Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC1C=CC(S(O)(=O)=O)=CC=1.[F:37][C:38]([F:46])([F:45])[C:39]([C:41]([F:44])([F:43])[F:42])=[O:40]>C1(C)C=CC=CC=1.O>[F:37][C:38]([F:46])([F:45])[C:39]([C:18]1[CH:19]=[C:14]([CH2:13][CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:5]=3)[C:9]2=[O:12])[CH:15]=[N:16][CH:17]=1)([OH:40])[C:41]([F:44])([F:43])[F:42]
Reactant: COc1cc2c(cc1N1CCOCC1)CC(Cc1cccnc1)C2=O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Temperature: 120 °C

Procedure:
To a stirred solution of 243 (0.08 g, 0.236 mmol) in toluene was added PTSA (0.090 g, 0.472 mmol) and kept stirring at 120° C. Hexafluoroacetone 244 (0.129 g, 0.590 mmol) was added to the reaction and heated to 100° C. for 16 h. Reaction was cooled to RT, diluted with water, extracted with ethyl acetate twice, the organic layer dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound at 30% ethyl acetate in hexane as thick sticky solid 2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 245. 1HNMR (400 MHz, CDCl3) δ ppm 7.06 (m, 2H), 6.88 (s, 1H), 6.90 (s, 1H), 6.123 (s, 1H), 3.88 (m, 7H), 3.49 (m, 1H), 3.08 (m, 2H), 3.03 (m, 6H), 2.29 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CBr)c1Cl

Procedure:
A suspension of 2-chloro-m-xylene (15 ml), N-bromosuccinimide (23.3 g) and benzoyl peroxide (200 mg) in carbon tetrachloride (150 ml) was heated under reflux for 6 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane) to give 2-bromomethyl-1-chloro-6-methylbenzene (16.0 g) as a colorless oil. 2-Bromomethyl-1-chloro-6-methylbenzene (25.4 g) and hexamethylenetetramine (32.4 g) were dissolved in acetic acid-water (1:1, 10 ml) and the mixture was heated under reflux for 5 hours. To the reaction mixture was added concentrated hydrochloric acid (40 ml) and the mixture was heated under reflux for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-chloro-3-methylbenzaldehyde (19.4 g) as a yellow oil. Subsequently, the title compound was prepared from 2-chloro-3-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][C@H:33]([C:41]([OH:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C[O-].[Na+]>COCCO>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][C@@H:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.073 mmol), L-phenylalanine (241 mg, 1.46 mmol), and NaOMe (59 mg, 1.09 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-40% EtOAc/hexanes+2% AcOH) to give 37 mg of the title compound. MS: (+) m/z 544.99 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[NH:21][C:22]1[C:31]2[C:26](=[CH:27][C:28](F)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:35]#[N:36].CS(C)=O>O1CCCC1>[CH2:3]([S:10][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:21][C:13]3[CH:14]=[C:15]([O:19][CH3:20])[C:16]([Cl:18])=[CH:17][C:12]=3[Cl:11])=[C:23]([C:35]#[N:36])[CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(SCc4ccccc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of sodium hydride (169 mg, 4.2 mmol), benzyl mercaptan (145 mg, 1.2 mmol) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (250 mg, 0.64 mmol) in 1 mL of tetrahydrofuran is heated at 70° C. for 1 hour, then stirred at room temperature overnight. Upon addition of 1 mL of dimethyl sulfoxide a solution is obtained. Additional amounts of sodium hydride and benzyl mercaptan are added and the reaction mixture is heated at 100° C. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography, eluting with 1:2 ethyl acetate:hexane to provide 150 mg of 7-benzylthio-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile, mp 123-125° C.
Reaction SMILES: [CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])Cl)[CH3:2].[CH3:9][NH:10][CH3:11]>C(OCC)C>[CH3:9][N:10]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])[CH2:1][CH3:2])[CH3:11]
Reactant: CNC
Reactant: CC[Si](Cl)(CC)CC
Solvent: CCOCC
Product: CC[Si](CC)(CC)N(C)C

Procedure:
Triethylchlorosilane, 75.4 g (0.5 mole), was added dropwise to a solution of 73 ml (1.1 mole) of dimethylamine in 500 ml diethyl ether at 10°-20°. A precipitate was removed by filtration, and the resulting filtrate distilled to provide 64.8 g of dimethylaminotriethylsilane as a colorless liquid, bp 88° (46 mm). A 47.8 g (0.3 mole) sample of the silane was added dropwise to a solution of 5 ml (0.09 mole) of sulfur tetrafluoride in 100 ml of ether cooled to -70°. The resulting mixture was allowed to warm to about 23° and stirred for one week. The resulting white solid precipitate was collected on a filter, washed with ether, and dried under nitrogen to give 6.8 g of tris(dimethylamino)sulfonium bifluoride as colorless crystals: mp 117°-120°; 19F NMR (CD3CN) δ-150.4 ppm; 1H NMR (CD3CN) δ+2.95 ppm.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.7 g, 2.364 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-methylbenzene (0.525 g, 2.84 mmol) and potassium carbonate (0.980 g, 7.09 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜70% EtOAc in Hexane) to give the product as oil (0.686 g, 73%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.31 (s, 3H) 2.57 (s, 3H) 3.01-3.18 (m, 4H) 3.75-3.92 (m, 4H) 5.24 (s, 2H) 6.64 (d, J=2.02 Hz, 1H) 6.75-6.89 (m, 2H) 7.03-7.17 (m, 2H) 7.18-7.26 (m, 1H); MS (ES+) m/e 400.0 [M+H]+.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19]CC)=O.Cl.[NH2:23][OH:24].[OH-].[K+].C(O)(=O)C>CO>[OH:24][NH:23][C:17]([C:2]1[S:1][C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=1)=[O:19]
Reactant: NO
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)NO)cc2C1
Temperature: 75 °C
Yield: 50.1 %

Procedure:
A mixture of 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (0.056 g, 0.18 mmol; prepared as described in J. Med. Chem. 2006, 49(15): 4623), hydroxylamine hydrochloride (0.037 mg, 0.54 mmol) and potassium hydroxide (0.1 mg, 1.8 mmol) in methanol (2 mL) was heated at 75° C. for 1 hour. Upon cooling to room temperature the reaction was quenched by the addition of acetic acid (100 μL, 1.8 mmol) and the solvent was evaporated to dryness. The residue was dissolved in DMSO (1 mL) and purified using a Gilson prep to afford a white solid (26.9 mg, 50%). LCMS (FA) ES+ 299; 1H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 4.46 (s, 2H), 3.71 (t, J=5.4 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=2)[N:25]=1>>[F:31][C:29]([F:30])([F:32])[C:26]1[N:24]2[N:25]=[C:20]([N:2]3[CH2:3][CH2:4][CH:5]([N:8]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=5[CH2:11][O:10][C:9]4=[O:18])[CH2:6][CH2:7]3)[CH:21]=[CH:22][C:23]2=[N:28][N:27]=1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Product: O=C1OCc2ccccc2N1C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-piperidin-4-yl-4H-3,1-benzoxazin-2-one hydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-4H-3,1-benzoxazin-2-one.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:20]=[CH:19][C:18](OC4C=CC=CC=4F)=[C:17]([O:29][CH3:30])[CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([S:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:17]([O:29][CH3:30])[CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Sc1ccccc1
Reactant: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Oc1ccccc1F
Product: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Sc1ccccc1

Procedure:
Prepared according to a procedure analogous to that described for 3-cyclobutyl-1-[4-(2-fluoro-phenoxy)-3-methoxy-phenyl]-imidazo[1,5-a]pyrazin-8-ylamine except using benzenethiol. 1H NMR (400 MHz, CDCl3)-6=1.99-2.11 (m, 1H), 2.13-2.26 (m, 1H), 2.45-2.55 (m, 2H), 2.57-2.69 (m, 2H), 3.75-3.85 (m, 1H), 3.97 (s, 3H), 5.44 (br. s., 2H), 6.82 (d, J=5.6 Hz, 1H), 7.00-7.08 (m, 3H), 7.17 (d, J=1.3 Hz, 1H), 7.34-7.43 (m, 3H), 7.45-7.51 (m, 2H). MS (ES+): m/z 402.96 (100) [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClC(Cl)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
p-Nitroaniline, 13.0 g (0.094 mole), is dissolved in 200 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at 50° C. while nonanoylchloride, 16.5 g (0.094 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column and crystallized at -20° C. There is obtained N-(4-nitrophenyl) nonanamide, (M.P. 76.0°-76.5°). Analysis shows 9.91% nitrogen as against a calculated value of 10.06% for C15H21N2O3.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12]1([CH2:18][C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]1([CH2:18][C:19]([CH:8]2[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]2=[O:7])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)Cc2ccccc2)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5.00 g, 32.05 mmol), phenylacetic acid (6.53 g, 48.03 mmol), 4-dimethylaminopyridine (1.95 g, 16.01 mmol) in dry CH2Cl2 (30 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (7.26 g, 35.22 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (150 ml) and the combined solution was washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from MeOH giving 5-phenylacetyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 8 (6.10 g, 69%).
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH3:6])[CH:3]=[O:4].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][N+:12]#[C-:13])[CH3:8]>>[CH2:7]([O:9][C:10]([CH:11]1[CH:3]([C:2]([CH2:5][CH3:6])=[CH2:1])[O:4][CH:13]=[N:12]1)=[O:14])[CH3:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)CC
Product: C=C(CC)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-butyraldehyde with isocyanoacetic acid ethyl ester in a manneranalogous to that described in Example 1 yields 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. A solution of 16g of 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in 100 ml of ethanol/water (1:1) is heated at the boil, under reflux, for 15 hours. Thewhole is concentrated by evaporation in vacuo, the residue is taken up in 200 ml of dichloromethane, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation to yield 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC(C)=O.C(=O)=O.[NH3:19]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH2:19])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Product: Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
2,4-Difluoronitrobenzene (1.0 eq) was placed in a dry round-bottomed flask equipped with a dry ice condenser charged with acetone/dry ice. Ammonia was condensed into the flask and the resulting solution was stirred at reflux for 7 hours. A yellow precipitate was formed within 1 hours. After 7 hours, the condenser was removed and the liquid ammonia was allowed to evaporate over several hours. The crude product was purified by flash chromatography on silica gel (85:15 hexanes:EtOAc, product at Rf=0.32, contaminant at Rf=0.51). GC/MS m/z 156.1 (M+), Rf 11.16 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:7]=3[C:6]=2[N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[C:14]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH:15]=[CH:16][C:7]=3[C:6]=2[N:18]=1
Reactant: COc1cccc(N)c1
Reactant: Nc1ncc2c(n1)-c1ccc(I)cc1NC(=O)C2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cccc(Nc2ccc3c(c2)NC(=O)Cc2cnc(N)nc2-3)c1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
2-Amino-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (200 mg, 0.568 mmol, 1.0 equiv), anhydrous K3PO4 powder (241 mg, 1.14 mmol, 2.0 equiv) and palladium bis-tri-t-butyl phosphine (58 mg, 0.1136 mmol, 20 mol %) were combined in a sealable vial with a magnetic stir bar under a nitrogen atmosphere (glove box). 3-Methoxyaniline (209 mg, 1.70 mmol, 3.0 equiv) was added, followed by 6 mL of anhydrqus N-methylpyrrolidinone. The vial was sealed with a silicone lined crimp cap and removed from the glove box. The vial was sonicated for 2 minutes and then heated to 90° C. (oil bath temperature) for 18 hours. The dark brown solution was diluted with 50 mL of water and the brown solids were collected by filtration and washed with water and then diethyl ether. Purification by silica gel chromatography (10% methanol, 85% dichloromethane, 5% formic acid) afforded an orange powder, which was recrystallized from methanol and diethyl ether to yield 120 mg (61%) of 2-amino-9-(3-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-225) as a yellow-orange powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH:24]([O:1][C:2]2[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc(SC)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
The methyl 2-hydroxy-4-(methylthio)benzoate (4.00 g, 20.2 mmol) was dissolved in THF (300 mL). The solution was cooled to 0° C. and the 1-Boc-4-hydroxypiperidine (4.07 g, 20.2 mmol) and triphenylphosphine (6.35 g, 24.2 mmol) were added, followed by diethyl azodicarboxylate (4.0 mL, 25.4 mmol). After 5 minutes, the reaction was allowed to warm to room temperature and left overnight. The reaction was concentrated in vacuo and the crude material was purified by flash column chromatography (about 500 g silica, 15% EtOAc/hexanes through 20% EtOAc/hexanes) to give the desired product (7.185 g, 18.83 mmol, 93%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C([O:17][CH:18]1[CH:22]([N:23]2[C:27]3[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=3[N:25]=[C:24]2Br)[CH2:21][CH:20]([CH2:35][O:36]C(=O)C)[CH:19]1[O:40]C(=O)C)(=O)C>CN(C)C=O>[Cl:32][C:30]1[C:29]([Cl:33])=[CH:28][C:27]2[N:23]([CH:22]3[CH:18]([OH:17])[CH:19]([OH:40])[CH:20]([CH2:35][OH:36])[CH2:21]3)[C:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:25][C:26]=2[CH:31]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC1CC(n2c(Oc3ccccc3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Phenol (72 mg, 0.77 mmol) and anhydrous potassium carbonate (106 mg, 0.77 mmol) were stirred in dry N,N-dimethylformamide (5 mL) under nitrogen for 1.0 hour. (±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (400 mg, 0.770 mmol) was added and the mixture stirred at 80° C. (oil bath) for 18 hours. Volatiles were removed in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried (sodium sulfate) and volatiles evaporated. The residual oil was stirred in 4N ammonia in methanol (30 mL) at ambient temperature for 18 hours. Evaporation and chromatography of the residue on silica gel with elution by 2% methanol-chloroform gave (±)-(1R*, 2S*, 3S*, 5S*)-5-(5,6-dichloro-2-phenoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as white solid foam from ethyl acetate (215 mg, 68%); 1H-NMR(DMSO-d6)δ: 7.98 and 7.71 (both s, 2, aromatic CH), 7.6-7.3 (m, 5, C6H5), 5.07 (d, J=6.4 Hz, 1, OH), 5.0-4.75 (m overlapping t at 4.95, J=3.1 Hz, total 2, NCH and OH), 4.71 (d, J=3.9 Hz, 1, OH), 4.5-4.35 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.3-1.9 (m, 3, CH2 and CH); mass spectrum (CI): 409 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>ClCCl>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 50 g (531 mmol) of 3-aminopyridine and 139 mL (797 mmol) of N,N-diisopropylethylamine in 800 mL of dichloromethane at 0° C. was carefully added through an addition funnel 72 mL (584 mmol) of pivaloyl chloride. The reaction mixture was stirred at 0° C. for 30 min then concentrated in vacuo. To the residue was added 600 mL of ethyl acetate and the organic solution was washed sequentially with water, 0.5N aqueous sodium bicarbonate solution and saturated aqueous brine (300 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. To the crude solid was added 150 mL of ethyl acetate. The mixture was stirred vigourously for 30 min, then 300 mL of hexane was added and the mixture was stirred for an additional 30 min. The resultant crystalline solid was filtered and washed with 400 mL of 10% ethyl acetate/hexane to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.57 (d, J=2.5 Hz, 1H), 8.36 (dd, J=4.8, 1.4 Hz, 1H), 8.21-8.19 (m, 1H), 7.47 (br s, 1H), 7.30-7.27 (m, 1H), 1.36 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>ClCCl>[CH3:21][S:22]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)[CH:8]=2)[CH2:3][CH2:2]1)(=[O:24])=[O:23]
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)NCC4)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)N(S(C)(=O)=O)CC4)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-6-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (Intermediate 16.1) (1.10 g, 4.19 mmol), methanesulfonyl chloride (0.65 ml, 8.39 mmol), and triethylamine (3.49 ml, 25.16 mmol) in dichloromethane (50 ml) is stirred for 15 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 1.40 g (98%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 99% purity, tR 7.03 min (tR(SM) 7.06 min). MS (ESI) m/z (C17H16N4O2S) 341.0 (M+1, 100) Finnegan LCQ.