Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3OC(=O)[S:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:17]([C:27]#[N:28])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[N:28]=[C:27]([S:17]([C:20]4[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[S:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=c1oc(C2(c3ccc(Cl)cc3)CC2)ns1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: CCCCC
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(S(=O)(=O)c2nc(C3(c4ccc(Cl)cc4)CC3)ns2)cc1
Yield: 83.5 %

Procedure:
5.00 g (19.71 mmol) of 5-[1-(4-chlorophenyl)cyclopropyl]-1,3,4-oxathiazol-2-one and 3.75 g (20.69 mmol) of tosyl cyanide are stirred in 14 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled, 10 ml of pentane are added and the precipitate is filtered off and dried under vacuum. 6.43 g of product are obtained (86.7% purity, 72.3% yield; log P (pH2.3)=4.97).
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:20]1([C:26]([N:28]=[C:29]=[O:30])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:26]([NH:28][C:29](=[O:30])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=O)NC(=O)c2ccccc2)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
tert-Butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.116 g, 0.41 mmol, 1 equiv.) and PhCONCO (0.06 mL, 0.5 mmol, 1.2 equiv.) were dissolved in THF (2 mL) and stirred at 50° C. for 16 h. The solvent was removed and the product was purified by preparatory HPLC (0-40% EtOAC:hexanes). The product was isolated as a white solid (0.105 g, 59% yield). 1H NMR (400 MHz, CDCl3) δ 13.26 (s, 1H), 9.81 (s, 1H), 8.13 (d, J=7.0 Hz, 2H), 7.65 (d, J=6.7 Hz, 3H), 4.72 (s, 2H), 2.75 (s, 2H), 1.64 (s, 9H), 1.32 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:3]=1.[Br:27]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[N:13]=2)=[O:9])[C:5]([Br:27])=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:3]=1
Reactant: COCc1cccc(CNC(=O)c2cc(-c3ccc(C)o3)nc(N)n2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: COCc1cccc(CNC(=O)c2nc(N)nc(-c3ccc(C)o3)c2Br)n1
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of 2-amino-N-(6-methoxymethyl-2-pyridylmethyl)-6-(5-methyl-2-furyl)pyrimidine-4-carboxamide (50 mg, 0.142 mmol) in acetic acid (10 mL) at room temperature was treated with N-bromosuccinimide (28 mg, 0.156 mmol), stirred for 2 h, concentrated in vacuo and partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was dried (MgSO4), concentrated in vacuo and the resulting solid was triturated with diethyl ether and filtered to give the title compound (50 mg, 82%) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:12][N:13](C=O)C>CCOCC.[NH4+].[OH-].[C-]#N.[C-]#N.[Zn+2].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>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[C:12]#[N:13]
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOCC
Product: N#Cc1cncc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
3-bromo-5-(trifluoromethyl)pyridine (1.0 g, 4.42 mmol, 1 eq) was dissolved in 20 mL anhydrous DMF. The solution was degassed by bubbling through with Ar. Zn(CN)2 (0.312 g, 2.65 mmol, 0.6 eq) and Pd(PPh3)4 were added, and the resulting solution was heated to 80° C. with stirring overnight. The reaction was cooled to room temperature and diluted with Et2O, NH4OH (28%) was added with stirring and the layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the reaction mixture was concentrated in vacuo. Purification via flash chromatography on silica gel yielded 0.310 g (1.95 mmol, 44% yield) of 5-(trifluoromethyl)nicotinonitrile.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=O)[N:10]2[C:11]([C:17]([OH:19])=O)=[C:12]([CH2:15]O)[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CC(C)=O.O>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[CH:9]2[S:14][CH:13]=[C:12]3[CH2:15][O:19][CH:17]=[C:11]3[N:10]2[CH2:20]1)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1CN2C3=COCC3=CSC12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
A solution of 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6 N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, to the residue was added water (1 ml). The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and ice-cooled for 1 hour. Precipitating crystals were collected by filtration, washed with water and dried to give 6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine-1,7(4H-dione (syn isomer) (0.23 g), mp 210° to 215° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C@@H:33]3[C@@H:37]([OH:38])[CH2:36][CH2:35][NH:34]3)[N:26]=2)[N:4]=1)[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:43](C)=O.[Na+]>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C@@H:33]3[C@@H:37]([OH:38])[CH2:36][CH2:35][N:34]3[CH3:43])[N:26]=2)[N:4]=1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1nn(Cc2cccc(OC[C@H]3NCC[C@@H]3O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1nn(Cc2cccc(OC[C@@H]3[C@@H](O)CCN3C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To N-(3-ethyl-1-((6-(((2R,3S)-3-hydroxypyrrolidin-2-yl)methoxy)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.0098 mmol; prepared as in Example 36) in MeOH (1 mL) was added HCHO as a 35% aqueous solution (16 mg, 0.20 mmol) and NaBH(OAc)3 (10 mg, 0.049 mmol). The reaction mixture was stirred for 30 minutes, concentrated under reduced pressure and purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (4 mg). MS (ES+APCI) m/z=526 (M+H).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3].[OH-].[Na+].[C:17](Cl)(Cl)=[O:18].N1C=CC=CC=1>O.O1CCCC1>[C:8]1([C:7]2[O:14][C:17](=[O:18])[N:4]([CH2:2][CH3:3])[CH2:5][N:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCNCNC(=O)c1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCN1CN=C(c2ccccc2)OC1=O
Reaction time: 2 h

Procedure:
A suspension of 21.5 g of N-(ethylaminomethyl)-benzamide hydrochloride (0.1 mole) in 300 ml of water is neutralised at 0°-25°C with 50 ml of 2 normal sodium hydroxide solution (0.1 mole). Extraction is performed with ethyl acetate, the organic phase is dried over magnesium sulphate and the solvent is evaporated off. The residue is taken up in 150 ml of tetrahydrofuran and the solution is treated dropwise with 9.9 g of phosgene (0.1 mole) in 150 ml of tetrahydrofuran. The addition is effected at 0°-25°C over the course of 1 hour. Then a solution of 15.8 g (0.2 mole) of pyridine in 150 ml of tetrahydrofuran is added over the course of a further hour. Stirring of the reaction mixture is continued for 2 hours and it is then refluxed for 3 hours. After the reaction mixture has cooled, the precipitate which has formed is filtered off and the filtrate is evaporated to dryness. The residue is taken up in chloroform and washed first with sodium bicarbonate solution and then with water. The solvent is evaporated off and crystallisation of the residue from ethyl acetate/n-hexane yields 6-phenyl-3-ethyl-3,4-dihydro-2H-1,3,5-oxadiazin-2-one with a melting point of 96°-98°C (compound 1).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Li+].Cl>CO.O>[N:26]1[C:27]2[C:22](=[CH:21][C:20]([CH2:19][N:16]3[C:14]4=[N:15][C:10]([C:7]5[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][CH:6]=5)=[CH:11][CH:12]=[C:13]4[N:18]=[N:17]3)=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
To a solution of Example 7 (0.095 g. 0.240 mmol) in methanol (1.4 ml), lithium hydroxide (0.028 g, 1.20 mmol) in water (0.36 ml) was added and stirred at RT. After 12 h, the pH was adjusted to (approx) 7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.070 g, 76%). M.P.: 245-247° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.18 (s, 1H), 8.88 (dd, J=4.1, 1.7 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.39 (d, J=1.1 Hz, 1H), 8.36 (d, J=8.5 Hz, 2H), 8.21 (d, J=8.7 Hz, 1H), 8.10 (d, J=8.5 Hz, 2H), 8.03 (d, J=9.2 Hz, 2H), 7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd. J=8.4, 4.2 Hz, 1H), 6.22 (s, 2H). MS (m/z): 381.88 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:8]2[CH:9]3[CH2:12][CH2:13][CH:7]2[C:6]([CH3:14])([C:10]3=C)[CH2:5][CH2:4][CH2:3]1.Br[CH2:17]C(O)=O>>[CH:2]([C:8]12[CH2:10][C:6]3([CH3:14])[C:7]([CH3:17])([CH2:13][CH2:12][CH2:9]1)[CH:3]2[CH2:4][CH2:5]3)([CH3:1])[CH3:15]
Reactant: O=C(O)CBr
Reactant: C=C1C2CCC3C2C(C)(C)CCCC13C
Product: CC(C)C12CCCC3(C)C1CCC3(C)C2
Yield: 134.7 %

Procedure:
In a 2 L four-necked flask, 1,000 g of longifolene (manufactured by Yasuhara Chemical Co., Ltd.) and 100 g of bromoacetic acid were placed and reacted at 170° C. for 18 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and with water and then refined by distillation. Thereafter, the refined product was placed in a 2 L autoclave together with 18 g of a palladium-carbon hydrogenation catalyst and subjected to hydrogenation (hydrogen pressure: 6 MPa, reaction temperature: 100° C., reaction time: 2 hours). After completion of the reaction, the catalyst was removed by filtration. The filtrate was subjected to fractional distillation to obtain 200 g of the desired 4-isopropyl-1,7a-dimethyl-octahydro-1,4-methano-indene (Fluid 3). The results of the measurements of the properties and the traction coefficient are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17].C1CCN2C(=NCCC2)CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:19]([CH3:21])([N+:16]([O-:18])=[O:17])[CH3:20])[CH2:9][C:8]2=[O:13])=[CH:14][CH:15]=1
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Reactant: CC(C)[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Reaction time: 48 h

Procedure:
To a solution 1-(4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (see Step 3 of Example 1) (0.75 g, 3.65 mmol) in 2-nitropropane (9.77 g, 109 mmol) was added DBU (0.56 g, 3.65 mmol). After stirring for 48 hours, the reaction mixture was concentrated under vacuum. The residual material was purified using silica gel column chromatography eluting with CH2Cl2. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.44 (m, 2H), 7.04 (t, J=9 Hz, 2H), 4.64 (d, J=15 Hz, 1H), 4.43 (d, J=15 Hz, 1H), 3.23 (m, 2H), 2.56 (m, 2H), 2.22 (m, 1H), 1.73 (m, 1H), 1.56 (s, 6H), 1.51 (m, 1H) ppm. ES MS M+1=295.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:22][CH3:23])[C:15]([O:17]C(C)(C)C)=[O:16])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:22][CH3:23])[C:15]([OH:17])=[O:16])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
543 mg (purity 59%, 0.86 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]butanoate (racemate) were hydrolysed with 20 eq. of TFA according to General Method 6A. Yield: 425 mg (purity 60%, 94% of theory)
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(OCC)(=O)C.CO>CC#N>[C:18]([C:4]1[CH:3]=[N:2][NH:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: C1=Cc2ccccc2NN=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: CC(=O)C1=Cc2ccccc2NN=C1
Temperature: 18.5 °C
Yield: 95 %

Procedure:
To a suspension of benzodiazapine (92.0 g, 0.62 mole) and K2CO3 (90.2 g, 0.65 mole, −325 mesh) in CH3CN (1000 ml) was added acetic anhydride (63.4 g, 58.6 ml, 0.62 mole) in 0.5 h (reaction mixture was cooled in ice water to maintain the reaction mixture temperature between 15-22° C.). The suspension was stirred for 0.5 h at room temperature (check TLC after 30 min, eluent ethyl acetate:MeOH 9:1). The reaction mixture was evaporated and to the residue water (400 ml) was added. The suspension was cooled in ice, filtered, washed with cold water (50 ml×2). Dried under vacuum to give 109.7 g of 4-acetylbenzodiazepine as a white solid, yield 93%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[C:14]2[C:9](=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=1)#[N:4]>C(O)C>[C:3]([CH:5]1[C:14]2[C:9](=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:6]1)#[N:4]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2C#N
Yield: 82.4 %

Procedure:
Sodium borohydride (6.8 g) was added to a suspension of 6.8 g (23.3 mmol) of 1-cyano-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene, from Step 1, in 100 mL of absolute ethanol and the reaction mixture was heated at reflux temperature for 1.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N aqueous hydrochloric acid solution, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was triturated with heptane to give 5.63 g (82% yield) of the title compound as a white crystalline solid, m.p. 118°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[N:13]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([Cl:22])=[O:18])[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a suspension of (E)-3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acrylic acid (5.7 g, 19 mmol) in DCM (20 mL) was added oxalyl chloride (4.8 g, 38 mmol) and 2 drops of DMF. The resulting mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure to give the crude desired product (6.0 g, 99% yield), which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][C@@H:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][C@@H:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:17])([F:18])[F:19])[C:7]([OH:9])=[O:8]
Reactant: Cc1cccc2c1NC(=O)[C@@H](NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)OC(C)(C)C)N=C2c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2c1NC(=O)[C@@H](NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O)N=C2c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 250 mL round-bottomed flask, a solution of Intermediate 1A (3.7 g, 5.86 mmol) in DCM (25 mL) was treated with TFA (25 mL) and the resulting pale orange solution was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated to give Intermediate 1B. HPLC: RT=3.12 min (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm). MS(ES): m/z=576.3 (M+H)+. 1H NMR (400 MHz, methanol-d4) δ 7.54 (t, J=4.5 Hz, 1H), 7.49-7.29 (m, 3H), 7.28-7.15 (m, 3H), 5.38 (br. s., 1H), 2.89 (td, J=10.3, 3.7 Hz, 1H), 2.67 (td, J=9.9, 4.2 Hz, 1H), 2.56-2.38 (m, 1H), 2.48 (s, 3H), 2.34-2.13 (m, 3H), 2.00-1.71 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
8.1 g (18.1 mmol) 2-[8,8-bis-(4-fluorophenyl)-octyl]-isoindol-1,3-dione and 1.8 ml (37.0 mmol) hydrazine hydrate are heated under reflux in 50 ml ethanol for two hours. The cooled solution is concentrated under vacuum and the residue is purified by chromatography over silica gel with CHCl3/CH3OH/TEA (98/2/2): Yield 2.4 g (42%).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:34][CH2:35][CH3:36])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:27]([N:17]([C:18](=[O:26])[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:9]([CH2:34][CH2:35][CH3:36])=[N:10][C:11]=2[CH:16]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(4-fluoro-benzoyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ8.02 (m, 1H), 7.29 (m, 7H), 7.01 (m, 3H), 6.87 (m, 1H), 5.11 (s, 2H), 4.98 (s, 2H), 2.68 (t, 2H), 1.71 (m, 2H), 0.95 (t, 3H). MS calculated for C26H24FN3O3+H: 446, observed: 446.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([CH3:9])=O)[CH3:2].[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:7]([CH3:9])=[N:20][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccccc1
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)nn(-c2ccccn2)c1-c1ccccc1
Yield: 64.4 %

Procedure:
6.0 grams 3-benzoyl-levulinic acid ethyl ester, 2.7 grams 2-hydrazino-pyridine and 25 milliliters glacial acetic acid were mixed and the mixture was heated to the boiling temperature under reflux for 3 hours. The reaction mixture was worked up by a procedure analogous to that described above. 5.0 grams 3-methyl-5-phenyl-1-(2-pyridyl)-pyrazol-4-acetic acid ethyl ester, melting at 89°-90° C., were obtained, representing a yield of 64%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].C(N(CC)CC)C.[F:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]([CH2:28][C:29](=O)[CH2:30][CH2:31][N:32]([O:34][CH3:35])[CH3:33])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:23]([O:22][C:21]([N:20]([CH2:28][CH:29]([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:30][CH2:31][N:32]([O:34][CH3:35])[CH3:33])[CH2:19][C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:38][CH:37]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CON(C)CCC(=O)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNC(CCN(C)OC)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of glycine methyl ester (2.78 g, 22.1 mmol) in anhydrous THF (13.5 mL) was treated with triethylamine (3.03 mL, 21.6 mmol), tert-butyl 4-fluorobenzyl{4-[methoxy(methyl)amino]-2-oxobutyl}carbamate (1.50 g, 4.23 mmol) in anhydrous THF (8.5 mL), sodium triacetoxyborohydride (5.11 g, 24.1 mmol), and acetic acid (485 μL, 8.46 mmol). The mixture was stirred at ambient temperature under inert atmosphere for 42 h. Saturated aqueous NaHCO3 solution was added and the mixture was stirred until gas evolution ceased. The mixture was extracted into EtOAc, and the aqueous layer was saturated with NaCl and extracted into EtOAc again. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to a pale yellow oil. Purification by silica gel chromatography using gradient elution (hexanes to 40% EtOAc/hexanes to EtOAc) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.19 (br s, 2H), 7.02-6.98 (m, 2H), 4.56-4.37 (m, 2H), 3.72 (s, 3H), 3.49 (s, 3H), 3.39 (br s, 2H), 3.05 (br s, 1H), 2.97 (br s, 1H), 2.66 (br s, 2H), 2.55 (s, 3H), 1.68-158 (m, 4H), 1.47 (br s, 9H). ES MS (M+1)=428.4.