Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1>O1CCCC1.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cnc(Cl)c(C(F)(F)F)c1

Procedure:
2-Chloro-5-nitro-3-(trifluoromethyl)pyridine 4 (1.57 g, 6.93 mmol) is dissolved in tetrahydrofuran (THF) (10 ml) and added to a suspension of Raney-Ni (200 mg) in THF (20 ml). Hydrogen gas is slowly bubbled through the stirred solution for 24 hours using a balloon. The mixture is filtered through Celite® (available from World Minerals, Inc., Lompoc, Calif.) and the solvent is removed under reduced pressure to obtain 6-chloro-5-(trifluoromethyl)pyridin-3-amine 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH2:13][CH2:14][CH2:15]O)[C:11](=[S:17])[NH:10][CH2:9]2)=[CH:4][CH:3]=1>ClCCCl.CS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]3[C:11]([S:17][CH2:15][CH2:14][CH2:13]3)=[N:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCCN1C(=S)NCC1c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: ClCCCl
Product: Fc1ccc(C2CN=C3SCCCN32)cc1

Procedure:
Dissolve 4.9 g of the product of Step C in 30 ml of 1,2-dichloroethane and 5.6 g of methane sulfonic acid (98%). Reflux the mixture for one (1) hour then remove the solvent in vacuo. Add 80 ml of ice-water then adjust to an alkaline pH with 10% sodium hydroxide solution. Extract with methylene chloride, dry the extract over sodium sulfate and concentrate to an oil which crystallizes from petroleum ether M.P. 69°-71° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH2:67][NH2:68])[CH:62]=1>CN(C)C=O>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:68][CH2:67][C:63]3[CH:62]=[N:61][CH:66]=[CH:65][CH:64]=3)=[CH:26][CH:25]=2)=[N:19][C:18]=1[CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CCCOC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CCCOC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 66.5 %

Procedure:
A solution of 4-[4-[3-([1-[(tert-butoxy)carbonyl]piperidin-4-yl]oxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoic acid (1.0 g, 2.25 mmol, 1.00 equiv), EDCI (560 mg, 2.92 mmol, 1.30 equiv), HOBt (400 mg, 2.96 mmol, 1.32 equiv), triethylamine (800 mg, 7.91 mmol, 3.51 equiv) and pyridin-3-ylmethanamine (480 mg, 4.44 mmol, 1.97 equiv) in N,N-dimethylformamide (30 mL) was stirred at 35° C. overnight. The product was precipitated by the addition of 50 mL of ice/water. The solid was collected by filtration, washed with 3×30 mL of water and dried in a vacuum oven to give 0.8 g (67%) of tert-butyl 4-[3-(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)propoxy]piperidine-1-carboxylate as a white solid LC-MS-PH: (ES, m/z): 535 [M+H]+, 435, 367, 352, 239, 102.
Reaction SMILES: C[O:2][C:3]1[CH:28]=[C:27]([C:29]2[S:30][C:31]3[CH2:37][CH2:36][CH2:35][CH2:34][C:32]=3[N:33]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>C(Cl)Cl>[OH:2][C:3]1[CH:28]=[C:27]([C:29]2[S:30][C:31]3[CH2:37][CH2:36][CH2:35][CH2:34][C:32]=3[N:33]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3O)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[2-methoxy-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 164, 400 mg, 0.787 mmol) dissolved in CH2Cl2 (10 mL) was added AlCl3 (511.2 mg, 3.834 mmol), and then the solution was cooled to 0° C. Ethanethiol (0.284 mL, 3.834 mmol) was added dropwise to the solution which was stirred at 0° C. for 3 h. The reaction mixture was poured onto ice-water (20 mL) with vigorous stirring. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by preparative HPLC, giving the desired product as a white solid (180.0 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.28 (d, 1H), 7.20 (dd, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.79 (s, 1H), 6.69 (dd, 1H), 4.07-4.18 (m, 6H), 3.39 (m, 1H), 2.72 (dd, 6H), 2.09-2.20 (m, 5H), 1.80-1.59 (m, 5H), 1.18 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.Br[C:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([N:24](CC3C=CC(OC)=CC=3OC)[C:25]3[S:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH3:41])[CH:13]=1>>[CH3:1][C:2]1[C:6]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[S:29][N:28]=[CH:27][N:26]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[N:14]([CH3:41])[CH:13]=2)=[C:5]([CH3:10])[O:4][N:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cc1noc(C)c1-c1cn(C)c2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3,5-dimethylisoxazol-4-yl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(3,5-dimethylisoxazol-4-yl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.13 (s, 3 H) 2.31 (s, 3 H) 3.89 (s, 3 H) 7.41-7.49 (m, 2 H) 7.64 (s, 1 H) 7.90-7.93 (m, 1 H) 7.98 (s, 1 H). m/z (ESI) 389.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)[CH3:2].Br[CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[Li+].[Br-].[H-].[Na+]>>[CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)cc(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Product: CCc1nc(-c2ccccc2)cc(=O)n1CCOc1ccc(C=O)cc1
Yield: 44.2 %

Procedure:
The title compound (2.0 g, 44%) was prepared from 2-ethyl-4-phenyl-1,6-dihydro-6-pyrimidone (2.6 g, 13.0 mmol), 4-[2-bromoethoxy]benzaldehyde (2.97 g, 13.0 mmol) and LiBr (2.59 g, 29.9 mmol) in the presence of NaH as base (0.4 g, 16.9 mmol) by a similar procedure to that described in preparation 1.
Reaction SMILES: C([O-])(=O)C.[Mn+2:5].C([O-])(=O)C.[OH:10][C:11]1[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=1[C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])=[O:14]>C(O)C>[OH:10][C:11]1[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=1[C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])=[O:14].[Mn:5]
Reactant: [Mn+2]
Agent: CC(=O)[O-]
Agent: O=C(NCCNC(=O)c1ccccc1O)c1ccccc1O
Solvent: CCO
Product: [Mn]

Procedure:
1.86 g of manganese(II) acetate (tetrahydrate) were added in portions to a solution of 21.6 g of N,N'-bis-(2-hydroxybenzoyl)-1,2-diaminoethane, [prepared in accordance with: Y. A. Ibrahim, A. H. M. Elwahy, Synthesis 503-508 (1993)] in 30 ml of ethanol and the mixture was heated at reflux for three hours. After the reaction solution had been cooled, the precipitate was separated off, washed with ethanol and dried; this gave 2.88 g of N,N'-bis-(2-hydroxybenzoyl)-1,2-diaminoethane-manganese complex.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:7][C:8]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>>[OH:7][C:8]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: c1ccccc1
Reactant: CCc1cccc(C(=O)Cl)c1O
Product: CCc1cccc(C(=O)c2ccccc2)c1O
Yield: 58.1 %

Procedure:
This compound (44.67 g) was prepared from benzene (172 g, 2.2 mole) and 2-hydroxy-3-ethyl benzoic acid chloride (63.15 g, 0.34 mole), using the same conditions as in Example 4. The b.p. of the compound was 123°-126° C./0.14 mm, ηD22 1.6081, γ max. (film) 1630 cm-1. The same compound was obtained using the method of Example 2.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.C([N:13]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:14]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[C:20]2[C:15]=1[C:16](=[O:34])[C:17]([C:29]([O:31]CC)=[O:30])=[CH:18][N:19]2[CH:26]1[CH2:28][CH2:27]1)(=O)C>O>[CH2:35]([NH:13][C:14]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[C:20]2[C:15]=1[C:16](=[O:34])[C:17]([C:29]([OH:31])=[O:30])=[CH:18][N:19]2[CH:26]1[CH2:27][CH2:28]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(N(Cc3ccccc3)C(C)=O)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Yield: 81.1 %

Procedure:
Twenty milliliters of a mixture of conc. sulfuric acid, glacial acetic acid and water (1:8:6) was added to 4.4 g of ethyl 5-(N-acetylbenzylamino)-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, and the mixture was heated under reflux for 6 hours. After cooling, water was added to the reaction mixture, and the crystals were collected by filtration and successively washed with water and ethanol. The crystals were recrystallized from chloroform/ethanol to give 3.0 g of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 214°-216° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([F:11])=[C:6]([CH2:12][NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([F:21])[CH2:18][N:17]2[C:22](=[O:36])[CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33](=[O:35])[CH3:34])=[CH:25]2)=[O:15])[CH:5]=1.O[Li].O>C1COCC1.CO.O>[C:33]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]([CH2:23][C:22]([N:17]2[CH2:18][C@H:19]([F:21])[CH2:20][C@H:16]2[C:14]([NH:13][CH2:12][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([Cl:10])[C:7]=2[F:11])[C:3]([OH:37])=[O:2])=[O:15])=[O:36])[CH:25]=1)(=[O:35])[CH3:34]
Reactant: COC(=O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2C(=O)Cn2cc(C(C)=O)c3ccccc32)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cc(C(=O)O)cc(Cl)c2F)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-[({(2S,4R)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carbonyl}-amino)-methyl]-5-chloro-4-fluoro-benzoic acid methyl ester Example 523 (35.0 mg, 0.066 mmol) in THF-MeOH—H2O (ratio 2:1:1; 1 mL) was added LiOH.H2O (2.76 mg, 0.066 mmol). The reaction mixture was stirred at RT for 4 h. Volatiles were evaporated and the residue was taken up in water, Acidification to pH=1 by addition of a 6M HCl solution formed a precipitate which was filtered and dried at 50° C. in vacuo for 1 h to afford the title compound as a solid. MS: 518.0 [M+H]+; tR (HPLC conditions c): 4.26 min.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:7]=1.[CH:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=1)[CH:19]=[O:20])=[O:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:8]([C:6]1[N:7]=[C:3]([CH2:2][O:22][C:17]2[CH:16]=[CH:15][C:14]([CH:12]=[O:13])=[CH:21][C:18]=2[CH:19]=[O:20])[S:4][CH:5]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: CC(C)(C)c1csc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(COc2ccc(C=O)cc2C=O)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
A mixture of 2-bromomethyl-4-tert-butylthiazole (1.05 g), 5-formyl-2-hydroxybenzaldehyde (0.74 g), potassium carbonate (0.89 g) and potassium iodide (small mass) in N,N-dimethylformamide was stirred at 50° C. for 5 hours. After being cooled, the resulting solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-(2,4-diformylphenoxymethyl)thiazole (1.0 g).
Reaction SMILES: [NH:1]([C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]1)=[S:4])[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[S:25][CH:26]=[C:27]([C:30]([CH3:32])=O)[C:28]=2[OH:29])[CH:20]=[CH:21][C:22]=1[Cl:23].CN(C)C=O.Cl>O>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[S:25][CH:26]=[C:27]([C:30](=[N:2][NH:1][C:3]([N:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:10]3)=[S:4])[CH3:32])[C:28]=2[OH:29])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: COC(=O)CN1CCN(C(=S)NN)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1CCN(C(=S)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)CC1
Yield: 18 %

Procedure:
Methyl 2-[4-hydrazinothiocarbonylpiperazin-1-yl]acetate (356 mg, 1.52 mmol) prepared in Reference Synthetic Example 10 and 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (147 mg, 0.512 mmol) were stirred with dimethylformamide (4 mL) and concentrated hydrochloric acid (42.6 μL, 1.52 mmol) at room temperature to 60° C. for 5 days. After addition of water, the reaction mixture was filtered, and the filter cake was dried. The filter cake was mixed with chloroform and filtered, and the filtrate was concentrated then mixed with chloroform, isopropyl alcohol and n-hexane and filtered. The filter cake was dried to give the crude desired product (yield 18%). The crude product was used directly for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])=[O:17])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Reactant: CCOC(=O)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.26 mmol) in 10 ml of anhydrous THF were added HATU (118 mg, 0.31 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol). The mixture was heated at 60° C. for 5 minutes, followed by addition of ethyl 4-aminobutyrate hydrochloride (67 mg, 0.40 mmol). The mixture was stirred for another 10 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate as white solid. Yield: 150 mg, 100%.
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7]([C:9]([NH:11][CH:12]([C:14]2[N:19]=[N:18][C:17]([NH:20][C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)=[N:16][CH:15]=2)[CH3:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:13][C:12]1[N:11]=[C:9]([C:7]2[NH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:19]2[C:14]=1[CH:15]=[N:16][C:17]([NH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)=[N:18]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc([N+](=O)[O-])[nH]3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc([N+](=O)[O-])[nH]4)n3n2)cc(OC)c1OC
Yield: 49.6 %

Procedure:
In a similar manner as described for Example 9, 5-nitro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-pyrrole-2-carboxamide (Intermediate 34) (201 mg, 0.45 mmol), and 1,2,4-triazole (190 mg, 2.72 mmol) in pyridine (10 mL) and phosphorous oxychloride (0.13 mL, 1.36 mmol) gave 5-methyl-7-(5-nitro-1H-pyrrol-2-yl)-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (95 mg, 49%) as a yellow solid. 1H NMR (DMSO-d6): δ13.04 (s, 1H), 9.63 (s, 1H), 9.25 (s, 1H), 7.98 (dd, J=3.30 and 1.65 Hz, 1H), 7.57 (t, J=2.01 Hz, 1H), 7.05 (s, 2H), 3.74 (s, 6H), 3.65 (s, 3H), 2.54 (s, 3H). MS m/z 425 (M+1).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].CCN(C(C)C)C(C)C.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>Cl.O1CCOCC1.O>[CH2:24]([S:26]([N:6]1[CH2:5][C:4](=[CH:3][C:1]#[N:2])[CH2:7]1)(=[O:28])=[O:27])[CH3:25]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 3-(cyanomethylidene)azetidine-1-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HCl in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to −10° C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5-70% EtOAc/heptane). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C7H10N2O2S [M+H]+: 187. Found: 187.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:5]=1.[OH-].[Na+]>C1COCC1>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C:11]3=[O:15])[CH:7]=2)[C:3]([OH:23])=[O:2])[CH2:17][CH2:18]1
Reactant: COC(=O)c1cc(N2CCN(C)CC2)cc(N2CCCC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(C(=O)O)cc(N3CCCC3=O)c2)CC1
Reaction time: 14 h
Yield: 138.2 %

Procedure:
To a solution 3-(4-methyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B115) (296 mg, 0.93 mmol, 1 equiv) in THF (10 ml) was added 1N aqueous NaOH solution (1.8 ml, 1.8 mmol, 2 equiv). The resulting mixture was stirred for 14 h then concentrated in vacuo. The residual solid was extracted thoroughly with MeOH and the extracts were concentrated in vacuo to give 3-(4-methyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A115) (390 mg, 138%) as an off white solid. [M+H]+=304.0, RT=1.64 min
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[C:7]2[OH:20])([O-:3])=[O:2].[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](Cl)=[O:25])[CH3:22].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](=[O:25])[O:20][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[CH3:22]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(O)c2c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1cc(-c2ccccc2)nc2ccc([N+](=O)[O-])cc12
Yield: 77.7 %

Procedure:
The procedure is as in Example 70, starting with 6-nitro-2-phenyl-4-hydroxyquinoline (6 g) in tetrahydrofuran (60 cc), N,N-diethylcarbamoyl chloride (6.1 g), triethylamine (6.3 cc) and 4-dimethylaminopyridine (1.3 g). The residue is recrystallized twice in ethyl acetate. 6-Nitro-2-phenyl-4-quinolyl diethylcarbamate (6.4 g), m.p. 40° C., is thereby obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1>>[C:4]1([CH3:9])[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:12]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])[CH2:11][CH2:10][CH2:14][O:13]1
Reactant: Cc1ccccc1Br
Reactant: C1CCOC1
Agent: [Mg]
Product: Cc1ccccc1C1(c2ccccc2C)CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium turnings (33 g) in dry THF (150 mL) was added 2-bromotoluene (4 ml ). The reaction mixture was heated to reflux and an exotermic reaction started. The heating mantle was removed and 2-bromotoluene (137 mL) in dry THF (500 mL) was added dropwise over an hour at reflux temperature (exotermic reaction). The resulting reaction mixture was boiled under reflux for additionally 1.5 hrs. The mixture was cooled to room temperature and excess Mg was filtered off in an inert atmosphere. A solution of 4-chlorobutyric acid methylester (56.4 g) in dry THF (200 mL) was added dropwise at 20° C. The reaction mixture was stirred at room temperature for additionally 1 hr and was then poured into an aqueous solution of NH4Cl and ice. The organic phase was worked-up according to the standard workup procedures. After evaporation of the organic solvent the residue was suspended in a mixture of n-heptane/ethyl acetate=4/1. Filtration of the resulting crystals afforded 2,2-di-(2-tolyl)-tetrahydrofuran 33a (32.5 g). 1H NMR (CDCl3) δ1.96 (s,6H), 1.96-2.10 (m,2H), 2.57 (t,2H), 4.02 (t,2H), 7.00-7.07 (m,2H), 7.07-7.23 (m,4H), 7.57-7.65 (m,2H)
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:8][CH:9]=1)=[O:4].[Li+].[I-].Cl>N1C=CC=CC=1>[C:3]([C:5]1[N:6]=[C:7]([CH2:10][CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:8][CH:9]=1)([OH:4])=[O:2]
Reactant: CCOC(=O)CC(Cc1nc(C(=O)OC)co1)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCOC(=O)CC(Cc1nc(C(=O)O)co1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
A solution of ethyl (±)-4-(4-methoxycarbonyl-1,3-oxazol-2-yl)-3-phenylbutanoate (267 mg, 0.84 mmole) and LiI (338 mg, 2.52 mmole) in pyridine (5 mL) was heated to reflux. After 18 hr, the mixture was cooled to RT, poured into 10% HCl (150 mL), then extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the title compound (205 mg, 80%) as a white solid: MS (ES) m/e 304 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:21])[CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][C:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:12][CH:13]=2)=[O:19])=[CH:13][CH:12]=1)=[O:7])[CH2:10][CH3:11]
Reactant: O=C(Cl)CCCC(=O)Cl
Reactant: CCCOC(=O)c1ccc(O)cc1
Product: CCCOC(=O)c1ccc(OC(=O)CCCC(=O)Oc2ccc(C(=O)OCCC)cc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 18 g of propyl p-hydroxybenzoate and 8.5 g of glutaric acid dichloride to yield di(p-propyloxycarbonylphenyl)glutarate, m.p. 74°-75° C., as white crystals.