Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2[C:26](=[CH:27]C=CC=2)[C@@:25]2([C:43]3C(=CC4OCCOC=4[CH:42]=3)OC2)C1=O>>[CH2:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])[CH2:26][CH2:25][CH2:43][CH3:42]
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Product: CCCCCN1C(=O)[C@]2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using (R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC>C1(C)C=CC=CC=1.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>[CH:31]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1)=[CH2:32]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (1.50 g) in toluene (20 mL) were added tributyl(vinyl)tin (900 μL) and tetrakistriphenylphosphinepalladium(0) (315 mg), and the mixture was stirred under argon atmosphere at 110° C. overnight. After cooling to room temperature, the reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography. The title compound (950 mg, yield 71%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 437 (MH+).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C(Cl)Cl.CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:10]([C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]2=[N:6][CH:7]=1)=[O:12])[CH3:20]
Reactant: O=C(O)c1cnc2occc2c1
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cnc2occc2c1
Reaction time: 0.5 h
Yield: 124.5 %

Procedure:
To a suspension of furo[2,3-b]pyridine-5-carboxylic acid (3.30 g, 20.2 mmol) in methylene chloride (80 mL), under a nitrogen atmosphere at room temperature, was added oxalyl chloride (4.2 mL, 48 mmol) and then four drops of dimethylformamide. The reaction mixture was stirred until gas evolution ceased (4-5 hours) and a clear solution resulted. This solution was evaporated in vacuo and the excess oxalyl chloride chased by evaporation with benzene. The residue was dissolved in chloroform (50 mL) and diethylamine (5.2 mL, 50 mmol) was added carefully. After 0.5 hours, the chloroform solution was washed with dilute hydrochloric acid, filtered through a pad of charcoal and evaporated to give crude product (5.49 g). This oil was distilled under vacuum to give purified product (3.62 g, 82% yield), bp: 168°-170° C./1.6 mmHg.
Reaction SMILES: [C:1]12[CH2:7][C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2>C(Cl)Cl>[CH2:7]1[CH:4]2[C@H:3]3[C@H:7]4[CH:4]5[CH2:3][CH:2]6[CH:6]([C@@H:5]5[C@@H:5]2[C@H:6]2[CH:1]1[C@H:2]23)[C@@H:1]46
Reactant: C1=C2CCC(=C1)C2
Solvent: ClCCl
Product: C1C2C3[C@H]4C1[C@@H]([C@@H]23)[C@@H]1C2CC3[C@@H]1[C@H]3[C@H]24

Procedure:
Norbornadiene (bicyclo[2.2.1]hepta-2,5-diene) was dimerized with the catalyst system CoBr2 -(triphenylphosphine)2 -boron trifluoride etherate. The structure of the diene is as follows: ##STR3## Afterwards methylene chloride was used to dissolve the organic phase of the reaction mixture and to separate the latter from the inorganic phase of catalyst components. Then the methylene chloride solution was washed with potassium carbonate to neutralize any free halogen acid and dried with the use of a drying agent such as anhydrous sodium sulfate. Upon cooling the treated methylene chloride solution Binor-S crystallized. The crystals were filtered from the liquid and then vacuum distilled to give solid Binor-S which had a grayish tinge. The foregoing procedure has been described in the literature. This procedure yields a Binor-S containing a trace amount of indigenous halide.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH:18]=[N:17]1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:25][C:20]3[C:19]4[CH:18]=[N:17][NH:16][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc3[nH]ncc23)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 22 using 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 1H-indazol-4-amine, and isolated as a yellow solid (13%). LCMS (API-ES) m/z 319 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 13.10 (s, 1H) 12.26 (s, 1H) 8.80 (d, J=7.82 Hz, 1H) 8.42 (d, J=4.50 Hz, 1H) 8.19 (s, 1H) 8.13 (d, J=7.43 Hz, 1H) 7.75 (br. s., 2H) 7.31 (t, J=8.02 Hz, 1H) 7.16 (d, J=8.41 Hz, 1H) 6.89-7.07 (m, 1H) 2.56 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][C:5]([CH3:15])([CH3:14])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:22][OH:23].Cl>O>[CH3:1][C:2]([CH3:16])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][C:5]([CH3:15])([CH3:14])[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: CC1(C)C=NC(C)(C)CC=CCCC=CC1
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 134.8 %

Procedure:
The procedure is carried out in the manner described in Example 1(b) but with the use of 110 g (0.5 mol) of 3,3,12,12-tetramethyl-1-aza-1,5,9-cyclododecatriene, 41 g (0.25 mol) of hydroxylamine sulfate, 50 ml of concentrated hydrochloric acid and 250 ml of water. There is obtained on distillation 85 g (0.337 mol) of 2,2,11,11-tetramethyl-11-amino-undeca-4,8-dienal-oxime; yield 67.4% of theory; b.p. 130° C./7 Pa.
Reaction SMILES: O[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ncnc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(C)n(Cc2ccccc2)c2ncnc(Cl)c12
Temperature: 25 °C

Procedure:
2.5 g of 4-hydroxy-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine are boiled at reflux with 20 ml of POCl3 for 2.5 hours. The brown solution is cooled to RT and poured onto ice-water. The brownish precipitate is filtered off with suction and dissolved in ethyl acetate. The ethyl acetate phase is washed with water, dried and concentrated in a rotary evaporator until white crystals form. 4-Chloro-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]-pyrimidine is obtained in the form of white crystals having a melting point of 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.[CH:18](OCC)(OCC)[O:19][CH2:20][CH3:21].C([O-])([O-])[O-]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:18][O:19][CH2:20][CH3:21])[C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Reactant: CCOC(OCC)OCC
Agent: [O-]C([O-])[O-]
Solvent: CCOCC
Product: CCOC=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Reaction time: 2 h
Yield: 140.1 %

Procedure:
1-(3-Chlorophenyl)-2(1H,3H)-indolone (2.4 g, 0.01 mole) and triethyl orthoformate (8.3 ml, 0.05 mole) were combined and heated at 150°±10° for 18 hours. An additional 20 ml of the orthoformate were added and heating continued 2 hours. The reaction mixture was cooled to 25°, diluted with ether, washed with H2O and then brine, dried over MgSO4, concentrated in vacuo to oily solids, and triturated with pentane to yield solids (4.2 g). The solids were chromatographed on silica gel (7.5×15 cm) with 4:1 hexane:ethyl acetate as eluant to yield purified title product, 0.5 g; m.p. 132°-134°; m/e 310/299.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]1.CO.[Li+].[OH-]>O>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1
Reactant: COC(=O)C1CCN(c2ccncc2N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cnccc1N1CCC(C(=O)O)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A microwave vial was charged with methyl 1-(3-amino-4-pyridyl)piperidine-4-carboxylate (prepared according to methods similar to the one depicted in Preparation N-1) (176 mg, 0.7106 mmol), MeOH (3 mL) and H2O (0.1 mL). LiOH (51.06 mg, 2.132 mmol) was added and the mixture was stirred overnight at 50° C. The reaction was quenched by addition of an aqueous solution of HCl until pH=3-4 is reached. The reaction mixture was then concentrated under reduced pressure to yield 1-(3-amino-4-pyridyl)piperidine-4-carboxylic acid that was used without further purification. MS (ES+) 222.1.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[NH2:36][C@@H:37]([CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:38]([OH:40])=[O:39]>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:36][C@@H:37]([CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:38]([OH:40])=[O:39])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC[C@H](N)C(=O)O
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
7.50 g (15.4 mmol) of the compound from example 1A was dissolved in 150 ml dichloromethane. 3.36 g (15.4 mmol) (2S)-2-Amino-4-[(tert-butoxycarbonyl)amino]butanoic acid was added. The reaction mixture was split into 10 portions. The portions were heated for 30 min in a sealed tube at 75° C. in a microwave synthesizer. The combined reaction mixture was extracted with approx. 100 ml saturated ammonium chloride solution. The aqueous phase was twice back extracted with approx. 50 ml dichloromethane each. The combined organic phases were extracted with approx. 50 ml brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 1 l silica gel. Solvents used were dicloromethane/ethyl acetate 4/1, dichloromethane/methanol 10/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 8.70 g (10.8 mmol, 70% of theory) of the desired product.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[S:11][C:10]([NH2:13])=[N:9][C:8]=2[C:7]([CH3:14])=[CH:6][C:5]=1[S:15]C#N)([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.P([O-])([O-])([O-])=O>CCO>[NH2:13][C:10]1[S:11][C:12]2[C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([SH:15])[CH:6]=[C:7]([CH3:14])[C:8]=2[N:9]=1
Reactant: Cc1cc(SC#N)c(C(C)C)c2sc(N)nc12
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCO
Product: Cc1cc(S)c(C(C)C)c2sc(N)nc12

Procedure:
The title compound was prepared according to General Method 14 using 7-isopropyl-4-methyl-6-thiocyanato-benzothiazol-2-yl-amine (Example L-5; 11.5 g, 43.7 mmol), dithiothreitol (27.0 g, 175 mmol), EtOH (200 mL), and phosphate buffer (50 mL). MS (APCI): 239 (M+H).
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:45](O)(=[O:48])[CH2:46][OH:47]>C(Cl)Cl>[OH:48][CH2:45][C:46]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)=[O:47]
Reactant: O=C(O)CO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)CO)C4)cc2)C(=O)O1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (300 mg, 0.72 mmol), in DCM (5 mL), were added EDC (180 mg, 0.94 mmol), HOBt (127 mg, 0.94 mmol) and NMM (0.32 mL, 2.89 mmol) and glycolic acid (60.4 mg, 0.79 mmol), at 0° C. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with DCM (20 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.35:9.65 MeOH:CHCl3) to provide the title compound (160 mg, 59%) as off white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>CS(O)(=O)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:12](=[O:14])[CH2:11][CH2:10]2
Reactant: COc1ccc(CCC(=O)O)cc1O
Agent: CS(=O)(=O)O
Product: COc1cc2c(cc1O)CCC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-(3-Hydroxy-4-methoxy-phenyl)-propionic acid in methanesulfonic acid (10 ml) was heated at 90° C. for 10 minutes under microwave irradiation. The mixture was poured into ice (300 g) and stirred for 1 hour. The precipitate was collected and dried to give 5-Hydroxy-6-methoxy-indan-1-one (2 g). LC-MS: m/e 179 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[O:32]1CCC[CH2:33]1.C[O-].[Na+]>CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[N:3]=[C:2]([O:32][CH3:33])[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: C1CCOC1
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Combine a mixture of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (47 mg, 1 mmol), tetrahydrofuran (1 mL), and a 21% solution of sodium methoxide in MeOH (0.5 mL). Let the reaction stir at 60° C. for 16 hours. Evaporate the mixture, add water (5 mL), and extract twice with EtOAc (5 mL each). Combine the organic layers, dry (Na2SO4), and purify by preparative TLC (8:1 hexanes/EtOAc) to obtain 4-(3-chloro-4-fluoro-phenyl)-2-methoxy-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine.
Reaction SMILES: [Li]C(C)(C)C.[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]=1[CH2:15][C:16]([O:18]CC)=O.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)[CH:25]=[CH:24][CH:23]=1>C1COCC1>[NH2:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:30]2[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]2)[NH:21][C:16](=[O:18])[C:15]=1[C:7]1[NH:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: CCN1CCN(c2cccc(N)c2C#N)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCN1CCN(c2cccc3[nH]c(=O)c(-c4nc5ccccc5[nH]4)c(N)c23)CC1
Reaction time: 8 h

Procedure:
t-BuLi (3.1 equivalents) was added to ethyl 2-benzimidazol-2-ylacetate (1.0 equivalent) and 6-amino-2-(4-ethylpiperazinyl) benzenecarbonitrile (1.0 equivalent) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with NH4Cl (aqueous saturated) and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. The crude material was triturated with CH2Cl2 and MeOH to provide a tan solid. LC/MS m/z 389.1 (MH+), Rt 1.80 minutes.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O.C(O)(=O)C=O.[CH3:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([CH3:24])=[O:23])=[CH:17][C:16]=1[Cl:25].C(OC(C)C)(C)C>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:21][C:20]1[CH:19]=[C:18]([C:22](=[O:23])[CH:24]=[CH:6][C:5]([OH:4])=[O:7])[CH:17]=[C:16]([Cl:25])[C:15]=1[CH3:14]
Reactant: CC(=O)c1cc(Cl)c(C)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
10.2 g (0.1 mole) of acetic anhydride were added to 9.3 g (0.1 mole) of glyoxylic acid monohydrate and the mixture was heated, with stirring, on an oil bath at 60° C. for 10 minutes to obtain a homogeneous solution. To this solution were added, in turn, 20.3 g (0.1 mole) of 3,5-dichloro-4-methylacetophenone, prepared as described in step (a) above, 28.8 g of acetic acid and a catalytic amount (300 mg) of concentrated sulphuric acid, whilst ice-cooling. The mixture was then heated, with stirring, on an oil bath at 105°-110° C. for 2 hours, after which it was cooled and 100 ml of diisopropyl ether were added. The mixture was stirred and the resulting crystals were collected by filtration and washed first with water and then with a small amount of diisopropyl ether, after which they were dried to give 20.8 g (yield 80.3%) of the desired 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid, melting at 206°-216° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@@H:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd]>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C@@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc([C@@H]2CCC[C@H](O)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CCC[C@H](O)C2)c(O)c1
Yield: 77 %

Procedure:
A mixture of 22.0 g. (0.0539 mol.) of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanol, 12.0 g. of sodium bicarbonate and 2.0 g. of 10% palladium on carbon was stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture was filtered through diatomaceous earth with ethyl acetate and the filtrate evaporated to a solid. The solid was recrystallized from hexane to yield 13.2 g. (77%) of the title product, m.p. 109°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[C:11]([NH2:14])(=[NH:13])[CH3:12]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:13][C:11]([CH3:12])=[N:14]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(=N)N
Solvent: CC(=O)N(C)C
Product: Cc1ncc2ccc(Br)cc2n1
Temperature: 140 °C
Yield: 4 %

Procedure:
The 4-Bromo-2-fluoro-benzaldehyde (1 g, 4.9 mmol), acetamidine and DMA were mixed and heated to 140° C. for 5 hours. The mixture was cooled to room temperature and dried under vacuum. The mixture was purified by flash column afforded 47 mg product in 4% yield. MS (ESI) m/e 223 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][S-:16].[Na+]>CS(C)=O.O>[CH3:15][S:16][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(2-bromoethyl)phthalimide (500 mg) in DMSO (8 mL) was added sodium thiomethoxide (152 mg) and the reaction stirred at room temperature for 16 h. Then with water (2 mL) was added and the mixture stirred at room temperature for 10 min. The reaction was diluted with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give 2-(2-methylsulfanyl-ethyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>COCCOC>[CH2:13]([O:1][CH2:2][CH:3]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)OCC(CO)CO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OCC(COCc2ccccc2)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 5-hydroxymethyl-2,2-dimethyl-1,3-dioxane (cf:Bates, H. A.; Farina, J.; Tong, M. J. Org. Chem. 1986, 51, 2637, 3.0 g, 20.5 mmol) in 25 mL of dry DME under argon was added via cannula to a slurry of NaH (0.740 g, 80% dispersion in oil, 24.6 mmol) in 60 mL of dry DME cooled to 0° C. The resulting grey slurry was stirred at room temperature for 0.5 h, then recooled to 0° C., and treated with a solution of benzylbromide (4.56 g, 26.7 mmol) in 20 mL of DME. The reaction mixture was stirred at room temperature (rt) overnight and then quenched with 100 ml of H2O. The aqueous layer was separated and extracted with two portions of ethyl acetate. The combined organic layers were then washed with saturated sodium chloride solution, dried over MgSO4, filtered, and concentrated to provide a yellow oil. Purification by column chromatography on silica gel (ethyl acetate/hexane) afforded 3.51 g (72%) of 5-benzyloxymethyl-2,2-dimethyl-1,3-dioxane as a clear colorless liquid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2(O)[C:14]3[O:13][CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[O:13][CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][CH:7]=2)=[CH:2]1
Reactant: OC1(c2ccoc2)CCCc2ccoc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(c2ccoc2)c2occc2CC1
Yield: 96.2 %

Procedure:
To a mixture of 16.3 g of the above alcohol in 400 ml of toluene was added 100 mg of p-toluenesulfonic acid and the mixture was placed on a Rotovap® and the solvent was distilled in vacuo (40 mm/50° C.) until a brown-red residue was obtained yielding 14.3 g (96%) of 4,5-dihydro-7-(3-furyl)-benzofuran as a red oil.