Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[C:9]1([S+:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:28][C:29]([F:40])([F:39])[C:30]([F:38])([F:37])[C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>CO.C[N+](C)(C)C.[Cl-]>[F:28][C:29]([F:39])([F:40])[C:30]([F:37])([F:38])[C:31]([F:35])([F:36])[C:32]([O-:34])=[O:33].[C:22]1([S+:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CO
Product: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In aqueous methanol solution were dissolved 20.6 g (50 mmol) of the resulting triphenylsulfonium trifluoromethanesulfonate, and passed through an activated strong base type anion exchange resin (Amberlite IRA-900 by Organo Corp.). To the elutant solution was added 24.8 g (60 mmol) of heptafluorobutyric acid and allowed reacting with stirring at room temperature for 1 hour. After completion of the reaction, the solvent was removed and the residue was dissolved in 200 ml methylene chloride, washed with water 3 times and concentrated under reduced pressure to give 28.4 g (yield: 84%) of triphenylsulfonium heptafluorobutanoate as a white crystal.
Reaction SMILES: [NH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[CH2:23][C:24]1[N:28]2[N:29]=[C:30]([C:33](=O)[CH3:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1>>[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[CH2:23][C:24]1[N:28]2[N:29]=[C:30](/[C:33](=[N:2]/[NH:1][C:3]3[O:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[N:7]=3)/[CH3:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1
Reactant: NNc1nc2ccccc2o1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\Nc1nc2ccccc2o1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 74 %

Procedure:
The title compound was prepared from 2-hydrazinylbenzo[d]oxazole and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 74% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.8-11.5 (m, 1H), 8.87 (dd, 1H), 8.4-7.9 (m, 4), 7.8-7.6 (m, 2H), 7.6-7.1 (m, 5H), 4.58 (s, 2H), 2.49 (s, 3H). LCMS (method C): [MH]+=452, tR=4.42 min.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:11]1[N:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13](OCC)=[O:14]>COCCOC>[OH:14][C:13]1[C:12]2[C:11](=[N:21][CH:20]=[CH:19][CH:18]=2)[O:3][C:2]=1[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CO
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1oc2ncccc2c1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Ethyl glycolate (7.00 g, 67.3 mmol) was added slowly into a suspension of sodium hydride (2.80 g of 60% dispersion in mineral oil, 70.0 mmol) in 60 mL of 1,2-dimethoxyethane (DME) at 0° C., and the mixture was then stirred for another 30 min. A solution of ethyl 2-chloronicotinate (4.60 g, 24.8 mmol) in 14 mL of DME was added into the reaction mixture slowly at room temperature. Then the mixture was heated at 70° C. overnight. After evaporation of the solvent, the residue was dissolved in 90 mL of water, washed three times with hexane, acidified with acetic acid, and extracted three times with chloroform. The combined chloroform layers were dried (MgSO4), and evaporated to give a yellow residue. The residue was crystallized from 20 mL of ether to give ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate as a pale-yellow solid (4.30 g).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15](=[O:42])[N:16]([CH:18]1[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH3:17])([CH3:13])([CH3:12])[CH3:11].[Cl:43][C:44]1[C:45]2[CH:55]=[CH:54][CH:53]=[CH:52][C:46]=2[S:47][C:48]=1[C:49](Cl)=[O:50]>ClCCl>[C:10]([O:14][C:15](=[O:42])[N:16]([CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([C:49]([C:48]2[S:47][C:46]3[CH:52]=[CH:53][CH:54]=[CH:55][C:45]=3[C:44]=2[Cl:43])=[O:50])[CH2:25][C:26]2[CH:27]=[C:28]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH3:17])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(CNC2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C#N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)c2sc3ccccc3c2Cl)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C#N)cc1
Yield: 92.8 %

Procedure:
N,N-Diisopropylethylamine (2.1 mL, 12.1 mmol) was added to a solution of amine 5 (2.2 g, 4.9 mmol), 3-chlorobenzo[b]thiophene-2-carbonyl chloride (1.3 g, 5.86 mmol) and anhydrous dichloromethane (22 mL), with stirring under argon. Once all of the starting material had been consumed as monitored by TLC (˜2.5 hours), the mixture was washed with water, saturated aqueous sodium hydrogen carbonate, and brine. The organic layer was dried (MgSO4), and concentrated in vacuo. The yellow residue was then purified by silica-gel chromatography using hexane/ethyl acetate 3:1 to give the title compound 6 (2.93 g, 93%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[C:3]=1[N+:11]([O-])=O>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[C:3]=1[NH2:11]
Reactant: C=C(C)c1cccc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 1-fluoro-2-nitro-3-(prop-1-en-2-yl)benzene (0.590 g, 3.26 mmol) in ethyl acetate (32.6 mL) in a 250 mL round-bottomed flask equipped with a magnetic stir bar and nitrogen inlet was added palladium on carbon (5% Pd/C, 0.693 g, 0.326 mmol). The reaction flask was evacuated and purged with hydrogen (2×) and then placed under 1 atmosphere (atm) of hydrogen and stirred at room temperature overnight. The reaction was filtered through Celite® and the pad was washed with ethyl acetate. The filtrate was concentrated to give the title compound (0.423 g, 2.76 mmol, 85% yield) as clear and colorless oil: IR (neat) 3476 (m), 3392 (m), 2966 (m), 2872 (m), 1628 (s), 1474 (s), 1270 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 6.92 (dt, J=7.7, 1.2 Hz, 1H), 6.86 (ddd, J=10.8, 8.1, 1.4 Hz, 1H), 6.69 (td, J=8.0, 5.6 Hz, 1H), 3.71 (bs, 2H), 2.92 (hept, J=6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 151.91 (d, J=237.6 Hz), 135.10 (d, J=2.3 Hz), 131.60 (d, J=11.8 Hz), 120.52 (d, J=3.0 Hz), 117.99 (d, J=8.0 Hz), 112.28 (d, J=19.6 Hz), 27.77 (d, J=2.9 Hz), 22.22.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=C=O>O1CCOCC1>[O:10]=[C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1.[CH3:22][CH2:21][CH:20]([C:2]([NH2:3])=[O:1])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCN=C=O
Agent: O=c1[nH]c2ncccc2o1
Solvent: C1COCCO1
Product: CCCCCCC(CC)C(N)=O

Procedure:
200 mg (1.47 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted in analogy to Example 1 with 298.4 mg (1.76 mmol) of 1-isocyanatononane in dioxane at 80° C. Yield: 40 mg (9%), M+H+: 306.20.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[N:7]([C:15]2([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][C:16]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[N:7]([C:15]2([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]([S:43]([C:40]3[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=3[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:16]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C)cc1C1(N2C[C@H](OC(C)=O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OC(C)=O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 69.1 %

Procedure:
With 500 mg of the compound obtained in Step 137-3 (Isomer B) and 329 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 526 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:21](=[O:22])[CH2:20][O:19][CH3:18])=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
55 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine was reacted with 26 mg of methoxyacetyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methoxyacetamide.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].[CH3:24][O:25][CH2:26]CCl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:24][O:25][CH3:26])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Reactant: COCCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2.37 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide is treated at 20°-25° C under nitrogen, with 0.38 g. of sodium borohydride. After one hour 1.6 ml. of chloroethyl methyl ether is added, and the mixture kept at 20°-30° C for a further three hours. Water is then added and the product filtered off. Recrystallization from cyclohexane gives 1-acetamido-2-nitro-4-methoxyethylthiobenzene.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24](OCC)=[O:25])C(OC(C)(C)C)=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>O1CCCC1>[C:7]([O:11][C:12](=[O:13])[NH:14][CH2:22][CH:23]([CH2:24][OH:25])[CH2:29][CH3:30])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCOC(=O)C(CC)CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CO)CNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Lithium aluminum hydride (153 mg) was suspended in tetrahydrofuran (20 mL). To the suspension, a solution of the compound obtained in Step 4 in tetrahydrofuran (2 mL) was added dropwise under ice cooling, and the mixture was then stirred overnight. To the reaction solution, sodium sulfate decahydrate was added under ice cooling. Subsequently, ethyl acetate was added thereto, and the mixture was stirred. After celite filtration, the solvent in the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=9/1-3/7) to obtain the title compound (168 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([Sn](C)(C)C)=[CH:29][N:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:30]2[CH:29]=[N:28][C:27]([O:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:32][CH:31]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Sn](C)(C)c1ccc(OCc2ccccc2)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1[N+](=O)[O-]
Yield: 103.9 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (728 mg, 2.0 mmol) and 2-(phenylmethoxy)-5-(trimethylstannyl)-pyridine (766 mg, 2.2 mmol) [CAS-No. [188881-22-3], WO 9709311] according to the general procedure E. Obtained as a yellow solid (876 mg).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=O.[CH3:7][C:8]1([CH3:37])[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][N:12]=[C:11]([N:18]3[CH2:24][C:23]4[CH:25]=[C:26]([C:29]5[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[N:33][CH:34]=5)[CH:27]=[CH:28][C:22]=4[O:21][CH2:20][CH2:19]3)[C:10]=2[CH2:9]1>>[F:1][CH:2]([F:6])[C:3]1[NH:35][C:32]2=[N:33][CH:34]=[C:29]([C:26]3[CH:27]=[CH:28][C:22]4[O:21][CH2:20][CH2:19][N:18]([C:11]5[C:10]6[CH2:9][C:8]([CH3:37])([CH3:7])[CH2:17][CH2:16][C:15]=6[N:14]=[CH:13][N:12]=5)[CH2:24][C:23]=4[CH:25]=3)[CH:30]=[C:31]2[N:36]=1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Reactant: O=C(O)C(F)F
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6[nH]c(C(F)F)nc6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 4 by omitting step 3, and using difluoroacetic acid and 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine in step 4. 1H NMR (400 MHz, Methanol-d4): 8.70 (br, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 7.64 (s, 1H), 7.55 (d, 1H), 7.12 (d, 1H), 7.05 (t, 1H), 4.63 (s, 2H), 4.37 (m, 2H), 3.95 (m, 2H), 2.79 (t, 2H), 2.49 (s, 2H), 1.66 (t, 2H), 0.88 (s, 6H); MS (EI) for C26H26F2N6O: 477 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:18][C:8]2=1)=O.[C:28]([O:34][CH2:35][C:36]([NH2:38])=[S:37])(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[C:16](=[O:26])[N:15]([CH3:27])[C:9]3[N:10]([CH3:14])[C:11]4[C:7]([C:8]=3[CH:18]=2)=[CH:6][C:5]([C:3]2[N:38]=[C:36]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[S:37][CH:2]=2)=[CH:13][CH:12]=4)=[CH:24][CH:23]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Reactant: CC(C)(C)C(=O)OCC(N)=S
Product: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4csc(COC(=O)C(C)(C)C)n4)ccc3n(C)c21

Procedure:
The process is carried out as for Example 8 above, using compound A, 6-(2-bromo-acetyl)-3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and 2-amino-2-thioxoethyl pivalate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]2[CH:18]=[CH:19][CH:20]=[C:9]2[CH2:8]1)=[O:6].[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH:20]1[CH:19]=[CH:18][N:10]2[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:5]([C:4]3[CH:21]=[CH:22][C:23]([NH:24][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:26]=4[Cl:25])=[C:2]([CH3:1])[CH:3]=3)=[O:6])[CH2:8][C:9]=12
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
A mixture of 0.40 g of 10,11-dihydro-10-(3-methyl-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.40 g of 2,4-dichlorobenzoyl chloride and 0.75 g of diisopropylethylamine in 50 ml of dichloromethane is stirred at room temperature for 16 hours. The mixture is washed with water, dried (MgSO4) and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and hexane added to give crystals. Recrystallization from dichloromethane-hexane gives 0.52 g of crystals, m.p. 213°-215° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:7]=1[N+:21]([O-])=O)=[O:5])[CH3:2].C(OCC)(=O)C>[NH4+].[Cl-].[Zn]>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][CH:16]=2)[C:7]=1[NH2:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1onc(-c2ccc(S(C)(=O)=O)cc2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1onc(-c2ccc(S(C)(=O)=O)cc2)c1N
Reaction time: 3 h

Procedure:
3-(4-Methanesulfonyl-phenyl)-4-nitro-isoxazole-5-carboxylic acid ethyl ester (6.2 g) was suspended in sat. NH4Cl (100 mL) and treated with Zn (10.0 g) at room temperature. The reaction was stirred for 3 h and ethyl acetate (100 mL) was added. After stirring for 1 h, zinc was filtered off. The ethyl acetate was taken and washed with H2O, dried over MgSO4 and concentrated under vacuum to afford the crude product (4.3 g, 77%). The product was crystallized in ethyl acetate/hexane (1/3) to afford the desired compound. LCMS 311.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1.Cl.O>CCO.CC(O)=O.[Fe]>[NH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[C:9]([F:10])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Cl)c(F)cc1C=O
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A mixture of 4-chloro-5-fluoro-2-nitrobenzaldehyde (1.50 g, 7.37 mmol), concentrated hydrochloric acid (0.30 ml, 3.68 mmol), and iron (1.32 g, 23.6 mmol) in EtOH (18 mL), AcOH (18 mL), and water (9 mL) was heated to reflux for 30 minutes, then cooled to RT. The resulting suspension was filtered through CELITE™ and the filtrate was then partitioned between EtOAc and water. The layers were separated, the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2-amino-4-chloro-5-fluorobenzaldehyde as a yellow solid (1.15 g, 90% yield). m/z=174 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]([S:16]Cl)=[O:15].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:14](=[O:15])[S:16][N:8]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: COc1cc(Cl)ccc1C(N)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1-c1nsc(=O)o1
Temperature: 90 °C
Yield: 95.6 %

Procedure:
To a solution of 4-chloro-2-methoxybenzamide (0.82 g, 4.42 mmol) in toluene (20 ml) was added chlorocarbonylsulfenyl chloride (0.73 ml, 8.84 mmol) under nitrogen atmosphere and the resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring) water was added followed by extraction with ether (3×50 ml). The combined organics was then sequentially washed with water, 10% NaHCO3 (aqueous solution) and finally again with water. The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated to get desired product (1.03 g, 96% crude yield) that was carried forward as such without further purification. MS: 244.16 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>>[OH:1][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:13][OH:14])=[O:5]
Reactant: COC(=O)c1ccncc1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NO)c1ccncc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
To a stirred suspension of methyl 3-hydroxy-isonicotinate (176 g; 1.15 mol) in water/ice (50/50, 1700 mL), was added hydroxylamine hydrochloride (127.9 g; 1.84 mol). The temperature fell to −5° C. and then aqueous NaOH solution (454 mL, 28% w/v) was added dropwise keeping the temperature below 5° C. during the addition. Hereafter the reaction mixture was stirred at ambient temperature for 1.5 h followed by heating to 60° C. At this temperature the pH was adjusted to 5.4 by the addition of aqueous hydrochloric acid (10 M) at which point a heavy precipitate forms. The reaction mixture was then stirred at ambient temperature followed by cooling to 5° C. The pH was then adjusted to 4.0 by the addition of aqueous hydrochloric acid (10 M), and then was stirred whilst cold for 1.5 h. The crystals were filtered off, rinsed with water (3×100 mL), dried on the filter and then dried further at reduced pressure and 40° C. overnight to give 3,N-dihydroxy-isonicotinamide (169.3 g, 96%; HPLC purity 98%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][CH2:13][C@H:14]([OH:26])[CH2:15][P:16]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:18])[O-:17])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[Li+]>O>[C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][CH2:13][C@H:14]([OH:26])[CH2:15][P:16]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:17])[OH:18])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: C[C@H](NC[C@H](O)CP(=O)([O-])CC1CCCCC1)c1cccc(C(=O)O)c1
Agent: [Li+]
Solvent: O
Product: C[C@H](NC[C@H](O)CP(=O)(O)CC1CCCCC1)c1cccc(C(=O)O)c1

Procedure:
A solution of 1.0 g of lithium 3-{N-[1(S)-(3-carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinate in 2 ml of water is applied to a DOWEX® 50 W×8 ion exchange column (40-60 mesh) and eluted with water. The ninhydrin-positive fractions are combined and concentrated to dryness by evaporation under reduced pressure. Crystallisation of the foamy residue of concentration by evaporation from ethanol/tetrahydrofuran gives 3-{N-[1(S)-(3-carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid having a melting point of 225°-228°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18](=O)[NH2:19])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:26][CH2:27]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C#N)N2C1=O
Reaction time: 1 h

Procedure:
295 mg of 2-trimethylsilanylethyl 4-((3R,6R,7aS)-6-tert-butoxycarbonylamino-3-carbamoyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-ylmethyl)piperidine-1-carboxylate were dissolved in 20 ml of THF. 166 μl of triethylamine and 91 μl of trifluoroacetic anhydride were successively added dropwise. The mixture was stirred for 1 h and then the same amounts of triethylamine and trifluoroacetic anhydride were again added. After stirring for a further hour, the mixture was partitioned between 150 ml of ethyl acetate and 150 ml of water. The organic phase was dried with MgSO4. The solvent was removed in vacuo and the residue was chromatographed on silica gel.