Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@H:8]([NH2:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>ClCCl>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:21](=[O:22])[NH:10][C@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:12])[CH3:11])=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of (R)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethylamine (693 mg, 3,66 mmol) (from Example 38a supra) and triethylamine (0.77 mL, 5.5 mmol) (Allied Signal) in dichloromethane was treated with 4-nitrophenyl chloroformate (885 mg, 4.39 mmol) (Aldrich) at room temperature for 30 minutes. The reaction was quenched with 1 N aqueous hydrochloric acid and then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution followed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (15% ethyl acetate in hexanes) to give (R)-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-carbamic acid 4-nitro-phenyl ester as a colorless oil that solidified upon standing. (Yield 0.49 g, 38%).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]=[N+:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl>C(O)C.O>[C:1]1([NH:7][C:8]([NH:10][N:11]2[CH2:12][CH:13]=[CH:14][CH2:15][CH2:16]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N=[N+]1C=CC=CC1)Nc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccccc1)NN1CC=CCC1
Reaction time: 4 h

Procedure:
To a solution of N-(phenylcarbamoylimino)pyridinium ylide (0.64 g) in a mixture of ethanol (30 ml) and water (10 ml) was added sodium borohydride (0.20 g) at ambient temperature. After being stirred for 4 hours, the reaction mixture was acidified with 1N hydrochloric acid, concentrated to a volume of ca. 15 ml. The crystalline precipitate was collected, washed with water and dried in vacuo. The crude product was dissolved in ethyl acetate and extracted with 10% hydrochloric acid (20 ml). The extract was adjusted to pH 3 with aqueous sodium bicarbonate and extracted with ethyl acetate (30 ml). The organic layer was washed with aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate and evaporated to give N-(phenylcarbamoylamino)-1,2,3,6-tetrahydropyridine (0.28 g), which was recrystallized from ethyl acetate to afford colorless needles (0.15 g). mp: 157°-159° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C@@H:10]([CH2:12][CH2:13][CH3:14])[N:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:23]([CH3:37])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].[BH3-]C#N.[Na+]>CC(O)=O.CO>[O:21]=[C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][C@@H:10]([CH2:12][CH2:13][CH3:14])[N:9]1[CH:15]1[CH2:20][CH2:19][N:18]([CH:23]([CH3:37])[CH2:24][CH2:25][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:17][CH2:16]1
Reactant: CCC[C@@H]1CN(c2ccccc2)C(=O)N1C1CCNCC1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC[C@@H]1CN(c2ccccc2)C(=O)N1C1CCN(C(C)CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
Following general procedure B: a solution of (R)-1-phenyl-3-piperidin-4-yl-4-propyl-imidazolidin-2-one (152 mg, 0.53 mmol), 2-(3-oxo-butyl)-isoindole-1,3-dione (230 mg, 1.06 mmol), NaBH3CN (108 mg, 1.72 mmol) and glacial AcOH (8 drops) in MeOH (2.5 ml) was stirred at 60° C. for 16.5 hours. Standard workup and purification by flash column chromatography on silica (CH2Cl2/MeOH, 29:1) gave 2-{3-[4-((R)-2-oxo-3-phenyl-5-propyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-isoindole-1,3-dione, contaminated with alcohol resulting from reduction of excess ketone (302 mg).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)=[CH:26][CH:25]=1)#[N:23]>C(N(CC)CC)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[NH:31][CH2:32][CH2:33][N:34]([C:2]3[C:3]([F:21])=[CH:4][C:5]4[C:6]([CH:20]=3)=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=4)[CH2:35]2)=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(C2CNCCN2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(C#N)cc5)C4)cc3nc21
Yield: 41.9 %

Procedure:
(RS)-8-[3-(4-Cyanophenyl)-1-piperazinyl]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 11, but starting with 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.84 g), (RS)-2-(4-cyanophenyl)piperazine (5.61 g) and triethylamine (1.7 cc). (RS)-8-[3-(4-Cyanophenyl)-1-piperazinyl]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.15 g) is obtained in the form of a yellow solid, decomposing at 332° C.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[S:18][C:17]3[CH:16]=[N:15][NH:14][C:13]=3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1.[I:19]I>CN(C)C=O>[I:19][C:16]1[C:17]2[S:18][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=3)=[CH:12][C:13]=2[NH:14][N:15]=1
Reactant: II
Reactant: COc1cccc(-c2cc3[nH]ncc3s2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc3[nH]nc(I)c3s2)c1
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
Crushed potassium hydroxide (1.35 g, 24.1 mmol) was added in one portion to a solution of 5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole [1.85 g, 8.03 mmol, Intermediate (53)] and dimethylformamide at 0° C. with stirring. After 10 minutes, iodine (3.05 g, 12.0 mmol) was added in one portion and the dark reaction was stirred at 0° C. for 30 minutes and then at room temperature for 5 hours. The reaction was quenched with 10% aqueous NaHSO3 (100 mL), the resulting white mixture diluted with water (100 ml) and the mixture aged at 5° C. overnight. The solid was collected by filtration, washed with water (3×30 mL) and dried under vacuum at 40° C. to give 3-iodo-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole [2.61 g, 91%, Intermediate (54)] as a tan powder. mp 159-163° C.; TLC Rf 0.54 (silica, 80% ethyl acetate/heptane); LC/MS: 357.0 (M+H), RT=3.60 minutes; 1H NMR (300 Mhz, CDCl3) δ 11.3 (br s, 1H), 7.33 (m, 1H), 7.28-7.20 (m, 2H), 7.14 (m, 1H), 6.91 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:23]=[CH:22][C:7]2=[C:8]3[C:17](=[CH:18][CH:19]=[C:6]2[CH:5]=1)[C:16](=[O:20])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]3=[O:21].CCCC[O:28][N:29]=O>O.C(O)CCC>[OH:3][C:4]1[CH:23]=[CH:22][C:7]2=[C:8]3[C:17](=[CH:18][CH:19]=[C:6]2[C:5]=1[N:29]=[O:28])[C:16](=[O:20])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]3=[O:21]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc1cc(O)ccc21
Reactant: CCCCON=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: O=Nc1c(O)ccc2c3c(ccc12)C(=O)c1ccccc1C3=O
Temperature: 60 °C

Procedure:
A solution of sodium hydroxide (0.72 g) in water (0.72 g) is added under stirring at ambient temperature to a suspension of 3-hydroxy-benzo[a]anthracene-7,12-dione, prepared as described in Journal Organic Chemistry (1986) 51 page 3502, (5 g; 18 mmoles) in butanol (25 ml). N-butylnitrite (2 g; 19.4 mmoles) is added over a period of 1 hour to the mixture, which is maintained at 60° C. The reaction mixture is maintained at 60° C. for 4 hours, cooled to ambient temperature and filtered. The solid is washed with toluene (2×10 ml), dried under vacuum and suspended in water (25 ml). Acetic acid (2 ml) is added to the suspension over a period of 30 minutes, operating at ambient temperature under stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cccc(-c2cc3nc(Cl)cc(Cl)n3n2)c1
Solvent: C1COCCO1
Product: Clc1cccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(3-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (200 mg, 0.670 mM), then morpholine (117 μL, 1.34 mM) was added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined together and dried over anhydrous sodium sulfate, then the solvent was distilled off and the resulting solid was washed with methanol to give the title compound (222 mg, yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.[F:14][C:15]([F:29])([F:28])[O:16][CH2:17][CH2:18][CH2:19]OS(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([O:12][CH2:19][CH2:18][CH2:17][O:16][C:15]([F:29])([F:28])[F:14])[CH:5]=1
Reactant: CCc1ccc(C(=O)OC)cc1O
Reactant: O=S(=O)(OCCCOC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccc(C(=O)OC)cc1OCCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-ethyl-3-hydroxy-benzoic acid methyl ester (250 mg, 1.32 mmol), crude trifluoro-methanesulfonic acid 3-trifluoromethoxy-propyl ester (590 mg, 1.58 mmol; purity of 74%) and anhydrous K2CO3 (276 mg, 1.98 mmol) in MeCN (2.0 mL) is stirred in a sealed glass vial overnight at room temperature. The crude product obtained after filtration and evaporation is purified by flash chromatography (hexane/AcOEt 1:1) to give the title compound as oil. TLC, Rf (hexane/AcOEt 3:1)=0.38. 1H-NMR (CDCl3): δ 1.24 (t, 3H), 2.25 (m, 2H), 2.70 (q, 2H), 3.94 (s, 3H), 4.18 (t, 2H), 4.24 (t, 2H), 7.25 (d, 1H), 7.52 (s, 1H), 7.64 (d, 1H) ppm. 19F-NMR (CDCl3): δ −61.1 ppm.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[Br:27]>>[Br:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[NH:20][S:2]([C:5]1[S:6][C:7]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: O=C(OCc1ccc(S(=O)(=O)Cl)s1)c1ccccc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(COC(=O)c3ccccc3)s2)c1Br
Yield: 30.3 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene-2-sulfonamide was prepared as described in Example 2 from 2-chlorosulfonyl-5-(benzoyloxymethyl)thiophene (520 mg, 1.72 mmol) and 5-amino-4-bromo-3-methyl isoxazole (319 mg, 1.8 mmol). Purification by column chromatography using 10% MeOH/CHCl3) gave 238 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzoyloxymethyl)thiophene-2-sulfonamide as brown semisolid (31% yield, m.p. 92° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:9]2[S:8][C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: COc1ccc2ccsc2c1
Product: COc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1

Procedure:
6-Methoxybenzo[b]thiophene (see WO 97/25033) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=2[F:21])[CH2:10][C:9]1=[O:22]>CO.[Pd]>[CH3:23][N:5]1[C:6]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[CH:2][CH:3]=[N:4]1
Reactant: Cn1ncc(Br)c1CN1CC(c2cc(F)cc(F)c2F)CC1=O
Agent: [Pd]
Solvent: CO
Product: Cn1nccc1CN1CC(c2cc(F)cc(F)c2F)CC1=O
Reaction time: 3 h
Yield: 58.2 %

Procedure:
In a 250 ml pressure jar, under inert atmosphere, 1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 182 (0.41 g, 1 mmol) is dissolved in MeOH (50 ml). Pd on charcoal (82 mg, 20% w/w) is added and the mixture is hydrogenated under a pressure of 40 psi at room temperature for 3 h. The mixture is filtered on Celite and concentrated to dryness. The residue is purified by column chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 98/1.8/0.2 (v/v/v)) and recrystallized from diisopropylether to afford 0.18 g of 1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 183.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[OH:16][CH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[OH:16][CH2:17][C:18]1[CH:23]=[C:22]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OCc1cccc(B(O)O)c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1cccc(CO)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-hydroxymethylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H14N4O, 291. Found, 291.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: O=C1CCC(c2cccc(O)c2)=NN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Yield: 60.9 %

Procedure:
A mixture of finely powdered 6-(3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (21.6 g, 0.11 mole), epichlorohydrin (90 ml, 1.1 mole), and piperidine (1ml) was heated on a steam bath for 90 minutes. Evaporation of the solution under reduced pressure gave an oil which was dissolved in dichloromethane and stirred with dilute sodium hydroxide solution (60 ml). The organic phase was washed with water, dried, and evaporated under reduced pressure to a viscous oil (27 g, 96%). Purification on a silica column by elution with chloroform gave 6-[3-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (16.5g, 59%) as an oil which when treated with ether gave a white solid (13.7g, 49%, m.p. 108°-112°C). The pure epoxide, recrystallised from methanol petroleum/ether (b.p. 60°-80°C), had m.p. 110°-112°C.
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:5]1=[O:16])([CH3:3])[CH3:2].C([Li])CCC.C[O:24][C:25](=O)[C:26]([N:28]([CH3:30])[CH3:29])=[O:27].O>O1CCCC1>[CH3:29][N:28]([C:26](=[O:27])[C:25]([C:14]1[C:9]([C:7]2[NH:6][C:5](=[O:16])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:17])[N:8]=2)=[N:10][CH:11]=[C:12]([CH3:15])[CH:13]=1)=[O:24])[CH3:30]
Reactant: COC(=O)C(=O)N(C)C
Reactant: Cc1ccc(C2=NC(=O)C(C)(C(C)C)N2)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)C(=O)N(C)C)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a stirred solution of 2.5 g (0.011 mole) of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2 -yl)-5-methyl pyridine in 100 ml of dry tetrahydrofuran cooled to -70° C. under the presence of nitrogen was added dropwise a 9.68 ml of 2.5 molar n-butyllithium, thereby temperature was maintained below -65° C. The solution was stirred at -70° C. for 3 hours and a solution 1.96 g of N,N-dimethyl oxamic acid methyl ester(0.015 mole) in 10 ml of anhydrous tetrahydrofuran was added dropwise while maintaining the temperature below -65° C. After stirring another hour at -70° C., the solution was poured into water and extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate, and evaporated under reduced pressure. Trituration of the residue with diethyl ether affored a crude solid which was recrystallized from a mixture of diethyl ether and methylene chloride to yield 1.67 g of a white solid (m.p=180°-182° C.).
Reaction SMILES: C([O:3][CH:4](O)[CH:5]([F:7])[F:6])C.[CH3:9][N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>O>[F:6][CH:5]([F:7])[CH:4]([OH:3])[CH2:9][N+:10]([O-:12])=[O:11]
Reactant: CCOC(O)C(F)F
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])CC(O)C(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 1-ethoxy-2,2-difluoroethanol (60 g, 0.47 mol), CH3NO2 (32.9 g, 0.56 mol) and Na2CO3 (3 g) was stirred at 60° C. for 3 hrs, then at rt overnight. The mixture was diluted with water (40 mL), extracted with tert-butyl methyl ether (200 mL) and the organic layer was dried over Na2SO4 and concentrated under low temperature to give the title compound, which was used for next step directly.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1([NH:11]S(C(C)(C)C)=O)[CH2:10][O:9][CH2:8]1>O1CCOCC1.CO>[ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1([NH2:11])[CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)S(=O)NC1(c2nccs2)COC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2nccs2)COC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.1 %

Procedure:
A 4.0 M solution of hydrochloric acid (117 μL, 467 μmol) in dioxane was added to a solution of 2-methyl-propane-2-sulfinic acid (3-thiazol-2-yl-oxetan-3-yl)-amide (Example 281a) (81 mg, 311 μmol) in methanol (0.5 mL) at 0° C. The mixture was stirred at 0° C. for 5 min before the solvents were removed under reduced pressure. The resulting white solid was triturated with diethyl ether and filtered off. The solid was further washed with diethyl ether and dried under high vacuum to yield the title compound (42 mg, 70%) as a white solid. MS (EI): m/e=157.1 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]2)[CH2:27][CH2:26]1.Cl.[NH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]2[CH2:58][C:57]3[CH:56]=[N:55][N:54]([CH3:59])[C:53]=3[NH:52][C:51]3[CH:60]=[CH:61][CH:62]=[CH:63][C:50]2=3)=[O:48])=[C:43]([F:64])[CH:42]=1>CN(C=O)C.CCN(C(C)C)C(C)C>[F:64][C:43]1[CH:42]=[C:41]([CH:46]=[CH:45][C:44]=1[C:47]([N:49]1[CH2:58][C:57]2[CH:56]=[N:55][N:54]([CH3:59])[C:53]=2[NH:52][C:51]2[CH:60]=[CH:61][CH:62]=[CH:63][C:50]1=2)=[O:48])[CH2:40][NH:39][C:35]([CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH:25]2[CH2:26][CH2:27]2)[CH2:34][CH2:33]1)=[O:37]
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CN)cc1F)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)C3CCN(CC4CC4)CC3)cc1F)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
HBTU (227 mg, 0.6 mmol) was added to a solution of 1-cyclopropylmethyl-piperidine-4-carboxylic acid from Example E15a (99 mg, 0.45 mmol) in DMF (5 ml) and DIEA (to pH9). The mixture was stirred at room temperature for 1 h. (4-Aminomethyl-2-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E90.2 (116 mg, 0.3 mmol) was added and the mixture was stirred at room temperature for 18 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% dichloromethane) to give a white solid identified as the title compound (71.5 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:15]([S:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[C:3]([O:2][CH3:1])=[O:22])[C:8]([OH:10])=[O:9])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(SCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cc1SCc1ccccc1

Procedure:
50G of benzylmercapto terephthalic acid dimethyl ester is suspended in a solution of 750 ml of methanol to which is added 200 ml of a solution of 15 g of sodium carbonate monohydrate in 350 ml of water. The reaction mixture is refluxed for 30 minutes, cooled and diluted with 750 ml of water. The solid is filtered and resuspended in 375 ml of methanol and 100 ml of the above sodium carbonate solution, refluxed 30 minutes, cooled, 375 ml of water is added thereto, filtered and the damp cake resuspended in 187 ml of methanol. The remaining 50 ml of the sodium carbonate solution is then added and the reflux process repeated. The combined aqueous filtrates are acidified with 50 ml of conentrated hydrochloric acid yielding a precipitate which is filtered, washed with water and the damp cake is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate and evaporated to yield 46 g of crude 3-benzylmercapto-4-carbomethoxy benzoic acid, which is used without further purification in part D.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[CH:13]2Cl)=[CH:4][CH:3]=1.O1CCOCC1.[NH3:26]>>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[CH:13]2[NH2:26])=[CH:4][CH:3]=1
Reactant: COc1cc(F)c2c(c1)C(Cl)c1cc(Br)ccc1O2
Reactant: N
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)C(N)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
7-Bromo-9-chloro-4-fluoro-2-methoxy-9H-xanthene (45 g, 131 mmol) was dissolved in saturated solution ammonia in dioxane (1310 mL, 655 mmol) and stirred for 60 hrs at RT. The solution was concentrated in vacuo. The material was treated with saturated aqueous sodium carbonate and extracted into EtOAc. The organic extracts were concentrated. The product was purified from the concentrate via silica gel column chromatography (RediSep 330 g column) using 10-100% EtOAc in hexane to afford 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-amine (10 g, 30:9 mmol).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-ylcarbamate (20 g, 55.0 mmol) and MeI (6.22 mL, 99.7 mmol) in DMF (700 mL) was added sodium hydride (60%, 3.1 g, 77.6 mmol) at 0° C. The reaction was stirred at 0° C. for 2 h then warmed to 10° C. for an additional 2 h at which point LC-MS analysis showed the reaction was complete. The reaction was quenched with saturated aq. NH4Cl solution (800 mL) and EtOAc (2 L). Water was then added to dissolve the solids. The organic layer was washed with water, brine, and dried over Na2SO4. The resulting residue was purified on silica gel column using a mixture of hexanes and EtOAc to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (16.9 g, 81%). LRMS (M+H+) m/z 230.2.