Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Br[C:9]1[CH:10]=[C:11]2[CH:29]=[C:27]([CH:28]=1)[NH:26][C:25]1=[N:30][C:21](=[C:22]([Cl:31])[CH:23]=[N:24]1)[NH:20][C:19]1=[CH:32][C:15](=[CH:16][CH:17]=[CH:18]1)[O:14][CH2:13][CH2:12]2.CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([N:47]3[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49][CH2:48]3)[CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:31][C:22]1[CH:23]=[N:24][C:25]2[NH:26][C:27]3[CH:28]=[C:9]([C:41]4[CH:46]=[CH:45][N:44]=[C:43]([N:47]5[CH2:48][CH2:49][NH:50][CH2:51][CH2:52]5)[CH:42]=4)[CH:10]=[C:11]([CH:29]=3)[CH2:12][CH2:13][O:14][C:15]3[CH:32]=[C:19]([NH:20][C:21]=1[N:30]=2)[CH:18]=[CH:17][CH:16]=3
Reactant: Clc1cnc2nc1Nc1cccc(c1)OCCc1cc(Br)cc(c1)N2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Clc1cnc2nc1Nc1cccc(c1)OCCc1cc(cc(-c3ccnc(N4CCNCC4)c3)c1)N2
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of 19-bromo-6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1(9,13)]tricosa-1(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate (40 mg, 96 μmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (45 mg, 0.12 mmol), and 2 M sodium carbonate (0.14 mL, 0.29 mmol) in toluene (0.36 mL) and ethanol (0.36 mL) was degassed with nitrogen, treated with tetrakis(triphenylphosphine)palladium(O) (8 mg, 6.7 μmol), and heated at 85° C. for 9 h. The reaction mixture was concentrated, stirred in TFA (1.5 mL) for 30 min, concentrated, and purified by preparative LCMS to give the desired product (11 mg, 14%) as a white solid. LCMS for C27H27ClN7O (M+H)+: m/z=500.0. 1H NMR (300 MHz, DMSO-d6): δ 9.59 (s, 1H), 9.25 (s, 1H), 8.88 (br s, 2H), 8.21-8.18 (m, 2H), 8.00 (s, 1H), 7.67 (s, 1H), 7.35-7.29 (m, 2H), 7.25-7.16 (m, 2H), 7.00-6.80 (m, 3H), 4.55 (br s, 2H), 3.80 (br s, 4H), 3.21 (br s, 4H), 2.82 (br s, 2H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[CH:4][C:5]([C:8]2[C:13]3[O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:31]1(C)C=CC=CC=1.CB1OB(C)OB(C)O1>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.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[CH:11]1[C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:8]([C:5]2[CH:4]=[C:3]([CH3:21])[C:2]([CH3:31])=[CH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: Cc1cc(-c2cccc3c2oc2ccccc23)ncc1Br
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: CB1OB(C)OB(C)O1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Cc1cnc(-c2cccc3c2oc2ccccc23)cc1C

Procedure:
5-Bromo-2-(dibenzo[b,d]furan-4-yl)-4-methylpyridine (28.7 g, 85 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.394 g, 3.39 mmol) and potassium phosphate monohydrate (58.6 g, 255 mmol) were added to toluene (500 mL) and water (50 mL) and degassed for 20 min. Trimethylboroxine (14.83 mL, 106 mmol) and Pd2(dba)3 (0.777 g, 0.849 mmol) were added and the reaction mixture heated to reflux overnight. After cooling, the organic layer was separated and the aqueous layer extracted 3×50 mL with EtOAc, dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel with 8/2 (v/v) dichloromethane/EtOAc in hexane to give 19.2 g of an off-white solid, which was recrystallized from hexane to give 16.8 g (83%) of the product as white needles. The product was confirmed by NMR and HPLC (99.97% pure).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[CH:7]=1.C[S-:16].[Na+]>CC(N(C)C)=O>[F:12][C:11]([F:14])([F:13])[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([SH:16])=[CH:7][N:6]2[CH:8]=1
Reactant: C[S-]
Reactant: FC(F)(F)c1cn2cc(Br)ccc2n1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cn2cc(S)ccc2n1
Temperature: 150 °C
Yield: 60.9 %

Procedure:
A mixture of 6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (500 mg, 1.89 mmol) (for the synthesis, see WO2005111047) and sodium thiomethoxide (400 mg, 5.67 mmol) in dimethylacetamide (5 ml) was heated to 150° C. for 90 minutes under a nitrogen atmosphere. The resultant mixture was cooled down to room temperature and partitioned between ethyl acetate and an aqueous solution of ammonium chloride. The aqueous phase was extracted with more ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a red oil (251 mg, 61% yield). MS (ES+) 219, (ES+) 217.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10](C)([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[N:26](O)[CH:27]=[CH:28][C:5]=21.[OH:30][CH2:31]N1C2C(=C(O)C=CC=2)C=C1.BrC1C(OC)=C(OC)C=C(C=1)C=O.C(#N)CC#N.N1CCCCC1>>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[N:26]([CH2:31][OH:30])[CH:27]=[CH:28][C:5]=21
Reactant: COc1cc(C2(C)C(C#N)=C(N)Oc3c2ccc2c3ccn2O)cc(Br)c1OC
Reactant: OCn1ccc2c(O)cccc21
Agent: COc1cc(C=O)cc(Br)c1OC
Solvent: C1CCNCC1
Solvent: N#CCC#N
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2CO)cc(Br)c1OC

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-hydroxy-methyl-4H-pyrrolo[2,3-h]chromene: The title compound was prepared from 1-hydroxymethyl-4-hydroxy-indole (550 mg, 3.37 mmol), 5-bromoveratraldehyde (826 mg, 3.37 mmol), malononitrile (222 mg, 3.37 mmol) and piperidine (0.17 mL, 1.7 mmol), similar to Example 16, to yield 1.15 g (75%) of a white solid. 1H NMR (CDCl3): 7.22-7.18 (m, 2H), 6.90 (d, J=1.8 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.64 (d, J=3.3 Hz, 1H), 5.61 (s, 21), 4.77 (s, 1M, 4.70 (brs, 2H), 3.83 (s, 31), 3.82 (s, 3H), 2.47 (brs, 1H).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=4[CH3:29])[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:32]([O:34]CC)=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=4[CH3:29])[CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:16]=2[C:32]([OH:34])=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1cccnc1
Reactant: CCOC(=O)c1[nH]c2c(-c3c(C)nn(C)c3C)cccc2c1CCCOc1cccc2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C)c1-c1cccc2c(CCCOc3cccc4ccccc34)c(C(=O)O)n(Cc3cccnc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 580A (90 mg), 3-(bromomethyl)pyridine hydrobromide (47.3 mg) and cesium carbonate (183 mg) in N,N-dimethylformamide (3.5 ml) was stirred at room temperature overnight. The insoluble material was filtered off and the filtrate was concentrated. The residue was suspended in tetrahydrofuran-methanol, and 10% NaOH was added. The resulting mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in a mixture of DMSO and methanol. The solution was purified by reverse phase HPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFA aqueous solution during 60 minutes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=5.22 Hz, 1H), 8.23-8.28 (m, 1 H), 7.85-7.90 (m, 1 H), 7.80-7.85 (m, 2 H), 7.49-7.57 (m, 3 H), 7.45-7.49 (m, 1 H), 7.38-7.43 (m, 1 H), 7.19 (d, J=7.67 Hz, 1 H), 7.10-7.15 (m, 1 H), 6.92 (t, J=7.67 Hz, 2 H), 5.65 (d, J=17.49 Hz, 1 H), 5.44 (d, J=17.80 Hz, 1 H), 4.26 (t, J=5.98 Hz, 2 H), 3.62 (s, 3 H), 3.35-3.49 (m, 2 H), 2.24-2.32 (m, 2 H), 1.67 (s, 3 H), 1.59 (s, 3 H).
Reaction SMILES: C([C@H:4]1[C@@H:21]([OH:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C:5]1=[CH:6][CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][C@@H:11]([OH:25])[C@@H:12]2[OH:24])(=O)C.C[OH:27]>[OH-].[Na+]>[CH3:14][C@:13]12[CH2:15][CH2:16][C@H:17]3[C@@H:8]([CH2:7][CH:6]=[C:5]4[C@:18]3([CH3:23])[CH2:19][CH2:20][C@H:21]([OH:22])[C@@H:4]4[OH:27])[C@@H:9]1[CH2:10][C@@H:11]([OH:25])[C@@H:12]2[OH:24]
Reactant: CO
Reactant: CC(=O)[C@@H]1C2=CC[C@H]3[C@@H]4C[C@@H](O)[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Product: C[C@]12CC[C@H]3[C@@H](CC=C4[C@@H](O)[C@@H](O)CC[C@@]43C)[C@@H]1C[C@@H](O)[C@@H]2O

Procedure:
The compound 7 (50 mg, 0.137 mmol) was dissolved in 1 N sodium hydroxide aqueous (1 mL) and methanol (5 mL) and the resulting solution was refluxed for 1 hr. Methanol was removed under vacuum and the residue was extract with ethyl acetate (3×30 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under vacuum to afford a solid. The crude product was purified by recrystallization from methanol to afford title compound 8 ((23 mg) as a white solid. Selected 1H NMR data: (CD3OD, 300 MHz): δ 5.62 (d, 1H, J=3.2 Hz), 4.05 (d, 1H, J=2.4 Hz), 4.02 (m, 1H), 3.43 (dt, br, 1H, J=11.7 Hz, 3.6 Hz), 3.36 (d, 1H, J=4.2 Hz), 1.197 (s, 3H), 0.76 (s, 3H). Melting Point: 238-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][CH2:15][O:16][C:17]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:18]=3[C:19]=2[N:20]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][CH2:15][O:16][C:17]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:18]=3[C:19]=2[N:20]=1)=[S:35]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccccc1Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: Cc1ccccc1
Product: S=C(Nc1ccccc1Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 5 h
Yield: 74.2 %

Procedure:
A mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-chloro-phenyl)-amide (260 mg), Lawesson's reagent (193 mg) and toluene (10 mL) was heated to reflux. After 5 hours, the reaction mixture was cooled and the precipitate was collected by filtration to yield the corresponding thioamide, 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbothioic acid (2-chloro-phenyl)-amide (160 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](O)=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C([O:44][CH:45]1[CH2:48][NH:47][CH2:46]1)C1C=CC=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([N:47]4[CH2:48][CH:45]([OH:44])[CH2:46]4)=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)O)cc32)cc1
Reactant: c1ccc(COC2CNC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)N4CC(O)C4)cc32)cc1

Procedure:
6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carboxylic acid (intermediate 58, 14 mg, 0.0277 mmol) was treated with 3-benzyloxyazetidine hydrochloride (6 mg, 0.03 mmol) and PyBOP according to the procedure described in Example 13, Step A. The desired product was obtained by column chromatography on silica gel. LC/MS: m/e 651.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[C:5]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:9])([CH3:6])[CH3:4]
Reactant: O=C(O)c1ccc(I)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(I)cc1
Temperature: 70 °C

Procedure:
4-Iodobenzoic acid (10 g, 40.3 mmol) was dissolved in dry toluene (100 ml, dried over mol. sieves). The solution was heated to 70° C. under a flow of nitrogen. A solution of N,N′-dimethylformamide di-tert-butyl acetal (24.6 g, 121 mmol) in toluene (25 ml) was added over ca. 30 min. The reaction was mixed for 16 h. At some point the heating unit failed, So the reaction cooled from 70° C. to rt. The solution was heated to 70° C. for and mixed for 5 h. The sample was concentrated under vacuum, and AcOEt (400 ml) was added. The solution was then washed with 1:1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCl (75 ml each). The organic phase was dried (MgSO4) and concentrated under vacuum to yield a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:30])=[N:9]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F:46][C:47]([F:52])([F:51])[C:48](O)=[O:49]>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([C:48](=[O:49])[C:47]([F:52])([F:51])[F:46])[CH2:28][CH2:29]4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Reactant: O=C(O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCN(C(=O)C(F)(F)F)CC1
Yield: 35 %

Procedure:
The procedure of Example 14 is followed but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(piperazin-1-yl)carbonyloxy-isoindolin-1-one (2.12 g.), N,N'-dicyclohexylcarbodiimide (2.05 g.) in anhydrous methylene chloride (50 cc.) and trifluoroacetic acid (1.71 g.). The crude product, after it has been filtered off, is washed with diethyl ether (50 cc.). The product is then dissolved in methylene chloride (110 cc.). The solution is filtered and concentrated to dryness and the residue is washed again with diethyl ether (45 cc.). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-(4-trifluoroacetylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (0.91 g.), which melts at 218° C., is thus obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19]([C:21]1[CH:29]=[CH:28][C:24]2=[N:25][O:26][N:27]=[C:23]2[CH:22]=1)=[O:20]>C1COCC1>[N:25]1[O:26][N:27]=[C:23]2[CH:22]=[C:21]([C:19](=[O:20])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])[CH:29]=[CH:28][C:24]=12
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CON(C)C(=O)c1ccc2nonc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc2nonc2c1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.49 g, 2.367 mmol) in dry THF (20 mL), n-BuLi (3.70 mL, 5.917 mmol, 1.6 M hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of N-methoxy-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide (0.557 g, 3.550 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −78° c. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc hexanes to afford 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 63%) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[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][CH:16]2[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.[NH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41].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:41][CH2:40][C:39]([NH:38][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[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]([CH3:32])([CH3:31])[CH3:33])[NH:17]1)=[O:35])([CH3:43])[CH3:42]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NC(C)(C)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 90.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 2-amino-2-methyl-1-propanol (Fluka) (0.2 g, 2.2 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.8 mmol) in CH2Cl2 (10 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide as a white solid (0.17 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1.[OH-:23].[Na+].C(Cl)(Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][O:23][CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1
Reactant: [OH-]
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccsc2)=NCC1CCl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccsc1)=NCC1COCCN21

Procedure:
A solution of 11 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(3-thienyl)-2,3-dihydro-1H-1,4-benzodiazepine in 60 ml of dioxane and 160 ml of 4.5% strength sodium hydroxide solution is heated under reflux for 5 hours. After the solvent has been stripped off in vacuo, the reaction product is isolated from chloroform and is then chromatographed on aluminum oxide of activity level II, using methylene chloride. After the methylene chloride has been stripped off, 6.5 g of 1,2,4,4a-tetrahydro-9-chloro-7-(3-thienyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine are obtained as an oil. This product is converted into its hydrochloride by reaction with alcoholic hydrogen chloride solution, and the product is crystallised as the hydrochloride.0.3H2O from isopropanol. Melting point: 207° to 212° C.
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[C:7]([O-:10])([O-])=[O:8].[K+].[K+].[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22]C=C(C)C)[N:15]=1>O.C(O)(C)(C)C>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22][C:7]([OH:10])=[O:8])[N:15]=1
Reactant: CC(C)=CCCc1cc(Cl)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)CCc1cc(Cl)nc(Cl)n1
Reaction time: 16 h
Yield: 49.8 %

Procedure:
The above synthesis may be carried out as follows: To a solution of LDA (1.28 g, 12 mmol) in THF (30 mL) at −78° C. was added 2,4-dichloro-6-methylpyrimidine (1.96 g, 12 mmol) in THF (15 mL). After stirring for 15 minutes, 3,3-dimethylallyl bromide (1.79 g, 12 mmol) in THF (5 mL) was added dropwise. After the reaction warmed to ambient temperature, water and ethyl acetate was added. The organic layer was separated, the solvent was removed in vacuo, and the residue was chromatographed (ethyl acetate/hexane, 1/19) to give 2.06 g (74%) of 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (1H NMR (CDCl3) δ7.15 (s, 1), 5.10 (t, 1), 2.80 (t, 2), 2.45 (m, 21, 1.70 (s, 3), 1.55 (s, 3)). To a solution of NaIO4 (17 g, 81 mmol) and KMnO4 (251 mg, 1.59 mmol) in water was added K2CO3 (1.29 g, 9.38 mmol) and 2,4dichloro-6-(4-methyl-3-pentenyl)pyrimidine (2.06 g, 8.9 mmol) in t-butanol. After stirring for 16 hours, the reaction was acidified to pH 3 and extracted with ethyl acetate. The organic layer was extracted with aqueous NaHCO3. The aqueous layer was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to give 980 mg of 3-(2,4-dichloropyrimidin-6-yl)propionic acid (the compound of formula (XIX)), 1H NMR (CDCl3) δ7.30 (s, 1), 3.05 (t, 2), 2.90 (t, 2). The acid was coupled to piperonylamine under standard conditions with isobutyl chloroformate and N-methylmorpholine to give the compound of formula (XX). Imidazole was added under standard conditions (1-trimethylsilylimidazole and CsF in DMF at 60° C.) to give N-[(1,3-benzodioxol-5-yl)ethyl]-6-chloro-2-(1H-imidazol-1-yl)pyrimidine-4-propionamide (the compound of formula (Ihh)); MS: 386 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C=C(C)C=O)C=CC=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC=Cc1ccccc1
Agent: CC(C=O)=Cc1ccccc1
Product: OCCCc1ccccc1

Procedure:
reducing an aldehyde which is 3-phenyl-prop-2-enal or 3-phenyl-2-methyl-prop-2-enal to produce the corresponding 3-phenyl propanol;
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.C(PC(C)(C)C)(C)(C)C.C[C:67]([N:69](C)C)=O>[C-]#N.[Zn+2].[C-]#N.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.[Zn]>[C:67]([C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20][CH2:21][CH2:22]4)=[CH:17][CH:18]=3)=[C:9]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:8][C:7]=12)#[N:69]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Agent: [Pd+2]
Agent: CC(C)(C)PC(C)(C)C
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C#N)nccc4c3=O)cc2)CCC1
Temperature: 95 °C
Yield: 61 %

Procedure:
tert-Butyl (1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.1 mmol), zinc (II) cyanide (38 mg, 0.058 mmol) and binaphthyl-di-tert-butyl phosphine (4 mg, 0.01 mmol), palladium(II) trifluoroacetate (4 mg, 0.01 mmol), zinc dust (2 mg) were suspended in DMA (1 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The reaction mixture was heated at 95° C. for 18 h. The resulting mixture was allowed to cool to RT, partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases were separated. The organic layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 50% ethyl acetate in cyclohexane) to afford the title compound (30 mg, 61%). LCMS (Method I): RT=7.63 min, [M+H]+=438 (-tBu), [M+Na]+=516.