Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH3:18][C:19]1([CH3:26])[CH2:22][CH:21]([C:23](Cl)=[O:24])[CH2:20]1>O1CCCC1.Cl.[Cu](I)I>[CH3:18][C:19]1([CH3:26])[CH2:22][CH:21]([C:23]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[O:24])[CH2:20]1
Reactant: CC1(C)CC(C(=O)Cl)C1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: I[Cu]I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 74.2 %

Procedure:
In a 3-neck flask at −30° C. (monitored with thermocouple) containing ethyl 4-iodobenzoate (25.0 g, 89.0 mmol) in anhydrous tetrahydrofuran (148 mL) was added isopropylmagnesium chloride (51.0 mL, 20.4 mmol) dropwise over 30 min. and then stirred at the same temperature for another 105 min. Copper iodide (5.07 g, 26.6 mmol) was then added quickly in one portion. The mixture was brought to −20° C. for 25 min. to ensure the solid has dissolved. The reaction is then brought back to −40° C. 3,3-dimethylcyclobutanecarbonyl chloride (15.6 g, 106 mmol) was then added over 5 min. the reaction was then warmed to 0° C. over 4 h. The mixture was then diluted with 1 N HCl and extracted three times with ethyl acetate. The combined organic layers were then washed two times with brine and then dried over sodium sulfate, filtered, and concentrated to provide 26.6 g of crude brown oil. Purification by silica gel flash chromatography twice (0-5% ethyl acetate in heptane) afforded ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (17.2 g, 74% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 8.11 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.89 (quin, J=8.8 Hz, 1H), 2.27-2.14 (m, 2H), 2.12-2.02 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.27 (s, 3H), 1.08 (s, 3H). MS (M+1): 261.2.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1cccc(F)c1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cccc(-c2nc(-c3cccnc3)no2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.51-7.67 (m, 2 H), 8.08-8.14 (m, 1 H), 8.18 (ddd, J=10.7, 7.5, 2.0 Hz, 1 H), 8.55 (dt, J=8.0, 1.9 Hz, 1 H), 8.74 (dd, J=5.2, 1.6 Hz, 1 H), 9.29 (dd, J=2.4, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:54])[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in pyridine (2 mL) was added benzoyl chloride (0.046 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave a solid which was isolated by filtration. (0.069 g, 55% yield): 1H NMR (DMSO-d6) δ 14.10 (br s, 1H), 13.44 (br s, 1H), 10.50 (s, 1H), 8.74 (s, 1H), 8.48 (s, 1H), 8.03 (td, 4H), 7.74 (m, 2H), 7.58 (m, 4H); ES-MS (m/z) 381 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C:11]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Brc1cc(Br)cc(-c2nc3ccccc3n2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g (75.8 mmol) of 3,5-dibromobenzaldehyde and 16.8 g (90.9 mmol) of N-phenyl-o-phenylenediamine were dissolved in 150 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. Next, 37 g (83.4 mmol) of lead(IV) acetate was added thereto. The resulting product was agitated at 50° C. for 1 hour. Then, water was poured into the obtained reactant. The resulting product was treated with ethyl acetate to perform extraction and the solvent was removed under a reduced pressure. The extract was separated through a column and dried, obtaining 9.5 g (Y=29%) of a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O>[NH2:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11]
Reactant: Cc1cc(Cl)cc(N)[n+]1[O-]
Reactant: C1CCNCC1
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCCCC2)cc(N)[n+]1[O-]
Temperature: 155 °C
Yield: 55 %

Procedure:
A quantity (1.50 g., 0.0077 mole) of 2-amino-4-chloro-6-methylpyridine-1-oxide hydrochloride (prepared in Part B, above) with 6.0 ml. piperidine, and 10.0 ml. water was sealed in a reinforced bottle and heated in an oil bath at the temperature 155° C. for 3.5 hrs. The aqueous reaction mixture was then cooled to 25° C. and diluted with 50 ml. water. The diluted reaction mixture was then extracted with three 50.0 ml. portions of chloroform. The combined chloroform extracts were treated with charcoal, dried over anhydrous sodium sulfate, filtered, and the chloroform was removed by evaporation under reduced pressure. The solid residue thus obtained was crystallized from acetone to give 0.88 g. (55% yield) of 2-amino-6-methyl-4-piperidinopyridine-1-oxide as off-white needles having a melting point at 260° C. (with decomposition). The crystals sinter at about 250° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH2:30](O)[CH2:31]CC>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:28][CH2:30][CH3:31])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: CCCCO
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 8.4 %

Procedure:
A solution of the compound (0.050 g, 0.12 mmol) of Example 108, 1-butanol (0.50 mL, 5.5 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 1.5 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0044 g, y. 6%).
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:59]([SH:67])(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O1CCCC1.C(OCC)(=O)C>[C:59]([S:67][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)[CH2:3]1)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(S)c1ccccc1
Reactant: Cn1nnnc1SC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nnnc1SC[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.23 g) and triphenylphosphine (1.23 g) in tetrahydrofuran (25 ml) was added dropwise a solution of diethyl azodicarboxylate (0.74 ml) in tetrahydrofuran (2 ml) under ice-cooling. After stirring at the same temperature for 30 minutes, to the solution was added thiobenzoic S-acid (0.55 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (19:1, V/V). The fractions containing the resired compound were collected and evaporated in vacuo to give (2S,4S)-4-benzoylthio-2-(1-methyl-1H-tetrazol- 5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.61 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][C:3]=1[O:13]C.N[C:16]1C=CC(O)=C(C)C=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH3:16])=[C:3]([OH:13])[CH:4]=2)[N:9]=1
Reactant: COc1cc2ccc(C)nc2cc1Cl
Reactant: Cc1cc(N)ccc1O
Product: Cc1ccc2cc(O)c(C)cc2n1

Procedure:
Compound 2B was prepared following the procedure used to prepare compound 1B of Example 1, except that 4-amino-2-methylphenol (2A) was used instead of compound 1A. LCMS-ESI+ (m/z): 174.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23](O)=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(Cl)(=O)C([Cl:31])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23]([Cl:31])=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)O)O2
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)Cl)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
201.0 g (0.57 mole) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid was dissolved in 1.0 L toluene and transferred to a 3 L three necked flask equipped with a Dean-Stark trap and condenser, magnetic stirrer and a thermometer connected to a heating mantle. The solution was refluxed 1 hour with no appreciable amount of water collecting in the Dean-Stark trap. This was removed, and the solution was cooled to 50° C. Then a pressure equalizing addition funnel was placed on top and the oxalyl chloride 58.5 mL (0.68 mole, 1.2 equiv.) was added dropwise at about one drop per second. The color became orange, and the temperature increased to about 60° C. as gas evolution began smoothly. The rate of addition was monitored so that gas evolution was not too vigorous. The gas evolved was bubbled through two aqueous sodium hydroxide traps. The slow addition was continued over about 1 hour and then heating was applied with a thermowatch keeping the heat at 60° C. The solution was then condensed on the rotovap, and after pumping off any residual solvent for 2 hours, 215.2 g (>100%) of (S)-(6-benzyloxy-2,5,7,8-tetramethyl chroman-2-yl)acetic acid chloride was obtained (211.45 g theoretical).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1N2CC[N:34](CC2)[CH2:33]1.[C-]#N.[K+].CCOC(C)=O>CS(C)=O.O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:33]#[N:34])[N:25]=3)[CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(COc2cccc(Oc3ccnc(Cl)n3)c2)cc1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(COc2cccc(Oc3ccnc(C#N)n3)c2)cc1
Reaction time: 0.33 h

Procedure:
{4-[3-(2-Chloro-pyrimidin-4-yloxy)-phenoxymethyl]-benzyl}carbamic acid tert-butyl ester (126 mg; 0.285 mmol; Stage 5.2), DABCO (16 mg; 0.143 mmol) and KCN (38 mg; 0.584 mmol) are dissolved in DMSO/water 4:1 (4 mL) at rt under an atmosphere of argon. After 20 min, more DABCO (16 mg) is added and the reaction is continued for a total of 1 h 50 min. The reaction mixture is poured onto brine, taken up into EtOAc, washed with water and brine and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure and the crude product is purified by flash chromatography over silica gel (eluting with Hexane/EtOAc 80:20) to give the title compound of Stage 5.3 as an oil; ES-MS: [M−H]−; m/z=431; Rf (Hexane/EtOAc 1:1)=0.45; HPLC: AtRet=5.19 min.
Reaction SMILES: CC1[NH:3][CH:4]=[C:5]([C:7](F)(F)F)[N:6]=1.[CH3:11][C:12]1([CH:16]=O)[CH2:15][O:14][CH2:13]1.O=C(C)C=O.FC(F)(F)C(=O)C=O>>[CH3:7][C:5]1[N:6]=[C:16]([C:12]2([CH3:11])[CH2:15][O:14][CH2:13]2)[NH:3][CH:4]=1
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Reactant: CC1(C=O)COC1
Agent: CC(=O)C=O
Agent: O=CC(=O)C(F)(F)F
Product: Cc1c[nH]c(C2(C)COC2)n1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 16.2, except 3-methyloxetane-3-carbaldehyde was used in place of acetaldehyde and 2-oxopropanal was used in place of 3,3,3-trifluoro-2-oxopropanal (compound 16.1). m/z (ES+) 153 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:6][N:7]=1.[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>C(O)C>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:6][N:7]=1)#[N:22]
Reactant: CSC(=NC#N)SC
Reactant: NCc1ncc(-c2csc(N=C(N)N)n2)s1
Solvent: CCO
Product: CSC(=NC#N)NCc1ncc(-c2csc(N=C(N)N)n2)s1

Procedure:
A mixture of 4-(2-aminomethylthiazol-5-yl)-2-(diaminomethyleneamino)thiazole (0.45 g) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N--CN] (0.26 g) in ethanol (10 ml) was refluxed for 5 hours with stirring to give 4-[2-(3-cyano-2-methylisothioureido)methylthiazol-5-yl]-2-(diaminomethyleneamino)thiazole as a crude product. After cooling to ambient temperature, 40% aqueous methylamine by weight (1.4 ml) was added to the suspension and the mixture was stirred for 12 hours at ambient temperature, The solvent was evaporated in vacuo and the residue was mixed with water (5 ml) and ethyl acetate (5 ml). The resulting precipitate was collected and recrystallized from aqueous N,N-dimethylformamide to give 4-[2-(2-cyano-3-methylguanidino)methylthiazol-5-yl]-2-(diaminomethyleneamino)thiazole (0.35 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:43]1([C:25]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH:32]3[C:15](=[O:16])[CH2:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2C(C(=O)Cc3ccccc3)NCC21
Reaction time: 24 h

Procedure:
0.35 cm3 of triethylamine and then 0.33 cm3 of phenylacetyl chloride are added to a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry methylene chloride at room temperature. The reaction mixture is stirred at this temperature for 24 hours, diluted with 200 cm3 of methylene chloride, washed with 100 cm3 of a saturated solution of sodium bicarbonate, with 100 cm3 of water (twice) and then with an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 11 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallised in 70 cm3 of acetonitrile and the crystals are filtered off and dried. 0.5 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-phenylacetyl-perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: N1CCCCC1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O.[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:15]>O1CCOCC1>[C:14]([C:16](=[CH:12][C:8]1[S:7][CH:11]=[CH:10][CH:9]=1)[C:17]([O:19][CH3:20])=[O:18])#[N:15]
Reactant: COC(=O)CC#N
Reactant: O=Cc1cccs1
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: COC(=O)C(C#N)=Cc1cccs1

Procedure:
A solution of 1.0 ml of piperidine in 10 ml of dioxane was added carefully to a stirred solution of 33.65 g thiophene-2-carboxaldehyde and 29.7 g of methyl cyanoacetate in 40 ml of dioxane. On standing the reaction mixture overnight at room temperature a crystalline precipitate was obtained which was filtered off, washed with cold dioxane and dried in vacuo to give 1, as a solid, mp 104°-106° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4]1.N1C(C)=CC=CC=1C.O1CCCC1.FC(F)(F)S(O[Si:62]([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:64])[CH3:63])(=O)=O>C(OCC)(=O)C>[Si:62]([O:1][CH2:2][C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:4][CH2:5][CH2:6]1)([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:64])[CH3:63]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO)CCC3)CC2)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO[Si](C)(C)C(C)(C)C)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4′-{[4-(trans-4-{[1-(hydroxymethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g), 2,6-lutidine (0.14 mL) and tetrahydrofuran (10 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.18 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.31 g, 86%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])[C@H:2]1[O:4][CH2:3]1.[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[ClH:12].[OH:4][C@H:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])[CH2:3][NH:26][C:15]([CH3:25])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: Clc1cccc(OC[C@@H]2CO2)c1Cl
Product: COc1ccc(CC(C)(C)NC[C@H](O)COc2cccc(Cl)c2Cl)cc1
Product: Cl
Yield: 103.6 %

Procedure:
Using the method of Example 6, supra, (S)-2,3-dichlorophenyl glycidyl ether (0.84 g, 3.82 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.75 g, 4.18 mmol) were used to prepare 860 mg of the title compound as a white solid: GC/EI-MS, m/z, (rel. int.) 382 (M−15, 0.1), 280 (10), 279 (9), 278 (63), 276 (100), 163 (11), 121 (28), 77 (7), 71 (21), 70 (23), 58 (10).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH2:18](O)[CH3:19]>>[F:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([O:10][CH2:18][CH3:19])=[O:9]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Under ice-cooling, thionyl chloride (8.02 mL) was added dropwise to ethanol (200 mL), and 2-fluoro-5-nitrobenzoic acid (13.81 g) was added. This mixture was stirred at 80° C. for 4 hrs. and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.77 g) as a pale-yellow oil.
Reaction SMILES: [CH:1](OC)(OC)[O:2][CH3:3].[NH2:8]/[C:9](/[C:14]#[N:15])=[C:10](\[NH2:13])/[C:11]#[N:12].CO>O1CCOCC1>[NH2:13]/[C:10](=[C:9](\[N:8]=[CH:1][O:2][CH3:3])/[C:14]#[N:15])/[C:11]#[N:12]
Reactant: COC(OC)OC
Reactant: N#C/C(N)=C(/N)C#N
Solvent: CO
Solvent: C1COCCO1
Product: COC=N/C(C#N)=C(\N)C#N
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Trimethyl orthoformate (31-8 g; 0.3 mol) was added dropwise to a slowly distilling solution of diaminomaleonitrile (32.4 g; 0.3 tool) in 1,4-dioxane (250 mL). The methanol that formed during the reaction was removed by distillation. The reaction mixture was concentrated in vacuo and cooled to room temperature. The precipitate was collected and crystallized from THF-pentane to yield 33.6 g (62%) of 2-amino-3-(methoxymethylenamino) maleonitrile having a melting point of 138°-139° C.