Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[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][CH2:24][CH3:25].[OH:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=1[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]1)=[O:43]>ClCCl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=1[CH2:41][C:42]([N:44]1[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]1)=[O:43])[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][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: COc1cc(CO)c(CC(=O)N2CCN(C)CC2)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCc1cc(OC)c(OC)cc1CC(=O)N1CCN(C)CC1
Reaction time: 15 h

Procedure:
Triethylamine (0.41 ml) and octadecyl isocyanate (0.91 ml) were added to a solution of 2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]-1-(4-methylpiperazinyl)-1-ethanone (0.82 g) in dichloromethane (8.5 ml) at room temperature. After being stirred for 15 hours, resulting insoluble materials were filtrated out under a vacuum and washed with chloroform. A mixture of the filtrate and chloroform used for washing was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-30:1), thereby yielding 0.83 g of the aimed compound as light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([NH:13][NH:12][C:10]1[CH2:9][N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: ClC(Cl)Cl
Product: CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 1 h

Procedure:
To a solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 30 parts by volume of chloroform is added with stirring 0.47 part by volume of acetic anhydride. The mixture is stirred for 1 hour and washed with a saturated aqueous solution of sodium bicarbonate and then with water. The chloroform layer is dried over sodium sulfate and the solvent is evaporated. Addition of methanol yields 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine as white crystals. Recrystallization from a mixture of chloroform and methanol yields powdery crystals melting at 202° C to 204° C (effervescence).
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[K+].[F:7][C:8]([F:22])([F:21])[O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][C:13]2=[O:20]>C(O)(=O)C>[NH:5]=[C:4]1[N:16]2[C:17]3[C:12]([C:13](=[O:20])[CH2:14][CH2:15]2)=[CH:11][C:10]([O:9][C:8]([F:21])([F:7])[F:22])=[CH:19][C:18]=3[S:3]1
Reactant: N#C[S-]
Reactant: O=C1CCNc2ccc(OC(F)(F)F)cc21
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N=c1sc2cc(OC(F)(F)F)cc3c2n1CCC3=O
Yield: 6.3 %

Procedure:
The procedure is carried out as in Example 1, but starting with 2.2 g of bromine in 10 ml of acetic acid, 3.09 g of potassium thiocyanate and 3.2 g of 6-trifluoromethoxy-2,3-dihydro-(1H)-quinolin-4-one in 35 ml of acetic acid. The organic phase is extracted with 170 ml of an approximately 0.1 N aqueous hydrochloric acid solution. The aqueous hydrochloric phase is alkalinized with 4 ml of a 10 N sodium hydroxide solution and extracted with three times 100 ml of ethyl acetate. The organic extracts are combined, washed with 100 ml of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa) at 40° C. The crude product obtained is chromatographed on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (80-20 by volume). The yellow solid isolated (0.3 g) is washed with a cold solution of petroleum ether and of isopropyl ether (60-40 by volume), and is then dried under reduced pressure (70 Pa) at 40° C. 0.25 g of 2-imino-8-trifluoromethoxy-2H,4H-thiazolo-[5,4,3-ij]quinolin-6-one is thus obtained in the form of a yellow powder melting at 192° C. [Analysis C11H7F3N2O2S, % calculated C: 45.84, H: 2.45, F: 19.77, N: 9.72, O: 11.1, S: 11.12, % found C: 45.5, H: 2.1, F: 19.4, N: 9.3, S: 11.1].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:29][CH2:28][CH2:27][C@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]1>>[CH2:25]([O:24][C:22]([C@H:21]1[CH2:27][CH2:28][CH2:29][N:19]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (S)-(+)-nipecotic acid, ethyl ester (TCI America, Portland Oreg., USA) by the method described in Example 2 Method B. Colorless solid (415 mg, 91%). 1H NMR (CDCl3) 1.19 (t, J=7.0, 3H), 1.50-1.60 (m, 1H), 1.66-1.82 (m, 2H), 2.02-2.12 (m, 1H), 2.29 (d, J=1.4, 3H), 2.46-2.56 (m, 1H), 3.13 (t, J=11.0, 1H), 3.28 (br s, 1H), 4.08 (q, J 7.0, 3H), 4.10 (obs m, 1H), 4.34 (br s, 1H), 7.28 (d, J=4.0, 1H), 7.39 (d, J=3.5, 1H). 19F NMR −63.12. LC/MS 6.74 min, [M+1]+ 417.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12]O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: OCCCc1ccc2c(c1)CCO2
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1ccc2c(c1)CCO2
Reaction time: 15 h
Yield: 89.4 %

Procedure:
Compound 76-1 (1.91 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.97 g) and N-bromosuccinimide (2.01 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (2.31 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([CH2:14]S([O-])(=O)=O)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[OH:22].[OH-].[Na+]>>[Cl:29][C:25]1[CH:24]=[C:23]([CH:21]([OH:22])[CH2:20][NH:19][CH:12]([CH3:14])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(C[C@H](C)CS(=O)(=O)[O-])cc1OC
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] was added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol, and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 161 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 46%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the title compound was 95.8% [(R,R)/(R,S)=95.8/4.2].
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH:31]=[CH:30]1.Cl>C1COCC1>[C:16]([C@@H:15]([NH:19][C:29](=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)/C=C/C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of S-trans, trans-farnesyl-L-cysteine (500 mg, 1.54 mmol) in THF and a first portion of K2CO3 (3 mmol) was cooled to 5° C. with vigorous stirring. To this stirred solution was added maleic anhydride (302 mg, 3.07 mmol) portionwise while maintaining the pH at 9.0-10.0 with another portion of K2CO3 (3 mmol). The mixture was stirred at room temperature for 3 h, HPLC analysis showed completion of the reaction. The pH of the reaction mixture then adjusted to 2.0 by the addition of 2 N HCl solution. The acidic solution was extracted three times with 15 mL of ethyl acetate. The combined organic extract was washed with water, brine and dried over Na2SO4 and then concentrated to afford crude Compound A, which was further purified by preparative HPLC (552 mg, 85%) to yield Compound A. 1H-NMR (500 MHz, CD3OD): δ 1.50(bs, 6H), 1.57(s, 3H), 1.59 (s, 3H), 1.85-2.10 (m, 8H), 2.68 (dd, J=6.5, 14.5, 1H), 2.95 (dd, J=4.5, 14.0 Hz, 1H), 3.07 (dd, J=7.0, 13.0 Hz, 1H), 3.17 (dd, J=8.5, 13.5 Hz, 1H), 4.59 (dd, J=4.5, 8.5), 4.97-5.02 (m, 2H), 5.12 (t, J=7.5, 1H), 6.21 (d, J=13.0 Hz, 1H), 6.47 (d, J=13.0 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.2, 16.3, 17.8, 25.3, 26.0, 27.4, 27.8, 30.3, 33.3, 40.8, 40.9, 54.0, 121.5, 125.1, 125.5, 132.1, 133.3, 134.4, 136.3, 140.7, 167.7, 168.0, 172.9; ES-MS: mass calcd for Chemical Formula: C22H33NO5S 423.6. Found (M+Na) m/z 446.
Reaction SMILES: Cl[C:2]1([Cl:8])[NH:7][CH:6]=[N:5][CH:4]=[CH:3]1.CN(C)C=O.[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:8][C:2]1[CH:3]=[C:4]([O:24][C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[F:14])[N:5]=[CH:6][N:7]=1
Reactant: ClC1(Cl)C=CN=CN1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)c(F)c1
Yield: 85.7 %

Procedure:
6,6-dichloropyrimidine (1.000 g, 7 mmol) was dissolved in N,N-dimethylformamide (5 ml, 7 mmol), then 2-fluoro-4-nitrophenol (1 g, 7 mmol) was added into the mixture. Then Cesium Carbonate (2 g, 10 mmol) was added into the mixture with stirring. The mixture was stirred at ambient temperature under nitrogen overnight. The progress of the reaction was monitored by LC/MS, which had confirmed completion. Then diluted the mixture with water was stirred an additional 3 hours. The precipitate was collected by filtration and washed with hexanes. The solid was dried in a reduced-pressure oven overnight to give the desired product 4-chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine (1.500 g, 6 mmol, 83% yield) as a yellow solid. MS (ESI pos. ion) m/z: 270 (MH+). Calc'd exact mass for C10H5ClFN3O3: 269. 1HNMR (300 MHz, CDCl3): 7.14 (s, 1H), 7.43 (s, 1H), 8.14 (s, 2H), 8.55 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[C:5]([N+:24]([O-])=O)[CH:4]=1.O.NN>C(O)C.[Ni]>[NH2:24][C:5]1[CH:4]=[C:3]([C:2]([F:28])([F:1])[F:27])[C:8]([Cl:9])=[CH:7][C:6]=1[NH:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(C(F)(F)F)cc2N)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(4-trifluoromethyl-5-chloro-2-nitrophenyl)amino]-1-piperidinecarboxylate (D61, 6.7 g) was dissolved in ethanol (100 ml) and Raney nickel (50% aqueous suspension, 5 ml) was added at room temperature; the mixture was heated to 50° C. and hydrazine monohydrate (3 ml) was added over 30 min. After 1 h more, the reaction mixture was cooled to room temperature, filtered through Celite, evaporated, re-evaporated from toluene, and the residue crystallised from dichloromethane to yield the subtitle compound, 4.0 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:25]1[CH2:28][C:27]([CH2:31][NH2:32])([CH2:29][NH2:30])[CH2:26]1>>[NH2:30][CH2:29][C:27]1([CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:28][O:25][CH2:26]1
Reactant: NCC1(CN)COC1
Reactant: O=S1CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2ccccc21
Product: NCC1(CNc2cc(N3CCS(=O)c4ccccc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.31 (d, 1 H), 7.85-7.74 (m, 4 H), 7.60-7.55 (m, 2 H), 6.22 (s, 1 H), 5.45 (d, 1 H), 5.11 (d, 1 H), 4.68 (brs, 1 H), 4.65-4.56 (m, 4 H), 4.47 (d, 1 H), 3.91 (m, 2 H), 3.55 (m, 2 H), 3.47 (s, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C(O)(C(F)(F)F)=O.C(#N)C>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[N:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=Cc1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Fc1ccc(N=Cc2cccc(F)c2)cc1

Procedure:
The reaction of 4-fluoroaniline and 3-fluorobenzaldehyde in TFA and acetonitrile provided the N-3-fluorobenzylidene-4-fluoroaniline. The cyclopentadiene was separately prepared from its dimer dicyclopentadiene. The dimer was heated at 180° C. to give monomer, which was reacted with N-3-fluorobenzylidene-4-fluoroaniline in acetonitrile in presence of TFA to provide the desired difluoro compound 100.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].C[O:13]CCOCCO.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:13])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCOCCO
Reactant: O=Cc1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(F)c(O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 2-chloro-4,5-difluoro-benzaldehyde (110, 0.40 g, 2.30 mmol, prepared as described in Example 37) in N,N-dimethylformamide (10.0 mL) were added 2-(2-methoxyethoxy)-ethanol, (0.327 g, 2.72 mmol) and cesium carbonate (0.886 g, 2.72 mmol). The reaction was stirred at 90° C. overnight. The reaction was poured into water, acidified to pH around 5, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (111, 0.24 g, 61.0%). MS (ESI) [M+H+]+=173.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:22]O)=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.CO.[BH4-].[Na+]>C(OCC)(=O)C>[CH:24]1([NH:27][CH2:22]/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: COC(=O)C=Cc1ccc(/C=C(/CO)c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C=Cc1ccc(/C=C(/CNC2CC2)c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of methyl 3-(1E)(4-(2-(4-fluorophenyl)-3-hydroxyprop-1-en-1-yl)phenyl)acrylate (0.44 g, 1.4 mmol) and cyclopropylamine (0.14 g, 2.4 mmol) was stirred with MeOH (40 mL) for 3 hours. To the reaction mixture, sodium borohydride (0.09 g, 2.3 mmol) was added and stirred for 30 minutes. Subsequently the reaction mixture was diluted with ethyl acetate (300 mL) and washed successively with water (2×100 ml) and brine (1×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure title compound as a pale yellow sticky compound (0.4 g, 80% yield).
Reaction SMILES: C(OC([N:11]([N:17]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]2[C:19]([N:20]([CH3:35])[C:21](=[O:34])[N:22]([CH3:33])[C:23]2=[O:32])=[CH:18]1)[CH2:12][CH2:13][C:14](O)=[O:15])=O)C1C=CC=CC=1.[OH-].[Na+]>O>[CH3:35][N:20]1[C:19]2=[C:18]3[C:14](=[O:15])[CH2:13][CH2:12][NH:11][N:17]3[C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:24]2[C:23](=[O:32])[N:22]([CH3:33])[C:21]1=[O:34]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(N(CCC(=O)O)C(=O)OCc3ccccc3)cc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CCN3
Temperature: 25 °C

Procedure:
3-[Benzyloxycarbonyl-(1,3-dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-amino]-propionic acid (step 3) (1.09 g, 2.288 mmol) and Polyphosphoric acid (3 g, 2.288 mmol) were heated together at 100° C. (block temp) for 30 mins. The reaction mixture was cooled to RT and the residue dissolved in minimum volume of water. The mixture was basified by slow addition of 2M NaOH(aq), and extracted with chloroform (4×). The combined organic extracts were passed through a hydrophobic frit and evaporated under reduced pressure. Purification of the residue by chromatography on silica, eluting with MeOH/DCM afforded the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CS(C)=O.C(OCC)(=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1c[nH]cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(F)c1
Temperature: 90 °C
Yield: 92.2 %

Procedure:
A solution of 2.14 g(31.4 mmol) of imidazole and 10.9 g(62.8 mmol) of dibasic potassium phosphate in 190 mL DMSO was treated with 5.25 g(3.7 mL, 50.9 mmol) of 3,4-difluoronitrobenzene followed by warming at 90° C. for 18 h. The solution was diluted with ethyl acetate and was extracted with water. The water layer was back-extracted with ethyl acetate and the combined organic layers were then extracted with water (2×). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a brown solid. This material was chromatographed over 250 g of 230-400 mesh silica gel, eluting with dichloromethane, and then with 1%(v/v) methanol in dichloromethane, and finally with 2%(v/v) methanol in dichloromethane. These procedures afforded 6.0 g(92%) of the title compound as a bronze colored solid. 1H NMR (CDCl3): δ8.17, 7.96, 7.63, 7.35, 7.26.
Reaction SMILES: C1O[C:4]2([CH2:8][CH2:7][CH2:6][CH:5]2[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[O:3]C1.Cl.[OH-].[K+]>>[N:10]1([CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][C:4]2=[O:3])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1cn(CC2CCCC23OCCO3)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C1CCCC1Cn1ccnc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
In an oil bath, 3.5603 g of 2-(lH-imidazol-1-ylmethyl)cyclopentanone ethyleneketal (IV) and 17.8 ml of 2N hydrochloric acid added thereto were stirred at 60° C for 5 hours. The resultant reaction solution was left cooling. Then, it was neutralized with an aqueous lN potassium hydroxide solution and extracted with methylene chloride, to obtain an organic layer. This organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under a reduced pressure.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10](Cl)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].[I-].[Na+]>CC(C)=O>[C:19]([NH:23][CH:10]1[CH2:11][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: ClC1C=CC(c2ccccc2)(c2ccccc2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1

Procedure:
A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.20 g), t-butylamine (2 ml) and a catalytic amount of sodium iodide in acetone (4 ml) was refluxed for 15 hours and cooled. The mixture was evaporated in vacuo and water was added thereto extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (0.15 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].C([Li])(C)(C)C.CN(C)[CH:21]=[O:22]>O1CCCC1>[F:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH:21]=[O:22])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c2[nH]ncc2c1
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc2cn[nH]c12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 112.1 %

Procedure:
To a solution of 7-bromo-5-fluoro-1H-indazole (1.66 g, 7.72 mmol) in tetrahydrofuran (35 mL) at 0° C. was added sodium hydride (0.618 g, 15.4 mmol). The ice bath was removed and stirring continued for 20 min. The solution was cooled to -78° C. and treated with tert-butyllithium (1.7 M in pentane, 9.08 mL, 15.4 mmol) dropwise. The reaction was stirred at −78° C. for 10 min, allowed to warm gradually in the dewar to −50° C., recooled to −78° C., and then treated with dimethylformamide (2.39 mL, 30.9 mmol). After 15 min, the ice bath was removed and stirring continued for 1 h. The reaction was poured onto ice/I M hydrochloric acid (26.5 mL). The mixture was extracted with ethyl acetate (2×). The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.42 g of 5-fluoro-1H-indazole-7-carbaldehyde (quant.) as a light yellow solid. LC/MS (HPLC method 3): tR=1.39 min, 165.17(MH)+.