Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH2:13][CH:14]3[CH2:18][O:17]C(C)(C)[O:15]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].Cl.[OH-].[Na+]>CO.C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[CH2:18][OH:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=1
Reactant: CC1(C)OCC(CCCn2ccc3ncnc(Cl)c32)O1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: OCC(O)CCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.1 %

Procedure:
The crude product was obtained by the reaction in the same manner as in Example 201 (iii) using 4-chloro-5-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2-d]pyrimidine (171 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (195 mg) and isopropyl alcohol (3.5 mL). The crude product was dissolved in methanol (1 mL), 1N hydrochloric acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3.5 hrs. The reaction mixture was treated with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→95:5) to give the title compound (179 mg) as white crystals.
Reaction SMILES: [CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:31])[O:30][CH2:29]1>>[CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[CH2:23][CH2:22]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)c(F)c1
Product: CC(C)(O)CN1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3F)on2)C2CC2)CC1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 1,1-dimethyloxirane following a procedure analogous to that described for Intermediate 2. LC (method 3): tR=1.21 min; Mass spectrum (ESI+): m/z=427 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[Cl:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:35]=1[C:36]([NH:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4])=[O:37]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)C(N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 23.38 g of methyl 2-amino-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 33 (0.2 TFA salt) in CH2Cl2 (50 ml) are added, at 0° C., triethylamine (22 ml) and 2,6-dichlorobenzoyl chloride (6.22 ml) dissolved in CH2Cl2 (6 ml). The reaction is stirred at RT for 2 h. The organic phase is washed with water, dried over MgSO4 and evaporated under vacuum. The residue is purified by silica gel chromatography using CH2Cl2/Hexane 95/5 as eluent.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CS(C)=O.CCOC(C)=O>[F:27][C:28]1([F:34])[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH2:30][CH2:29]1
Reactant: FC1(F)CCNCC1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC(F)(F)CC3)n2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of triazine A1 (270 mg, 0.9 mmol) in DMSO (0.9 mL) were added K2CO3 (370 mg, 2.7 mmol) and 4,4-difluoropiperidine hydrochloride (140 mg, 0.9 mmol). The mixture was stirred for 2 hours at 80° C. After cooling to room temperature it was diluted with EtOAc and extracted with water. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was stirred with DCM to give the solid title compound B2 which was isolated by filtration and dried in vacuo (white powder, 110 mg, 32%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.90-2.15 (m, 4H), 3.81-3.98 (m, 4H), 4.21 (s, 2H), 6.88 (s, 2H), 6.98-7.04 (m, 1H), 7.21-7.34 (m, 1H), 7.44-7.60 (m, 1H), 7.78-7.90 (m, 1H), 8.25 (s, 1H), 9.77 (s, 1H). MS (ES) C15H18F2N6O2S requires: 384. found: 385 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[C:22]1([CH:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH2:31]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:30][CH2:31][S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: ICCCC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(SCCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 43 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 4,4-diphenylbutyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 43%.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[S:29]1[CH2:33][CH:32]([CH2:34][OH:35])[NH:31][CH2:30]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:31]1[CH:32]([CH2:34][OH:35])[CH2:33][S:29][CH2:30]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CSCN1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CSCC1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
1.9 g (8.4 mmol) of o-benzoylbenzoic acid and 1.13 g (8.4 mmol) of 1-hydroxybenzotriazole hydrate were combined in 50 ml of methylene chloride and stirred for 20 minutes at room temperature. 1.0 g (8.4 mmol) of 4-thiazolidinemethanol was added, followed by 1.6 g (8.4 mmol) of ethyl-3-(3-dimethylaminopropyl)carbodiimide. The reaction mixture was stirred for 18 hours at room temperature and washed with water, first at pH 2.5 and then at pH 9.5. The organic phase was dried and evaporated to give a foam which was chromatographed on silica gel using 1:1/chloroform:ethyl acetate as the eluant to yield 1.1 g (40%) of the title compound. 1H NMR (CDCl3) δ: 7.4-7.85(m,9H); 4.65(m,1H) ; 4.20-4.40(m,2H); 3.96(m,1H); 3.60-3.70(m,2H); 3.0-3.30(m,2H). High Resolution Mass Spectrum: m/e=328.1015±0.8 ppm (calculated for C18H18NO3S).
Reaction SMILES: BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(C(C)(C)C)=CC=3)(=O)=O)C=2C=1.[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:51])[F:50])[CH:47]=[CH:48][C:42]=3[CH2:41][NH:40][C:39]=2[CH:53]=1.[F:54][C:55]([F:70])([F:69])[C:56]1([C:59]2[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=2)[CH2:58][CH2:57]1.BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CNC=2C=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)(C)C>>[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:50])[F:51])[CH:47]=[CH:48][C:42]=3[CH2:41][N:40]([S:65]([C:62]3[CH:61]=[CH:60][C:59]([C:56]4([C:55]([F:54])([F:69])[F:70])[CH2:58][CH2:57]4)=[CH:64][CH:63]=3)(=[O:67])=[O:66])[C:39]=2[CH:53]=1
Reactant: O=S(=O)(Cl)c1ccc(C2(C(F)(F)F)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(n1)Nc1ccc(I)cc1NC2
Agent: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: FC(F)(F)c1ccc2c(n1)Nc1ccc(Br)cc1NC2
Product: O=S(=O)(c1ccc(C2(C(F)(F)F)CC2)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21

Procedure:
The title compound was prepared following procedure described for intermediate 53 substituting 8-iodo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 37) and 4-[1-(trifluoromethyl)-cyclopropyl]benzenesulfonyl chloride (intermediate 48) for 8-bromo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine, and [(4-tert-butylphenyl)-sulfonyl chloride. LC/MS: m/e 639.8 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.93 (1H, d, J=2.1 Hz), 7.58 (1H, d, J=7.8 Hz), 7.55 (1H, dd, J=8.5, 2.1 Hz), 7.22 (2H, d, J=8.2 Hz), 7.10 (1H, d, J=7.6 Hz), 7.03 (2H, d, J=8.5 Hz), 6.75 (1H, s), 6.52 (1H, d, J=8.5 Hz), 4.70-4.90 (2H, br), 1.37-1.40 (4H, m), 0.95-1.05 (4H, m).
Reaction SMILES: S([O:5][CH2:6][C@@H:7]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)(=O)C.[N-:24]=[N+:25]=[N-:26].[Na+].[I-].[Na+]>CN(C=O)C>[C:12]([O:11][C:9]([NH:8][C@@H:7]([C:6]([N:24]=[N+:25]=[N-:26])=[O:5])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)COS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)N=[N+]=[N-]
Temperature: 50 °C
Yield: 73 %

Procedure:
The product from (B) (12.6 mmol) was dissolved in DMF (25 mL) and sodium azide (NaN3) (50 mmol) and sodium iodide (NaI) (50 mmol) were added. This solution was warmed at 50° C. for 24 hr then cooled to room temperature, washed with H2O (3×50 mL), extracted with EtOAc (2×50 mL) and washed with brine (1×25 mL). The organic layer was dried over Na2SO4, filtered dried to give the title compound (2.8 g, 77%) as an oil.
Reaction SMILES: O[C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])([CH:4]=[CH2:5])[CH3:3].C([O-])(=O)[CH2:18][C:19]([CH3:21])=[O:20]>>[CH3:3][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:4][CH2:5][CH2:18][C:19](=[O:20])[CH3:21]
Reactant: CC(=O)CC(=O)[O-]
Reactant: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
Nerolidol [compound (5) (manufactured by Takasago International Corporation] to be used as a starting material was subjected to Carroll reaction using acetoacetate in accordance with the method of W. Kimel et al. [J. Org. Chem., 23(2), pp. 153-157 (1958)] to give 6,10,14-trimethyl-5,9,13-pentadecatrien-2-one [compound (6)].
Reaction SMILES: [BH4-].[Na+].[Te].Br[C:5]1(Br)[CH2:9][CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=2)[NH:7][C:6]1=[O:17]>C(O)C>[Br:16][C:14]1[CH:15]=[C:10]([CH:8]2[NH:7][C:6](=[O:17])[CH2:5][CH2:9]2)[CH:11]=[N:12][CH:13]=1
Reactant: O=C1NC(c2cncc(Br)c2)CC1(Br)Br
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: CCO
Product: O=C1CCC(c2cncc(Br)c2)N1
Temperature: 80 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
Sodium borohydride (0.74 g, 19.6 mmol) is suspended in ethanol (17 mL) and tellurium metal powder (1.25 g, 9.78 mmol) is added in portions. The mixture is heated under reflux (external temperature 80° C.) for 15 min and the mixture becomes a light purple color. The mixture is cooled to room temperature. 3,3-Dibromo-5-(5-bromo-pyridin-3-yl)-pyrrolidin-2-one (0.65 g, 1.63 mmol) dissolved in EOH (5 mL) is added slowly. The mixture is stirred at room temperature over the weekend (72 h). The mixture is filtered through diatomaceous earth and washed with MeOH. The filtrate is concentrated. The resulting crude product is purified by normal phase chromatography using 0-6% MeOH in DCM as the gradient to afford 5-(5-bromo-pyridin-3-yl)-pyrrolidin-2-one (291 mg, 74% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[CH:15](=[O:17])[CH3:16]>CCOCC>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:15]([OH:17])[CH3:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C(C)O)cn1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 5-bromo-2methoxy-pyridine (19.3 g, 193 mmol) in anhydrous Et2O (200 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 50 mL) over 30 min. The resulting mixture was stirred at that temperature for addition 30 min before acetaldehyde (5 mL) was added. The reaction was slowly warmed up to room temperature and the solvent was removed in vacuo. The residue was purified by flash column chromatography to afford the desired product (14.3 g, 91% yield). 1H NMR (400 MHz, CDCl3): δ 1.50 (d, J=8.0 Hz, 3H), 3.93 (s, 3H), 4.87-4.92 (m, 1H), 6.75 (d, J=8.0 Hz, 3H), 7.63-7.66 (m, 1H), 8.12-8.14 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:11]([O-:13])=[O:12])=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc(N)c([N+](=O)[O-])c(C)c1Br
Reaction time: 0.33 h

Procedure:
4 g (20 mmol) of the product obtained in Stage A are dissolved in 16 ml of concentrated sulfuric acid with stirring and cooling in ice. The solution is brought to 55° C. and 1.3 ml of concentrated nitric acid are added dropwise, care being taken to maintain the temperature between 55° and 60° C. The stirring is continued for 20 minutes and the mixture is then poured onto crushed ice. The product is precipitated by addition of 40% sodium hydroxide. It is filtered off, washed with water and then dried. 3.7 g of product are thus collected. The product is recrystallized from 95° C. ethanol.
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1.[Br:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[C:40]([NH:42][C:43]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:27][CH:28]=1)=[S:44])=[O:41]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 74%).
Reaction SMILES: [Cl-].C1(C)C=CC=CC=1.C1([Li])C=CC=CC=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)#[N:17].[O:33]1[CH2:37]CC[CH2:34]1>O>[CH3:34][O:33][CH:37]=[CH:31][CH2:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]#[N:17])=[CH:23][CH:22]=2)[CH2:29][CH2:28]1
Reactant: C1CCOC1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Commercially available methoxymethyltriphenylphosphornium chloride (15.7 g, 0.0458 mol) was added to tetrahydrofuran (100 ml), followed by dropwise adding a toluene solution (23 ml) of 25% by weight of phenyllithium in argon atmosphere with stirring at -10° C. over 10 minutes, agitating the reaction solution at 0° C. for 30 minutes, dropwise adding a solution of trans-4-(4-cyanophenyl)cyclohexylacetaldehyde (VII) obtained in Example 2(i) (7.3 g, 0.032 mol) in tetrahydrofuran (90 ml) at -10° C. over 10 minutes, agitating the reaction solution at 0° C. for 2 hours, adding toluene (100 ml) and water (200 ml), washing, subjecting the resulting toluene solution to three times washing with water (200 ml) and separating, drying with anhydrous sodium sulfate, separating the drying agent, distilling off toluene, dissolving the resulting residue in ethyl acetate (20 ml) on heating, allowing the solution to stand still at room temperature for one day, filtering off deposited crystals, concentrating the resulting mother liquor, dissolving the concentrate in heptane and purifying according to silica gel chromatography to obtain trans-1-(3-methoxy-2-propenyl)-4-(4-cyanophenyl)cyclohexane (4.4 g, 0.017 mol), adding to the total quantity thereof, tetrahydrofuran (70 ml) and 2N-hydrochloric acid (18 ml), heating the mixture under reflux with stirring for one hour, cooling the reaction solution, adding diethyl ether (50 ml) and water (50 ml) to the solution, subjecting the resulting diethyl ether to three times washing with water (50 ml) and separating, drying with anhydrous sodium sulfate, separating the drying agent and distilling off diethyl ether to obtain trans-4-(4-cyanophenyl)cyclohexylpropylaldehyde (4.2 g, 0.017 mol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.N#N.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(NC(C)C)(C)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu](I)I>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1cc(Br)cs1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: N#N
Solvent: CC(C)NC(C)C
Solvent: N#Cc1ccccc1
Product: O=Cc1cc(C#Cc2ccccc2)cs1
Temperature: 70 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
Under a N2 atmosphere, 4-bromothiophene-2-carbaldehyde (1.0 g, 5.2 mmol) was taken up in diisopropylamine (20 mL). TPP (549 mg, 2.1 mmol), bis(benzonitrile)palladium chloride ([Pd(PhCN)2]Cl2) (400 mg, 1.0 mmol), and copper iodide (199 mg, 1.0 mmol) were added. The mixture was degassed with N2 before phenylacetylene (1.15 mL, 10.4 mmol) was added, and the reaction was stirred at 70° C. for 16 h. The mixture was concentrated to a dark brown solid and chromatographed in 0-15% EtOAc in heptane to yield 4-(phenylethynyl)thiophene-2-carbaldehyde (981 mg, 88%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.93 (d, 1H), 7.88 (t, 1H), 7.85 (d, 1H), 7.53 (m, 2H), 7.38 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[CH2:15](C([Sn])=C(CCCC)CCCC)[CH2:16]CC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:15]=[CH2:16])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)OC)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
To a solution of 4-bromo-2-nitro-benzoic acid methyl ester (1 g, 3.85 mmol) in dioxane (5 mL) were added tributylvinyltin (1.7 mL, 5.76 mmol) and Pd(Ph3P)2Cl2 (275.4 mg, 0.385 mmol). The reaction mixture was stirred at 80° C. for 18 h, was cooled to r.t. and was diluted with EtOAc. After removal of the precipitate by filtration, the solution was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes→1:1 hexanes:EtOAc) to provide the title compound (820 mg, 100%, 97% purity by HPLC) as a yellow oil. ESI-MS: m/z 208.2 [M+H]+, rt 5.14 min.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH:2]=[O:1])=[O:11])=[CH:18][CH:19]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CO)c(-c2ccc(F)cc2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2C=O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of rac-cis-(2-(hydroxymethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in DCM was added Dess-Martin periodinane (1.5 eq) and stirred at rt for 4 h. The reaction mixture was transferred to a seperatory funnel, diluted with more DCM, water and the layers were separated. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to give a crude residue which was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 347.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.C([Li])CCC.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Cl)[N:17]=1>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[N:17]=2)[CH2:4][CH2:3]1
Reactant: Clc1cccc(Cl)n1
Reactant: CNC1CCN(C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(NCc2cccc(Cl)n2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Dissolve 1-methyl-4-(methylamino)piperidine (10 mL, 68.8 mmol) in tetrahydrofuran (50 mL) and cool to −78° C. Slowly add n-butyllithium (1.6 N in hexane, 43 mL, 68.8 mmol) to the reaction mixture and stir at −78° C. for 30 min. Warm the reaction mixture to room temperature and stir for 30 min. Then cool the reaction mixture to −78° C. and add 2,6-dichloropyridine (11.2 g, 75.7 mmol) in tetrahydrofuran (50 mL). Stir the reaction mixture at −78° C. for 15 min, warm to room temperature, and then heat to 60° C. for 19 hr. Cool the reaction mixture to room temperature and partition between ethyl acetate and water. Separate the organic layer and extract the aqueous layer with dichloromethane (2×50 mL). Combine organic extracts, dry (MgSO4), filter, and concentrate in vacuo. Purify the residue by column chromatography on silica gel using a gradient of 2%-10% (2M NH3 in methanol) in CH2Cl2 to give of the title intermediate (11.91 g, 72%): mass spectrum (ion spray): m/z=240.1 (M+1); 1H NMR: δ (CDCl3, ppm) 7.34 (t, J=7.6, 16.0 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 4.41 (m, 1H), 2.94 (m, 2H), 2.86 (s, 3H), 2.32 (s, 3H), 2.15 (m, 2H), 1.84 (m, 2H), 1.68 (m, 2H).