Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[C:14]([N+:15]([O-])=O)=[C:13](/[CH:18]=[C:19](\[O-])/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+]>C(O)(=O)C.[Fe]>[CH2:26]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:15][C:14]=12)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)/C([O-])=C/c1ccnc(N(Cc2ccccc2)Cc2ccccc2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 60 °C
Yield: 67.6 %

Procedure:
Potassium (1Z)-1-[2-(dibenzylamino)-3-nitropyridin-4-yl]-3-ethoxy-3-oxoprop-1-en-2-olate (1.63 g, 3.46 mmol) was dissolved in glacial acetic acid (21 mL) and treated with iron powder (851 mg, 15.2 mmol). This mixture was warmed to 60° C. for 3.5 h and cooled to room temperature. The slurry was filtered through diatomaceous earth to remove the catalyst, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, gradient 0-50% ethyl acetate/dichloromethane) to provide ethyl 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (902 mg, 68%) as a tan solid: Rf 0.55 (silica gel, 67:33 hexanes/ethyl acetate); mp 120-123° C.; 1H NMR (300 MHz, CDCl3) δ1.27 (3H, t, J=7.1 Hz), 4.28 (2H, q, J=7.0 Hz), 4.91 (4H, s), 7.03 (1H, J=5.9 Hz), 7.06 (1H, d, J=1.8 Hz), 7.27-7.38 (10H, m), 7.89 (1H, d, J=5.7 Hz), 8.67 (1H, br s); APCI MS m/z 386 [C24H23N3O2+H]+; HPLC (Method A) >99% (AUC), tR=17.7 min.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][CH2:9][C:10](=S)[N:11]([CH:12]([CH3:18])[C:13](OCC)=[O:14])[C:6]=2[CH:5]=1)([O-:3])=[O:2].O.[NH2:23][NH2:24]>CCO>[CH3:18][CH:12]1[C:13](=[O:14])[NH:24][N:23]=[C:10]2[CH2:9][S:8][C:7]3[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[N:11]12
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)CSc2ccc([N+](=O)[O-])cc21
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2CSc3ccc([N+](=O)[O-])cc3N21
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a solution of ethyl 2-(6-nitro-3-thioxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)propanoate (0.475 g, 1.455 mmol) in EtOH (30 mL) was added hydrazine hydrate (0.364 g, 7.28 mmol) and the mixture was then heated at reflux for 16 h. After cooling to ambient temperature gradually, the precipitate was collected by filtration to give 1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]thiazino[3,4-c][1,2,4]-triazin-2(1H)-one (0.312 g, 77%), which was used in the next step directly without further purification. TLC (eluting with 33% EtOAc in petroleum ether) Rf=0.3.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:31]([O-:33])=[O:32])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11].[N+](C1C=C2C(=CC=1)N=C(N1C=C(C(O)=O)C=N1)NC2=O)([O-])=O.Cl[CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62]>C1COCC1>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:29]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:31]([O-:33])=[O:32])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)c1
Agent: O=C(O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)n2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
DIEA (4.41 mL, 25.6 mmol) was added to a suspension of 1-(6-nitro-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 164, product from Step D) (4.21 g, 12.8 mmol) in THF (64 mL), followed by (2-chloromethoxy-ethyl)-trimethylsilane (2.49 mL, 14.1 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The residue was partitioned between water (75 mL) and EtOAc (75 mL), and the organic layer was washed with water (2×75 mL) and brine (50 mL), dried (MgSO4), and concentrated to yield the titled compound (5.92 g, 86% yield, 85% pure). This material was carried on to the next step without further purification. MS (ESI/Cl): mass calcd. for C20H25N5O6Si, 459.2; m/z found, 402.1 [M+H−58]+.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C[N:30]1[S:34](=[O:36])(=[O:35])[N:33]([CH2:37]OCC[Si](C)(C)C)[C:32]2[CH:45]=[CH:46][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:48][C:31]1=2.[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>>[F:61][C:60]([F:63])([F:62])[C:58]([OH:64])=[O:59].[CH3:37][N:33]1[C:32]2[CH:45]=[C:46]([C:2]3[N:7]4[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)[CH:47]=[CH:48][C:31]=2[NH:30][S:34]1(=[O:35])=[O:36]
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CN1c2cc(B3OC(C)(C)C(C)(C)O3)ccc2N(COCC[Si](C)(C)C)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1c2cc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)ccc2NS1(=O)=O

Procedure:
Compound 2b was subjected to Suzuki coupling conditions with (3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydrobenzo[c][1,2,5]thiadiazole 2,2-dioxide and the resulting product was deprotected with TFA using the methods described in Example 37, Steps B and C) to obtain the title compound 43. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.79 (d, J=9.0 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.07-8.18 (m, 4H), 8.02 (td, J=7.8, 1.2 Hz, 1H), 7.78-7.87 (m, 2H), 7.72 (s, 1H), 7.32 (s, 1H), 7.27 (dd, J=8.1, 2.0 Hz, 1H), 7.10 (d, J=1.7 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.39 (m, 4H), 3.91-3.99 (m, 4H), 3.34 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H25N7O3S: 540.2 (M+H). Found 540.4.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>CO>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:3]2[N:4]=[CH:5][NH:6][C:2]=2[CH3:1])=[CH:12][CH:11]=1
Reactant: Cc1[nH]cnc1-c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: Cc1[nH]cnc1-c1ccc(N)cc1

Procedure:
Prepared by hydrogenation of 5-methyl-4-(4-nitro-phenyl)-imidazole in MeOH on palladium/charcoal (10%) at 20° C. and 3.5 bar.
Reaction SMILES: CC1CC(=O)CCC(C2N(C)N=CC=2[N+]([O-])=O)O1.[CH3:19][N:20]1[C:24]([CH:25]2[O:32][C:29]3([CH2:31][CH2:30]3)[CH2:28][CH:27]([CH2:33][CH3:34])[O:26]2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=[N:21]1>>[CH2:31]([CH:29]1[CH2:28][C:27](=[O:26])[CH2:33][CH2:34][CH:25]([C:24]2[N:20]([CH3:19])[N:21]=[CH:22][C:23]=2[N+:35]([O-:37])=[O:36])[O:32]1)[CH3:30]
Reactant: CCC1CC2(CC2)OC(c2c([N+](=O)[O-])cnn2C)O1
Agent: CC1CC(=O)CCC(c2c([N+](=O)[O-])cnn2C)O1
Product: CCC1CC(=O)CCC(c2c([N+](=O)[O-])cnn2C)O1

Procedure:
Following the procedure for Intermediate 5 starting from 1-methyl-5-(5-ethyl-6,8-dioxaspiro[2.5]octan-7-yl)-4-nitro-pyrazole gave 2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-one as a colourless solid (240 mg, 13% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 5.67 (dd, J=11.0, 2.4 Hz, 1H), 4.02 (s, 3H), 3.94 (dd, J=10.2, 5.2 Hz, 1H), 3.04 (td, J=13.3, 3.3 Hz, 1H), 2.79-2.63 (m, 3H), 2.20-2.12 (m, 1H), 2.05-1.92 (m, 1H), 1.67-1.57 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:5].S(=O)(=O)(O)[OH:18].O.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:3]1(=[O:18])[C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:7]2[NH:6][C:4]1=[O:5])[N:13]=[CH:12][CH:11]=[CH:10]3
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc2ncccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccc3ncccc3c2C1=O
Temperature: 120 °C
Yield: 60 %

Procedure:
2-Hydroxyimino-N-(6-quinolinyl)acetamide (7.00 g, 32.5 mmol) was combined with 70 mL of concentrated sulfuric acid with stirring and heated to a reaction temperature of 120° C. for 20 min, followed by an hour at 95° C. The reaction was allowed to cool to room temperature and was added dropwise to a mixture of 155 g (1.25 mole) of sodium carbonate monohydrate and 200 g of ice. After the addition was complete, water (600 mL) was added gradually to the mixture with stirring until all inorganic white solid was dissolved. The aqueous mixture was neutralized to pH 7 with 1 M hydrochloric acid and the product was collected by filtration. The collected solid was added to 200 mL of water and dissolved by dropwise addition of 1 M hydrochloric acid to free entrapped salts. The product was then precipitated by addition of saturated aqueous sodium bicarbonate to pH 7. The product was collected by filtration and dried under vacuum at 55° C. to give 3.89 g (60%) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione as a red-brown solid. Mass spectrum (negative ion chemical ionization): m/z=197 (30%). NMR (DMSO-d6): δ7.43 (d, 1H, J=8.8 Hz), 7.66 (dd, 1H, J=4.1, 8.4 Hz); 8.29 (d, 1H, J=8.8 Hz); 8.72 (d, 1H, J=8.4 Hz); 8.82 (d, 1H, J=3.3 Hz); 11.2 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[C:4]=1[CH2:5][S:6][C:7](=[NH:11])[CH2:8][C:9]#[N:10].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[S:28])[CH:21]=1>C(OCC)(=O)C>[CH3:19][O:18][C:12]1[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][S:6][C:7](=[NH:11])[C:8]([C:9]#[N:10])=[C:27]([SH:28])[NH:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1
Reactant: S=C=Nc1cccnc1
Reactant: COc1cc(OC)c(CSC(=N)CC#N)c(OC)c1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(CSC(=N)C(C#N)=C(S)Nc2cccnc2)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
To compound 11 (6.76 g, 24.1 mmol) in ethyl acetate (18 mL) is added 3-pyridylisothiocyanate (3.9 ml-, 36.2 mmol) at room temperature. The reaction is then heated to 60° C. and stirred for 4 hours. More ethyl acetate is added (12 mL) and the reaction is stirred for an additional 4 hours. The reaction is cooled to room temperature and filtered. The solids are washed with ethyl ether twice and with methanol once. The solids are further dried in vacuo to obtain compound 12 (5.88 g, 59%). 1H NMR (d6 DMSO): δ 10.12 (1H, br. s), 8.46 (1H, d, J=2.4 Hz), 8.36 (1H, d, J=5.2 Hz), 7.71 (1H, d, J=9.0 Hz), 7.37 (1H, dd, J=9.0, 5.2 Hz), 6.27 (2H, s), 4.25 (2H, s), 3.81 (6H, s), 3.77 (3H, s).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][C:5]([N:7]1[CH2:13][C@H:12]([NH:14]C(OC(C)(C)C)=O)[C:11](=[O:22])[N:10]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:9]2[CH:28]=[CH:29][CH:30]=[CH:31][C:8]1=2)=[O:6].[ClH:34]>O1CCOCC1>[ClH:34].[F:33][C:2]([F:1])([F:32])[CH2:3][O:4][C:5]([N:7]1[CH2:13][C@H:12]([NH2:14])[C:11](=[O:22])[N:10]([CH2:23][C:24]([F:25])([F:26])[F:27])[C:9]2[CH:28]=[CH:29][CH:30]=[CH:31][C:8]1=2)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCC(F)(F)F)c2ccccc2N(CC(F)(F)F)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(C(=O)OCC(F)(F)F)c2ccccc2N(CC(F)(F)F)C1=O

Procedure:
In an analogous manner to that described in Example 1d), the treatment of the (S)-3-tert-butoxycarbonylamino-4-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 2,2,2-trifluoro-ethyl ester [Example 10a)] with hydrochlorid acid (37%) in dioxane yielded (93% of theory) the title compound as a light yellow solid; MS (m/e): 386 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:25]=2)=[CH:20][CH:19]=1>C(#N)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]([NH:1][C:2]3[N:3]=[CH:4][S:5][C:6]=3[C:7]([O:9][CH3:10])=[O:8])=[O:33])[CH:25]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)Cl
Reactant: COC(=O)c1scnc1N
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1scnc1NC(=O)Cc1cc(-c2ccc(Cl)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
1.8 g (11.38 mmol) of methyl 4-amino-1,3-thiazole-5-carboxylate were dissolved in 40 acetonitrile, and 1.8 ml (22.76 mmol) of pyridine were added. After 5 min of stirring at room temperature (RT), a solution of 3.18 g (11.38 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetyl chloride (obtained from (4′-chloro-4-methylbiphenyl-3-yl)acetic acid according to WO 99/48869 A1) in 20 ml of acetonitrile was added dropwise. The mixture was stirred at RT for 12 h. The precipitate formed was filtered off, washed with water and dried under reduced pressure. The resulting mother liquor was concentrated by evaporation, dissolved in chloroform and chromatographed (ethyl acetate/n-heptane: 20/80 to 80/20). This gives a total of 1.81 g of methyl 4-{[(4′-chloro-4-methylbiphenyl-3-yl)acetyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(F)ccc32)CC1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CCn2c(=O)cnc3cc(F)ccc32)CC1
Yield: 92.3 %

Procedure:
tert-Butyl{1-[2-(6-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 142, 380 mg, 0.97 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 260 mg (93%) of the crude product as an oil.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[I:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH2:33][C:32]4[CH:35]=[CH:36][C:29]([I:28])=[CH:30][CH:31]=4)[CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCNCC2
Reactant: O=Cc1ccc(I)cc1
Agent: Cl
Product: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(I)cc1)CC2

Procedure:
Reductive amination using methyl 4-[4-(cyclohexylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate dihydrochloride and 4-iodo-benzaldehyde using a similar procedure as described in the preparation of intermediate I.1.d.1. LRMS (M+1)=567.5.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([O:10][P:11]([O:15]CC)[O:12][CH2:13][CH3:14])[CH3:9]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([P:11]([O:12][CH2:13][CH3:14])([O:10][CH2:8][CH3:9])=[O:15])[CH3:7]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)C(C)Br
Product: CCOP(=O)(OCC)C(C)C(=O)OC
Temperature: 110 °C
Reaction time: 48 h

Procedure:
Methyl 2-bromopropionate (100 g, 0.60 mol) and triethylphosphite (109 g, 0.66 mol) were mixed, and the mixture was stirred at 110° C. for 2 days. The reaction mixture was dried under reduced pressure to give the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]([F:33])=[C:24]([C:26](=[O:32])[C:27]([O:29]CC)=[O:28])[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)(=O)C>C(O)C.O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]([F:33])=[C:24]([C:26](=[O:32])[C:27]([OH:29])=[O:28])[CH:25]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(=O)O)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 2-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-oxoacetate (Intermediate 114, 0.785 g, 3.00 mmol) was dissolved in ethanol (60 ml) and stirred at room temperature with 1 ml of 10% KOH. After 3 hours the reaction appears to have gone approximately 40-50% by LCMS. An additional 1 ml of 10% KOH was added and the reaction was stirred at room temperature for 30 minutes. The reaction has 70-80% by LCMS. An additional 1 ml of 10% KOH was added and the reaction was stirred at room temperature for 60 minutes. The reaction was made acidic with acetic acid, diluted with water and extracted three times with ethyl acetate. The organic layers were washed twice with brine, dried over MgSO4 and concentrated. The resulting sticky oil was dissolved in ethyl acetate, washed with sat. NaHCO3, dried over MgSO4 and concentrated. The resulting oil was dried under vacuum for 2 hours to give the title compound as a yellow solid.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:38]1([C@H:36]([C@@H:32]2[O:33][CH2:34][CH2:35][N:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31]2)[OH:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(c1ccccc1)[C@H]1CN(Cc2ccccc2)CCO1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Product: O[C@H](c1ccccc1)[C@H]1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (+)-DIP chloride (49.6 g, 155 mmol) in dry TBF (150 ml) under nitrogen was added (2R)-(4-benzyl-morpholin-2-yl)-phenyl-methanone (16.54 g, 58.89 mmol) in one portion. The reaction mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the crude oil taken up in methanol and absorbed onto 250 g SCX-2 ion exchange resin. After elution of borane residues with methanol the product was eluted with 2M ammonia in methanol. Removal of solvent in vacuo yielded the product as yellow oil. (11.23 g, 67%); MW 283.37; C18H21NO2; 1H NMR (CDCl3): 7.32-7.45 (10H, m), 4.67 (1H, d, 7.3 Hz), 4.03 (1H, dt, 11.4 Hz, 2.7 H), 3.86-3.73 (2H, m), 3.64 (1H, d, 13.2 Hz), 3.39 (1H, d, 13.2 Hz), 3.30 (1H, br. s), 2.68 (1H, d, 12.7 Hz), 2.56 (1H, d, 10.9 Hz), 2.28-2.15 (2H, m); LCMS: m/z 284 [M+H]+ @ Rt 0.95 min.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl.[NH2:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[Cl:28])[CH3:18]>>[CH2:1]([O:8][C:9]([NH:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[Cl:28])[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(C(=O)O)cc1Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1Cl
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Benzyloxycarbonyl chloride (750 mg) was dropwise added to an aqueous solution (10 ml) of (R)-4-(1-aminoethyl)-3-chlorobenzoic acid hydrochloride (690 mg) and sodium hydroxide (410 mg) at room temperature, and the mixture was stirred for 3 hours. After the reaction, conc. hydrochloric acid was added to the reaction mixture to make the same acidic, and the mixture was extracted with chloroform. The extract was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 680 mg of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a 2-(tert-butoxycarbonylamino)acetic acid (800 mg, 4.57 mmol), N,O-dimethylhydroxylamine hydrochloride (535 mg, 5.48 mmol), EDCI (1.05 g, 5.48 mmol), HOBt (740 mg, 5.48 mmol) in DCM (25 mL) was added NMM (2.77 g, 27.42 mmol) at rt. The reaction mixture was stirred overnight. After the reaction was completed, DCM was evaporated in vacuo. The residue was dissolved in MeOH, filtered through a syringe filter, and then purified by reverse-phase prep HPLC to provide the desired product (705 mg, 71%) as white solid
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][N:11]([C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1)[NH2:12]>O1CCOCC1>[CH3:1][NH:2][C:3]([NH:12][N:11]([CH3:10])[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: CN(N)c1ncc(C(F)(F)F)cc1Cl
Solvent: C1COCCO1
Product: CNC(=C[N+](=O)[O-])NN(C)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 33.7 %

Procedure:
500 mg of N-methyl-1-methylthio-2-nitroetheneamine, 770 mg of 1-methyl-1-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazine and 7 ml of 1,4-dioxane were stirred for about 4 hours under heating and refluxing and then cooled to room temperature, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 370 mg of N-methyl-1-(2-methyl-2-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazino)-2-nitroetheneamine (Compound No. 35) having a melting point of from 159 to 160° C. (decomposed).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To tert-butyl 7-(benzyloxy)-9H-carbazol-2-ylcarbamate (220 mg, 0.56 mmol) in 50 mL MeOH was added Palladium on activated carbon (80 mg). The mixture was stirred at rt under H2 atmosphere for 3 h. Solid was filtered off and the filtrate was concentrated to afford tert-butyl 7-hydroxy-9H-carbazol-2-ylcarbamate as a brown solid (165 mg, 100%). This material was used directly for the next reaction without purification. MS (ESI) m/z 619 (2M+Na+).
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+:38]>>[K+:38].[CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([O-:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [K+]
Agent: [OH-]
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)[O-]

Procedure:
To the oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline, (2.72 g, 5 m mole) 0.1N potassium hydroxide (50 ml) was added, and the thus produced solution was freeze-dried to obtain an amorphous powder of the dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline potassium salt (2.8 g).