Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([NH2:14])[C:11]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([O:36][CH3:37])[CH:28]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([NH:14][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][C:29]=2[O:36][CH3:37])[C:11]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N)C1
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: Br
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(Cl)cc2OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of 0.060 g (0.18 mmol) of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester hydrobromide (1:1) dissolved in 1.80 mL of dimethylformamide was added 0.037 g (0.20 mmol) of 4-chloro-2-methoxy-benzoic acid. To the resulting mixture was added 40 μL (0.22 mmol) of diethyl cyanophosphonate and 30 μl (0.20 mmol) of triethylamine at 0° C. The resulting mixture was stirred at room temperature for 2 hours and evaporated to dryness. Water was added and the mixture extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium carbonate, saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride dried and evaporated. The residue was triturated with a mixture of diethyl ether/ethyl acetate and filtered to afford 0.048 g (53%) of the pure product as a powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[O:4].[CH3:31][NH2:32]>>[CH3:31][NH:32][CH2:2][C:3]([N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[O:4]
Reactant: CN
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N(C(=O)CCl)c3ccccc3)cccc21
Product: CNCC(=O)N(c1ccccc1)c1cccc2c1ccn2[Si](C(C)C)(C(C)C)C(C)C

Procedure:
A solution of 2-chloro-N-phenyl-N-(1-triisopropylsilanyl-1H-indol-4-yl)-acetamide XXII (192 mg, 0.435 mmol) and MeNH2 (33% w in EtOH, 2 ml) was stirred for 2.5 h. The solvent was evaporated and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and the resulting crude 2-methylamino-N-phenyl-N-(1-triisopropylsilanyl-1H-indol-4-yl)-acetamide XXIII (180 mg) was used without further purification for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:10](=[O:28])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:10](=[O:28])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:8]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nc2ccc(Br)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc2ccc(-c3ccccc3)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone synthesized in Example 34 (100 mg, 0.25 mmol) and phenylboronic acid (40 mg, 0.32 mmol) were dissolved in dimethoxyethane (1 mL), and the atmosphere in the system was replaced by nitrogen. 2M sodium carbonate aqueous solution (0.3 mL) and palladium tetrakis (triphenylphosphine) complex (10 mg, 0.012 mmol) were added, and stirred at 80° C. for 3 hours. Ethyl acetate and distilled water were added to the reaction mixture to perform an ethyl acetate extraction. The organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (chloroform/methanol=20/1), and the target substance (61 mg, 61%) was obtained as a colorless solid. 1HNMR (400 MHz,CDCl3,δppm): 1.45 (2H, brs), 1.58-1.63 (4H, m), 2.00-2.04 (2H, m), 2.27 (3H, s), 2.42 (4H, brs), 2.50 (2H, t, J=7.2 Hz), 4.07 (2H, t, J=6.4 Hz), 7.04 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 7.36 (1H, t, J=7.6 Hz), 7.46 (2H, t, J=7.6 Hz), 7.67 (2H, d, J=7.2 Hz), 7.72 (1H, d, J=8.4 Hz), 7.98 (1H, d, J=2.0 Hz), 8.46 (1H, s)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:21]([F:28])([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]([F:28])([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=2)=[CH:9][CH:10]=1)[CH3:19]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCOC(=O)Cc1ccc(-c2ccnc(Br)c2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccnc(C(F)(F)C(=O)OCC)c2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a sealed tube were added ethyl 2-(4-(2-bromopyridin-4-yl)phenyl)acetate 203-3 (440 mg, 1.37 mmol), ethyl 2-bromo-2,2-difluoroacetate (1.7 mL, 13.7 mmol), Cu (1.3 g, 20.6 mmol) and DMF (5 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 80° C. for 1 hour. After cooling to room temperature, the mixture was filtered through a layer of Celite and concentrated. The residue was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give ethyl 2-(4-(4-(2-ethoxy-2-oxoethyl)phenyl)pyridin-2-yl)-2,2-difluoroacetate 203-4. MS m/z 364.2 (M+1).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8][C@H:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][NH:5]1.[CH3:25][O:26][CH2:27][CH2:28]Br>CN(C)C=O>[CH3:25][O:26][CH2:27][CH2:28][N:5]1[CH2:6][C@H:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:9][C@@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1=[O:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](c2ccccc2)CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C[C@H](c2ccccc2)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 6.2 mg, 0.158 mmol) was added to a solution of tert-butyl (3R,6R)-2-oxo-6-phenylazepan-3-ylcarbamate (40 mg, 0.131 mmol) and 2-bromoethyl methyl ether (0.013 mL, 0.138 mmol) in N,N-dimethylformamide (2 mL) at 0° C. After addition, the mixture was allowed to warm to ambient temperature. After 4 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (41 mg). MS 363 (M+1).
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: O=P(O)(O)CCl
Reactant: NCCCCCCN
Solvent: O
Product: NCCCCCCNCP(=O)(O)O

Procedure:
Chloromethanephosphonic acid (6.5 g, 49.8 mmoles) and 1.6-diaminohexane (34.8 g, 300 mmoles) were dissolved in water (130 cm3) and heated under reflux for 20 hours. The water was removed and ethanol (250 cm3) was added to the solid residue. The phosphonic acid was filtered off and dried. The crude yield was 10.4 g (92%). A sample was purified by recrystallization from water/ethanol to give N-(6-aminohexyl)-aminomethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](OC)=[O:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([OH:11])[C:6]([CH3:12])=[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:4]=1[OH:26]
Reactant: COC(=O)CCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1c(O)c(C)c(CCCCCCCCCCO)c(O)c1OC

Procedure:
2,3-Dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the form of methyl ester) (1 part) was treated with lithium aluminum hydride in the same manner as Example 53 to give 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-hydroquinone (formula III-2 wherein R=H3CO, X=Y=OH, n=8, in the free form). The product was treated with ferric chloride in the same manner as Example 53 and then crystallized from ligroin. The procedure provided 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone (formula IV-2 wherein R=H3CO, n=8, in the free form) (0.65 part) as orange needles melting at 46°-50° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=[C:19]([CH:30]([NH2:32])[CH3:31])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:21][N:20]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ncc1OCCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCCC(F)(F)F
Yield: 63 %

Procedure:
The title compound is prepared in 63% yield (400 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (470 mg, 1.7 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (460 mg, 1.6 mmol, Amine-62, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20](=[O:24])[CH2:21][NH:22][CH3:23].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:14]([N:22]([CH3:23])[CH2:21][C:20]([O:19][CH3:18])=[O:24])=[O:16])[CH3:13])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCC(=O)OC
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a mixture of N-{[(phenylmethyl)oxy]carbonyl}-D-alanine (133.53 g, 598.2 mmol) in DCM (1100 mL) was added powdered sarcosine methyl ester hydrochloride (83.49 g, 598.2 mmol), 1-hydroxybenzotriazole (80.81 g, 598.1 mmol), and 4-methylmorpholine (242 mL, 2201 mmol). The mixture was stirred for 10 min, and then EDC (114.68 g, 598.2 mmol) was added. The mixture was stirred overnight, and was then washed with water (500 mL), 1 N aqueous HCl (2×300 mL), and brine (300 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude methyl N-{[(phenylmethyl)oxy]carbonyl}-D-alanyl-N-methylglycinate (162.35 g, 88% yield) as a yellow oil. LCMS: (M+H)+: 309.0.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:25][CH:24]3[O:26][CH:21]([CH2:22][CH2:23]3)[CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:25][CH:24]5[O:26][CH:21]([CH2:22][CH2:23]5)[CH2:20]4)=[N:3][C:2]([C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CC5CCC(C4)O5)c3s2)CC1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
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: CCOC(C)=O
Solvent: COCCOC
Product: CN1CCN(Cc2cc3nc(-c4ccc([N+](=O)[O-])cc4)nc(N4CC5CCC(C4)O5)c3s2)CC1

Procedure:
In a 100 mL microwave vial was placed 3-(2-chloro-6-((4-methylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (168 mg, 0.426 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (127 mg, 0.512 mmol) in DME (5 ml) to give a yellow solution. Na2CO3 (2M solution in water) (0.853 ml, 1.706 mmol) was added. The mixture was degassed by bubbling N2 through the solution. Pd(PPh3)4 (49.3 mg, 0.043 mmol) was added. The mixture was heated under reflux (oil bath at 95 C). LC MS (RT 2.8, M+H=481) showed complete conversion after 7.5 h. The reaction mixture was diluted with ethyl acetate and washed with a sat. solution of NaHCO3. A precipitate remained that was insoluble in either organic or aqueous phase. LCMS showed that both the precipitate and the organic phase contained product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH2:30]([NH:32][CH2:33][CH2:34][OH:35])[CH3:31]>CN(C)C(=O)C>[CH2:30]([N:32]([CH2:33][CH2:34][OH:35])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)[CH3:31]
Reactant: CCNCCO
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCCOC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 509 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10])=[CH:2]1.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:23][C:22]([Si:19]([CH3:21])([CH3:20])[O:10][CH2:9][CH2:8][CH2:7][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[OH:11])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCC(O)c1ccsc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCC(O)c1ccsc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
The product from step (a) (0.79 g, 4.58 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (1.28 ml, 9.16 mmol) and 4-dimethylaminopyridine (0.02 g) added. The solution was cooled to 0° C. and t-butyldimethylsilylchloride (0.655 g, 4.35 mmol), as a solution in dimethylformamide (35 ml), was added dropwise over half an hour. The reaction was stirred at 0° C. for 2 h, then allowed to warm to room temperature slowly. After stirring for a further 18 h, water (50 ml) was added and the reaction extracted with ethyl acetate (3×70 ml). The combined extracts were washed with water (3×20 ml), dried (magnesium sulphate) and evaporated. The residue was chromatographed on flash silica, eluting with hexane:ethyl acetate (4:1) to give the title compound as a colourless oil (1.164 g, 89%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][NH2:11])=O)=[CH:4][C:3]1=[O:12].[CH3:13][N:14]=[C:15]=[S:16].[OH-].[Na+]>CO.O>[SH:16][C:15]1[N:14]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:12])[CH:4]=2)=[N:10][N:11]=1
Reactant: CN=C=S
Reactant: Cn1ccc(C(=O)NN)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(S)nnc1-c1ccn(C)c(=O)c1
Reaction time: 0.25 h

Procedure:
The title compound of example 31.1 (1.0 g, 5.98 mmol) was stirred in methanol (6 mL) at 60° C. Methyl isothiocyanate (481 mg, 6.58 mmol) was dissolved in methanol (2 mL) and added to the reaction mixture which was stirred for 15 min. After 15 min a solution of sodium hydroxide (263 mg) in water (2 mL) was added to the reaction mixture which was kept stirring at 60° C. overnight. The reaction mixture was then concentrated in vacuo to remove the methanol and the remaining residue was stirred in 3 M HCl (aq) to precipitate the product which was collected by vacuum filtration (off-white powder, 1.2 g, 90%).
Reaction SMILES: BrC1C=CC([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)=CC=1.C1(NC2C=CC=CC=2N)C=CC=CC=1.[Br:37][C:38]1[CH:45]=[CH:44][C:41](C=O)=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:39]=[C:40]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH:41]=[CH:44][CH:45]=1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Nc1ccccc1Nc1ccccc1
Product: Brc1cccc(-c2nc3ccccc3n2-c2ccccc2)c1

Procedure:
2-(3-Bromophenyl)-1-phenyl-1H-benzo[d]imidazole (m-BPBI) was prepared as the same procedure as 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazole from N-phenyl-o-phenylenediamine and 4-bromobenzaldehyde. The isolated yield of the compound was 85%. It has the same spectroscopic data as that as the bona fide compound.11
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)=[CH:4][CH:5]=[C:6]2[C:15]=1[CH2:14][CH2:13][C:12]1[CH:11]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:9]=[CH:8][C:7]2=1.BrN1C(=O)CCC1=O.O>C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)=[CH:4][CH:5]=[C:6]2[C:15]=1[CH:14]=[CH:13][C:12]1[CH:11]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:9]=[CH:8][C:7]2=1
Reactant: CCCc1ccc2c(c1)CCc1c-2ccc(-c2cc(F)c(F)c(F)c2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: c1ccccc1
Product: CCCc1ccc2c(ccc3c(F)c(-c4cc(F)c(F)c(F)c4)ccc32)c1

Procedure:
8-fluoro-2-propyl-7-(3,4,5-trifluorophenyl)-9,10-dihydrophenanthrene produced in Example 1 was dissolved in benzene, NBS (N-bromosuccinimide) and AIBN (2,2-azobis isobutyronitrile) were added, and the temperature was gradually raised to benzene reflux temperature. Stirring was then continued for a further 2 hours, before water was added and the reaction halted, and the organic layer was then separated. The aqueous layer was extracted with toluene and this extract was combined with the organic layer, which was then washed with water and a saturated aqueous solution of sodium chloride, before being dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the whole crude product was dissolved in ethyl acetate, and 5% palladium/carbon (wet) was then added, and the mixture was stirred in an autoclave under a hydrogen pressure of 4 Kg/cm2. After 5 hours stirring at room temperature, the catalyst was removed by filtration through celite, and the solvent was then removed by evaporation. The crude product was purified by silica gel column chromatography (hexane) and then recrystallized 3 times from ethanol to yield 8-fluoro-2-propyl-7-(3,4,5-trifluorophenyl)phenanthrene.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:10]2[C:5](=[CH:6][C:7]([N:11]([C:20]([O:22]C(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:9]=2)[C:4]([CH3:28])([CH3:27])[CH2:3]1.FC(F)(F)C(O)=O.[C:37](OCC)(=O)[CH2:38][C:39](C)=O>C(O)(=O)C>[CH3:37][C:38]1[CH2:39][C:20](=[O:22])[N:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[C:2]([CH3:29])([CH3:1])[CH2:3][C:4]3([CH3:28])[CH3:27])[N:12]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2(C)C
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3(C)C)C(=O)C1
Temperature: 100 °C
Yield: 12.5 %

Procedure:
Di-tert-butyl 1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 19c (2.70 g, 7.18 mmol) was dissolved in 10 mL of acetic acid followed by addition of 13 mL of trifluoroacetic acid. After the mixture was reacted at room temperature for 30 minutes, ethyl acetoacetate (502 mg, 3.86 mmol) was added. The reaction mixture was heated to 100° C. and reacted for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The mixture was neutralized by saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-methyl-2-(1,1,3,3-tetramethyl-indan-5-yl)-2,4-dihydro-pyrazol-3-one 19d (130 mg, yield 13.6%) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:24]([O:26]C)=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:12].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:24]([OH:26])=[O:25])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:12]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccc(F)cc2F)C(=O)O)cc1
Yield: 96.7 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 47 (2.9 g), 1 mol/L of an aqueous sodium hydroxide solution (12 mL), and methanol (120 mL), to give the captioned compound (2.7 g, 96%) as crystals.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[NH:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:7]1([CH2:6][CH2:5][O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1CNCCNC1
Reactant: Brc1ccccc1OCCN1CCOCC1
Product: c1ccc(N2CCCNCC2)c(OCCN2CCOCC2)c1

Procedure:
The title compound was prepared in a manner similar to Preparation 63A except that 4-[2-(2-bromo-phenoxy)-ethyl]morpholine was coupled to homopiperazine.