Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:8][CH:9]=[CH:10][C:11]=1[Br:12].[CH2:13]1[O:15][CH2:14]1.[Cl-].[NH4+]>C(OCC)C>[Br:12][C:11]1[CH:10]=[CH:9][O:8][C:7]=1[CH2:13][CH2:14][OH:15]
Reactant: C1CO1
Reactant: Brc1ccoc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OCCc1occc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.5M in hexanes, 12.9 mL) was added to a solution of 2,3-dibromofuran (6.63 g) in diethyl ether (40 mL) at −78° C. under nitrogen and the mixture was stirred for 15 minutes. A solution of ethylene oxide (15 mL) in diethyl ether (40 mL) was then added. The reaction mixture was stirred for a further 10 minutes then warmed to room temperature and stirred for 30 minutes. Saturated aqueous ammonium chloride was added and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give 2-(3-bromofuran-2-yl)-ethanol (3.81 g) as a yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-])=O)[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C>CCO.[Fe]>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(N)c1

Procedure:
The mixture of 4-(tert-butyldimethylsilyloxy)-2-nitrobenzenamine (0.5 g, 1.9 mmol), Fe powder (1.1 g, 19 mmol) and acetic acid (1.0 mL, 18 mmol) in EtOH (10 mL) was stirred at reflux for 4 hrs. The mixture was filtered through celite pad and the filtrate was concentrated.
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.N1C=CN=C1>ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)[C@H](C)Nc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N(c1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 22 %

Procedure:
A solution of ethyl N-phenylalaninate (9.65 g, 50 mmol) and 2,4-dichloro-5-nitropyrimidine (9.7 g, 50 mmol) in anhydrous dichloromethane (100 mL) was stirred for 5 minutes at rt under nitrogen. The solution was then cooled to 0° C. (Ice bath) followed by addition of imidazole (3.41 g, 50 mmol). The resulting reaction mixture was allowed to warm up to rt in 30 min and further heated at 50° C. for 2 h. The reaction was then cooled to rt, washed with water, dried over sodium sulfate and evaporated to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate-hexane mixture (5:95)) to afford desired product (22%). 1HNMR (300 MHz, CDCl3): δ 1.29 (t, J=7.2 Hz, 3H), 1.63 (d, J=7.5 Hz, 3H), 4.18-4.27 (m, 2H), 4.90 (q, J=7.2 Hz, 1H), 7.19 (d, J=6.9 Hz, 2H), 7.26-7.39 (m, 3H) and 8.52 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:26]1([F:35])[CH2:29][N:28]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:27]1.[CH3:36][N:37](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>[CH:32]1([C:30]([N:28]2[CH2:29][C:26]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH2:12][C:11]([C:17]5[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=5)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=4)=[CH:7][C:2]=3[C:36]#[N:37])([F:35])[CH2:27]2)=[O:31])[CH2:33][CH2:34]1
Reactant: CN(C)C=O
Reactant: O=C(C1CC1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: N#Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C1(F)CN(C(=O)C2CC2)C1
Temperature: 150 °C
Yield: 56 %

Procedure:
To a solution of (3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)(cyclopropyl)methanone (Example 83, 35 mg, 0.06 mmol) in DMF was added ZnCN (15 mg, 0.12 mmol) and the reaction was degassed with N2 purge. Pd(PPh3)4 (4 mg, 0.003 mmol) was added and the reaction mixture was heated under microwave irradiation at 150° C. for 15 minutes. Next, the reaction mixture was diluted with water and extracted with EtOAc (75 mL). The organic phase was dried (Na2SO4) and concentrated under vacuum. Crude product was chromatographed (12 g Redi-Sep column) eluting from 100% heptane to 60:40 EtOAc:heptane to afford the final product (18 mg, 56%) as a solid. 1H NMR (CDCl3) δ ppm: 8.08 (1H), 8.00 (1H), 7.70 (1H), 7.66 (2H), 4.98-4.52 (4H), 4.12 (1H), 3.73 (1H), 1.49 (1H), 1.10-0.81 (4H); m/z (Cl) 560 ([M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([CH2:19][NH:20][S:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][C:32](Cl)=[O:33])[CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:32](=[O:33])[CH:31]=[CH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([S:21](=[O:23])(=[O:22])[NH:20][CH2:19][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:25]=1
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine-hydrochloride (0.30 g, 4.35 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (16a) (0.33 g) in tetrahydrofuran (4 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate-acetonitrile affording the title compound (0.13 g, 40%) as a lightly pink crystals. M.p. 177° C. 1H NMR (DMSO-d6, HMDSO) δ: 4.45 (2H, d, J=6.0 Hz); 6.58 (1H, d, J=16.0 Hz); 7.29-8.38 (13H, m); 9.12 (1H, br s); 10.83 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 1.5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.25 mg/ml; flow rate 1.2 ml/min; detector UV 220 nm). Anal. Calcd for C20H18N2O4S, %: C 62.54, H 4.70, N, 7.21. Found, %: C 62.81, H 4.74, N 7.32.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9]([CH:12]([CH3:14])[CH3:13])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH:12]([N:9]1[CH2:10][CH2:11][C:6]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)([CH3:14])[CH3:13]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(C)C)CC2)cc1

Procedure:
1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.6 g, 15.2 mmol) dissolved in methanol (75 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.18 g (42%); white powder; mp 204° C.; MS: 341.9 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl.C(N(CC)CC)C>[C:24]([NH:2][CH:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCc1ccc(CCC(N)C(=O)OC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)C(=O)OC)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 2-amino-4-(4-octylphenyl)butyrate hydrochloride (16 g) in methylene chloride (300 ml), triethylamine (16 ml) and acetyl chloride (3.8 ml) were added and the mixture was stirred at room temperature for an hour. Then, methylene chloride (500 ml) was further added to the mixture, the whole mixture was washed with a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine in order and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel chromatography (eluent; hexane-ethyl acetate=1:2) to give the subject compound (11 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6](C)[C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>CN(C=O)C.CCOC(C)=O>[C:42]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:2]3[N:10]=[C:9]4[C:5]([NH:6][C:7](=[O:16])[N:8]4[CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH2:41][CH2:40]1)(=[O:44])[CH3:43]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCC(CC)n1c(=O)n(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)[nH]c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 29.5 %

Procedure:
To a mixture of 2-chloro-9-(1-ethyl-propyl)-7-methyl-7,9-dihydro-purin-8-one (102 mg, 0.4 mmol) and TsOH (1.6 mL, 0.2 M in 1,4-dioxane) in DMF (0.25 mL) is added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (105 mg, 0.5 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organics are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 50 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].[CH3:13][NH2:14]>C(Cl)CCl>[CH3:13][NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCCl
Product: CNC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Commercially available 3-nitrobenzoic acid is reacted with methylamine and EDC under standard conditions to afford N-methyl-3-nitrobenzamide, which is reduced with LAH under standard conditions to afford N-methyl(3-nitrophenyl)methanamine, which is protected with benzylchloroformate under standard conditions to yield t-butyl 3-nitrobenzylmethylcarbamate. This material is nitrosated and reduced to yield t-butyl 3-hydrazinobenzylmethylcarbamate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:16])=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>O1CCCC1>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ccccn4)cc2)CO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4cccc[n+]4[O-])cc2)CO3)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.7 %

Procedure:
To a solution of N-[4—(2-pyridylmethyl)phenyl]-6—(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (250 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0° C., and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added sodiumithiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3) concentrated to give crystals, which were recrystallized from chloroform-ethanol to give N-[4—(1-oxidopyridin-2-ylmethyl)phenyl]-6—(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (Compound 200) (191 mg) as pale yellow crystals.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[N:13]3[C:14]([CH3:27])=[C:15](SC4C=CC=CC=4)[C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.[Ni]>[N:1]1([CH2:7][CH:8]2[N:13]3[C:14]([CH3:27])=[CH:15][C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1c(Sc2ccccc2)c2cccc3c2n1C(CN1CCOCC1)CO3
Agent: [Ni]
Solvent: CCO
Product: Cc1cc2cccc3c2n1C(CN1CCOCC1)CO3
Yield: 90.2 %

Procedure:
Similarly 7.9 g of (+)-3-(4-morpholinylmethyl)-5-methyl-6-phenylthio-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine in 300 ml of ethanol was reduced with three teaspoons of Raney nickel to give 5.1 g of (+)-3-(4-morpholinylmethyl)-5-methyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine, [α]D25 =+64.8°.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 201.1) and pyrimidin-5-ylboronic acid to afford a white powder. HPLC (Condition 4) tR=4.98 min, UPLC-MS (Condition 3) tR=0.97 min, m/z=478.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.65 (m, 1H) 1.84 (m, J=6.60 Hz, 1H) 2.15-2.29 (m, 1H) 2.96 (dd, J=10.75, 6.84 Hz, 1H) 3.06-3.42 (m, 5H) 4.60 (t, J=5.28 Hz, 1H) 7.47-7.64 (m, 2H) 7.96 (dd, J=13.10, 2.15 Hz, 1H) 8.06 (d, J=2.35 Hz, 1H) 8.77 (d, J=2.74 Hz, 1H) 8.84-8.94 (m, 2H) 9.17 (s, 1H) 10.29 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:14]([O:21][CH2:22][CH2:23][OH:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CN1CCOCC1>C(Cl)Cl>[Si:14]([O:21][CH2:22][CH2:23][O:24][C:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=1)=[O:10])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)OCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 604 mg (3.00 mmol) sample of p-nitrophenoxycarbonylchloride in 3 mL of methylene chloride was added to a solution of 0.528 g (3.00 mmol) of 2-(t-butyldimethylsilyloxy)ethanol and 0.330 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The solution was stirred for 2 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.453 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9](=[O:12])[CH2:10][CH3:11])=[C:5]([CH2:7][CH3:8])[N:6]=1.[Br:13]Br>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]([C:9](=[O:12])[CH:10]([Br:13])[CH3:11])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: CCC(=O)c1sc(N)nc1CC
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1nc(N)sc1C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.7 %

Procedure:
Compound 14z (0.53 g, 1.99 mmol; HBr form) in acetic acid (2 mL) was treated dropwise with bromine (103 μL, 1.99 mmol), and the reaction mixture was stirred at room temperature for 3 h. The white precipitate was collected by filtration and washed with cold acetone to yield 15z as a white powder (0.59 g, 86%). Mp decomposition at 122° C. 1H NMR (600 MHz, DMSO-d6): δ 4.99 (q, J=6 Hz, 1H), 2.88 (q, J=6 Hz, 2H), 1.69 (d, J=6 Hz, 3H), 1.16 (t, J=6 Hz, 3H). 13C NMR (150 MHz, DMSO-d6): δ 185.5, 170.7, 115.5×2, 47.6, 47.5, 24.0, 20.8, 13.5. MS m/z (ESI) 263.00 [M+H]+, 264.96 [(M+2)+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[OH-].[Na+].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
3,4-dichloroaniline (150 g) was dissolved in 1.0 L TBME and the solution was cooled to 10° C. Sodium hydroxide (140.7 g of a 30% aqueous solution) was added under mechanical stirring. Pivaloyl chloride (125.9 mL) was added dropwise while keeping the internal temperature under 35° C. After the addition, the temperature of the reaction was maintained at 30-35° C. for a further 30 min. The reaction mixture was then allowed to cool to room temperature and subsequently kept at 0-5° C. for 1 h. The resulting precipitate was filtered of and washed with 600 mL water/MeOH (90/10) and then with 900 mL water. The resulting solid was the dried in a vacuum oven at 55° C. for 4 days. Yield: 162 g. 1H-NMR (DMSO-d6) δ 9.46 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.65 (dd, J=9.0. 2.4 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 1.22 (9H, s).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:29]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:30])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)C(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)C(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (310 mg, pale brown solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.60 mmol, Intermediate-18, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)NCc2ccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c3c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) and triethylamine (0.27 mL, 1.9 mmol) in THF (10 mL) at 5˜10° C., was added 3-chloro-4-methyl-phenyl isocyanate (0.24 mL, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.38 min (98.4%); mp, 186-188° C.; 1HNMR (DMSO-d6) 2.15-2.23 (m, 4H, CHH and CH3Ar), 2.56-2.86 (m, 6H, CHCH2, CH3), 4.40 (d, J=6 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=5 Hz, 1H, CH2NH), 7.11-7.95 (m, 6H, Ar), 8.75 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.71, 20.93, 23.39, 30.61, 42.34, 56.53, 116.45, 117.66, 120.01, 123.67, 126.54, 127.39, 130.99, 132.96, 133.95, 139.05, 139.58, 145.76, 154.51, 155.08, 160.47, 169.47, 172.60. LCMS MH=468, 470; Anal Calcd For C23H22N5O4Cl+0.6H2O: C, 57.71; H, 4.88; N, 14.63; Cl, 7.41. Found: C, 57.63; H, 4.96; N, 14.50; Cl, 7.64.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([O:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc2c(Oc3ccc(C(N)=O)cc3)cc(-c3cccc4[nH]ncc34)nc21
Temperature: 155 °C
Yield: 18.5 %

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmoles) was dissolved in 2 mL DMF. 4-Hydroxybenzamide 8d (0.038 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered and the organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed and purified to obtain 109 as a white solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.72 (s, 1H), 8.04 (d, J=8.7, 3H), 7.83-7.59 (m, 3H), 7.59-7.29 (m, 4H), 7.23 (s, 1H), 4.16 (d, J=9.1, 3H). MS (ESI) m/z 385.1 (M+1)+