Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N+:7]([C:10]1[CH:21]=[CH:20][C:13]([CH2:14][CH:15]([C:17](O)=[O:18])[NH2:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].O.[OH-].[Na+]>O1CCCC1>[NH2:16][CH:15]([CH2:14][C:13]1[CH:20]=[CH:21][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)[CH2:17][OH:18]
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC(CO)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Lithium aluminum hydride (271 mg) was suspended in tetrahydrofuran, the suspension was added with 4-nitro-DL-phenylalanine (1.0 g) under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was added successively with distilled water, 15% aqueous sodium hydroxide and distilled water, and the mixture was stirred for 12 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure to obtain the title compound (516 mg).
Reaction SMILES: [O:1]=[C:2]1[C@:6]2([CH:10]=[CH:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]2)[CH2:5][CH2:4][O:3]1.[BH4-].[Na+]>CO>[OH:3][CH2:4][CH2:5][C@@:6]1([CH2:2][OH:1])[CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH:9]=[CH:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@]2(CCOC2=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](CO)(CCO)C1

Procedure:
To a solution of the product of Step E (255.9 g, 1.01 mol) and MeOH (2 L) chilled to 2° C. was added NaBH4 (75 g) over ˜2.5 h. The reaction was quenched by addition of aqueous NH4Cl, concentrated under reduced pressure and the mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organics were washed with brine, dried (MgSO4) and evaporated to give the product of Step F as a thick oil. 1H NMR (400 MHz, CHLOROFORM-d) d=5.74 (d, J=2.0 Hz, 2H), 4.81-4.92 (m, 1H), 4.67-4.79 (m, 1H), 3.71 (t, J=6.1 Hz, 2H), 3.50 (d, J=11.7 Hz, 2H), 2.14-2.28 (m, 2H), 1.70 (td, J=1.6, 6.2 Hz, 4H), 1.52-1.60 (m, 1H), 1.44 (s, 9H)
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:38])[C@@H:11]([N:20]2[C:24](=[O:25])[C@@H:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=3)[NH:22][C:21]2=[O:37])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:47])C=1>O1CCCC1>[CH2:1]([S:3]([C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:38])[C@@H:11]([N:20]2[C:24](=[O:25])[C@@H:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=3)[NH:22][C:21]2=[O:37])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7][CH:8]=1)=[O:47])[CH3:2]
Reactant: CCSc1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCOC)cc3)C2=O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCS(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCOC)cc3)C2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
(2S,3S)-N-(4-Ethylsulfanyl-thiazol-2-yl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (0.135 g, 0.24 mmole) (prepared as described in Example 16) was dissolved in anhydrous tetrahydrofuran (15 mL). To this solution was added a solution of m-chloroperbenzoic acid (0.066 g, 0.27 mmole) in tetrahydrofuran (8 mL). After stirring at room temperature for 30 minutes, the reaction was concentrated. The residue was dissolved in cold methylene chloride and washed twice with saturated sodium bicarbonate and twice with brine. Each aqueous phase was backwashed with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by chromatography over silica gel eluted with a gradient of 50-100% v/v ethyl acetate in hexanes followed by 5% v/v methanol in ethyl acetate to yield (2S,3S)-N-(4-ethanesulfinyl-thiazol-2-yl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (0.103 g, 75%). This material was combined with another batch of material, dissolved in methylene chloride and added to hexanes to precipitate the product, (2S,3S)-N-(4-ethanesulfinyl-thiazol-2-yl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (0.117 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=3[CH3:40])=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:19]3[C:24]=2[CH:23]=[C:22]([Br:25])[CH:21]=[CH:20]3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:25][C:22]1[CH:21]=[CH:20][N:19]2[C:24]([CH:23]=1)=[C:16]([C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[C:17]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[CH3:40])=[C:18]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccn2c1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCNCC2)c2cc(Br)ccn2c1-c1ccccc1
Reaction time: 8 h
Yield: 25.8 %

Procedure:
A solution of the compound of step 3 (70 mg, 115 μmol) in DCM (4 ml) and TFA (2 ml) was stirred at room temperature for 2 h. The solvents were evaporated and the resulting solid was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. The obtained solid was dissolved in a small quantity of MOH, mixed with 0.1 N hydrochloric acid and the mixture lyophilized overnight to give 15 mg of the title compound in the form of [7-bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone hydrochloride with the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:11]=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc(-c2ccncc2)c(-c2cccc(F)c2)n1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(-c2nc(Nc3cccnc3)cnc2-c2ccncc2)c1
Reaction time: 20 h
Yield: 69.3 %

Procedure:
An oven dried resealable Schlenk tube was charged with 6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine (Example 1, 100 mg, 0.37 mmol), 3-bromopyridine (43 μL, 0.45 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (17 mg, 0.03 mmol), cesium carbonate (171 mg, 0.52 mmol) and dioxane (2 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and tris(dibenzilideneacetone) dipalladium (14 mg, 0.01 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 100° C. oil bath. After 20 h, the mixture was cooled and water was added. The solid was collected by filtration, washed with water, diethyl ether and dried, to give the title compound as a yellow solid (88 mg, 63%).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19].CC(O)C>CCCCCC>[CH:18]([C@@H:17]([C@H:5]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH:16]=[O:21])([CH3:20])[CH3:19]
Reactant: CC(C)CC=O
Reactant: O=[N+]([O-])/C=C/c1cccc2ccccc12
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC(C)[C@H](C=O)[C@@H](C[N+](=O)[O-])c1cccc2ccccc12

Procedure:
The title compound was prepared from (E)-1-(2-nitrovinyl)naphthalene and isovaleraldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 254 nm (2-propanol:hexane=10:90), 1 mL/min, tmajor=13.7 min, tminor 16.8 min, the diastereomeric ratio was determined by
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:8])[C:5]([OH:19])=[CH:4][CH:3]=1.O1CC[CH2:23]OO1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:23][N:9]([CH2:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:7](=[O:8])[C:6]=2[CH:18]=1
Reactant: CCN(CC)CCCNC(=O)c1cc(Cl)ccc1O
Reactant: C1COOOC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCCN1COc2ccc(Cl)cc2C1=O
Reaction time: 16 h

Procedure:
1.70 Grammes (6.0 mmoles) of 5-chloro-N-[3-(diethylamino)propyl]salicylamide and 540 milligrammes (6.0 mmoles) of trioxane are dissolved in 30 ml of trifluoroacetic acid and thereaction mixture is kept at room temperature for 16 hours.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccccc2)C(=O)OC1=O

Procedure:
To a boiling solution of 3.0 g. (0.014 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 25 ml. of benzene is added 1.4 g. (0.015 m.) of aniline and the resulting mixture is refluxed overnight. The reaction mixture is cooled and filtered to give 5-acetyl-4-hydroxy-3-[1-(phenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 184° -186° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[Cl:18])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][N:7]=1.C(N(C(C)C)C(C)C)C.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([NH2:46])([CH3:45])[CH3:44])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.O>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH:46][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:45])[CH3:44])[C:3]2=[O:19])[CH:9]=1
Reactant: COC(=O)c1ccc(Cl)c(-n2ccnc(Br)c2=O)c1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(-n2ccnc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A solution of methyl 3-(3-bromo-2-oxopyrazin-1(2H)-yl)-4-chlorobenzoate (Example 330e, 3 g) dissolved in toluene (15 mL) was treated with N-ethyldiisopropylamine (2.99 mL) and 2-(2-(benzyloxy)phenyl)propan-2-amine (Example 198d 2.107 g) under nitrogen. The resulting mixture was stirred at 125° C. for 8 h in a sealed tube. The reaction mixture was diluted with water (150 mL), and extracted with ethyl acetate (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. Purification (SiO2 chromatography eluting with 50% diethyl ether in isohexane) gave the subtitle compound (2.230 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:20]=[C:19]3[C:14]([C:15]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:16][C:17]([C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Cl:34][C:35]([Cl:42])([Cl:41])[CH2:36][O:37][C:38](Cl)=[O:39]>C(Cl)Cl>[Cl:34][C:35]([Cl:42])([Cl:41])[CH2:36][O:37][C:38](=[O:39])[NH:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[N:16]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14]3[C:19](=[CH:20][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=4)=[CH:12][CH:13]=3)[N:18]=2)=[CH:26][N:25]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3c2)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)OCC(Cl)(Cl)Cl)nc4)nc3c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57934.4 %

Procedure:
To a cooled solution (0° C.) of 5-[7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-ylamine (125 mg, 0.000271 mmol) in DCM (4 mL) was added 2,2,2-trichloroethylchloroformate (0.054 mL, 0.0004 mol) and TEA (0.056 mL, 0.0004 mol). The reaction mixture was allowed to stir at ambient temperature for 5 h. The volatiles were evaporated to get the crude product (100 mg). This material was taken to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=O)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:35]([C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:33]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3cccc(CN4CCOCC4)c3)nc2c1N1CCN(Cc2cccnc2)CC1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.060 g, 0.15 mmol) and EtOH (4.5 ml) was added 3-morpholin-4-ylmethyl-benzaldehyde (0.035 g, 0.17 mmol) followed by a freshly prepared 1M aqueous solution of Na2S2O4 (0.55 ml, 0.55 mmol). The reaction mixture was stirred at 70° C. for 9 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, and the free-running powder was placed on a 10 g isolute silica column. Elution of the column with a gradient of methanol (2 to 10%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid which was triturated with diethyl ether. The pale yellow precipitate was collected by filtration, and was successively washed with diethyl ether, water, and diethyl, then dried in vacuo (0.003 g, 4%). 1H-NMR (500 MHz, DMSO-d6) 2.40 (br s, 4H) and 3.59 (t, J=4.50 Hz, 4H) (morpholine N(CH2)2, and morpholine O(CH2)2), 2.63 (br s, 4H, piperazine N(CH2)2), 3.68 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H) and 3.62 (s, 2H) (NCH2-pyridyl and C6H4CH2), 7.40 (dd, J=4.5, 7.7 Hz, 1H, pyridine 5-H), 7.45 (d, J=7.7 Hz, 1H, PhH), 7.49 (t, J=7.7 Hz, 1H, PhH), 7.78 (d, J=7.8 Hz, 1H, pyridine 4-H), 8.07 (d, J=7.6 Hz, 1H, PhH), 8.14 (s, 1H, PhH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.5, 4.8 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.4 Hz, 1H, pyridine 2-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Br>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:15][C:14]2[C:13]([F:12])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: Fc1cccc(F)c1CBr
Agent: [Na+]
Solvent: COCCOC
Product: O=S(=O)(Cc1c(F)cccc1F)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To dimethoxyethane (10 ml) were added sodium 4-chlorobenzenesulfinate (205 mg, 1.03 mmol) and 2,6-difluorobenzyl bromide (214 mg, 1.03 mmol). The resulting mixture was stirred at 70° C. for 18 hours. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue and from the resulting mixture, the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the ether eluate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=10:1) eluate was concentrated under reduced pressure, whereby the title compound (289 mg, 93%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].N1C=CC=CC=1.[C:52](OC(=O)C)(=[O:54])[CH3:53]>ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:52](=[O:54])[CH3:53])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(C)=O
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (200 mg, 0.32 mmol), Pyridine (1.26 mL), and acetic anhydride (0.3 mL, 2.9 mmol) in 6.0 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CO[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:21][Si](C)(C)C)([C:19]#[N:20])[CH2:14][CH2:13][CH2:12]2.[F-].[Na+].O.[O:29]1CCC[CH2:30]1>>[NH2:20][CH2:19][C:15]1([OH:21])[C:16]2[C:11](=[C:10]([O:29][CH3:30])[CH:9]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc2c(c1)CCCC2(C#N)O[Si](C)(C)C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Product: COc1cccc2c1CCCC2(O)CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, to the slurry of lithium aluminum hydride (11.4 g) in tetrahydrofuran (200 ml) was added 6-methoxy-1-(trimethylsilanyloxy)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (41.3 g) in tetrahydrofuran (200 ml) dropwise at 5° C., and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. To the mixture were added sodium fluoride (12.6 g) and water (16.2 ml) at 5° C., and the mixture was vigorously stirred at room temperature for 30 minutes. The precipitate was removed by filtration and the filter cake was washed with ethyl acetate-ethanol (95:5). The filtrate was evaporated in vacuo to afford 1-aminomethyl-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (28.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:23])=[N:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>COCCOC.C1COCC1.O>[NH2:23][C:13]1[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:26]4[CH:27]=[C:28]([C:31]([F:32])([F:34])[F:33])[CH:29]=[CH:30][C:25]=4[F:24])=[O:37])=[CH:7][CH:6]=3)=[CH:9][S:10][C:11]=2[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:15][N:14]=1
Reactant: Nc1ccc(-c2csc3c(-c4ccncc4)cnc(N)c23)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOC
Product: Nc1ncc(-c2ccncc2)c2scc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A −20° C. solution of Example 121B (0.18 g, 0.57 mmol) in DME (3 mL) and THF (3 mL) was treated dropwise with 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.085 mL, 0.57 mmol) and warmed to room temperature over 1.5 hours. The resulting mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was purified by flash column chromatography on silica gel with 3-5% methanoLdichloromethane to provide 138 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 5.74 (s, 2H), 7.44 (d, J=8.48 Hz, 3H), 7.51 (d, J=10.85 Hz, 1H), 7.55 (s, 1H), 7.64 (d, J=8.82 Hz, 2H), 7.71-7.72 (m, 1H), 7.74 (d, J=1.70 Hz, 1H), 8.10 (s, 1H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.67-8.69 (m, 1H), 8.70 (d, J=1.70 Hz, 1H), 8.98 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI(+)) m/e 524 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7](CCCC)[C:6](=[O:12])[N:5](CCCC)[C:4](=[O:17])[C:3]=1[N:18]=O>[Pd].CN(C=O)C>[NH2:18][C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:12])[NH:7][C:2]=1[NH2:1]
Reactant: CCCCn1c(N)c(N=O)c(=O)n(CCCC)c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1[nH]c(=O)[nH]c(=O)c1N
Yield: 96 %

Procedure:
15.0 g (52.8 mmol) 6-amino-1,3-di-n-butyl-5-nitrosouracil, 1.5 g 10% Pd/C and 150 mL DMF were hydrogenated at 40 psi in a Parr shaker for 4 h. After completion, the reaction mixture was filtered through Celite, and evaporated to give crude 5,6-diaminouracil as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][C:4]=1[OH:11].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][C:4]=1[O:11][CH2:21][O:22][CH3:23]
Reactant: COc1ccc(C=O)cc1O
Reactant: COCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCOc1cc(C=O)ccc1OC
Temperature: 0 °C
Yield: 85 %

Procedure:
In 100 ml of dimethylformamide was dissolved 10 g of isovaniline, and 14 ml of N,N-diisopropylethylamine was added to the solution and the mixture was stirred. The liquid mixture was cooled to 0° C. and 7.2 ml of chloromethyl methyl ether was added to the mixture, and the temperature was elevated to room temperature and the mixture was stirred for 5 hours. After the reaction, a large quantity of water was added to the reaction mixture, and the mixture was extracted with diethyl ether, washed with water and dried. Removal of the solvent by distillation gave 11.0 g (yield=85%) of 4-methoxy-3-methoxymethoxybenzaldehyde in the form of a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](Cl)=[O:5].[CH3:8][C:9]1([CH3:17])[O:16][C:14](=[O:15])[CH2:13][C:11](=[O:12])[O:10]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][C:9]1([CH3:17])[O:16][C:14](=[O:15])[CH:13]([C:4](=[O:5])[CH2:3][CH:2]([CH3:7])[CH3:1])[C:11](=[O:12])[O:10]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)CC(=O)C1C(=O)OC(C)(C)OC1=O
Reaction time: 1.75 h

Procedure:
3-Methyl-butyryl chloride (7.40 mL, 60 mmol) was mixed at 0° C. with Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione; 8.7 g, 60 mmol), and 4-dimethylaminopyridine (DMAP, 15.1 g, 124 mmol) in DCM. The reaction mixture was allowed to reach r.t. over 1.75 hr. and completion of the reaction was verified by TLC. The reaction mixture was diluted with DCM, was washed 3× with 5% aq. solution of potassium bisulfate and brine. The organic phase was than dried with MgSO4. Crude product 9, 13.36 g) obtained after evaporation was used for next reaction without purification. 1H NMR (500 MHz, CDCl3): δ 1.02 (d, 6H), 1.74 (s, 6H), 2.21 (hp, 1H), 2.99 (d, 2H).