1[NH:13][C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([O-:19])=[O:18].[Na+:5]
Reactant: O=C([O-])O
Reactant: O=C(O)/C=C\C(=O)Nc1cccc(O)c1
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)Nc1ccccc1O
Reaction time: 4 h

Procedure:
A dry 2-liter beaker was charged with 135 ml of distilled water and 84 grams (1.0 moles) of sodium bicarbonate. The resulting mixture was stirred as 207 grams (1.0 mole) of N-(3-hydroxyphenyl)maleamic acid was slowly added with gas evolution. The thick mixture was stirred for 4 hours after the addition was complete and vacuum filtered to remove as much aqueous as possible. The filter cake was dried below 50° C. in a draft hood to give sodium N-(hydroxyphenyl)maleamate which is a tan solid melting above 200° C.
Reaction SMILES: O1CCCC1.[F:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39]Br>O>[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39][O:9][CH2:8][CH2:7][F:6]
Reactant: OCCF
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc2c(c(COCCF)c(Br)n2COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To 15 ml of dehydrated tetrahydrofuran solution containing 1.02 g (16 mmol) of 2-fluoroethanol was added 0.32 g (8.0 mmol) of sodium hydride (60% dispersed material in mineral oil) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, 0.90 g (1.6 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was further added to the mixture, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 802 mg of the title compound as a white solid. (Yield: 91%)
Reaction SMILES: [O:1]1[CH2:29][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][C@@H:12]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1.[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>N1CCCCC1.C(O)C>[C:33]1(=[O:35])[N:34]([CH2:29][CH:2]([OH:1])[CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([C@@H:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[CH2:14][CH2:13][C@@H:12]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:9][CH:10]=2)[C:30](=[O:36])[CH2:31][CH2:32]1
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCC2CO2)cc1
Reactant: O=C1CCC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCC(O)CN2C(=O)CCC2=O)cc1

Procedure:
A mixture of 3.0 g. of cis-1-[p-(2,3-epoxypropoxy)phenyl]-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene, 0.80 g. of succinimide and 4 drops of piperidine in 100 ml. of absolute ethanol is heated under reflux for 17 hours. The resulting mixture is concentrated to approximately one-third volume by distillation under reduced pressure and the residue is diluted with water. The mixture so obtained is extracted with methylene chloride and the methylene chloride extract is washed with water and saturated sodium chloride solution before being evaporated to dryness. The residue is recrystallized from aqueous alcohol to yield cis-1-[p-(3-succinimido-2-hydroxy-propoxy)phenyl]-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene. The latter compound is then heated under reflux for 20 hours with a solution of 16 g. of sodium hydroxide in 320 ml. of ethanol. The resulting product is concentrated by distillation under reduced pressure and the residue is extracted with a mixture of methylene chloride and water. The methylene chloride solution is separated, washed with water, and taken to dryness. Hydrogen chloride is bubbled through a solution of the residue in ether. The solid which separates is isolated by filtration, and dried. There is thus obtained cis-1-[p-(3-amino-2-hydroxy-propoxy)phenyl]-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride. The corresponding free base is obtained by dissolving the hydrochloride in methylene chloride, washing the resulting solution with an aqueous sodium bicarbonate solution, and evaporating the methylene chloride solution to dryness.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].C(OC(=O)[NH:14][C@@H:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([C:27]2[CH:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=2)=[O:26])[C:19]=1[F:34])[CH2:16][CH3:17])(C)(C)C>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:15]([NH2:14])[CH2:16][CH3:17])=[C:19]([F:34])[C:20]=1[C:25]([C:27]1[CH:28]=[N:29][C:30]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:31][CH:32]=1)=[O:26]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(Cl)nc2)c1F
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(-n3cccn3)nc2)c1F
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To Pyrazole (0.016 g, 0.23 mmol) in DMF (2 ml) added sodium hydride (60%) (0.01 g, 0.25 mmol) then stirred at ambient for 15 minutes. {(R)-1-[4-Chloro-3-(6-chloro-pyridine-3-carbonyl)-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester [from Example 1, step 1] (0.1 g, 0.23 mmol) in DMF (2 ml) added dropwise, stirred at ambient for 1 hour, reaction quenched using water and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated, MS: [M+H] 459. Residue treated with saturated HCl/EtOAc stirred at ambient for 1 hour. Mixture was concentrated, solid triturated with EtOAc, filtered and washed with EtOAC to give (1R)-1-(4-chloro-2-fluoro-3-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]carbonyl}phenyl)propan-1-amine (0.06 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH:16]([CH3:18])[CH3:17].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH:16]([CH3:18])[CH3:17])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
20% palladium hydroxide (wet, 60 mg) was added to a solution of tert-butyl cis(±)-4-(benzylamino)-3-isopropoxypiperidine-1-carboxylate obtained in Example (147d) (120 mg, 0.345 mmol) in methanol (1.2 mL), and the mixture was catalytically hydrogenated at room temperature for three hours. The catalyst was filtered off, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the resulting residue, and the organic substance was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 74 mg of tert-butyl cis(±)-4-amino-3-isopropoxypiperidine-1-carboxylate as a colorless oily substance (83%). The resulting amine was dissolved in DMF (1 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 54 mg, 0.29 mmol) was added, and the mixture was cooled in an ice water bath. 1-Hydroxybenzotriazole (44 mg, 0.31 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (60 mg, 0.31 mmol) were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, sequentially washed with brine, water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol) to obtain 60.6 mg of the title compound as a colorless solid (50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(N(CC)CC)C.[N:23]1[C:30]([Cl:31])=[N:29][C:27](Cl)=[N:26][C:24]=1[Cl:25]>CO>[Cl:25][C:24]1[N:23]=[C:30]([Cl:31])[N:29]=[C:27]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(Cl)nc(Cl)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (1.0 g, 4.92 mmol) and triethylamine (0.75 ml, 5.42 mmol) in 15 ml of methanol was cooled in an ice-bath and cyanuric chloride (889 mg, 4.82 mmol) added portionwise. The mixture was stirred for 1 hour at 0° C. Filtration of the precipitate gave the title compound (1.115 g, 65%) as a slightly brownish solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH2:30][CH2:31][CH3:32])=[N:23][C:24]=2Cl)(=O)C.[CH2:33]([NH2:35])[CH3:34]>O1CCOCC1.O>[CH2:33]([NH:35][C:24]1[C:25]2[N:26]=[CH:27][N:19]([C:20]=2[N:21]=[C:22]([S:29][CH2:30][CH2:31][CH3:32])[N:23]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4])[CH3:34]
Reactant: CCCSc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Reactant: CCN
Solvent: O
Solvent: C1COCCO1
Product: CCCSc1nc(NCC)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-(propylthio)purine (1.3 g) and ethylamine (1.6 ml) in dioxane (30 ml) and water (30 ml) were heated in a sealed autoclave at 110° for 20 hours. On cooling to room temperature, evaporation gave a residue which was recrystallised from ethyl acetate. Further purification by chromatography (SiO2, methanol:ethyl acetate, 1:15 as eluant) gave the sub-title compound (0.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:16]1([S:21]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([S:21]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)(=[O:23])=[O:22])=[CH:25][CH:26]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=Cc1ccc(S(=O)(=O)N2CCCC2)cc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (3.5 ml) was added 4-(pyrrolidin-1-ylsulfonyl)benzaldehyde (118 mg, 492 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (65.7 mg, 615 μmol) was added and the stirring was continued for 6 days. The reaction mixture was poured into 0.1N HCl solution (25 ml) to give a suspension, which was filtered to give a white solid as desired product (151 mg, 79% yield). MS +m/z: 467 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[CH2:9][CH2:10]I)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH:21]2[CH2:24][NH:23][CH2:22]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[CH2:9][CH2:10][N:23]1[CH2:24][CH:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:26][CH:25]=2)[CH2:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(OC2CNC2)cc1
Reactant: C[C@H](CCI)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C

Procedure:
A solution of ((R)-3-iodo-1-methyl-propyl)-carbamic acid tert-butyl ester (0.038 mg, 0.13 mmol), 3-(4-chloro-phenoxy)-azetidine hydrochloride (0.030 g, 0.13 mmol) and triethylamine (0.073 ml, 0.52 mmol) in DMF (1 ml) is stirred at room temperature for 18 hours. The reaction mixture is partitioned between ethylacetate and a saturated solution of sodium bicarbonate. The organic phase is washed with water and brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 1:1 ethylacetate:hexane as eluent to afford {(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamic acid tert-butyl ester. [M+H] 355.33
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:23]1[CH:36]=[CH:35][C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH:24]1[C:25]2[C:34](=[CH:33][C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:35]=[CH:36][C:23]=1[C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:18]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:9]=1
Reactant: Brc1ccc2cc3ccccc3cc2c1
Reactant: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
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: [Na+]
Solvent: COCCOC
Product: c1ccc2cc3cc(-c4cc5ccc6ccccc6c5c5ccccc45)ccc3cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Under an argon atmosphere, 5.98 g of benzo[c]phenanthrene-5-boronic acid, 5.14 g of 2-bromoanthracene, 0.462 g of tetrakis(triphenylphosphine)palladium(0), 30 mL of 1,2-dimethoxyethane and 15 mL of a 2M aqueous solution of sodium carbonate was charged, and the mixture was refluxed with stirring for 8 hours. After cooling to room temperature, deposited crystals were separated by filtration. The resulting solids were recrystallized with toluene-hexane and washed repeatedly, whereby 6.07 g (yield: 75%) of 5-(2-anthryl)benzo[c]phenanthrene was obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.O[N:17]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl.O>[NH2:17][O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(CON)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.2 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5 g, 23 mmol) in CH2Cl2 (250 mL) was added 2-hydroxyisoindoline-1,3-dione (5.6 g, 34.5 mmol) and triphenylphosphine (15 g, 57.5 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (11.1 ml, 57.5 mmol) was slowly added dropwise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture H2O (300 mL) was added and extracted with CH2Cl2. The organic layers were washed with brine. Dried over anhydrous MgSO4, filtered and concentrated to provide clear oil, which was purified by flash chromatography (50% EtOAc-Hexane). The resultant clear oily compound 2S was dissolved in CHCl3:CH3OH (50 ml). Hydrazine hydrate (25 mL, 0.25 mol) was added. The reaction mixture was stirred at ambient temperature overnight. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear oil, which was purified by flash chromatography (10% CH3OH—CH2Cl2) to afford 3 g (56%, over two steps) of tert-butyl 2-(aminooxymethyl)morpholine-4-carboxylate (2T) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9H) 3.46-3.62 (m, 2H) 3.61-3.79 (m, 4H) 3.79-4.04 (m, 3H). [M+H] calc'd for C10H20N2O4, 233; found, 233.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32]([O:34]CC(Br)CBr)=O.[CH3:40][NH2:41].C1COCC1>>[CH3:40][N:41]1[C:32](=[O:34])[C:4]2[CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:30])=[O:29])[NH:6][C:7](=[O:19])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=3)[C:3]=2[CH2:2]1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(CBr)=C1C(=O)OCC(Br)CBr
Reactant: CN
Solvent: C1CCOC1
Product: CN1CC2=C(C1=O)C(c1ccc(C#N)cc1S(C)(=O)=O)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Under an argon protective gas atmosphere, (rac)-2,3-dibromopropyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (758.2 mg, 1.0 mmol; Example 7A) was mixed with a 1 M solution of methylamine in THF (20 ml, 20.0 mmol, 20 eq.), and the mixture was stirred at RT for 30 min. The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (328 mg, 67% of theory).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16]Cl)[CH:10]=1)[C:6]([OH:8])=[O:7])=[O:3].[H][H]>O.[Pd]>[NH2:1][C:2]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=1)[C:6]([OH:8])=[O:7])=[O:3]
Reactant: [H][H]
Reactant: NC(=O)NC(C(=O)O)c1ccc(O)c(CCl)c1
Agent: [Pd]
Solvent: O
Product: Cc1cc(C(NC(N)=O)C(=O)O)ccc1O

Procedure:
A mixture of α-(aminocarbonyl)amino-3-chloromethyl-4-hydroxybenzeneacetic acid (0.1 mole) and 10% Pd on charcoal (1 g) catalyst in 50 ml of water is subjected to hydrogen gas at a pressure of about 60 pounds/in2 at room temperature for a period of about 16 hours. Removal of the catalyst followed by evaporation of the water gives the title compound.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][CH2:16][C:17]1[N:18]([C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[C:26]([CH3:33])=[CH:25][CH:24]=2)[C:19]([SH:22])=[N:20][N:21]=1>ClCCl>[F:15][CH2:16][C:17]1[N:18]([C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[C:26]([CH3:33])=[CH:25][CH:24]=2)[C:19]([S:22][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:20][N:21]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2c1CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSc1nnc(CF)n1-c1ccc(C)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Triethylamine (0.087 mL, 0.623 mmol) and ethyl 2-bromoacetate (63 μL, 0.571 mmol) were added to a solution of 5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.144 g, 0.519 mmol) in dichloromethane (2.1 mL) and stirred at room temperature for 2 hours. The crude reaction mixture was purified by SGC (0-100% EtOAc/Hexanes) to afford ethyl 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as an off-white solid (0.168 g, 89%).