Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH3:35])O)=[CH:11][C:10]=1[S:36]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)(=[O:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([O:24][Si:25]([CH:26]([CH3:28])[CH3:27])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:30])[CH3:31])=[CH:19][C:18]=2[CH3:35])=[CH:11][C:10]=1[S:36]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)(=[O:37])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1C(O)c1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Cc1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 1.5 h

Procedure:
575 mg (0.89 mmol) of {4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]phenyl}{2,6-dimethyl-4-[(triisopropylsilyl)oxy]phenyl}methanol (Example VIII) are dissolved in 10 ml of tetrahydrofuran. At 0° C., 1030.35 mg (8.86 mmol) of triethylsilane are initially added, and 78.78 mg (0.35 mmol) of trimethylsilyl trifluoromethane-sulphonate are then added dropwise. The reaction mixture is stirred for 1.5 hours, and saturated ammonium chloride solution is then added. The mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate and the solvent is removed under reduced pressure. This gives 611 mg (53% of theory) of (4-{4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzyl}-3,5-dimethylphenoxy)(triisopropyl)silane.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][C:21]1([O:24][CH2:23]1)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:20][C:21]([CH3:23])([OH:24])[CH3:22])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 80 °C
Yield: 51.3 %

Procedure:
A 5 L pressure vessel fitted with a pressure relief valve, bursting disc, pressure gauge, and oil-filled thermometer well, and containing a 3″×½″ octagonal stir bar was charged with a solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-indazole (prepared according to Example 25, Steps A-D; 150 g, 0.46 mol) and isobutylene oxide (82 mL, 0.92 mol) in N,N-dimethylacetamide (1000 mL). The solution was magnetically stirred, and granular potassium carbonate (191 g, 1.38 mol) was added. The vessel was sealed and stirring was continued. The apparatus was placed behind a blast shield. The vessel was heated with a heating mantle connected to a J-Kem Model 150 temperature controller. The temperature setting was initially set to 55° C., and the temperature was increased to 80° C. over 6 hr. The temperature was maintained at 80° C. for a further 16 hr. The reaction mixture was then cooled to 28° C. and the vessel was opened. The thermometer well was removed and the reaction mixture was decanted from the inorganic salts and filtered through a coarse fritted sintered glass funnel. The salts that remained in the vessel were stirred with DMA (3×200 mL) and the solution decanted as before. The filtrates were combined and the solvent evaporated under reduced pressure to afford a dark brown oil. Meanwhile, the solid remaining in the vessel was partitioned between water (2000 mL) and diethyl ether (1000 mL), and the resulting mixture stirred for 16 hr. The water/ether mixture was transferred to a separatory funnel, and the organic layer was added to the brown oil. Additional ether (2000 mL) was added to completely dissolve the oil. The resulting solution was transferred to a separatory funnel and washed with a mixture of water (500 mL) and brine (500 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residual dark brown oil (an approximate 1:1 mixture of N-1 [less polar] and N-2 [more polar] regioisomers) was purified by chromatography on silica gel, using 70/30 EtOAc/hexanes as eluent. Fractions containing product were pooled and the solvent removed under reduced pressure to afford the title compound as a red-orange solid (93.8 g, 51%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1>O1CCOCC1.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]>[CH3:20][C:21]1[C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)N(C)C(=O)N2

Procedure:
A solution of 6-Bromo-3-methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (15 g, 50.44 mmol) in dioxane (200 mL) is added NaCO3 (5.03 g, 474 mmol) and 3,5-dimethylisoxazole-4-boronic acid (7.8 g, 55.498 mmol) and Pd(dppf)Cl2 (4.268 g, 5.044 mmol) then the mixture is refluxed at 100° C. overnight in dioxane (200 mL). The reaction is concentrated and was purified by chromatography on silica gel to give product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])(C)C)=[O:15])[C:3]1=[O:21].O.[C:23]1(C)[CH:28]=[CH:27]C(S(O)(=O)=O)=[CH:25][CH:24]=1.C(O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O.C1(C)C=CC=CC=1>[NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][C:20]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)=[O:15])[C:3]1=[O:21]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Yield: 69.9 %

Procedure:
10.5 g of tert-butyl 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation, see Example 3I), 8.25 g of p-toluenesulfonic acid hydrate and 20.1 ml of benzyl alcohol were added to 174 ml of toluene. The reaction mixture was boiled for 4 hours on a water separator, during which period a precipitate which had originally separated out went slowly in solution. After that, the toluene was swept off under reduced pressure and the remaining residue was stirred with methyl tert-butyl ether and then filtered off. The solid residue which was obtained in this way was dissolved in dichloromethane and the solution was rendered alkaline by adding aqueous sodium carbonate solution while cooling with ice. After that, the dichloromethane phase was separated, washed with water, dried over sodium sulfate and evaporated. The resulting crude product was recrystallized, for purification, from methyl tert-butyl ether. 8.2 g of benzyl 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate were obtained with a melting point of from 105° to 107° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:18][NH:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCC(=O)c1ccncc1
Solvent: CCO
Product: CCC(=NNC(=O)OC(C)(C)C)c1ccncc1
Yield: 42.3 %

Procedure:
A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 3.96 gm (0.03 mole) of t-butylcarbazate and 100 ml of absolute ethanol is refluxed 6 hr. The reaction mixture is treated with decolorizing carbon and filtered. The filtrate yields crystals on cooling. The product is collected, washed with Skellysolve B and dried to yield 3.16 gm (40%) of the title compound having a melting point of 170.1° C.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:5](=[CH2:13])[C:4](=[O:14])[CH2:3]1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][C:4](=[O:14])[C@@:5]2([O:23][CH2:13]2)[C:6]21[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1C(=O)CC(C)C12CCCCCC2
Solvent: ClCCl
Product: C[C@H]1CC(=O)[C@]2(CO2)C12CCCCCC2
Yield: 17.6 %

Procedure:
Following the same general procedure of Example 3, 4-methyl-1-methylenespiro[4.6]undecan-2-one (5.29 g, 27.5 mmol) was reacted with 70% 3-chloroperbenzoic acid (13.6 g, 55.0 mmol) in CH2Cl2 (75 mL+150 mL) at room temp. for 4 d, with additional portions of 70% 3-chloroperbenzoic acid (7.00 g, 28.4 mmol) being added after every day. Work-up with aq. 20% NaHSO3 (250 mL) and purification by silica-gel FC (pentane/Et2O, 9:1, Rf=0.19) provided (3R*,11S*)-11-methyl-1-oxadispiro[2.0.6.3]tridecan-13-one (1.01 g, 18%), besides the (3R*,11R*)-diastereomer (Rf=0.14, 820 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:10]([NH2:13])[NH:11][N:12]=1.C([O:23][C:24](=O)[CH:25]([CH3:29])[C:26](=O)[CH3:27])C.C(OCC)C>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:12][N:11]3[C:24]([OH:23])=[C:25]([CH3:29])[C:26]([CH3:27])=[N:13][C:10]=23)=[CH:19][CH:18]=1
Reactant: Nc1[nH]nc(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(O)c1C
Temperature: 100 °C

Procedure:
To a mixture of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-1b; 0.642 g, 2.11 mmol) in acetic acid (2.6 ml) was added 2-methyl-3-oxobutyric acid ethyl ester (366 mg, 2.53 mmol). The reaction was heated at 100° C. for 5 hours. After cooling to room temperature, the precipitated solid was isolated by vacuum filtration and then repulped from diethyl ether to afford I-4A-1a (292 mg, 36%) as a colorless solid: +ESI MS (M+1) 384.1; 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.45–7.33 (m, 6H), 7.11 (d, J=8.7 Hz, 2H), 2.33 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](O)=[O:19])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](=[O:19])[N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: C1CCNC1
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCCC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with pyrrolidine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate and isolating the product by crystallization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.[NH:11]([CH2:13][CH2:14][OH:15])[NH2:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:12]/[NH:11][CH2:13][CH2:14][OH:15]
Reactant: NNCCO
Reactant: O=Cc1c(Br)cncc1Br
Product: OCCN/N=C/c1c(Br)cncc1Br
Temperature: 120 °C
Yield: 92.8 %

Procedure:
In analogy to GP1, 468 mg of 3,5-dibromo-pyridine-4-carbaldehyde (1.77 mmol, 1 eq; commercially available or prepared as described in U.S. Pat. No. 6,232,320 or WO2005110410) were dissolved in 8 mL 1-propyl alkohol, treated with 0.36 mL 2-hydrazino-ethanol (5.3 mmol, 3 eq.) and heated to 120° C. for 30 min (employing a Biotage Initiator® microwave oven). The reaction mixture was concentrated, the residue partitioned between water and ethyl acetate, the aqueous layer reextracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo to yield 530 mg of the desired product (1.64 mmol, 93% yield), which was used in the subsequent cyclization without further purification steps.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ccc[nH]1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1cccn1-c1ccccn1
Temperature: 120 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
A mixture of 10 g of 2-pyrrolecarbaldehyde, 10 g of 2-fluoropyridine, 24 g of cesium carbonate and 100 ml of N-methylpyrrolidone was stirred at 120° C. for 1 day. The reaction mixture was allowed to cool to room temperature. Water was poured into the 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 magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 7.7 g of 1-(2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([C:12]#[C:11][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[CH:7]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1c(C)cc(C)cc1C
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), 2-ethynyl-1,3,5-trimethylbenzene (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% ethyl acetate in hexane to give 3-chloro-5-(mesitylethynyl)picolinonitrile a as white solid.
Reaction SMILES: C(NC1C=C(O[C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH:18]([C:22]([NH:24]C4C=C(C(F)(F)F)C=C(OC[C@H]5COC(C)(C)O5)C=4)=[O:23])[CH2:19]3)=[CH:14][CH:13]=2)C=CN=1)(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>CO.O>[CH2:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:21]=2)[CH2:16][CH2:17][CH:18]1[C:22]([NH2:24])=[O:23]
Reactant: CC(=O)Nc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(OC[C@H]4COC(C)(C)O4)cc(C(F)(F)F)c2)CC3)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: NC(=O)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 285.3 %

Procedure:
A mixture of 7-{[2-(acetylamino)pyridin-4-yl]oxy}-N-[3-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (100 mg, 0.16 mmol) and pTSA (28 mg, .16 mmol) in MeOH (7 mL) and water (1 mL) was allowed to stir at rt overnight and then at 70° C. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 7-{[2-(acetylamino)pyridin-4-yl]oxy}-N-3-{[(2R)-2,3-dihydroxypropyl]-oxy}-5-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (I-412) (80 mg, 68%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.52 (s, 1H), 8.24 (d, 1H), 7.66 (br s, 1H), 7.56 (br s, 1H), 7.29-7.17 (m, 2H), 7.06-6.86 (m, 4H), 4.07-3.75 (m, 3H), 3.46-3.40 (m, 2H), 3.00-2.74 (m, 5H), 2.19-2.05 (m, 4H), and 1.89-1.71 (m, 1H). LCMS: (FA) ES+560.1, ES−558.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a light brown solid (303 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>O>[C:1]([NH:4][C:5]1[C:13]([N+:15]([O-:17])=[O:16])=[C:9]([C:8]([Br:14])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Solvent: O
Product: CC(=O)Nc1ccc(Br)c(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
5-(Acetylamino)-2-bromobenzoic acid (5.00 g, 19.4 mmol) was gradually added to fuming nitric acid (10 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to give the title compound (2.19 g, yield 37%).
Reaction SMILES: [NH3:1].[CH2:2]([C:4]1([CH2:14][CH3:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[O:13])[CH3:3]>CO.O>[CH2:2]([C:4]([CH2:14][CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6])[C:5]([NH2:1])=[O:13])[CH3:3]
Reactant: CCC1(CC)C(=O)Oc2ccccc21
Reactant: N
Solvent: O
Solvent: CO
Product: CCC(CC)(C(N)=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7N Ammonia in methanol (10 mL) was added to 3,3-diethyl-2(3H)-benzofuranone (Example 266a, 1.14 g) and the reaction stirred at room temperature for 16 h. 880 Ammonia (20 mL) was added and the mixture stirred for 5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product (1.21 g).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=O)=[CH:4][C:3]=1[Cl:16].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:26])=[CH:4][C:3]=1[Cl:16]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(Br)c(Cl)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CNC(=S)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-benzamide (Example I12) (4.6 g) in toluene (150 ml) was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson reagent) (5.8 g). The reaction mixture was stirred at ambient temperature for 30 minutes and then at 110° C. for 1.5 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:5) to give 4-bromo-3-chloro-N-trimethylsilanylmethylthiobenzamide (4.64 g). 1H-NMR (400 MHz, CDCl3): 1H-NMR (400 MHz, CDCl3): 7.60 (d, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 7.25 (d, 1H), 3.33 (d, 2H), 0.00 (s, 9H) ppm.
Reaction SMILES: O.O.[C@@H:3]1([N:12]2[C:22]3[NH:21][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:15]=3[N:14]=[CH:13]2)[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1[OH:5].[C:23](Cl)(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:23]([C@@:3]1([N:12]2[C:22]3[NH:21][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:15]=3[N:14]=[CH:13]2)[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1[OH:5])(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=c1[nH]c(=O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(=O)[nH]c32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 50 mL flask was added xanthosine dihydrate (1.0 g, 3.52 mmol) and N,N-dimethyl-4-aminopyridine (0.0086 g, 0.07 mmol). N,N-dimethylformamide (16 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (8 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and palmitoyl chloride (1.6 mL, 9.2 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was poured into 300 mL of ice-cold 0.1 M sodium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×100 mL hot water, air dried, and recrystallized from hot methanol.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.COCCOC>O>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]21[C:17]1[C:5](=[CH:4][CH:3]=[C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:18]=1)[CH2:6][CH2:7]2
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Solvent: O
Solvent: COCCOC
Product: NC1=N[C@@]2(CCc3ccc(-c4cncnc4)cc32)C(F)(F)CO1
Yield: 19 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with pyrimidin-5-ylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (19% yield) as an off-white solid. MS (ISP): m/z=317.0 [M+H]+.
Reaction SMILES: [Cl-].[Na+].[C:3]([O:6][CH2:7]C)(=[O:5])C.[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:7][O:6][CH2:3][O:5][C@H:12]([CH:11]=[CH2:10])[CH2:13][OH:9]
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Na+]
Product: C=C[C@H](CO)OCOC

Procedure:
Example 8-(2) (11.3 g) in tetrahydrofuran (220 mL), and the mixture was stirred at room temperature for two hours. Saturated aqueous sodium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. Ethyl acetate was added to the aqueous layer, and the organic layer was separated again. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (4.15 g).