Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH3:23][Sn](C)(C)C.CN(C=O)C>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.CN(P(N(C)C)(N(C)C)=O)C>[CH3:23][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Temperature: 120 °C

Procedure:
5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (106 mg, 0.273 mmol, 1.0 equiv), dichlorobis(triphenylphosphine)palladium(II) (50 mg, 0.07 mmol, 0.15 equiv) and tetramethyltin (270 μL, 1.91 mmol, 4.0 equiv) were combined in 5 mL of a 1:1 solution of DMF:HMPA. The solution was degassed and heated to 120° C. for 24 hours. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C14H18N3O4S (M+H+): 324.1013. Found 324.1014.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5](B(O)O)=[C:4]([O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:3]=1.[CH2:18]([O:21][C:22]1([CH3:55])[CH2:27][CH2:26][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39](Br)[CH:38]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:24][CH2:23]1)[CH:19]=[CH2:20].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=CC(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[C:51]([O:50][C@@H:45]([C:29]1[C:30]([CH3:44])=[CH:31][C:32]2[N:33]([CH:34]=[C:35]([C:37]3[CH:38]=[CH:39][CH:40]=[C:41]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:42]=3)[N:36]=2)[C:28]=1[N:25]1[CH2:24][CH2:23][C:22]([CH3:55])([O:21][CH2:18][CH:19]=[CH2:20])[CH2:27][CH2:26]1)[C:46]([O:48][CH3:49])=[O:47])([CH3:52])([CH3:53])[CH3:54]
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B(O)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 72 %

Procedure:
Prepared in 72% yield from (S)-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (400 MHz, CDCl3) δ 8.07-7.88 (m, 3H), 7.51-7.38 (m, 3H), 7.32 (br. s., 1H), 6.92-6.74 (m, 1H), 6.14-6.00 (m, 2H), 5.80-5.65 (m, 1H), 5.51-5.40 (m, 1H), 5.12-4.97 (m, 3H), 4.28-4.17 (m, 1H), 4.05-3.95 (m, 3H), 3.86-3.77 (m, 1H), 3.69 (s, 3H), 3.07-2.97 (m, 1H), 2.79-2.65 (m, 1H), 2.47 (s, 3H), 2.41-2.30 (m, 1H), 2.29-2.18 (m, 1H), 2.04-1.92 (m, 2H), 1.88-1.68 (m, 2H), 1.33 (s, 3H), 1.27 (s, 9H), 1.19 (d, J=6.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −137.17-−137.33 (d, J=23 Hz, 1F), −147.78-−147.92 (d, J=23 Hz, 1F); LCMS (ESI, M+1): 702.25.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>>[CH3:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:30]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C(C)(C)C)c4)CC3)cccc2n1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2,2-dimethylpropanoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])=[N:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([Br:1])[C:3]([O:11][CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH3:14])=[N:4]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1[nH]nc(OC[C@H](C)NC(=O)OC(C)(C)C)c1Br
Reactant: BrCc1ccccc1
Product: COC(=O)c1c(Br)c(OC[C@H](C)NC(=O)OC(C)(C)C)nn1Cc1ccccc1

Procedure:
Using methyl 4-bromo-3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate and benzyl bromide, and in the same manner as in Example 1, step A, the title compound was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[C:10]([O:13][CH2:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([O:29][C:30](=[O:32])[CH3:31])[C@H:17]([N:33]2[C:41]3[C:36](=[C:37]([CH3:42])[CH:38]=[CH:39][CH:40]=3)[C:35]([CH2:43][C:44]3[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[CH2:52][CH2:53][N:54]4[CH2:59][C:58]5([CH2:64][CH2:63][NH:62][CH2:61][CH2:60]5)[CH2:57][CH2:56][CH2:55]4)=[CH:46][CH:45]=3)=[CH:34]2)[O:16]1)(=[O:12])[CH3:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:77]([O:81][C:82]([NH:84][CH2:85][C:86](O)=[O:87])=[O:83])([CH3:80])([CH3:79])[CH3:78]>ClCCl>[C:10]([O:13][CH2:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([O:29][C:30](=[O:32])[CH3:31])[C@H:17]([N:33]2[C:41]3[C:36](=[C:37]([CH3:42])[CH:38]=[CH:39][CH:40]=3)[C:35]([CH2:43][C:44]3[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[CH2:52][CH2:53][N:54]4[CH2:59][C:58]5([CH2:60][CH2:61][N:62]([C:86](=[O:87])[CH2:85][NH:84][C:82]([O:81][C:77]([CH3:79])([CH3:78])[CH3:80])=[O:83])[CH2:63][CH2:64]5)[CH2:57][CH2:56][CH2:55]4)=[CH:46][CH:45]=3)=[CH:34]2)[O:16]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCN4CCCC5(CCNCC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCN4CCCC5(CCN(C(=O)CNC(=O)OC(C)(C)C)CC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 450 %

Procedure:
Add 4N HCl in 1,4-dioxane (112 5 mmol) to a solution of tert-butyl 4-[(E)-4-[4-[[4-methyl-1-[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenyl]but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (22.5 mmol) in dichloromethane (200 mL) at room temperature. Stir for 3 hours, then concentrate under reduced pressure to yield crude [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-(4,9-diazaspiro[5.5]undecan-4-yl)but-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate dihydrochloride (22.5 mmol): MS (m/z): 758.0 (M+H). Add triethylamine (112 5 mmol) to a solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-(4,9-diazaspiro[5.5]undecan-4-yl)but-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate dihydrochloride (22 5 mmol) in dichloromethane (200 mL). In a separate flask, add CDI (28.1 mmol) portion wise to a solution of 2-(tert-butoxycarbonylamino)acetic acid (27 mmol) in dichloromethane (50 mL). After stirring for 45 minutes at room temperature, add the solution to the previously prepared amine solution and stir at room temperature for 1 hour. Wash with a concentrated sodium bicarbonate solution (200 mL) and brine (200 ml). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield crude title compound (21.6 g, 22.5 mmol): MS (m/z): 915.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N+:10]([O-:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:27]([N:29](CC)[CH2:30][CH3:31])[CH3:28].N1CCCC1>ClCCl>[N:29]1([C:4]([C:3]2[C:2]([CH3:1])=[N+:10]([O-:11])[CH:9]=[CH:8][CH:7]=2)=[O:6])[CH2:30][CH2:31][CH2:28][CH2:27]1
Reactant: CCN(CC)CC
Reactant: Cc1c(C(=O)O)ccc[n+]1[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: C1CCNC1
Product: Cc1c(C(=O)N2CCCC2)ccc[n+]1[O-]
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a suspension of 2-methylnicotinic acid-1-oxide (0.701 g) and N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.243 g) in dichloromethane (30 ml) was added dropwise a solution of triethylamine (0.570 g) in dichloromethane (5 ml) and followed a solution of pyrrolidine (0.407 g) in dichloromethane (5 ml) under stirring at cooling in an ice-bath. After completion of the addition, the mixture was allowed to stand to room temperature overnight. The reaction mixture was washed with water and dried over sodium sulfate. Removal of the solvent gave a crude product. The crude product was purified by column chromatography on silica gel with a mixture of chloroform and methanol (50:1) as an elunet to give 3-(1-pyrrolidinylcarbonyl)-2-methylpyridine-1-oxide (0.530 g).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[C:12]1([O:18]C2C=CC=CC=2)C=CC=[CH:14][CH:13]=1.CCCC(C)C>C(#N)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:5]=1[N:6]=[CH:14][CH:13]=[C:12]2[OH:18]
Reactant: Nc1ccccc1OC(F)F
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCCC(C)C
Solvent: CC#N
Product: Oc1ccnc2c(OC(F)F)cccc12

Procedure:
2-difluoromethoxyaniline (7.63 g) and the product from step a) were stirred in acetonitrile (100 ml) overnight. The solvent was removed by evaporation and the solid triturated with 4:1 isohexane/diethyl ether (200 ml) before filtering to give a light green solid. The solid was added portionwise to refluxing diphenylether (120 ml) and continued heating for a further 10 minutes before cooling. The solution was poured into isohexane (600 ml) and the solid filtered off to give the title compound (12.0 g).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[Mg].[CH:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:18][CH:16]([CH3:17])[CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1
Reactant: CC=O
Reactant: BrCC1COC(c2ccccc2)OC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)CC1COC(c2ccccc2)OC1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
To a solution of 19.39 g (75.4 mM) of 5-bromomethyl-2-phenyl-1,3-dioxane m2 in 200 ml of tetrahydrofuran is added 1.923 g (79.17 mM) of magnesium and the mixture is allowed to react for 7 hours under ultrasonic bibration. The mixture is cooled to -70° C. and 21.27 ml (377 mM) of acetaldehyde is added and then the mixture is stirred at 0° C. for 15 hours. The mixture is poured into an ice-cooled saturated aqueous ammonium chloride solution and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. By eliminating the polar impurity by passing short column of silica gel, 11.353 g of the crude titled compound m3 is obtained which is used to the next reaction without further purification.
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[NH2:14][C@@H:15]([C:19]([OH:21])=[O:20])[C@H:16]([CH3:18])[OH:17].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:14][C@H:15]([C@@H:16]([OH:17])[CH3:18])[C:19]([OH:21])=[O:20])=[CH:3][CH:4]=1)#[N:13]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Temperature: 75 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
4-fluoro-1-naphthonitrile (13916-99-9) (1.0 g, 5.84 mmol) was mixed together with H-D-Thr-OH (835 mg, 7.01 mmol) in DMSO (20 mL). K2CO3 (1.61 g, 11.68 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc and then with EtOAc, 100% to get the pure final product (1.1 g): 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.25 (d, J=9 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.84 (d, J=9 Hz, 1H), 7.75 (t, J=9 Hz, 1H), 7.65 (t, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 6.32 (d, J=9 Hz, 1H), 4.53 (m, 1H), 4.38 (m, 1H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=2[S:7][C:6]=1[CH:18]=O)[CH2:2][CH2:3][CH3:4].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([CH3:35])[CH:24]=1)(=[O:22])[CH3:21]>>[CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]=2[S:7][C:6]=1[CH:18]=[CH:21][C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([CH3:35])[CH:24]=1)=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Reactant: CCCCc1c(C=O)sc2cc(C(F)(F)F)ccc12
Product: CCCCc1c(C=CC(=O)c2ccc(C=CC(=O)OC)c(C)c2)sc2cc(C(F)(F)F)ccc12

Procedure:
The titled compound was prepared from the above-mentioned 3-butyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde (88 mg, 0.31 mmol) and methyl 3-(4-acetyl-2-methylphenyl)acrylate (67 mg, 0.31 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (77 mg, yield 51%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:23]([CH3:24])[CH:22]3[CH2:25][CH:18]([CH2:19][CH2:20][N:21]3[CH3:26])[C:17]=2[CH:27]=1)(=[O:11])[CH3:10].C(=O)(O)[O-].[Na+]>CO.ClCCl>[C:9]([O:12][C:13]1[CH:14]=[C:15]([Br:1])[C:16]2[N:23]([CH3:24])[CH:22]3[CH2:25][CH:18]([CH2:19][CH2:20][N:21]3[CH3:26])[C:17]=2[CH:27]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Oc1ccc2c(c1)C1CCN(C)C(C1)N2C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Oc1cc(Br)c2c(c1)C1CCN(C)C(C1)N2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.5 %

Procedure:
N-Bromosuccinimide (2.40 g) was added in three portions to a solution of 3.50 g of crude 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol acetate in 135 ml of deoxygenated methanol. The resulting solution was stirred at room temperature for five minutes and then diluted with dichloromethane and a saturated sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane, and the combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. Column chromatography of the oil (silica gel elution with triethylamine-methanol-ethyl acetate) afforded 1.80 g (33%) of 10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocine-8-ol acetate as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13](I)=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])(=[O:28])=[O:27])=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:42])=[CH:38]B(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13]([CH:36]=[C:37]([CH3:42])[CH3:38])=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: O=c1c(I)ccc2n1[C@H](c1ccc(Cl)cc1)[C@H](c1ccc(Cl)cc1)N2S(=O)(=O)c1ccccc1F
Reactant: CC(C)=CB(O)O
Product: CC(C)=Cc1ccc2n(c1=O)[C@H](c1ccc(Cl)cc1)[C@H](c1ccc(Cl)cc1)N2S(=O)(=O)c1ccccc1F

Procedure:
rac-cis-2,3-Bis-(4-chloro-phenyl)-1-(2-fluoro-benzenesulfonyl)-6-(2-methyl-propenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-2,3-bis-(4-chloro-phenyl)-1-(2-fluoro-benzenesulfonyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 2,2-dimethylethenylboronic acid. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 569.06; the expected mass is 568. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH:11][CH2:12][C:13]([OH:15])=O)[C:7]=2[CH:16]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH:30][C:13](=[O:15])[CH2:12][NH:11][C:8]2[C:7]3[CH:16]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:4]=[CH:5][C:6]=3[O:10][N:9]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)CNc1noc2ccc(C(F)(F)F)cc12
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2noc3ccc(C(F)(F)F)cc23)C1

Procedure:
(5-Trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetic acid (2.6 g, 9.99 mmol), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (1.72 g, 9.99 mmol), EDCI (2.3 g, 12.0 mmol), HOBt (1.62 g, 12.0 mmol) in DCM (20 mL) were stirred at room temperature for 4 hours. The reaction was then partitioned between DCM and water. The aqueous layer was extracted two times with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was purified by silica gel column (hexanes:ethyl acetate 1:1) to afford the title compound as white foam.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([OH:23])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:3][C:2]#[CH:1])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: C#CCBr
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 15 h

Procedure:
1.73 g (14.6 mmol) of propargyl bromide were added dropwise to a mixture of 3.00 g (9.74 mmol) of 3-chloro-2-(4-chloro-3-hydroxyphenyl)-5-trifluoromethylpyridine, 4.0 g (29 mmol) of potassium carbonate and 100 ml of anhydrous dimethylformamide. The mixture was stirred at 20°-25° C. for about 15 hours and then poured into 400 ml of water. The solution was kept cold for a few hours, and the resulting crystals were then separated off, washed with water and dried under reduced pressure. Yield: 3.1 g (92%) of colorless crystals of melting point 102°-103° C.
Reaction SMILES: [NH3:1].[Cl-].[NH4+].Cl[C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][N:8]=[CH:7][N:6]=1>C(O)C>[NH2:1][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: N
Reactant: Clc1ncncc1Oc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ncncc1Oc1ccccc1
Yield: 66 %

Procedure:
To a solution of 125 ml. of absolute ethanol saturated with ammonia was added 2.0 g. ammonium chloride and 25.7 g. (0.124 mol) of 4-chloro-5-phenoxy pyrimidine and the mixture was heated in a 250 ml. stainless steel pressure bomb at 160° for six hrs. The bomb was cooled and the contents poured into a 1000 ml. rb flask. The bomb was rinsed with 4 × 100 ml. boiling ethanol and the combined ethanol solutions were stripped to an oily mixture on the rotary evaporator. The residues were extracted with 4 × 150 ml ether and the ether solution concentrated on the steam bath until a solid began to precipitate. Cooling gave a yellow solid which was collected by vacuum filtration. The solid was taken up in hot ethyl acetate and treated with activated charcoal filtered and concentrated on the steam bath. Careful addition of hexane and cooling gave 15.3 g (66%) white crystals mp 118°-120°.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[C:40]([CH:41]=[O:42])=[CH:39][N:38]=[CH:37]1.[Li]N1C(C)(C)CCCC1(C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:41]([C:40]2[S:36][CH:37]=[N:38][CH:39]=2)[OH:42])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: O=Cc1cncs1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3cncs3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 1,3-thiazole-5-carbaldehyde and lithium 2,2,6,6-tetramethylpiperidide.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-]>CO>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: C=[N+]=[N-]
Reactant: Nc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-5-bromo-3-nitro-benzoic acid (5 g, 19.15 mmol) in methanol (100 mL) was added a saturated ethereal solution of diazomethane gas (75 mL) until the starting material was consumed. The reaction mixture was concentrated to dryness and the residue obtained was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain the title compound as yellow solid which was directly used for the next step (5 g, 94.3%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:12](=[O:21])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O>[C].[Pd].C(O)=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]2[CH:8]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][C:12]2=[O:21])=[CH:19][CH:18]=1
Reactant: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccc(F)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=C1CCCC(c2ccccc2)N1c1ccc(F)cc1
Yield: 60.8 %

Procedure:
A mixture of 2.32 g of 6-(4-chlorophenyl)-1-(4-fluorophenyl)-2-piperidone, 25 ml of dimethylformamide, 5 ml of formic acid, and 1.0 g of palladium-carbon was refluxed for 6 hours. The catalyst was filtered off, and the filtrate was extracted with ethyl acetate. The ethyl acetate solution was washed with water and an aqueous sodium hydrogen carbonate solution and dried. After removal of the solvent, the residue was recrystallized from a mixture of isopropyl ether and n-hexane to give 1.25 g of 1-(4-fluorophenyl)-6-phenyl-2-piperidone as colorless prisms.