Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:20][C:12]3=[CH:13][C:14]([OH:19])=[C:15]([OH:18])[C:16]([OH:17])=[C:11]3[C:9](=[O:10])[CH:8]=2)=[CH:5][CH:6]=1.[CH2:21]=O.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CO>[OH:17][C:16]1[C:15]([OH:18])=[C:14]([OH:19])[C:13]([CH2:21][N:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]2)=[C:12]2[C:11]=1[C:9](=[O:10])[CH:8]=[C:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[O:20]2
Reactant: C=O
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)c(O)c(O)c12
Reactant: OCCN1CCNCC1
Solvent: CO
Product: O=c1cc(-c2ccccc2)oc2c(CN3CCN(CCO)CC3)c(O)c(O)c(O)c12
Temperature: 51 °C
Reaction time: 4 h

Procedure:
The mixture of Baicalein (27 g), methanol (350 ml), 37% formaldehyde solution (8.04 ml), 4-N-hydroxyethyl-piperazine (13.1 g) was stirred under for 4 hours at 51° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 55° C. to get the product as yellow solid 40.3 g of purity 98.5%. m.p.: 192° C. MS: (API-ES) m/z 413.3 [M+H]+, 435.2 [M+Na]+, 825.5[2M+H]+, 847.5[2M+Na]+; 1H NMR (DMSO-d6/CFCOOD, 400 MHz): δ 8.18˜8.19 (m, 2H, Ar-2′,6′-H), 7.61˜7.67 (m, 3H, Ar-3′,4′,5′-H), 7.09 (s, 1H, 3-H), 4.73 (s, 2H, CH2), 3.76 (t, 2H, —CH2—OH), 3.59-3.69 (m, 8H, CH2), 3.33 (t, 2H, N—CH2).
Reaction SMILES: C1COCC1.CO.C[O:9][C:10](=[O:40])[C@H:11]([CH2:36][CH2:37][S:38][CH3:39])[NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][C:15]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].O.[OH-].[Li+]>O>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][O:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C@H:11]([C:10]([OH:40])=[O:9])[CH2:36][CH2:37][S:38][CH3:39])=[O:35])=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COCc2cccs2)cc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(COCc2cccs2)cc1-c1ccccc1C)C(=O)O
Reaction time: 3.5 h

Procedure:
To a solution in 1:1 THF-methanol of [4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 272C was added a solution of lithium hydroxide hydrate (40 mg, 0.95 mmol) in water (0.5 mL) and the reaction mixture was stirred for 3.5 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ether and water. Aqueous 2N HCl (1 mL) was added to the aqueous phase. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give [4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoyl]methionine. The acid was dissolved in acetonitrile (5 mL) and a solution of lithium hydroxide hydrate (18 mg, 0.43 mmol) in water (8 mL) was added. The mixture was concentrated and the residue was dissolved in water, frozen and lyophilized to give [4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoyl]methionine lithium salt (204 mg) as a light-yellow solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[NH:19][C:18]2=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=[C:17]2[O:16][CH2:15]1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH3:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:19]2[C:2](=[O:4])[NH:24][C:20]3=[CH:21][CH:22]=[CH:23][C:17](=[C:18]23)[O:16][CH2:15]1
Reactant: CC1(c2ccccn2)COc2cccc(N)c2N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h

Procedure:
Triphosgene (40 mg, 0.1 mmol) was added to the solution of 3-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (90 mg, 0.4 mmol) in tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (100 μL) at room temperature. The reaction was stirred for 1 h and was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a semisolid (0.10 g. 90%). LCMS calculated for C15H14N3O2 (M+H)+: m/z=268.1. found: 268.0.
Reaction SMILES: CO.[CH:3]1([NH:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][C:15]=2[NH2:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.Cl.[C:31](=N)(OC)[CH3:32]>O>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[C:18]1[CH:19]=[CH:20][C:14]2[N:13]([CH:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][CH2:5][CH2:4]3)[C:31]([CH3:32])=[N:16][C:15]=2[CH:17]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCCc2ccccc21
Reactant: COC(C)=N
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCCc2ccccc21
Yield: 49.4 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(1,2,3,4-tetrahydronaphthalen-1-yl)aminoanilin-5-yl)benzoxazole (see Working Example 87-1) (0.30 g, 0.8 mmol) was added methyl acetimidate hydrochloride (0.10 g, 0.9 mmol), and this was heated to reflux for 3 hours. After the reaction solution was cooled, water was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.15 g, 47% yield) as a colorless amorphous mass.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.CS(C)=O.N12CCCN=C1CCCCC2.[OH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>C(OCC)(=O)C>[Br:8][C:4]1[N:3]=[C:2]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[OH:24])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncc(Br)n1
Reactant: NCc1ccccc1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Oc1ccccc1CNc1cncc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Introduced into a 50 ml round-bottomed flask is 1 g (4.2 mmol) of 2,6-dibromopyrazine (starting material 3), to which 15 ml of dimethyl sulphoxide, 638 mg (4.2 mmol, 1eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1.03 g (8.4 mmol, 2 eq) of 2-hydroxybenzylamine (starting material 4) are added; the mixture is left stirring for 2 h at room temperature. The reaction medium is diluted with 50 ml of ethyl acetate and then the mixture is washed with 50 ml of a saturated solution of ammonium chloride, and then twice with 50 ml of water. The organic phases are dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography over silica with, as eluent, a heptane/ethyl acetate (8/2) mixture. 2-[(6-Bromopyrazin-2-ylamino)methyl]phenol is obtained in the form of a white solid.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9]>C1COCC1>[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(Br)C(=O)O
Reactant: CC(C)Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
67 ml of a 1.5 M solution of a mixed magnesium chloride complex of α-bromopropionic acid in THF was slowly added to 67 ml of a 1.5 M solution cooled to 10° C. of p-isobutylphenyl magnesium bromide in THF at such a rate that the temperature of the mixture was maintained at not more than 55° C. The resulting slurry was stirred at 50° C. for 1 hour, and then heated under reflux to allow about 50% of THF to distill. The reaction mixture was cooled, and diethyl ether and dilute hydrochloric acid were added. The organic layer was washed with water, dried, concentrated, and purified by silica gel column chromatography to give 4.4 g (yield 21.3%) of α-(p-isobutylphenyl)propionic acid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([Mg]Br)[CH:2]=1.C([O:12][CH2:13][C:14]([O:16][CH3:17])=O)C>O1CCCC1.C(O)=O>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([C:13]([C:3]2[CH:2]=[C:1]([CH3:9])[CH:6]=[CH:5][CH:4]=2)([OH:12])[CH2:14][O:16][CH3:17])[CH:2]=1
Reactant: CCOCC(=O)OC
Reactant: Cc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: COCC(O)(c1cccc(C)c1)c1cccc(C)c1

Procedure:
A solution of 1,1-bis(3-tolyl)-2-methoxyethanol (24.66 g) (obtained by the reaction of 3-tolylmagnesium bromide with methyl 2-ethoxyacetate in tetrahydrofuran) in formic acid (30 cc) is heated to reflux for 12 hours, cooled and poured into a mixture of saturated sodium carbonate solution (400 cc) and ethyl acetate (400 cc). The organic phase is washed with water (3×300 cc) and with saturated sodium chloride solution (300 cc) then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-tolyl)acetaldehyde (20.45 g) in the form of a yellow oil.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.N([O-])=O.[Na+].[ClH:19]>O>[Cl:19][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Cl
Reactant: Nc1cc2c(c(C(=O)O)c1)OCCO2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1OCCO2
Temperature: 5 °C
Yield: 92.7 %

Procedure:
49 g of 7-amino-1,4-benzodioxane-5-carboxylic acid, 200 ml of water and 50 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 5° C. and then a solution of 17.5 g of sodium nitrite in 38 ml of water was added. The suspension was then poured into a solution of 20 g of cuprous chloride in 75 ml of hydrochloric acid. The precipitate was dried off, washed and dissolved in a solution of 42 g of sodium bicarbonate in 420 ml of water. The solution was filtered and treated with 100 ml of hydrochloric acid. 50 g of 7-chloro-1,4-benzodioxane-5-carboxylic acid was produced (M.P.: 180° C.; yield: 92.7%).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6](=[CH:11]OS(C1C=CC(C)=CC=1)(=O)=O)[C:7]([O:9][CH3:10])=[O:8].[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>COC(C)(C)C>[CH3:11][C:6](=[CH:5][S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Sc1ccccc1
Reactant: COC(=O)C(C)=COS(=O)(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)C(C)=CSc1ccccc1
Temperature: 50 °C
Reaction time: 9 h
Yield: 76.7 %

Procedure:
To chloroform (100 mL) were added methyl 2-methyl-3-(p-toluenesulfonyloxy)acrylate (11.0 g) and thiophenol (6.3 g), and then added dropwise triethylamine (33 mL), and the mixture was stirred at 50° C. for 9 hours. To the reaction mixture were added tert-butyl methyl ether, and then a 1N aqueous sodium hydroxide solution, thereby layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain methyl 2-methyl-3-(phenylthio)acrylate (6.5 g).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[NH2:15][C:16]1[C:17]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[NH:28][CH2:27][CH2:26]3)=[N:18][C:19](Br)=[CH:20][N:21]=1>C(O)CCC>[NH2:15][C:16]1[N:21]=[CH:20][C:19]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH3:5])([CH3:4])[C:1]#[N:2])=[CH:7][CH:8]=2)=[N:18][C:17]=1[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[NH:28][CH2:27][CH2:26]2
Reactant: Nc1ncc(Br)nc1-c1ccc2c(c1)CCNC2=O
Reactant: CC(C)(C#N)c1ccc(B(O)O)cc1
Solvent: CCCCO
Product: CC(C)(C#N)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1
Yield: 81.7 %

Procedure:
General method B was applied to 4-(2-cyanopropan-2-yl)phenylboronic acid (79 mg, 0.42 mmol) and 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (150 mg, 0.38 mmol) in n-butanol (2 mL) to give 2-{4-[5-amino-6-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-pyrazin-2-yl]-phenyl}-2-methyl-propionitrile (119 mg, 82% yield) after purification by column chromatography on silica (2-5% MeOH/DCM eluent).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[C:6]([CH3:12])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)=O.[CH:14]1([CH:17]([CH:25]2[CH2:27][CH2:26]2)[N:18]([CH2:22][CH2:23][CH3:24])[C:19]([NH2:21])=[S:20])[CH2:16][CH2:15]1.NC(N)=S>>[CH3:11][C:8]1[CH:7]=[C:6]([CH3:12])[C:5]([C:3]2[N:21]=[C:19]([N:18]([CH:17]([CH:25]3[CH2:27][CH2:26]3)[CH:14]3[CH2:15][CH2:16]3)[CH2:22][CH2:23][CH3:24])[S:20][C:2]=2[CH3:13])=[CH:10][N:9]=1
Reactant: CCCN(C(N)=S)C(C1CC1)C1CC1
Reactant: Cc1cc(C)c(C(=O)C(C)Br)cn1
Agent: NC(N)=S
Product: CCCN(c1nc(-c2cnc(C)cc2C)c(C)s1)C(C1CC1)C1CC1

Procedure:
This compound was prepared according to the process described in Example 1, Step A, using 2-bromo-1-(2,4-dimethyl-5-pyridyl)-1-propanone (Coapound 27) as the ketone and N-(dicyclopropylmethyl)-N-propylthiourea (Compound 66) as the thiourea.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][NH:12][C:13]=2[NH:14]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19].Cl>C(Cl)Cl.O1CCOCC1>[CH2:18]([O:20][CH:21]([N:12]1[C:13]([NH2:14])=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11]1)[CH3:22])[CH3:19]
Reactant: CC(=O)Nc1[nH]ncc1C#Cc1ccccc1
Reactant: C=COCC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(C)n1ncc(C#Cc2ccccc2)c1N
Temperature: 75 °C
Yield: 80.3 %

Procedure:
A solution of N-(4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (17.6 g, 78 mmol), ethoxyethene (11.2 mL, 117 mmol) and HCl in 1,4-dioxane (1 mL, 4 mmol) in CH2Cl2 (520 mL) was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in ethanol (260 mL) and 25% aq. NaOH solution (260 mL) and the reaction mixture was heated to 75° C. for 4 h and cooled to room temperature. The ethanol was part concentrated in vacuo and the resulting solid collected by filtration, washed with water and minimum cold ethanol and dried in vacuo to provide the title compound as a solid (16 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].FC1C=C(N[C:61](=[O:67])[C:62]([O:64][CH2:65][CH3:66])=[O:63])C=CC=1OC1C=CN=C2C=C(C3C=CC(OCCN4CCOCC4)=C(OC)C=3)SC=12>>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:61](=[O:67])[C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:9]=[C:8]([C:6]3[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[CH:7]=3)[S:16][C:15]=12
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Product: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(CC)cn4)sc23)c(F)c1
Yield: 14 %

Procedure:
Starting from the amine 15 (scheme 4) and following the same procedure as described for the synthesis of compound 140 (scheme 40), title compound 142 was obtained as white solid in 14% yield. MS (m/z): 455.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:19][N:20]=[C:21]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC>CN1C(=O)CCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:17])[N:20]([CH3:21])[CH3:19])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (2.43 g, 10 mmol), EDCI (6.52 g, 34 mmol) and HOBt (4.59 g, 34 mmol) in NMP (20 mL) was stirred at RT for 3 h. A solution of dimethylamine (2.0 M in THF, 15 mL, 30 mmol) was added, and the resulting mixture was stirred at RT for 64 h. Water and EtOAc were then added, and the organic layer was separated and washed twice with a saturated aqueous solution of K2CO3, aqueous HCl (1 M), a saturated aqueous solution of K2CO3, and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give (4-dimethylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.6 g, 59% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].[CH3:29][NH:30][NH2:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[CH:24]=[C:25]([CH3:26])[N:30]([CH3:29])[N:31]=1)=[O:4]
Reactant: CNN
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)n(C)n1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with methyl-hydrazine (CAS Reg. No. 60-34-4) to give the title compound as yellow solid. MS (ESI): m/z=432.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([O-])(O)=O.[Na+]>CCO>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:21][CH2:20]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
2,4-Dichloropyrimidine (5.0 g, 33.56 mmol) and 1-Boc-piperazine (6.25 g, 33.56 mmol) were dissolved in EtOH (40 mL). NaHCO3 (5.07 g, 60.41 mmol) was added and the reaction mixture was heated to reflux for 1.5 h, cooled to room temperature, and concentrated under reduced pressure. The mixture was diluted with CH2Cl2 and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 5% MeOH in CH2Cl2) to get tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate (3.5 g, yield 35%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.05 (d, J=6.0 Hz, 1H), 6.40-6.39 (d, J=6.3 Hz, 1H), 3.65 (m, 4H), 3.54-3.51 (m, 4H), 1.48 (s, 9H). MS (ESI) m/z: Calculated for C13H19ClN4O2: 298.12. found: 299.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[N:17][CH:18]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>ClCCl.CN(C=O)C.C(N(CC)C(C)C)(C)C>[CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[N:17][CH:18]=2)=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Cc1nc(-c2ccccc2)c(-c2ccc(NN)nc2)o1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(-c2ccc(NNC(=O)C(C)C)nc2)o1

Procedure:
To a stirred, cold (0° C.) solution of 5-(2-Methyl-4-phenyl-oxazol-5-yl)-pyridin-2-yl-hydrazine in 0.5 mL of dichloromethane and 0.3 mL of DMF and 0.325 mL of N,N-diisopropylethylamine was added 0.02 mL of isobutyryl chloride. After 5 minutes an additional 0.005 mL of isobutyryl chloride was added and the reaction was quenched a minute later with water. The mixture was extracted with dichloromethane (3×), washed with water (2×), brine (1×), dried (sodium sulfate), filtered, and the filtrate was concentrated to a dark orange oil. This oil was purified by flash chromatography (eluting with 5:1 ethyl acetate/hexanes) to give 23 mg of isobutyric acid N′-[5-(2-methyl-4-phenyl-oxazol-5-yl)-pyridin-2-yl]-hydrazide as an orange solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1COCC1.[Cl-].[NH4+].CO>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)c1ccccc1
Reaction time: 13 h

Procedure:
To this reaction mixture was added dropwise a liquid mixture of 182.2 g (1.1 mol) of benzophenone (8a; Ar=R=Ph) and 365 ml of dry THF at 35 to 40° C. over a period of 30 minutes. This mixture was stirred at that temperature for 2 hours and for further 13 hours to complete the reaction. The reaction mixture was poured into 1.4 kg of cooled 10% aqueous ammonium chloride solution with cooling with ice. This mixture was stirred for 30 minutes, allowed to stand, and then subjected to liquid separation, followed by washing with aqueous common salt solution, drying with magnesium sulfate, and concentration to obtain 200.2 g of a crude carbinol (theoretical yield based on the benzophenone, 98.6%). Into a 1-liter reaction flask were introduced 200.2 g of the crude carbinol, 400 ml of toluene, and 1 g of p-toluenesulfonic acid (PTSA). Azeotropic dehydration was conducted for 2 hours with toluene refluxing (94-116° C.). After cooling, this reaction mixture was washed with water, with 2% aqueous soda ash solution, and then with water, dried with magnesium sulfate, and concentrated to obtain 190.1 g of crude 1,1-diphenylethylene. This crude reaction product was distilled with a Claisen flask equipped with a vigreux to obtain 174.1 g of 1,1-diphenylethylene (9a; Ar=R=Ph). b.p., 103° C./1 mmHg.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)=[O:18].O.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Diisopropylethylamine (6.2 mL, 36.0 mmol) and pyrrolidine (2.3 mL, 27.6 mmol) were added to a THF (90 mL) solution of 2-bromo-1-(4-bromophenyl)ethanone (5.0 g, 18.0 mmol), and stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction liquid, extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (C-200, methanol:chloroform=1:99 to 3:97) to obtain the entitled compound (2.35 g, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([CH3:14])([OH:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: Oc1ccccc1Br
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)COc1ccccc1Br
Temperature: 90 °C
Yield: 0.6 %

Procedure:
To a solution of 2-bromophenol (3.0 g, 1.745 mmol, Aldrich) and 1-chloro-2-methylpropan-2-ol (2.8 g, 6.397 mmol, Spectrochem) in DMF (15 mL) was added sodium carbonate (1.23 g, 11.63 mmol). The reaction mixture was heated at 90° C. for 12 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material that was purified by combiflash silica gel column chromatography (column size: 12 g; elution: 0-5% ethyl acetate in hexane) to yield 1-(2-bromophenoxy)-2-methylpropan-2-ol (2.7 mg, 64.2%) as a transparent liquid. m/z (ESI) 243.3 (M+H)+.