Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.O.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>[NH2:1][C:2]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccccc2)cc1N
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A mixture of 2-amino-5-bromobenzonitrile (1.0 g, 5 mmol), phenylboronic acid (0.92 g, 7.5 mmol), tetrakis(triphenylphosphine)palladium (50 mg) and potassium carbonate (3.5 g, 25 mmol) in dimethoxyethane/water 2:1 (60 mL) was heated at reflux for 4 hours. After cooling to room temperature the reaction was diluted with water and extracted with ethyl acetate. The organic phase was dried and solvent evaporated. Trituation with petroleum ether gave 0.89 g of the desired compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:32]=[C:18]3[C:19]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[C:24]=4[F:31])=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[C:10]([F:34])([F:33])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:10]1([F:33])[CH:11]([NH:14][C:15]2[N:32]=[C:18]3[C:19]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[C:24]=4[F:31])=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4ccc(F)c(F)c4F)cccn3n2)C(F)(F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2cccn3nc(NC4CCNCC4(F)F)nc23)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To solution of 3,3-difluoro-4-[8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (110 mg, 228 μmol) in CH2Cl2 (4 mL) at 0° C. was added TFA (182 mg, 123 μl, 1.59 mmol) and stirred at room temperature for 18 hours. Further TFA (182 mg, 123 μl, 1.59 mmol) was added and stirred at 50° C. for 6 hours. The reaction mixture was extracted with saturated NaHCO3 solution and ethyl acetate, the organic layers combined, dried over Na2SO4, filtered and the solvents evaporated. The product was coevaporated four times with toluene. The title compound was obtained as light yellow foam (87 mg, 100%). MS ISP (m/e): 384.2 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH3:11])[CH3:2].CN1C([N+]([O-])=[O:19])=CN=C1C>>[CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]=[O:19])[CH3:2]
Reactant: CCn1c([N+](=O)[O-])cnc1C
Reactant: Cc1ncc([N+](=O)[O-])n1C
Product: CCn1c([N+](=O)[O-])cnc1C=O

Procedure:
With regard to the dimethylamino compound, said compound is prepared by employing the procedure set forth in Example 3, with the exception that 1-ethyl-2-methyl-5-nitroimidazole is utilized instead of 1,2-dimethyl-5-nitroimidazole. The process yields 1-ethyl-5-nitro-2-imidazolecarboxaldehyde, 4',4'-dimethyl-3'-thiosemicarbazone, which is cyclized as in Example 3 to 2-(2-dimethylamino-5-thiadiazoly)-1-ethyl-5-nitroimidazole.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a solution of 1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone (IX-1) (14.90 g, 0.043 mol) in THF (300 mL) at 0° C. were added portion wise LiAlH4 (2.05 g, 0.051 mol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (SR)-1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-1) 4.69 g (31%) as awhite solid ES-MS m/e: 350.2 (M+H+) and (RS)-1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (X-A-1) 5.30 g (35%) as awhite solid ES-MS m/e: 350.2 (M+H+).
Reaction SMILES: [C:1]([CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].OO.[Mn]([O-])(=O)(=O)=[O:28].[K+]>CO.O>[C:1]([CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:18][CH2:19][N+:20]3([O-:28])[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCc2c(c3ccccc3n2CCN2CCCC2)C1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C1CCc2c(c3ccccc3n2CC[N+]2([O-])CCCC2)C1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The product of Example 1 as free base (22.25g) in methanol (300 ml) was cooled to 0° (ice/water bath). Aqueous 30% w/v hydrogen peroxide (31.4g) was added dropwise over about 15 minutes, with cooling and stirring. The mixture was kept at ambient temperature for 3 days, and the excess hydrogen peroxide was then decomposed with a trace of potassium permanganate. The mixture was evaporated to dryness and the residue was dissolved in hot isopropanol (40 ml). Water (500 ml) was added with stirring and the mixture was refrigerated overnight, yielding a precipitate which was dissolved in hot water, filtered, and cooled, yielding a precipitate of 14.5g of 1-[2-(3-tert-butyl-1,2,3,4-tetrahydrocarbazole-9-yl) ethyl]pyrrolidine-N-oxide quarter-hydrate, m.p. 163-5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:35]=[CH:34][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][C:27]2[CH:34]=[CH:35][C:24]([C:23]([F:22])([F:36])[F:37])=[CH:25][CH:26]=2)[CH2:30]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: FC(F)(F)c1ccc(CC2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(Cc2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)benzyl]pyrrolidine oxalate (19.2 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (9.2 mg). Calcd for C22H18ClF3N2O2: 434.1009, found 434.1003.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][CH:13]([N:21]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]([NH:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:22]1=[O:56])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[Cl:12][CH:13]([N:21]1[CH:24]([S:25]([CH2:26][C:27]#[C:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:9])[CH:23]([NH:36][C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:22]1=[O:56])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1S(=O)CC#CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (30mg) in ethanol-free chloroform (3ml) was added in 10 minutes to a stirred solution of 1-(1-chloro-1-t-butoxycarbonylmethyl)-4-(4-phenylbut-2-ynylthio)-3-(triphenylmethylamino)azetidin-2-one (99mg) in ethanol-free chloroform (3ml) at 0°C. The mixture was stirred for a further 30 minutes at 0°C. The reaction mixture was diluted with ethanol-free chloroform (10ml) and washed successively with saturated sodium bicarbonate solution (5ml) and brine (2 × 5ml). The dried(MgSO4) organic layer was evaporated to give a gum which upon re-evaporation from dry ether gave 1-(1-chloro-1-tert-butoxycarbonylmethyl)-4-(4-phenylbut-2-ynylsulphinyl)-3-triphenylmethylamino-azetidin-2-one as a solid foam (92mg, 91%)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[Br:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1
Reactant: Oc1cccc(Br)c1
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2cscn2)c1
Reaction time: 18 h
Yield: 88.3 %

Procedure:
4-(Chloromethyl)thiazole hydrochloride (3.0 g), 3-bromophenol (2.77 g) and potassium carbonate (7.30 g) were heated in dimethylformamide at 60° C., with stirring, for 18 h. The mixture was partitioned between diethyl ether (50 ml) and water (50 ml) and the aqueous phase was extracted further with ether (50 ml). The combined organics were washed with 2M aqueous sodium hydroxide (100 ml) and water (100 ml), dried (magnesium sulphate) and concentrated in vacuo to give the product as a yellow crystalline solid (3.82 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[CH3:11][O:12][C:13]([C:15]#[C:16][C:17](OC)=[O:18])=[O:14]>CO.CCCCCC>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[C:4]2[C:3]=1[C:17](=[O:18])[CH:16]=[C:15]([C:13]([O:12][CH3:11])=[O:14])[NH:5]2
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1cc(=O)c2c(Cl)c(Cl)c(Cl)cc2[nH]1
Temperature: 240 °C
Yield: 32.4 %

Procedure:
3,4,5-Trichloroaniline (25 g, 0.127 mol) and dimethylacetylene dicarboxylate (10.9 ml, 0.12 mol) were dissolved in dry methanol (300 ml) at 0° C. then heated at reflux for 14 h. The mixture was allowed to cool, then diluted with hexane (200 ml) and the yellow solid which precipated was collected by filtration and heated in diphenyl ether (200 ml) at 240° C. for 10 minutes. The reaction mixture was allowed to cool to room temperature and diluted with hexane. The solid which deposited was collected and recrystallised from acetone (500 ml) to give methyl 5,6,7-trichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (11.91 g), m.p. 295°-296° C. (decomp), δ (360 MHz, DMSO-d6) 3.96 (3H, s, CH3), 6.63 (1H, s, 3-H) and 8.17 (1H, s, 8-H) (Found C, 43.09; H, 1.70; N, 4.47%, C11H16NO3Cl3 requires C, 43.10; H, 1.97; N, 4.57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[C:33]([N:36]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][CH2:42][N:36]([C:33](=[O:35])[CH3:34])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CC(=O)N1CCCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCCN(C(C)=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with N-acetylhomopiperazine. A yellow solid 112 was obtained (0.0246 g, 50%). 1H-NMR (CDCl3, 400 MHz) δ 2.02–2.10 (m, 2H), 2.08 (s, 3H), 3.55 (t, J=5.9 Hz, 1H), 3.59 (t, J=5.5 Hz, 1H), 3.79 (t, J=6.2 Hz, 1H), 3.83 (s, 3H), 3.84–3.92 (m, 3H), 4.05 (t, J=5.3 Hz, 1H), 4.15 (t, J=5.5 Hz, 1H), 6.86 (s, ⅓H), 6.89 (s, ⅔H), 6.92–7.08 (m, 4H), 7.45–7.53 (m, 3H), 7.84 (s, ⅓H), 7.85 (s, ⅔H), 8.26–8.30 (m, 1H); MS (APCI) m/z 502 (M+H)+.
Reaction SMILES: [CH:1]1(OC(=O)[C@@H](NC(OCC2C=CC=CC=2)=O)COC(C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([S:31][CH2:32][C@@H:33]([NH:37][C:38]([O:40][CH2:41][CH:42]1[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[C:34]([OH:36])=[O:35])([CH3:30])([CH3:29])[CH3:28]>>[CH:1]1([O:35][C:34](=[O:36])[C@H:33]([NH:37][C:38]([O:40][CH2:41][CH:42]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=3[C:49]3[C:54]2=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:39])[CH2:32][S:31][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)SC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Product: CC(C)(C)SC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC1CCCC1

Procedure:
This was prepared in the same manner as (S)-2-Benzyloxycarbonylamino-3-tert-butoxy-propionic acid cyclopentyl ester (Method A, Stage 1) but from (S)-3-tert-Butylsulfanyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid. 1H NMR (300 MHz, CDCl3), δ: 1.30 (9H, s, (CH3)3), 1.55-1.95 (8H, m, CH2×4), 3.05 (2H, d, CH2, J=4.8 Hz), 4.20-4.30 (1H, m, CH), 4.40 (2H, d, CH2, J=7.5 Hz), 4.65 (1H, m, CH), 5.25 (1H, m, CH), 5.70 (1H, d, NH, J=7.8 Hz), 7.30-7.50 (4H, m, ArH×4), 7.65 (2H, d, J=7.5 Hz, ArH×2), 7.80 (2H, d, J=7.5 Hz, ArH×2).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[CH:2]
Reactant: CCCCCc1ccc(-c2ccc(C=C(Br)Br)cc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(-c2ccc(CCCCC)cc2)cc1
Temperature: -10 °C

Procedure:
In an analogous manner to Example 1, solution of 4-(2,2-dibromovinyl)-4'-pentylbiphenyl in absolute tetrahydrofuran was placed in a sulphonation flask and treated within 5 minutes with a solution of butyl lithium in hexane. After completion of the addition, the mixture was warmed to -10° C. within 10 minutes, then poured into water and extracted with diethyl ether. The organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography of the residue on silica gel with hexane and recrystallization from methanol gave 4-ethynyl-4'-pentylbiphenyl as colourless crystals (purity 99.5%); m.p. (C-N) 56.4° C., cl.p. (N-I) 82.7° C.
Reaction SMILES: [CH2:1]([C:3](O)([CH2:6][CH2:7][CH:8]=[C:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:4]=[CH2:5])[CH3:2].P(Br)(Br)[Br:17]>>[Br:17][CH2:2][CH:1]=[C:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: BrP(Br)Br
Reactant: C=CC(O)(CC)CCC=C(C)CC(C)C
Product: CCC(=CCBr)CCC=C(C)CC(C)C

Procedure:
By the procedure described in Example 2, 33.65 g. of 3-ethyl-7,9-dimethyl-1,6-decadien-3-ol and 6.6 ml. of phosphorus tribromide are reacted to produce 1-bromo-3-ethyl-7,9-dimethyl-2,6-decadiene.
Reaction SMILES: [CH:1]([N:4]([C:8](Cl)=[O:9])[C:5](Cl)=[O:6])([CH3:3])[CH3:2].I.[CH3:12][S:13][C:14](=[NH:20])[NH:15][N:16]=[C:17]([CH3:19])[CH3:18]>C(N(CC)CC)C>[CH:1]([N:4]1[C:8](=[O:9])[NH:20][CH:14]([S:13][CH3:12])[N:15]([N:16]=[C:17]([CH3:19])[CH3:18])[C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CSC(=N)NN=C(C)C
Reactant: CC(C)N(C(=O)Cl)C(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(C(C)C)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-isopropyl-bis-(chlorocarbonyl)-amine (prepared analogously to Synthesis 1970, pages 542-543; boiling point 66-67° C/12 mm Hg) and acetone-S-methylisothio-semicarbazone hydroiodide, with addition of triethylamine, yielded 1-isopropyl-3-isopropylideneamino-4methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a pale yellow powder of melting point 110-112° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:24][CH3:25])[C:12]2[C:13](=[O:23])[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([O:24][CH3:25])[C:12]2[C:13](=[O:23])[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)cc2oc3ccccc3c(=O)c12
Agent: [Pd]
Solvent: CCO
Product: COc1cc(O)cc2oc3ccccc3c(=O)c12

Procedure:
The compound (120 mg) prepared in Step 2 of Example 9, Pd/C (60 mg), and anhydrous ethanol (30 mL) were added and a hydrogen gas was supplied at a pressure of 50 psi, followed by hydrogen reduction reaction for 12 hours. The reaction mixture was filtered through celite and washed with 20 mL of DMF. The filtrate was combined, and the solvent was removed under reduced pressure. The resulting residue was directly used in the next reaction without further purification.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:31]=[CH:30][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=2)[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:15])=[C:8]([N+:32]([O-:34])=[O:33])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([N+:32]([O-:34])=[O:33])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=3)[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=3)=[O:15])[CH:30]=[CH:31][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)c([N+](=O)[O-])c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a solution of potassium thiocyanate (740 mg, 7.64 mmol) in acetic acid (22 mL) was added 3-(4-amino-2-nitrophenoxy)-N-[3-(trifluoromethyl)phenyl]benzamide (800 mg, 1.91 mmol), and the mixture was stirred at room temperature for 10 min. A solution of bromine (320 mg, 2.00 mmol) in acetic acid (12 mL) was slowly added dropwise to the obtained solution, and the mixture was stirred at room temperature for 6 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (290 mg, 32%) as a red-orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CCCC1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and ethyl cyclohexanone-2-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclohexen-1-yl]ureido}-benzoate, m.p. 129°-130° C.,
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:3]1=[O:21].[F:22][C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([F:33])=[CH:25][C:24]=1F.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:22][C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([F:33])=[CH:25][C:24]=1[NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)[C:3]1=[O:21]
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](N)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 130 °C
Yield: 72.3 %

Procedure:
(S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.0 g, 13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 4.2 g, 20 mmol) and Na2CO3 (2.9 g, 27 mmol) were dissolved in DMF (30 mL) and heated at 130° C. overnight. The reaction was concentrated and purified over silica gel (25-75% EtOAc in hexanes) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.6 g, 9.4 mmol, 70% yield) as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH3:19])[C:11]=2[OH:18])[O:17][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(OCc2ccccc2)ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1O

Procedure:
The title compound was prepared by Method A using 4'-benzyloxy-2'-hydroxy-3'-methylacetophenone (1.29 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (2.11 g, 12.6 mmol), chlorotrimethylsilane (1.60 mL, 12.6 mmol), THF (127 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 147°-148° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.14 (s, 3 H), 2.77 (t, 2 H), 2.98 (t, 2 H), 5.17 (s, 2 H), 5.29 (s, 1 H), 6.79 (d, 1 H), 7.30 (m, 13H), 9.36 (s, 1 H), 11.85 (bs, 1 H).