Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1>C1COCC1.O.[Zn+2].[Br-].[Br-]>[CH2:3]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([O:8][CH3:7])=[O:17])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CCBr
Reactant: COC(=O)c1cccc(Br)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
In an oven-dried round bottom flask Mg turnings (1.13 g, 46.6 mmol) are suspended in THF (1 mL). 1-Bromo-3-methylbutane (6.37 g, 46.5 mmol) is carefully added while the mixture is initially heated to reflux. The mixture is stirred for approximately 30 min until the Mg has dissolved. The mixture is then added to a cold (5° C.) solution of ZnBr2 (10.47 g, 46.5 mmol) in THF (80 mL). The thick suspension is stirred at 0° C. for 20 min before it is cooled to −75° C. 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (184 mg, 0.225 mmol) followed by methyl-3-bromobenzoate (5.0 g, 23.3 mmo) is then added. The mixture is warmed to rt and stirred for 24 h. The reaction mixture is diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 20:1 to give methyl 3-isobutyl-benzoate (4.34 g) as a colourless oil. This material is dissolved in methanol (50 mL) and 2 N aq. LiOH (10 mL) and stirred at rt for 16 h. The mixture is acidified by adding 1 N aq. HCl and extracted with EA. The org. extracts are dried over MgSO4, filtered and evaporated to give 3-isobutyl-benzoic acid (3.84 g) as a colourless oil; LC-MS: tR=0.91 min; 1H NMR (CDCl3): δ 0.87 (d, J=6.7 Hz, 6H), 1.77-1.94 (m, 1H), 2.48 (d, J=7.0 Hz, 2H), 7.29-7.35 (m, 2H), 7.86 (s, 1H), 7.88-7.94 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:16])=[C:8]2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CCO>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:16])=[C:8]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)c2ccccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)n(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 32 h

Procedure:
ethyl 1-(4-chlorobenzyl)-3-methyl-1H-indole-2-carboxylate (480 mg, 1.46 mmol) was dissolved in EtOH (15 mL) and 10% aq. NaOH was added (6 mL). The reaction was allowed to stir at rt for 32 h, at which time as much solvent was stripped off as possible, water was added, and the mixture cooled in an ice bath. The mixture was acidified with concentrated HCl and the precipitate collected over a filter. The title compound was obtained as a white powder that was not purified or characterized further. (Yield: 430 mg, 1.435 mmol, 98%)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:20]([NH:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26])(=[O:22])[CH3:21].CC[O-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[C:20]([NH:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][S:26][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])(=[O:22])[CH3:21]
Reactant: O=C(O)CCCBr
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@@H](CSC(=O)CCCBr)C(=O)O
Reaction time: 1 h

Procedure:
A solution of 4-bromobutyric acid (5.1 g, 30.6 mmoles) and 1,1′-carbonyldiimidazol (5.61 g, 34.6 mmoles)) in chloroform (50 ml) is left at room temperature under stirring for 1 hour. To the reaction mixture N-acetyl cysteine (5 g, 30.6 mmoles) dissolved in N,N-dimethylformamide (5 ml) and sodium ethylate (50 mg) is added under stirring. After 24 hours the solution is washed with HCl 1% and brine, the organic phase is anhydrified with sodium sulphate and evaporated at reduced pressure. The obtained crude product is purified by chromatography on silica gel column, eluting with ethyl acetate/chloroform 7/3. N-acetyl-S-(4-bromobutyroyl) cysteine is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([N:14](CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:12]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: OCCCc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: N#CCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(3-Bromophenyl)propane-1-ol (0.59 g), triethylamine (0.57 mL) and 4-dimethylaminopyridine (0.03 g) were dissolved in dichloromethane (6.8 mL), p-toluenesulfonyl chloride (0.62 g) was added, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was partitioned between ethyl acetate (35 mL) and 10% aqueous citric acid (10 mL) The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylsulfoxide (9.1 mL), sodium cyanide (0.17 g) was added, and the resulting mixture was stirred at 50° C. for 24 hours. The reaction mixture was partitioned between ethyl acetate (55 mL) and water (30 mL) The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.59 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CC(C)COC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OCC(C)C)C3)cc1

Procedure:
Compound er was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with isobutyl chloroformate. LC-MS: m/z=+497 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([F:27])[C:25]=1[F:26].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:22]1[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS No. 183890-36-0, 7.5 g) in THF (200 mL), 3,4,5-trifluorophenylmagnesium bromide (0.35 M solution in diethyl ether, 100 mL) was added dropwise at −40° C., and the reaction solution was stirred at room temperature for six hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 4.0 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a mixture of ethyl 3-[({4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]phenyl}carbonyl)amino]propanoate (273 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (253 mg, 97%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]3[N:10]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH:11]=[C:12](I)[C:7]3=[CH:6][C:5]=2[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH2:3][CH2:2]1.[F:43][C:44]1[CH:45]=[C:46]([CH:64]=[CH:65][CH:66]=1)[CH2:47][N:48]1[C:52]([CH3:53])=[C:51](B2OC(C)(C)C(C)(C)O2)[C:50]([CH3:63])=[N:49]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[CH:1]1([C:4]2[N:9]=[C:8]3[N:10]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH:11]=[C:12]([C:51]4[C:50]([CH3:63])=[N:49][N:48]([CH2:47][C:46]5[CH:64]=[CH:65][CH:66]=[C:44]([F:43])[CH:45]=5)[C:52]=4[CH3:53])[C:7]3=[CH:6][C:5]=2[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)c(C4CC4)nc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)c(C4CC4)nc32)cc1
Yield: 90.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(6-cyclopropyl-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 47) (115 mg, 0.161 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (81.53 mg, 0.24 mmol) in sodium carbonate (51.9 mg, 0.483 mmol), Pd(PPh3)2Cl2 (5.6 mg, 0.008 mmol), 1,2-dimethoxyethane/water (10/2 ml) to afford 113 mg (89% yield) of titled compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:11]([OH:13])=O)=[C:7]([CH3:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][CH3:62])=[CH:57][CH:56]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1.C(N(CC)CC)C>ClCCl>[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N:61]([CH3:62])[C:11]([C:6]5[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:9][S:8][C:7]=5[CH3:10])=[O:13])=[CH:59][CH:60]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: CC(=O)Nc1csc(C)c1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1csc(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
A mixture of 4-acetylamino-2-methyl-thiophene-3-carboxylic acid (45 mg, 0.17 mmol) in dichloromethane (3 mL) at 25° C. was treated with triphenylphosphine (71 mg, 0.22 mmol). This mixture was cooled to 0° C. and then was treated with N-chlorosuccinimide (36 mg, 0.22 mmol). This mixture was stirred at 0° C. for 15 min and then was warmed to 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (75 mg, 0.17 mmol). This solution was then cooled to 0° C. and was treated with triethylamine (38 μL, 0.22 mmol). The reaction was warmed to 25° C. and was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 4-acetylamino-2-methyl-thiophene-3-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (27.8 mg, 26.1%): EI-HRMS m/e calcd for C32H31N6O4SF (M+Na)+ 637.2004, found 637.2018.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:42][C:39]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4F)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 582.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:24][O:25]/[N:26]=[C:27]1/[C@@H:28]([NH2:33])[CH2:29][CH2:30][CH2:31][CH2:32]/1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][O:25]/[N:26]=[C:27]1/[C@@H:28]([NH:33][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[O:21])[CH2:29][CH2:30][CH2:31][CH2:32]/1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CO/N=C1\CCCC[C@@H]1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C1\CCCC[C@@H]1NC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To a solution of 0.050 g 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid in 2.0 ml dimethylformamide was added 0.030 g (S)-2-amino-cyclohexanone-(E)-O-methyl-oxime hydrochloride, 0.053 g TBTU and 0.097 g N,N-diisopropyl ethyl amine and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under high vacuum and the residue was purified by chromatography on silica gel with a gradient of heptane to ethyl acetate to yield 0.045 g of the title compound as colorless oil. MS (EI): 465.1 (M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([NH2:30])=[CH:28][C:27]([N+:31]([O-])=O)=[CH:26][C:25]=3[CH3:34])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:45][O:46][C:47](=[O:55])[CH2:48][CH2:49][CH2:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl>[CH3:45][O:46][C:47](=[O:55])[CH2:48][CH2:49][CH2:50][CH2:51][C:52](=[O:53])[NH:30][C:29]1[CH:28]=[C:27]([NH2:31])[CH:26]=[C:25]([CH3:34])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:37])=[NH:9])[S:11][C:12]=2[S:35][CH3:36])(=[O:17])=[O:16])[CH:19]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2N)c1
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(=O)Nc1cc(N)cc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of {[4-(6′-amino-2′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 130 mg, 0.23 mmol), and Et3N (192 μL, 1.38 mmol) in DCM (5 mL) at 0° C. was added 5-chlorocarbonyl-pentanoic acid methyl ester (53 mg, 0.29). After stirring for 1 h, the solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. The solution was concentrated and the residue was purified by SiO2 flash column chromatography to yield 36 mg of the amide product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4Cl (1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture was vigorously stirred at 80° C. for 30 min. The solution was filtered through a 0.22 μm filter and was then partitioned between EtOAc (70 mL) and water (20 mL). The layers were separated, the organic solution was dried over sodium sulfate, and the solution was concentrated to give the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ 8.0 (m, 2H), 7.84 (s, 1H), 7.96 (m, 2H), 7.59 (t, 1H, J=7.7 Hz), 7.43 (m, 1H), 7.23 (br s, 1H), 6.86 (br s, 1H), 6.45 (br s, 1H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.60 (m, 3H), 2.35 (m, 2H), 2.00 (m, 2H), 1.90 (s, 3H), 1.67 (m, 2H), 1.90 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:6]=1[CH2:7][N:8]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[F:17][C:2]([F:1])([F:16])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:6]=1[CH2:7][NH2:8]
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1OCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)-5-chlorobenzyl azide (1.76 g, 6.63 mmol) in THF (20 mL) was added triphenylphosphine (2 g, 7.63 mmol). After stirring at room temperature for 2 h, water (0.5 mL) was added and the reaction mixture then heated at 65° C. for 2 h. After cooling back to room temperature the solvents were removed under reduced pressure. Following azeotroping with benzene, the residue was dissolved in ether and treated with an excess of cold 1M HCl in ether. The hydrochloride salt of the title compound was filtered off and washed well with ether and dichloromethane. Drying gave a white powder: 1H NMR (CD3OD) δ7.46 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 4.70 (q, J=8.4 Hz, 2H), 4.14 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[Se](=O)=[O:19]>C(Cl)Cl>[C:12]1([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([CH:1]=[O:19])=[CH:3][CH:4]=3)[N:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2ccc(-c3ccccc3)nc2c1
Solvent: ClCCl
Product: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 160 °C

Procedure:
A mixture of 7-methyl-2-phenylquinoline (2.49 g, 11.4 mmol) and selenium dioxide (1.92 g, 17.3 mmol, 1.5 eq.) is heated to 160° C. (bath temp.) for 22 h. The cooled melt is suspended in CH2Cl2 with the aid of sonication and filtered through Celite and then through a plug of silica gel. This effectively removes the red color and the major lower spots. The material thus obtained is crystallized from hexanes/CHCl3, yielding a pale beige solid, mp. 108° C. The mother liquor is concentrated and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with hexanes:CH2Cl2 1:1 (1-25)→1:3 (26-53)→CH2Cl2 (54-73)→3% EtOAc in CH2Cl2 (74-85)] to obtain as pale yellow solid, mp. 109° C. 1H NMR (CDCl3, 400 MHz) δ 7.48-7.60 (m, 3H), 7.94 (d, J=8.8 Hz, 1H), 8.01-8.05 (m, 2H), 8.18-8.23 (m, 2H), 8.29 (d, J=8.8 Hz, 1H), 8.64 (s, 1H), 10.26 (s, 1H). MS (ES+): m/z 234.2 (100) [MH+]. HPLC: tR=3.0 min (MicromassZQ, nonpolar—5 min); 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 121.22 (+), 122.80 (+), 127.51 (2C, +), 128.65 (+), 128.94 (2C, +), 129.83 (+), 130.69 (Cquart), 135.84 (+), 136.68 (+), 137.21 (Cquart), 138.79 (Cquart), 147.91 (Cquart), 158.48 (Cquart), 192.14 (+); IR (film): ν=3059 cm−1, 3034, 2824, 2717, 1954, 1812, 1684, 1601, 1554, 1510, 1491, 1448, 1420, 1392, 1320, 1280, 1168, 1145, 1120, 1075, 1052, 1025, 971, 926, 897, 850, 812, 787, 757, 692, 673, 627.