Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[OH:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.S(OC)(O[CH3:23])(=O)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:23][O:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COS(=O)(=O)OC
Reactant: OCCOC1CCCCCCCCCCC1
Agent: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COCCOC1CCCCCCCCCCC1
Reaction time: 1 h

Procedure:
25 g of sodium amide was introduced into 150 ml of xylene and heated to boiling under agitation. Within one hour, 114 g (0.5 mol) of 2-hydroxyethyl-cyclododecyl-ether, dissolved in 750 ml of xylene, was allowed to drip into the boiling suspension. To complete the alcoholate formation, the mixture was heated under reflux for another two hours. Thereafter 44 g (0.35 mol) of dimethyl sulfate was added dropwise and the reaction mixture heated under reflux for another four hours. Then, the reaction mixture was poured into a mixture of ice and 35 g of sodium hydroxide. The organic phase was washed with water, dried over Na2SO4, and then fractionated.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.Cl.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:8][C:9]=4[O:16][CH3:17])=[O:13])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Agent: Cl
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 73 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (271 mg) described in Preparation Example 19 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (343 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21]>C1COCC1>[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:4]2)[C:19]=1[C:20]#[N:21]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)CC(=O)N1CCC[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@@H](COc2cccc(N)c2C#N)C1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
To a solution of (R)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one (Example 34c) (145 mg, 0.73 mmol) in THF (15 mL) was added NaH (44 mg, 1.09 mmol, 60% dispersion in mineral oil) at 0° C. The reaction was warmed to room temperature and stirred for 15 minutes, at which time 2-amino-6-fluorobenzonitrile (109 mg, 0.80 mmol) was added. The mixture was heated at 80° C. overnight, quenched with water, concentrated under reduced pressure to remove THF and extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (EtOAc/hexanes). The residue was further purified by chiral HPLC (normal phase, ethanol/isopropanol/methanol/hexanes) to give the title compound as a white solid (96 mg, 41%). MS 316 (MH+).
Reaction SMILES: [BH4-].[Na+].Cl[C:4]1[N:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.[SH:19][C:20]1[CH:36]=[CH:35][C:23]2[N:24]=[C:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[S:26][C:22]=2[CH:21]=1>C(O)C>[N:13]1([C:10]2[CH:11]=[CH:12][C:7]3[N:8]([C:4]([S:19][C:20]4[CH:36]=[CH:35][C:23]5[N:24]=[C:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[S:26][C:22]=5[CH:21]=4)=[N:5][N:6]=3)[N:9]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(S)cc2s1
Reactant: Clc1nnc2ccc(N3CCOCC3)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc2ccc(Sc3nnc4ccc(N5CCOCC5)nn34)cc2s1
Reaction time: 8 h
Yield: 42.5 %

Procedure:
68 mg of sodium borohydride are added to a mixture of 430 mg of 3-chloro-6-(morpholin-4-yl)[1,2,4]triazolo[4,3-b]pyridazine and 510 mg of 1,1-dimethylethyl (6-sulphanyl-1,3-benzothiazol-2-yl)carbamate in 9 cm3 of degassed ethanol and then the reaction is refluxed for 23 h. The suspension is left at 20° C. overnight and is then concentrated to dryness under vacuum. The product is chromatographed by solid deposit on a Merck cartridge of 70 g of silica 15-40 μm, elution being carried out with a gradient of 100% dichloromethane to 95/5 dichloromethane/methanol. 370 mg of 1,1-dimethylethyl (6-{[6-(morpholin-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:7][CH2:6][CH2:5][N:4]([CH:8]([CH3:10])[CH3:9])[CH:1]([CH3:3])[CH3:2])[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: CC(C)N(CCN)C(C)C
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CC(C)N(CCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1)C(C)C

Procedure:
Using 2-(diisopropylamino)-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:14][C:15](=[O:16])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3.[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[C:25]1[CH3:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([N:11]2[CH2:10][CH2:9][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[C:15](=[O:16])[O:14]3)[CH2:13][CH2:12]2)=[O:34])=[C:25]1[CH3:36])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1OC2(CCNCC2)c2ccc(Br)cc21
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Product: Cc1c(C(=O)N2CCC3(CC2)OC(=O)c2cc(Br)ccc23)c2ccccc2n1Cc1ccccc1

Procedure:
Following the general procedure I as described above, the acylation of 5-bromo-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (preparation described in example 1), gave the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3].[NH2:22][C:23]([NH2:25])=[S:24].C(O)C.[ClH:29]>O>[ClH:29].[Si:15]([O:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH2:3][NH:25][C:23](=[NH:22])[SH:24])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: NC(N)=S
Reactant: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1c(CCCNC(=N)S)ccc2ccccc12
Yield: 86 %

Procedure:
A mixture of the product of Example 122 Part C (1.55 g, 0.004 mole), thiourea (0.31 g, 0.004 mole), and absolute ethanol (8.0 mL) was heated at reflux for 7 hours. The cooled solution was treated with water (5.0 mL), cooled to 0°, and treated with concentrated hydrochloric acid (5.0 mL). The precipitated solid was isolated by filtration, rinsed with water and air-dried to provide the title compound (1.45 g, 86%) as a white powder, mp 190°-194°.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[N-:8]=[N+:9]=[N-:10].[Na+]>O>[N:8]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[N+:9]=[N-:10]
Reactant: OCCOCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCOCCO
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of 2-(2-chloro-ethoxy)-ethanol (15 g, 0.12 mol) and sodium azide (15.7 g, 2 equiv.) in H2O (50 ml) was heated at 90° C. for 16 h. The reaction mixture was cooled down to RT then extracted with CH2Cl2 (6×50 ml). The combined organic layers were dried over MgSO4 and filtrated. The solvents were removed under reduced pressure to give azide 2 as a colorless liquid (15 g, 95%). 1H and 13C NMR spectra matched the literature data (Cheng, H. et al. J. Med. Chem. 2005, 48, 645-653).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:24][C:13]2=[C:14]3[C:19](=[C:20](I)[CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26](C)C=O>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:24][C:13]2=[C:14]3[C:19](=[C:20]([C:25]#[N:26])[CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCC1Cc2cc(I)c3[nH]c(=O)ccc3c2O1
Product: CC(C)(C)OC(=O)NCC1Cc2cc(C#N)c3[nH]c(=O)ccc3c2O1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
2-(t-Butoxycarbonyl)aminomethyl-5-iodo-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (610 mg) and cuprous cyanide (134 mg) were dissolved in dimethylformamide (30.5 ml), and stirred at 150° C. for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent=chloroform:methanol=70:1). As a result, 347 mg of 2-(t-butoxycarbonyl)aminomethyl-5-cyano-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one was obtained (73.7%). This compound was recrystallized from a solvent mixture of chloroform-n-hexane to obtain pale yellow powdery crystals (mp.: 200°-202° C. (dec.)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:20])[CH3:19])=[C:3]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Yield: 120.2 %

Procedure:
A solution of intermediate (2) (0.328 mol) and acetic acid, anhydride (0.656 mol) in toluene (1200 ml) was stirred and refluxed for one night. The mixture was evaporated and the product was used without further purification, yielding 139 g (quant.) of N-[4-bromo-2-(3-chlorobenzoyl)phenyl]-acetamide (intermediate 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:21]([OH:23])=[O:22])[CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH2:9][N:8]=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3Cl)[C:6]=2[CH:31]=1.[N+](=[CH2:34])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:21]([O:23][CH3:34])=[O:22])[CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH2:9][N:8]=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:6]=2[CH:31]=1
Reactant: C=[N+]=[N-]
Reactant: CN(C)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Product: COC(=O)C(CCCN(C)C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 7-chloro-2-[[1-carboxy-4-(dimethylamino)butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-4-(dimethylamino)butylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A mixture of 4-(methylamino)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol), dihydrofuran-3-one (145 μl, 161 mg, 1.87 mmol), 4 Å powdered molecular sieves (550 mg) and DIPEA (323 μl, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an oil (132 mg, 50%). 1H NMR (CDCl3, 300 MHz): δ 4.33-4.05 (m, 2 H); 4.01-3.91 (m, 1 H); 3.90-3.73 (m, 2 H); 3.68-3.48 (m, 1 H); 3.47-3.23 (m, 1 H); 2.72-2.56 (m, 2 H); 2.21 (s, 3 H); 2.11-1.94 (m, 1 H); 1.93-1.78 (m, 1 H); 1.76-1.63 (m, 2 H); 1.76-1.63 (m, 1 H); 1.54-1.46 (m, 2 H); 1.46 (s, 9 H).
Reaction SMILES: C([SiH](C)C)(C)(C)C.C(N(CC)CC)C.C([O:22][C:23]([CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[C:44]([CH:46]([CH3:48])[CH3:47])[CH:45]=2)[O:42][C:41]([CH3:50])([CH3:49])[CH2:40][C:39]3([CH3:52])[CH3:51])=[O:35])=[CH:29][CH:28]=1)=[O:24])C1C=CC=CC=1.C(O)(=O)C>ClCCl.O.O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([CH:25]=[CH:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[C:44]([CH:46]([CH3:47])[CH3:48])[CH:45]=2)[O:42][C:41]([CH3:50])([CH3:49])[CH2:40][C:39]3([CH3:51])[CH3:52])=[O:35])=[CH:31][CH:32]=1)([OH:24])=[O:22]
Reactant: CC(C)c1cc(C(=O)Oc2ccc(C=CC(=O)OCc3ccccc3)cc2)cc2c1OC(C)(C)CC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[SiH](C)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)Oc2ccc(C=CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
A suspension of t-butyldimethyl silane (0.3 mL, 1.85 mmol), palladium(II)acetate (0.013 g, 0.06 mmol) and triethyl amine (0.03 mL, 0.2 mmol) in anhydrous dichloromethane (2 mL) under argon was treated with a solution of 8-isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4-(2-benzyloxycarbonyl-vinyl)-phenyl ester (Intermediate 35, 0.063 g, 0.123 mmol) in dichloromethane (2 mL) and the resulting reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with water and extracted with diethyl ether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was subjected to flash column chromatography to yield an intermediate that was treated with acetic acid (1 mL) in water (0.3 mL) and tetrahydrofuran (0.3 mL) at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was subjected to preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title compound (0.007 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=2[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])=[C:5]([F:25])[CH:4]=1)#[CH:2]>C1COCC1.CO.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=2[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])=[C:5]([F:25])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Reaction time: 14.8 h

Procedure:
A mixture of the product of Example 7A, 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxy-ethoxy)benzamide (11.0 g, 31.40 mmol), Pd—C (10%, 1.0 g) in THF (100 mL) and MeOH (100 mL) was subject to hydrogenation (25 psi) for 14.8 hrs (The reaction was followed by HPLC until all SM peak disappeared.). The mixture was filtered through Celite® and the filtrates were concentrated to give a light yellow solid. The solid was recrystallized from heptane-EtOAc to give the title compound as a white solid, 6.97 g, 62.8%, mp 112-112.5° C. Anal.: C, 58.00 (57.63); H, 4.99 (4.84); N, 7.59 (7.91); F, 15.55 (16.09).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].C1COCC1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:22]([NH:24][CH:25]1[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:35][C:36]#[N:37])[C:26]1=[O:38])=[O:23])=[CH:16]2>CO>[NH2:37]/[C:36](=[N:2]\[OH:3])/[CH2:35][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH:25]([NH:24][C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([Cl:12])=[CH:21][CH:20]=3)=[O:23])[C:26]1=[O:38]
Reactant: NO
Reactant: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N/C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21)=N\O
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
A solution hydroxylamine hydrochloride (147 mg, 2.11 mmol) in MeOH (4 mL) was added to a solution of sodium methoxide in methanol (0.5 M, 4.2 mL, 2.1 mmol) that had been further diluted with methanol (4 mL). After stirring for 10 minutes, THF (4 mL) was added followed by portionwise addition of 5-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Method 11, 400 mg, 1.06 mmol). The reaction mixture was stirred at ambient temperature for 18 h, partitioned between EtOAc (80 mL) and diluted brine (80 mL), filtered and the layers of the filtrate separated. The organic phase was dried (Na2SO4) and the volatiles removed under reduced pressure to give the title material (191 mg, 44%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:6][C:7](=[O:21])[C@H:8]([CH3:20])[NH:9]C(OCC1C=CC=CC=1)=O)[CH3:2].C(OCC)C.[BrH:35]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH:6][C:7](=[O:21])[C@H:8]([CH3:20])[NH2:9])[CH3:2].[BrH:35]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reaction time: 1 h

Procedure:
Synthesis of p-hydroxybenzoyl-L-alanyl-L-phenylalanine: 0.1 g (0.1 mol) of triethylamine was added to a suspension of 23.0 g (0.1 mol) of L-phenylalanine ethyl ester·HCl in 500 ml of dichloromethane, and to this mixture in an ice bath was added 22.3 g (0.1 mol) of carbobenzoxy-L-alanine, and then 19.2 g (0.1 mol) of 1-ethyl-3(3-dimethyaminopropyl) carbodiimide·HCl was added to the mixture. This mixture was stirred for three hours. This reaction mixture was washed with a 0.1% aqueous solution of Na2CO3 three times and with a 0.1 N HCl solution three times, and then with distilled water three times. Thereafter, the mixture was dried over anhydrous sodium sulfate, and dichloromethane was removed from the mixture under reduced pressure to obtain carbobenzoxy-L-alanyl-L-phenylalanine ethyl ester. This ester was dissolved in 260 ml of 25% HBr in glacial acetic acid, and this solution was stirred for one hour. To this solution was added 5 l of absolute ethyl ether to produce a precipitate. The precipitate was filtered and washed with ethyl ether to obtain L-alanyl-L-phenylalanine ethyl ester·HBr.
Reaction SMILES: CO[C:3]([CH:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7](=O)(=O)[N:6]1[CH3:18])=[O:4].[NH2:19][C:20]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[O:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[CH3:18][N:6]1[CH:5]([C:3]([NH:19][C:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH:21]=2)=[O:4])[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1
Reactant: Nc1coc2ccccc2c1=O
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1Sc2ccccc2C(=O)C1C(=O)Nc1coc2ccccc2c1=O
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A 500 ml round flask, which is connected to a distillation head and a condenser, is charged with 3.5 g (0.013 mole) of 2-methyl-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide, 2.1 g (0.013 mole) of 3-amino-4-oxo-4H-1-benzopyrane and 100 ml of dry xylene. Then nitrogen gas is blown into the resulting suspension for 5 minutes. The reaction mixture is subsequently subjected to a slow distillation lasting 15 hours, in the course of which procedure complete solution is attained after heating for only 10 minutes. The solvent is replaced every 2 hours. The reaction mixture is then cooled to 50° C. The precipitate which has formed is collected by filtration, washed with ethanol and dried, yielding 2-methyl-3,4-dihydro-4-oxo-N-(4-oxo-4H-1-benzopyran-3-yl)-2H-1,2-benzothiazine-3-carboxamide, 1,1-dioxide in the form of brownish crystals with a melting point of 290° C. (with decomp.).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1.O>ClCC(Cl)(Cl)Cl>[Br:2][CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1
Reactant: BrP(Br)Br
Reactant: OCC1COc2ccccc2O1
Agent: ClCC(Cl)(Cl)Cl
Solvent: O
Product: BrCC1COc2ccccc2O1

Procedure:
0.11 mole of phosphorus tribromide in 500 ml of tetrachloroethane was slowly added to 0.3 mole of 2-hydroxymethyl-1,4-benzodioxane and the mixture was warmed at 80°-90° C. for 2 hours. After the mixture had been cooled, it was poured into water, the organic layer was separated off, washed with dilute sodium hydroxide solution and water, dried and concentrated and the residue was distilled. Boiling point: 102°-103° C. (1.3 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]([OH:14])=[O:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C>>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH2:11][C:12](=[O:13])[O:14][C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1C(=O)O
Solvent: CC(=O)Cl
Product: O=C1Cc2ccc(Br)cc2C(=O)O1
Temperature: 25 °C

Procedure:
A oven-dried 10 mL round-bottomed flask containing a stirring bar was charged with 5-bromo-2-(carboxymethyl)benzoic acid (500 mg, 1.93 mmol). Freshly distilled acetyl chloride (5.0 ml) was added, the flask was fitted with a condenser and the reaction mixture was refluxed under an argon atmosphere for 16 h. The reaction was then cooled to room temperature and the excess acetyl chloride was removed in vacuo. The solid obtained was triturated with Et2O (5.0 mL), filtered and dried to give 7-bromoisochroman-1,3-dione as an off white solid (404.7 mg, 87%). Spectral data for this compound were consistent with those in the literature. M.p. 176-178° C. (lit.7 M.p. 171-173° C.); 1H NMR (400 MHz, DMSO-d6): δ=8.13 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 4.23 (s, 2H).