Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(OCC)C.C([Li:21])(C)(C)C>CCCCC>[F:1][C:2]1[C:7]([Li:21])=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: Fc1cc(F)c(F)c(F)c1F
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Temperature: -65 °C

Procedure:
Inside of a 100 ml volume glass three-neck flask equipped with a 50 ml volume glass dropping funnel, temperature resistor and septum rubber was sufficiently replaced with nitrogen. Into the flask, 5 g (29.8 mmol) of pentafluorobenzene and 30 ml of diethyl ether were charged, of which solution was cooled to -65° C. Thereafter, 12.3 g (29.8 mmol) of 15.5 wt. % pentane solution of tert-butyllithium charged into the dropping funnel were added dropwise while making the inner temperature not to exceed -55° C. After the completion of dropwise addition, the reaction mixture was kept at a temperature of -65°~-55° C. with stirring to give pentafluorophenyllithium.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(N(Cc2ccccc2)Cc2ccccc2)C(OC)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of racemic ethyl 4-amino-3-methoxypiperidine-1-carboxylate (1 part by mole) in DMF were added benzyl bromide (about 2.2 part by mole), potassium carbonate (about 2.4 part by mole) and potassium iodide (about 0.2 part by mole) respectively. The reaction was heated to about 80° C. After about 6 hours, the reaction was slowly diluted with water (about 12 parts by volume) and extracted with, for example, ethyl acetate. The organic layer was washed with brine and then dried over anhyh. Na2SO4. Subsequent filtration and concentration of the solvent provided the 1 as the yellow-orange oil (1 part by mole).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=O)[CH:7]=1.[C:22](#N)[CH3:23].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH2:21]([O:20][C:3]1[CH:4]=[C:5]([Cl:19])[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:7][C:2]=1[Br:1])[CH:22]=[CH2:23]
Reactant: CC#N
Reactant: CCOc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1Br
Temperature: 0 °C

Procedure:
To a stirred −10° C. solution of (5-Bromo-2-chloro-4-methoxyphenyl)(4-ethoxyphenyl)methanone (54.3 mmol) from Step 4 in dichloromethane (150 mL)/acetonitrile (150 mL) was added triethylsilane (20 mL, 109 mmol) followed by boron trifluoride diethyl etherate (16 mL, 109 mmol) at −10° C. The solution was allowed to warm to 0° C. over 2 h prior to quenching with saturated sodium carbonate solution. After removal of organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and water. Following extraction of the aqueous layer with ethyl acetate, the combined organic layers were washed with water prior to drying over magnesium sulfate. Filtration and concentration under reduced pressure yielded the title compound as a yellowish solid which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[NH:9][N:8]=2)[CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:9]([C:30]([C:28]3[S:29][C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[CH:26][CH:27]=3)=[O:31])[N:8]=2)[CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: Oc1ccccc1C1CC(c2cccnc2)=NN1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccn2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (1.01 g, 4.22 mmol) and 5-pyridin-2-ylthiophene-2-carboxylic acid (0.886 g, 4.32 mmol) in DCM (50 mL) was added EDCI (0.970 g, 5.10 mmol). The reaction mixture was allowed to stir at rt overnight. The solution was filtered and the resulting precipitate was washed with DCM to give a light tan solid. The filtrate was concentrated and the resulting residue was purified by column chromatography to give a yellow solid. The two batches of product were combined to give 2-{3-pyridin-3-yl-1-[(5-pyridin-2-yl-2-thienyl)carbonyl]4,5-dihydro-1H-pyrazol-5-yl}phenol (I-76) (1.293 g, 72%) as a tan solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 9.71-9.84 (bs, 1H), 9.11-9.16 (m, 1H), 8.72-8.77 (m, 1H), 8.60-8.65 (m, 1H), 8.35-8.42 (m, 1H), 8.06 (d, 1H), 8.01-8.04 (m, 1H), 7.84-7.94 (m, 2H), 7.66-7.73 (m, 1H), 7.34-7.41 (m, 1H), 7.04-7.12 (m, 1H), 6.93-6.99 (m, 1H), 6.82-6.87 (m, 1H), 6.73 (t, 1H), 5.87 (dd, 1H), 3.92 (dd, 1H), and 3.22 (dd, 1H). LCMS: (FA) ES+ 427.5, ES-425.4.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11])#[N:2].[S:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>O1CCCC1>[F:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10]([N:16]2[CH2:17][CH2:18][S:14][CH2:15]2)(=[O:12])=[O:11])[C:3]=1[C:1]#[N:2]
Reactant: C1CSCN1
Reactant: N#Cc1c(F)cccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1S(=O)(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
440 mg of 2-cyano-3-fluoro-benzenesulfonyl chloride in 10 ml of tetrahydrofuran are treated with 0.36 ml of thiazolidine and the mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated in vacuo. Purification by Flash chromatography (eluent: cyclohexane/ethyl acetate 1:1) followed by acidic washing with a 1M HCl solution affords 318 mg of 2-fluoro-6-(thiazolidine-3-sulfonyl)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.NN.C1CN([P+](O[N:45]2[N:53]=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:6]([CH2:8][C:9]([NH:45][NH2:53])=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (23.6 mg, 0.066 mmol) and hydrazine (6.3 uL, 0.13 mmol) in 1 mL of DMF were added PyBOP (69 mg, 0.13 mmol) and triethylamine (31 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour. The crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a white solid (5.0 mg, yield 16%). MS calcd for (C15H17BN4O5S): 376.1. MS found (ESI negative): (M−H)−=375.1. 1H NMR (DMSO-d6) δ (ppm): 10.4 (bs, 1H), 9.74 (s, 1H), 9.11 (bs, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.34 (m, 2H), 5.89 (bs, 2H), 4.81 (s, 2H), 3.76 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[C:13]([Si:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(F)cc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenol (35, 5.00 g, 38.4 mmol) in N,N-dimethylformamide (100 mL) were added tert-butyldimethylsilyl chloride (7.00 g, 46.4 mmol) and imidazole (6.28 g, 92.2 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane. The appropriate fractions were combined and concentrated to provide the compound (36, 7.50 g, 80.0%). MS (ESI) [M+H+]+=245.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[CH3:16][C:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>O1CCCC1>[CH3:16][C:17]1([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]4[CH:11]([C:12](=[O:15])[NH:13][N:14]=3)[CH2:10]4)=[CH:6][CH:7]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: C1CCOC1
Product: CC1(C(=O)Nc2ccc(C3=NNC(=O)C4CC34)cc2)CC1
Yield: 53.3 %

Procedure:
6.0 g (29.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, 4.2 g (35.4 millimoles) of 1-methylcyclopropanecarboxylic acid chloride and 150 ml of absolute tetrahydrofuran are refluxed for 7 hours. The product is filtered off at 10° C., washed with water and recrystallized twice from a dimethylformamide/water mixture. 4.5 g (53% of theory) of 2-[p-(1-methylcyclopropylcarbonylamino)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as pale beige crystals, of melting point 253°-255° C.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[OH-].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.Cl>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(S)cc1
Reactant: Ic1cccs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc(Sc2cccs2)cc1
Temperature: 135 °C
Yield: 68.9 %

Procedure:
To a degassed mixture of 2-iodothiophene (0.87 mL, 7.88 mmol), Cu2O (0.56 g, 3.9 mmol) and KOH (0.44 g, 7.8 mmol) in DMF (7.8 mL) was slowly added 4-fluorobenzenethiol (0.33 mL, 7.8 mmol). The resulting mixture was heated at 135° C. for 15 h, allowed to cool to room temperature and poured into a 0° C. 6N HCl solution. After 15 min. the precipitate was filtered and washed with benzene. The filtrate was extracted with benzene, dried (MgSO4) and concentrated under reduced pressure to give 2-(4-fluorophenylthio)thiophene (1.13 g, 69%) as a pale yellow oil: TLC (10% EtOAc/hex) Rf 0.49; HPLC ES-MS m/z (rel intensity) 210 (M+, 100).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:51]=[CH:52][CH:53]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]([CH2:27][CH2:28][O:29][CH3:30])[CH2:23][CH2:24][O:25][CH3:26])[CH:19]=[CH:18][C:17]=2[NH:31][C:32]([C:34]2[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=2)[CH2:37][S:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[O:33])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:55][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([CH:51]=[CH:52][CH:53]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]([CH2:27][CH2:28][O:29][CH3:30])[CH2:23][CH2:24][O:25][CH3:26])[CH:19]=[CH:18][C:17]=2[NH:31][C:32]([C:34]2[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=2)[CH2:37][S:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:33])[CH:11]=1)=[O:9]
Reactant: COCCN(CCOC)c1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(CCOC)c1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(bis(2-methoxyethyl)amino)phenyl)-carbamoyl)benzylthio)propanoate (160 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (8 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (125 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 81.1 mg (41%) of as a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.86 (s, 1H), 9.49 (t, J=5.7 Hz, 1H), 8.94 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 8.12 (d, J=6.5 Hz, 1H), 7.82 (s, 2H), 7.71 (m, 2H), 7.62 (m, 5H), 7.15 (d, J=2.4 Hz, 1H), 6.90 (m, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.87 (s, 2H), 3.56 (m, 8H), 3.27 (s, 6H), 2.63 (m, 2H), 2.51 (m, 2H). MS (ES, m/z): 725 [M+H]+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.CS(C)=O.[NH2:17][C:18]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][S:20][CH:19]=1>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:17][C:18]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][S:20][CH:19]=1)=[O:4]
Reactant: CCOc1cscc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cscc1NC(=O)c1ccccc1N

Procedure:
A mixture of 14.4 g. of isatoic anhydride, 22 ml. of dimethylsulfoxide and some ground glass is stirred and put in an oil bath at 120° C. A mixture of 12.6 g. of 3-amino-4-ethoxythiophene in 17 ml. of dimethylsulfoxide is added dropwise over 30 minutes at 120°-129° C. The mixture is heated at 125°-129° C. for one hour, cooled, poured into ice and water and extracted with dichloromethane. The extract is dried over magnesium sulfate, filtered and evaporated to an oil. This oil is dissolved in methanol, filtered, cooled and a few drops of water are added. The solid is removed by filtration and the filtrate is evaporated to an oil. This oil is dissolved in methanol, a few drops of water are added and the mixture is chilled overnight. The solid is collected by filtration giving o-amino-N-(4-ethoxy-3-thienyl)-benzamide.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br.CC(O)=[O:14]>>[OH:14][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[C:1](=[O:10])[CH:2]=[CH:3]2
Reactant: O=C1C=Cc2ccccc21
Reactant: CC(=O)O
Agent: Br
Product: O=C1C=Cc2cc(O)ccc21

Procedure:
The indenone compound prepared in Step 5 is mixed with HBr/AcOH (1:2), and then the resulting mixture is allowed to reflux for 14 to 16 h with stirring, to obtain the 5-hydroxyindenone of formula 19.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1.CO>ClCCl>[NH:12]1[C:16]2=[N+:17]([O-:9])[CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CO
Solvent: ClCCl
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(Antonini, Ippolito; Claudi, Francesco; Cristalli, Gloria; Franchetti, Palmarisa; Grifantini, Mario; Martelli, Sante; J. Med. Chem. 1982, 25(10), 1258-1261) 540 g (2.35 mol) of 3-chloroperbenzoic acid are dissolved in 6.11 l of dichloromethane, and the water that separates off is removed. The organic phase is dried over sodium sulfate and cooled to 0° C. A solution of 163 g (1.38 mol) of 1H-pyrrolo[2,3-b]pyridine (Hands, D.; Bishop, B.; Cameron, M.; Edwards, T. S.; Cottrell, I. F.; Wright, S. H. B.; Synthesis 1996 (7), 877-882) in 1.00 l of dichloromethane is then added, and the temperature is allowed to rise to room temperature. After 2 hours, such an amount of methanol is added that the precipitate formed redissolves. The mixture is filtered through silica gel (mobile phase: dichloromethane/methanol 95:5). After concentration, the product fractions are dried under high vacuum.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:24])[CH:14]=2)[N:9]=1.O>CN(C=O)C>[Cl:24][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([S:1][CH2:2][CH2:3][OH:4])[N:17]=[C:16]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCSc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 86 mg of 2-mercaptoethanol in DMF (7.5 ml) was added 44 mg of sodium hydride (60%), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3), followed by stirring at room temperature for 2 hours. The reaction solution was poured into 100 ml of water and extracted with ethyl acetate. The resultant extract was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 266 mg of the titled compound. Mp.124.4° C. 1H NMR (CDCl3): 3.50 (2H, t, J=5.5 Hz), 3.64 (1H, br. t), 4.07 (2H, q-like, J=5.5 Hz), 7.57-7.61 (3H, m), 7.71-7.74 (2H, m), 7.77 (1H, dd, J=8.9, 2.3 Hz), 7.85 (1H, d, J=8.9 Hz), 7.97 (1H, d, J=2.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[CH2:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCC>[CH2:31]([N:30]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Nc1cccc(Br)c1)Oc1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 1.46 g. of phenyl N-(3-bromophenyl)carbamate in 15 ml. of tetrahydrofuran is added to a solution of 2.32 g. of dibenzylamine in 20 ml. of tetrahydrofuran and the mixture is stirred under reflux for 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords 1,1-di-benzyl-3-(3-bromophenyl)urea, m.p. 102°-103° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.[C:44]([O:48][C:49]([N:51]1[CH2:55][CH:54]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=2)[CH:53]([C:64](O)=[O:65])[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl>[Cl:63][C:58]1[CH:57]=[C:56]([CH:54]2[CH:53]([C:64]([N:40]3[CH2:39][CH2:38][N:37]([C:35]4[C:36]5[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:42][CH2:41]3)=[O:65])[CH2:52][N:51]([C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])[CH2:55]2)[CH:61]=[CH:60][C:59]=1[Cl:62]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4CN(C(=O)OC(C)(C)C)CC4c4ccc(Cl)c(Cl)c4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (35 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (50 mL) and washed with brine (5×50 mL). The organic phase was dried and concentrated to afford tert-butyl 3-(3,4-dichlorophenyl)-4-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (LCMS (APCI+) [M+H]+576.1; Rt: 2.90 min). The product was treated with 4N HCl in dioxane to afford (4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone as the HCl salt (30 mg, 64%).
Reaction SMILES: C(OC([N:8]([C:28]1[CH:40]=[CH:39][C:31]([C:32](N2C=CN=C2)=[O:33])=[CH:30][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=O)(C)(C)C.[OH-].[Na+].[NH2:43][CH2:44][CH:45]([OH:48])[CH2:46][OH:47]>C(Cl)(Cl)Cl>[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:28]1[CH:40]=[CH:39][C:31]([C:32]([NH:43][CH2:44][CH:45]([OH:48])[CH2:46][OH:47])=[O:33])=[CH:30][CH:29]=1)([O:26][CH3:27])=[O:25]
Reactant: NCC(O)CO
Reactant: COC(=O)CCCCCCCCCCCCCCCN(C(=O)OC(C)(C)C)c1ccc(C(=O)n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)NCC(O)CO)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-[N-(t-butyloxycarbonyl)-N-(15-carbomethoxypentadecyl)amino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. and 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield the product as a light yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:7]=1.[NH2:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][N:13]=[C:8]2[CH2:9][CH3:10]
Reactant: NN
Reactant: CCC(=O)c1cc(Br)ccc1F
Product: CCc1n[nH]c2ccc(Br)cc12
Temperature: 72.5 °C
Yield: 40 %

Procedure:
To 1-(5-bromo-2-fluorophenyl)propan-1-one (10 g, 43 mmol), anhydrous hydrazine (53 mL) was added and heated at reflux (70-75° C.) for 2 days. Excess hydrazine was distilled out under vacuum from the reaction mixture. To this was added xylene (60 mL) and the mixture heated to 145-150° C. for 3 days. Xylene was concentrated completely under vacuum to give a crude product, which was purified by column chromatography using 8% ethyl acetate/pet-ether as eluents to afford 5-bromo-3-ethyl-1H-indazole (4 g, 40%) as a solid. 1H NMR (CDCl3): δ 9.6-10.0 (br, 1H), 7.9 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 3.0 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10](=O)/[CH:11]=[CH:12]/N(C)C)[C:7]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:5]=1[NH:21][C:22](=[O:24])[CH3:23].[CH3:26][O:27][CH2:28][CH2:29][NH:30][NH2:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[N:30]([CH2:29][CH2:28][O:27][CH3:26])[N:31]=[CH:12][CH:11]=2)[C:7]([C:17]([F:18])([F:20])[F:19])=[CH:6][C:5]=1[NH:21][C:22](=[O:24])[CH3:23]
Reactant: COC(=O)c1cc(C(=O)/C=C/N(C)C)c(C(F)(F)F)cc1NC(C)=O
Reactant: COCCNN
Solvent: Cc1ccccc1
Product: COCCn1nccc1-c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 40 h
Yield: 54.7 %

Procedure:
A mixture of 2-acetylamino-5-((E)-3-dimethylamino-acryloyl)-4-trifluoromethyl-benzoic acid methyl ester (600 mg, 1.67 mmol) and (2-methoxy-ethyl)-hydrazine (151 mg, 1.68 mmol) in toluene (10 mL) was stirred at 90° C. for 40 h. Four portions of (2-methoxy-ethyl)-hydrazine (one equiv each day) were added over 4 d and the mixture was kept at 90° C. The mixture was concentrated to dryness in vacuo. The crude product was purified by flash chromatography (silica gel, DCM/MeOH (100:0 to 60:40)) to provide the title compound as a yellow syrup (352 mg, 55%). ES-MS: m/z 386.3 [M+H]+, rt 5.50 min.