Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH2:19]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[I:32])[CH:27]=O)[CH2:20][CH2:21][CH3:22].[Cl-].[NH4+]>O1CCCC1>[CH2:19]([O:23][C:24]1[CH:25]=[C:26](/[CH:27]=[C:3](\[CH2:2][CH3:1])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:29]=[CH:30][C:31]=1[I:32])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1cc(C=O)ccc1I
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCOc1cc(/C=C(\CC)C(=O)OCC)ccc1I
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
A solution of 9 mL (37.8 mmol) of triethyl 2-phosphonobutyrate in 20 mL of tetrahydrofuran is added to a mixture of 1.52 g (37.8 mmol) of sodium hydride in 15 mL of tetrahydrofuran. The reaction medium is stirred for 20 minutes. A solution of 3.83 g (12.6 mmol) of 3-butoxy-4-iodobenzaldehyde (prepared as described in Example 19g) in 15 mL of tetrahydrofuran is then added to the reaction mixture and the reaction medium is stirred at room temperature for 2 hours 30 minutes. The reaction medium is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated off and the residue (11.49 g) is purified by chromatography on silica gel eluted with a 95/5 heptane/ethyl acetate mixture. 4.90 g (97%) of ethyl 2-[1-(3-butoxy-4-iodophenyl)meth-(E)-ylidene]butyrate are obtained in the form of a yellow oil that crystallizes.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][C:16]2([CH3:37])[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.[NH2:38][CH2:39][CH2:40][CH2:41][OH:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:42][CH2:41][CH2:40][CH2:39][NH:38][C:34]([C:16]1([CH3:37])[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17]1)=[O:35]
Reactant: NCCCO
Reactant: CC(C)(C)CC1NC(C)(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C)(C(=O)NCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 59.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 33c (0.4 g, 0.7 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1 g, 7.7 mmol) in CH2Cl2 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide as a white solid (0.21 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1cccn1-c1ncccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To a solution of 1.0 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 15 ml of N,N-dimethylformamide was added 0.68 g of N-chlorosuccinimide. The resulting mixture was stirred at 50° C. for 2 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 4-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C@H:10]([CH3:15])[C@H:9]1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C@H:10]([CH3:15])[C@H:9]1[C:16]([O:18][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 85.3 %

Procedure:
A mixture of (2R,3S)-4-benzyl-2-methyl-5-oxomorpholine-3-carboxylic acid (1.07 g, 4.25 mmol) (The compound was synthesized according to the procedure as described in Helvetica Chimica Acta, 87, 2004), (bromomethyl)benzene (0.87 g, 5.1 mmol) and potassium carbonate (1.16 g, 8.5 mmol) in acetonitrile (20 mL) was stirred at 65° C. for 6 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=4/1) to give the title compound as colorless oil (1.23 g, 85%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:16]([CH3:18])[CH3:17].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]([CH3:18])[CH3:17]
Reactant: Oc1ccccc1Br
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
2-Bromophenol (500 mg, 2.9 mmol) was dissolved in dry dimethylformamide (5 mL) under a dry nitrogen atmosphere. Powdered dry cesium carbonate (1.41. g, 4.34 mmol) was added, followed by the addition of 2-bromopropane (404 μL, 4.05 mmol) over a 2 min period. The mixture was stirred at room temperature overnight. Water (50 mL) was added and the mixture extracted with ethyl acetate (2×50 mL). The combined extracts were successively washed with water (25 mL) and saturated salt solution (25 mL) and dried over anhydrous magnesium sulfate. The dried solution was filtered and the solvents removed rotoevaporation to yield the title compound as an oil (522 mg, 84% yield).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].II.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19](=[O:27])[C:20](=[O:26])[C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH2:13][CH2:12]1.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19](=[O:27])[C:20]([OH:26])([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1
Reactant: Brc1cccs1
Reactant: CN1CCC(COC(=O)C(=O)c2cccs2)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCC(COC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromothiophene (2.15 ml, 22.2 mmol) in THF (15 ml) is added dropwise to a mixture of magnesium (0.54 g, 22.2 mmol) and a single crystal of iodine in THF (15 ml). After addition of just under one half of the 2-bromothiophene the addition is suspended until reaction has initiated (judged by an exotherm). The addition is then completed maintaining the reaction temperature to below 40° C. After the addition is completed the reaction mixture is heated to reflux for 20 minutes. This mixture is then cooled and added to a solution of oxo-thiophen-2-yl-acetic acid 1-methyl-piperidin-4-ylmethyl ester (4.6 g, 17.2 mmol) in THF (40 ml). After the addition is completed the reaction mixture is stirred at room temperature for 1 hour and then heated to reflux for 2.5 hours. After cooling to room temperature saturated aqueous ammonium chloride solution (100 ml) is added together with diethylether. The solution is extracted with diethylether dried over magnesium sulphate, filtered and concentrated. Purification by flash silica column chromatography gives the title product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:34][CH2:35][NH:36][S:37]([CH3:40])(=[O:39])=[O:38]>C(#N)C.C(Cl)(Cl)Cl>[CH3:40][S:37]([NH:36][CH2:35][CH2:34][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1)(=[O:39])=[O:38]
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Reactant: CS(=O)(=O)NCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NCCN1CCC(CNC(=O)c2c3n(c4ccccc24)CCCO3)CC1
Yield: 11.2 %

Procedure:
A stirred solution of N-(4-piperidylmethyl) 3,4-dihydro-2 H-[1,3]oxazino[3,2-a]indole-10-carboxamide (E21, 220 mg, 0.70 mmole) in acetonitrile (8 ml) was treated with diisopropylethylamine (0.24 ml, 1.4 mmole) and N-(2-bromoethyl)methanesulphonamide (D14, 160 mg, 0.77 mmole) and the mixture heated under reflux for 2.5 h. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1). The colourless oil obtained was dissolved in chloroform (30 ml) and washed with water (2×20 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was passed through a short plug of basic alumina eluting with ethyl acetate to afford the title compound as a colourless oil (34 mg, 11%). This was converted to its oxalate salt and crystallised from acetone to give a white solid mp 80°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:40][C:41](=O)[CH2:42][CH3:43]>>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:24][CH2:23][CH2:4][N:5]([CH3:6])[CH2:40][C:41]2[CH:11]=[CH:10][CH:9]=[CH:43][CH:42]=2)=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CCC(C)=O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COC(=O)[C@H](Cc1ccc(OCCCN(C)Cc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared via O-alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with 3-(N-benzyl,N-methyl)aminopropyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide to provide a solid, mp=60-70° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=[O:2].[Cl-].[NH4+].C1COCC1.C(Cl)Cl>O.[Zn]>[OH:2][NH:1][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1NO
Reaction time: 2 h
Yield: 50 %

Procedure:
To a stirring solution of ethyl 2-nitrobenzoate (32.0 g, 0.164 mol), ammonium chloride (22.28 g, 0.416 mol) in solvent mixture of water (240 mL) and THF (288 mL) was added zinc powder (26.8 g, 0.410 mol) slowly at 0° C. Reaction mixture was stirred at 0° C.-10° C. for 2 h. Reaction mixture was then diluted with water followed by DCM and filtered through Hyflow bed. The organic layer was separated and distilled out to get crude product which was column purified using 0-5% EtOAC in hexane to get titled compound as light yellow solid in 50% yield.
Reaction SMILES: BrC1C=N[C:5]2[N:6]=[CH:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:9](=[O:10])[C:4]=2C=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37]([C:5]4[CH:4]=[CH:9][C:5]5[N:6]=[CH:7][N:8]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=6[F:17])[C:9](=[O:10])[C:4]=5[N:6]=4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=c1c2cc(Br)cnc2ncn1-c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4ncn(-c5ccccc5F)c(=O)c4n3)cc12
Temperature: 80 °C
Yield: 41.7 %

Procedure:
To a degassed mixture of 6-bromo-3-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (75 mg, 0.234 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol) in N, N-dimethyl-formamide (5 mL) were added Pd(dppf)Cl2 (15 mg) and K3PO4 (127 mg, 0.468 mmol) under N2. The mixture was heated to 80° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by prep-HPLC to give 2-(4-fluorophenyl)-5-(3-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 8.22 (d, J=8.8 Hz, 1H), 8.08˜8.14 (m, 3H), 7.96˜7.99 (m, 2H), 7.65 (s, 1H), 7.47˜7.57 (m, 2H), 7.32˜7.38 (m, 2H), 7.19 (t, J=8.8 Hz, 2H), 6.47 (br s, 1H), 3.27 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.93 (s, 3H). MS (M+H)+: 616.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1.[C:32]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.O.CN(C=O)C>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([NH:40][C:15]([C:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH:13]=2)=[O:17])=[CH:41][CH:42]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)C1=CCN(c2ncccc2C(F)(F)F)CC1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)C2=CCN(c3ncccc3C(F)(F)F)CC2)cc1
Reaction time: 1.5 h

Procedure:
3′-(Trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (0.300 g, 1.10 mmol) and a catalytic amount of DMF were combined in CH2Cl2 (4.0 mL) and treated with (COCl)2 (0.14 mL, 1.6 mmol). The mixture was stirred for 90 minutes, diluted with toluene (0.5 mL) and concentrated to dryness. The residue was dissolved in CH2Cl2 (4.0 mL) treated with pyridine (0.14 mL, 1.7 mmol), a catalytic amount of DMAP, and 4-tert-butylaniline (0.21 mL, 1.3 mmol). After 1 hour, the mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (2.5% ethyl acetate/CH2Cl2) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.42 (dd, 1H), 7.89 (dd, 1H), 7.47 (d, 3H), 6.98 (dd, 1H), 6.76 (s, 1H), 4.06 (q, 2H), 3.53 (t, 2H), 2.67 (m, 2H); MS (m/z) 404.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-].C(N(CC)CC)C>C(#N)C>[Cl:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:5]#[N:6])[N:12]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccccc1Cc1ccccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cc2ccccc2Cl)n1
Temperature: 25 °C
Yield: 33.5 %

Procedure:
Trimethylsilyl cyanide (36.15 g, 48.6 ml, 0.36 moles) was added dropwise to a solution of 2-(o-chlorobenzyl)-pyridine-N-oxide (32.0 g, 0.15 moles) and triethylamine (22.13 g, 30.5 ml, 0.22 moles) in acetonitrile (100 ml) at 20° C. under a nitrogen atmosphere. After complete addition the reaction mixture was heated under reflux for 48 hours, cooled to room temperature and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer was washed with water and saturated sodium chloride solution and was then dried over anhydrous magnesium sulphate. Removal of the solvent gave an orange brown oil which was purified by column chromatography (silica gel eluted with hexane:ethyl acetate 4:1) to give 2-(o-chlorobenzyl)-6-cyanopyridine (11.5 g, 35%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C@@H:27]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])[C:30](=[O:43])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>O1CCCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[C:15]([C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:26]\[C@@H:27]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])[C:30](=[O:43])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2C#Cc2ccc(C(C)(C)C)cc2)c(OC)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Bis(tricyclohexylphosphine)palladium(II) dichloride (230 mg) and tributyltin chloride (1.0 mL) were sequentially added to a solution of (5R)-5-[(4-tert-butylphenyl)ethynyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (1.24 g) in tetrahydrofuran (15 mL) in a nitrogen gas stream, and the mixture was stirred at room temperature for two hours. The reaction solution was filtered through celite, and then the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give the title compound as a colorless powder (2.16 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][S:27](=[O:44])(=[O:43])[CH2:28][CH2:29][C@:30]([C:35]3[CH:40]=[C:39](Br)[CH:38]=[CH:37][C:36]=3[F:42])([CH:32]([F:34])[F:33])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:81](=[NH:94])([C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[C:81](=[N:94][C:39]1[CH:38]=[CH:37][C:36]([F:42])=[C:35]([C@:30]2([CH:32]([F:34])[F:33])[CH2:29][CH2:28][S:27](=[O:44])(=[O:43])[CH2:26][C:25]([NH:24][C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:31]2)[CH:40]=1)([C:88]1[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=1)[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(NC2=N[C@@](c3cc(Br)ccc3F)(C(F)F)CCS(=O)(=O)C2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(NC2=N[C@@](c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)(C(F)F)CCS(=O)(=O)C2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
In a tube under an atmosphere of argon a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-yl]-amine (356 mg, 518 μmol) in toluene (5 ml) was treated successively with sodium tert-butoxide (149 mg, 1.55 mmol), 2-di-tertbutylphosphino-2′,4′,6′-triisopropylbiphenyl (33 mg, 77.7 μmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (26.8 mg, 26 μmol), and benzophenonimine (188 mg, 1.04 mmol). The tube was sealed and the mixture was heated at 105° C. under stirring for 4 hours. For the workup, the brown solution was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate 100:0 to 50:50 as the eluent. The {(S)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-yl}-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine (207 mg, 51% yield) was obtained as a light yellow foam. MS (ISN): m/z=786.5 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[NH2:17].CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH3:23])=[C:14]([Br:13])[CH:15]=1)=[O:12])([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CCOc1ccc(N)cc1Br
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOc1ccc(NC(=O)Nc2ccccc2[N+](=O)[O-])cc1Br
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Nitrophenyl isocyanate (3.34 g) in 100 mL of toluene was added 3-Bromo-4-ethoxyaniline (3.1 g). The mixture was stirred at 20° C. for 30 min. Hexane (300 mL) was added and the resulting solid was filtered and dried to yield N-(2-Nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-:23])=[O:22])=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].COC1C([N+]([O-])=O)=C(C=CC=1)C=O.CO[CH2:39][N:40]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:41][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:46]([N:40]1[CH2:41][CH:6]([C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([O:2][CH3:1])[C:4]=2[N+:21]([O-:23])=[O:22])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:39]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCOC(=O)C(=Cc1cccc(OC)c1[N+](=O)[O-])C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: COc1cccc(C=O)c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)CC1c1cccc(OC)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of diethyl 2-(3-methoxy-2-nitrobenzylidene)malonate, which was prepared from 3-methoxy-2-nitrobenzaldehyde following the procedure described in Example 1, Part C (162 mg, 0.5 mmol) in 10 mL of methylene chloride was added added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (237 mg, 1.0 mmol) and trifluoroacetic acid (0.010 mL, 0.125 mmol). The solution was allowed to stir at 40° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (elution with 4:1 hexane/EtOAc) to afford 201 mg (88%) of the title compound. 1H NMR (CDCl3): δ 7.40-7.25 (m, 7H), 6.93-6.85 (m, 1H), 4.36-4.30 (m, 1H), 4.32-4.15 (m, 2H), 3.87 (s, 3H), 3.77 (q, 2H), 3.69 (s, 2H), 3.60-3.50 (m, 1H), 3.05-2.97 (m, 1H), 2.85-2.78 (m, 1H), 2.75-2.68 (m, 1H), 1.23 (t, 3H, J=7.2 Hz), 0.83 (t, 3H, J=7.2 Hz). LRMS (ESI): 457.4 (M+H)+.