Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:13][C:14]1[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]2[CH2:25][CH2:26][O:27][CH2:28][C:16]=2[CH:15]=1.[N:29]1([S:34]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C([SiH](CC)CC)C>C(Cl)Cl>[OH:27][CH2:26][CH2:25][C:17]1[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]([CH3:13])=[C:15]([CH2:41][C:40]2[CH:43]=[CH:44][C:37]([S:34]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:36])=[O:35])=[CH:38][CH:39]=2)[C:16]=1[CH3:28]
Reactant: CCOC(=O)Cn1c(C)cc2c1CCOC2
Reactant: O=Cc1ccc(S(=O)(=O)N2CCCC2)cc1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)N3CCCC3)cc2)c(C)c1CCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a flame-dried vial was charged with DCM (2 ml) and trimethylsilyl trifluoromethanesulfonate (0.081 ml, 0.448 mmol) was added at 0° C., followed by a solution of ethyl 2-(2-methyl-6,7-dihydropyrano[4,3-b]pyrrol-1(4H)-yl)acetate (50 mg, 0.224 mmol) and 4-(pyrrolidin-1-ylsulfonyl)benzaldehyde (53.6 mg, 0.224 mmol) in CH2Cl2 (5 ml) (cannulated), the mix was stirred at 0° C. for 15 min, neat triethylsilane (0.143 ml, 0.896 mmol) was added slowly, stirred for 30 min at 0° C., then slowly warmed to r.t. TLC confirmed that reaction was done. Therefore, it was quenched with sat. NaHCO3, extracted with DCM. Combined DCM was dried with Na2SO4, filtered and concentrated under vacuum. The residue was chromatographed on silica using a Biotage automated system (5-30-50% ethyl acetate/hexanes) to give ethyl 2-(2-(2-hydroxyethyl)-3,5-dimethyl-4-(4-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (34 mg, 0.076 mmol, 33.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2ccccc2[N+](=O)[O-])c1
Temperature: 110 °C

Procedure:
3-Methoxyphenyl boronic acid (7.4 g, 48.71 mmol), 1-bromonitrobenzene (10.25 g, 40.59 mmol) and K2CO3 (28.05 g, 202.9 mmol) were dissolved in H2O (85 mL) and ethylene glycol dimethyl ether (170 mL). The solution was degassed, Pd(PPh3)4 (1.7 g, 1.50 mmol) was added and the vessel was heated to 110° C. under argon for 5 hours. The reaction was cooled, diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from EtOAc/Hex. The mother liquor was concentrated in vacuo and chromatographed on silica gel, eluting with a gradient of 1 to 10% EtOAc in hexanes, to yield the above-titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]1([CH:33]2[CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[N:35]1[CH2:36][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:34]1
Reactant: c1ccc(C2CNC2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(N3CC(c4ccccc4)C3)c2CC1)C(F)(F)F
Temperature: 95 °C
Yield: 35 %

Procedure:
Use 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (prepared essentially as described in Preparation 1) (183 mg, 0.43 mmol), 3-phenylazetidine (75.2 mg, 0.56 mmol), palladium (II) acetate) (9.0 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), BINAP (racemic, 37 mg, 0.06 mmol), cesium carbonate (195 mg, 0.6 mmol), anhydrous toluene (10 mL) and degas and fill with nitrogen (3 times). Seal the system with septum and tighten it with copper wire when necessary. Heat the mixture at 95° C. for 8 h. Dilute with EtOAc, wash with saturated aqueous sodium bicarbonate solution, brine, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound (61 mg, 35%).
Reaction SMILES: C(O[C:5]([O:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][CH3:17])=[O:15])[C@H:11]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[C@@H:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)=O)C=C.O1CC[CH2:38][CH2:37]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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:5]([O:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][CH3:17])=[O:15])[C@H:11]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[O:19])[C@@H:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)[CH:37]=[CH2:38]
Reactant: C1CCOC1
Reactant: C=CCOC(=O)O[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)N2CCN(c3ccccc3)CC2)N(C(=O)OC)C1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCO[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)N2CCN(c3ccccc3)CC2)N(C(=O)OC)C1

Procedure:
A mixture of dimethyl(2S,3S,5S)-5-[(allyloxy)carbonyl]oxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) and tetrakis(triphenylphosphine)palladium(O) (24 mg, 0.000020 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) was refluxed for 2 h. The mixture was concentrated to dry and used directly in next step.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CCO.O>[N:31]1([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([N:26]6[CH:30]=[CH:29][CH:28]=[CH:27]6)[CH:24]=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[O:6][CH:7]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Solvent: O
Solvent: CCO
Product: O=C1CC(c2cccc(-c3nc(CN4CCOCC4)co3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
A mixture of 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78a) (125 mg), morpholine (0.25 mL) and KI (5 mg) in EtOH (1 mL) was stirred at 60° C. for 2 h. in H2O (20 mL) was added to the cooled solution and the precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) the pH of the mixture being set to 11 by addition of 1N NaOH solution, and the solid was subsequently isolated by filtration to give the title compound (60 mg) as yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[C:6]([CH3:11])=[N:7][C:8]=1[O:9]C)[CH3:2].[I-].[K+].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:11])=[C:5]([C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C=O)o2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(-c2ccc(C=O)o2)c(C)[nH]c1=O
Temperature: 60 °C
Yield: 178.9 %

Procedure:
To a mixture of 5-(5-ethyl-6-methoxy-2-methylpyridin-3-yl)furan-2-carbaldehyde (0.7 g, 2.9 mmol) prepared in accordance with the procedures of Step 1 as described above, potassium iodide (1.43 g, 8.6 mmol) and acetonitrile (15 mL) is added chlorotrimethylsilane (1.1 mL, 8.6 mmol) at room temperature then the reaction is heated at 60° C. for 0.5 hr. Solid product begins to form so more solvent is added to facilitate stirring. The solids are collected by filtration, washed with water, with ether and dried to afford 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-carbaldehyde (1.2 g, 61% yield). MS: m/e=232 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:18]2[CH:19]=[CH:20][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (12 g, 50.7 mmol) was added to a solution of 4-isopropylphenol (8.3 g, 60.8 mmol), and K2CO3 (14.0 g, 101 mmol) in DMF (70 mL). The mixture was heated at 80° C. for 16 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (13.5 g, 92%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26]>O1CCOCC1.O.Cl>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])(=[O:26])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NC(CC(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
4.13 g of 3-amino-3-phenylpropionic acid are dissolved in 100 ml of dioxane and 25 ml of 1N sodium hydroxide and 5.6 g of 2-naphthalenesulphonyl chloride are added portionwise, while maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 400 ml of water and 2N HCl is added in order to obtain pH=2. This mixture is extracted with EtOAc and the extracts are washed with a KHSO4/K2SO4 buffer, dried over Na2SO4 and evaporated to dryness. The residue is triturated from heptane and the product is isolated by decanting and is then dried under vacuum. 7.33 g of the expected product are obtained, m.p.=126-129° C.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:40]([C:42]1[CH:51]=[C:50]2[C:45]([CH:46]=[C:47]([C:54]3[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=3[CH3:60])[C:48](=[O:53])[N:49]2[CH3:52])=[CH:44][N:43]=1)[CH3:41]>CN(C=O)C>[CH2:40]([C:42]1[CH:51]=[C:50]2[C:45]([CH:46]=[C:47]([C:54]3[CH:55]=[C:56]([NH:61][C:62]4[N:63]=[C:1]([CH:2]([CH3:4])[CH3:3])[O:6][N:65]=4)[CH:57]=[CH:58][C:59]=3[CH3:60])[C:48](=[O:53])[N:49]2[CH3:52])=[CH:44][N:43]=1)[CH3:41]
Reactant: CC(C)C(=O)O
Reactant: CCc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
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: CN(C)C=O
Product: CCc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)C)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of isobutyric acid (8 μL, 0.09 mmol) in DMF (1 mL) were added DIPEA (16 μL, 0.09 mmol) and HATU (33 mg, 0.09 mmol). After stirring at rt for 15 min 17a (30 mg, 0.09 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17a was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 7-ethyl-3-(5-(5-isopropyl-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (A104). 1H NMR (400 MHz, d6-DMSO) δ 9.91 (s, 1H), 9.10 (s, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 7.41 (dd, J=8, 2 Hz, 1H), 7.33 (d, J=2 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.19 (m, 1H), 3.01 (q, J=7.6 Hz, 2H), 2.08 (s, 3H), 1.36 (t, J=7.6 Hz, 3H), 1.31, (d, J=6.8 Hz, 6H). MS m/z 404.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:11](C)=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].C(Cl)Cl.[OH-].[Na+].[C:18]([Cl:22])(Cl)([Cl:20])[Cl:19]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:1]([C:4]1[C:5]([CH3:6])=[CH:8][CH:9]=[CH:10][C:11]=1[C:18]([Cl:22])([Cl:20])[Cl:19])([O-:3])=[O:2]
Reactant: Cc1cccc(CCl)c1[N+](=O)[O-]
Reactant: ClC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C(Cl)(Cl)Cl)c1[N+](=O)[O-]
Temperature: 47 °C

Procedure:
1 gm of 2-nitro-3-methyl benzyl chloride dissolved in 12 ml of carbon tetrachloride was charged into a reaction vessel with 0.25 gms of tetrabutyl ammonium chloride and 13 ml of methylene chloride. 20 ml of 50% aqueous sodium hydroxide was added to the mixture and the mixture heated for about 31/2 hours at 47° C. After reaction stopped, the organic phase was separated and a fresh charge of aqueous caustic phase with catalyst was added to the organic phase. The mixture was diluted with water, solvent evaporated to give 0.80 gms of crude which was purified by distillation at 110° C. to 120° C. (0.02-0.05 mm/Hg 0.026-0.067×105 pascals) to give a colorless oil which crystallized. Recrystallization from methanol gave colorless crystals. m.p. 61-62° C. Elemental analysis for C8H6Cl3NO2 :
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.[ClH:20].[NH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[SH:27]>C(O)C>[ClH:20].[C:16]([C:7]1[CH:6]=[C:5]([C:3]2[CH2:2][S:27][C:23]3=[N:24][CH:25]=[CH:26][N:22]3[N:21]=2)[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nn1ccnc1S
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(C2=Nn3ccnc3SC2)cc(C(C)(C)C)c1O

Procedure:
A solution of 18.0 g (0.055 mol) of 2-bromo-1-(3,5-ditert.butyl-4-hydroxyphenyl)-ethanone and 7.6 g (0.05 mol) of 1-amino-2-mercaptoimidazole hydrochloride from step (a) in 150 ml of ethanol was refluxed for 9 hours. The residue remaining after evaporation of the solution was rendered alkaline by means of 50 ml of 2N sodium hydroxide solution and extracted with chloroform. In order to convert the product into the hydrochloride, an equimolar amount of ethereal hydrochloric acid was added to the dried chloroform phase, and the batch of crystals produced was filtered off under suction and crystallized from ethanol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.C[O:13][C:14]([NH:16][NH2:17])=[S:15]>C(#N)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[CH2:2][S:15][C:14](=[O:13])[NH:16][N:17]=2)=[CH:6][CH:7]=1
Reactant: COC(=S)NN
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CC#N
Product: O=C1NN=C(c2ccc(Cl)cc2)CS1
Yield: 48.4 %

Procedure:
A mixture of 2-bromo-p-chloroacetophenone (9.16 g), methoxythiocarbonylhydrazine (13.0 g) and acetonitrile (75 ml) was refluxed overnight and then cooled and filtered. The light yellow solid was washed with hexane and dried yielding 5-(4-chlorophenyl)-3H,6H-1,3,4-thiadiazin-2-one (4.3 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.[C:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1)([OH:22])=[O:21].O>C1COCC1>[OH:28][CH:27]([C:26]1[CH:25]=[CH:24][C:23]([C:20]([OH:22])=[O:21])=[CH:30][CH:29]=1)[C:13]#[C:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCSc2ccc(C#CC(O)c3ccc(C(=O)O)cc3)cc21
Reaction time: 0.5 h

Procedure:
2 g (9.9 mmol) of (4,4-dimethylthiochroman-6-yl)acetylene and 25 ml of THF were introduced into a three-necked flask under a stream of nitrogen, 4 ml (9.9 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at -50° C. and stirring was carried out for 30 min. A solution of 743 mg (4.9 mmol) of 4-carboxybenzaldehyde in 25 ml of THF was then added and stirring was carried out at room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue was recrystallized from diisopropyl ether. After filtration, 730 mg (42%) of the expected acid, with a melting point of 168°-169° C., were obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:1][C:2]2[C:11]3[CH2:10][O:9][C:8](=[O:12])[N:7]([CH2:13][C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[C:6]=3[CH:5]=[N:4][C:3]=2[CH3:22])=[CH:26][CH:27]=1)#[N:32]
Reactant: Cc1ncc2c(c1O)COC(=O)N2Cc1ccc(C#N)cc1
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1ncc2c(c1OCc1ccc(C#N)cc1)COC(=O)N2Cc1ccc(C#N)cc1
Yield: 75.2 %

Procedure:
The coupling of 4-(5-hydroxy-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1-ylmethyl)-benzonitrile (82) (874 mg, 3.24 mmol) and α-bromo-p-tolunitrile (1.2 g, 6.17 mmol), as described in Example 1, gave 4-[5-(4-cyano-benzyloxy)-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1ylmethyl]-benzonitrile (83) (1.0 g, 84% yield) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([N:12]1[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:32]1[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)n1c(-c2ccccc2Br)nc2cc(-c3cnc(N)nc3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)cn1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of 5-[2-(2-bromo-phenyl)-1-tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (70 mg, 0.17 mmol) in DMF (5 mL) and H2O (1 mL) are added 1-methylpyrazole-4-boronic acid pinacol ester (52 mg, 0.25 mmol), Pd(PPh3)4 (19 mg, 0.017 mmol) and K2CO3 (23 mg, 0.17 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and then filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (24 mg, 34%) as a white solid. LCMS (ESMS): m/z 424.20 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C1C[O:23]CC1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:23]
Reactant: Cc1cccc(Cl)c1C#N
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: Cc1cccc(Cl)c1C=O
Reaction time: 3 h

Procedure:
To a stirred solution of 2-chloro-6-methylbenzonitrile (1 g, 6.6 mmol) in THF (15 mL) under argon at 0° C. a solution of DIBAL (1 M in THF, 7 mL, 7 mmol) was added dropwise over 5 minutes. After 3 hr at 0° C., the reaction mixture was brought to room temperature and further stirred overnight. The reaction mixture was quenched with 5% sulfuric acid at 0° C., extracted with ether, washed with brine and dried (MgSO4). Concentration provided 2-chloro-6-methylbenzaldehyde (0.92 g) which was used without further purification.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(Cl)Cl.C(OC([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C@H:27]2[C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=3[F:39])[C@:30]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=3[F:49])([C:40]#[N:41])[C@H:29]([CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])[NH:28]2)=[O:26])[CH2:20][CH2:19]1)=O)(C)(C)C>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]([CH:27]2[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=3[F:39])[C:30]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=3[F:49])([C:40]#[N:41])[CH:29]([CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])[NH:28]2)=[O:26])[CH2:22][CH2:23]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NC2CCNCC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of a mixture of TFA/CH2Cl2 (5 mL/10 mL), rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (example 92, 510 mg, 0.79 mmol) was added and the mixture was stirred at rt for 15 min. The solvent was removed and the residue dried to give a white solid after precipation from methylene chloride and ethyl acetate. 492 mg.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[CH2:32][C@@H:33]([OH:34])[C@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f5) and commercially available acetyl chloride the title compound is obtained as colorless solid.