Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1.Cl>CN(C=O)C.O>[Cl:20][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([Cl:10])[CH:19]=1)[C:14]([N:64]1[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:51][CH:52]=2)[CH2:62][CH2:63]1)=[O:16]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)cc(Cl)c2)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
DIPEA (125 mg, 0.17 mL, 0.97 mmol) was added drop wise to 3,5-dichloro-benzoic acid (74 mg, 0.389 mmol) in DMF (5 mL). EDCI (74 mg, 0.389 mmol) and HOBT (52 mg, 0.389 mmol) were added consecutively and, after 10 minutes, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenylamino-benzamide in its HCl salt form (110 mg, 0.32 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 39 mg (15% yield) of N-{2-[4-(3,5-Dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 95.72%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 3H), 7.5 (s, 2H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (m, 2H), 3.6 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:16][N:15]=[CH:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][C:12]3[N:8]4[C:9]5[C:4](=[CH:3][CH:2]=[CH:1][C:10]=5[C:11]=3[CH2:16]2)[CH2:5][CH2:6][CH2:7]4)=[CH:28][CH:27]=1
Reactant: C1=NCc2c(n3c4c(cccc24)CCC3)C1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CCc2c(c3cccc4c3n2CCC4)C1)c1ccc(F)cc1
Yield: 28 %

Procedure:
The title compound (0.060 g, 28%) was prepared by the general method of Example 402 from 5,6,8,11-tetrahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.12 g, 0.57 mmol), 4-chloro-4′-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic) and K2CO3(0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.80–2.15 (m, 2H), 2.15–2.30 (m, 2H), 2.71 (t, J=7.0 Hz, 2H), 2.82 (d, J=5.1 Hz, 2H), 2.90 (t, J=5.8 Hz, 2H), 2.97 (t, J=6.1 Hz, 2H), 3.02–3.20 (m, 2H), 3.73 (s, 2H), 3.98 (t, J=5.7 Hz, 2H), 6.84 (d, J=6.9 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 7.02–7.20 (m, 2H), 7.25 (d, J=7.7 Hz, 1H), 7.20–7.25 (m, 1H), 7.95–8.20 (m, 2H) ppm.
Reaction SMILES: [I:1][C:2]1[NH:3][C:4]([I:9])=[C:5]([I:8])[C:6]=1[I:7].C[O:11][Na].CO.[CH3:15][CH2:16][OH:17]>CN(C=O)C>[I:1][C:2]1[N:3]([CH2:15][C:16]([OH:11])=[O:17])[C:4]([I:9])=[C:5]([I:8])[C:6]=1[I:7]
Reactant: CCO
Reactant: CO[Na]
Reactant: Ic1[nH]c(I)c(I)c1I
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)Cn1c(I)c(I)c(I)c1I
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of 22.9 g of compound A), 2,3,4,5-tetraiodopyrrole (40.13 mmol), in 170 mL of DMF, 16.05 mL of 2.5 M MeONa in MeOH (40.13 mmol) are added under stirring for 15 min in nitrogen atmosphere. MeOH is removed under reduced pressure and 10 g of ethyl iodoacetate (product instantly prepared from BrCH2COOEt and 4 KI equivalents in acetone) (46.73 mmol) are dropwise added (30 min) to the residue. The solution is kept at room temperature for 1.5 h. After dilution with H2O, an intensely coloured solid precipitates, then is filtered, redissolved in DMF and treated with carbon Carbopuron 4N. The solution is filtered, concentrated to dryness and crystallized from abs. EtOH, to obtain 20 g of 2,3,4,5-tetraiodopyrrol-l-acetic acid (30.45 mmol) ethyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[S:33]([Cl:36])(=[O:35])=[O:34].N1C(C)=CC=CC=1C>O1CCCC1>[ClH:36].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][S:33]([C:27]3[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])(=[O:35])=[O:34])=[CH:14][CH:15]=2)[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(c2cn(Cc3ccccc3)c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CN1CCC(c2cn(Cc3ccccc3)c3ccc(OS(=O)(=O)c4c(F)cccc4F)cc23)CC1
Product: Cl

Procedure:
By a method similar to Example 48, using 1-benzyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (320 mg, 1.0 mmol), 2,6-difluorobenzenesulfonyl chloride (234 mg, 1.1 mmol) in tetrahydrofuran (20 mL), 2,6-lutidine (255 μL, 2.2 mmol) provided 382 mg (77%) of the free base of the desired compound as a colorless oil. A portion of this oil (182 mg) was dissolved in methanol (10 mL) and treated with ammonium chloride (19.6 mg, 0.37 mmol, dissolved in 10 mL methanol). The resulting solution was placed in an ultrasound bath for 5 minutes before removing the solvent in vacuo. The resulting residue was triturated with diethyl ether. Filtration and drying of the precipitate afforded 160 mg (82%) of the title hydrochloride as a white solid: mp=225-227° C.; 1H NMR (400 MHz, dmso-d6): 7.93-7.82 (m, 1H), 7.46-7.30 (mm, 5H), 7.30-7.12 (m, 5H), 6.78 (dd, 1H, J=8.8, 2.0 Hz), 5.33 (s, 2H), 3.42-3.24 (m, 2H, overlapping with H2O), 3.04-2.84 (m, 3H), 2.68 (s, 3H), 2.00-1.78 (m, 4H); MS (ES+): m/e 496.9 (M+1); Calculated (for C27H26F2N2O3S.HCl): C 60.84, H 5.11, N 5.26; found: C 60.69, H 5.00, N 5.26.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([OH:29])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:30]([C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)=[O:33])[NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH:31][NH:30][C:32]([N:34]1[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]1)=[O:33])=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NN)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
DIPEA (3.7 g, 10 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.45 g, 5.3 mmol, 0.8 eq.) and tert-butyl 4-(hydrazinecarbonyl)piperazine-1-carboxylate (1.6 g, 6.6 mmol) in dry DMF (50 mL), followed by the addition of HATU (1.45 g, 5.3 mmol). The reaction mixture was allowed to warm to rt then was stirred at rt overnight. The mixture was then diluted with water (200 mL) and the resulting precipitated material was collected by filtration, rinsed with water, and then recrystallized (3:1 petroleum ether/EtOAc) to afford tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)piperazine-1-carboxylate (1.4 g, 54%), ESI-MS (EI+, m/z): 503 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
5-Bromonicotinic acid (1.00 g; 4.95 mmol) is dissolved in 30 mL anhydrous THF and triethylamine (0.76 mL; 5.44 mmol) is added by syringe, the flask is flushed with argon and cooled to 0° C. Ethylchloroformate (0.52 mL; 5.44 mmol) is then added dropwise by syringe and the mixture is stirred at RT for 60 min. The crude mixture is filtered and the residue is washed twice with 5 mL THF, the filtrate is transferred to a 100 mL RBF and cooled to 0° C. Sodium borohydride (468 mg: 12.4 mmol) is added in portions, followed by 5 mL H2O which is added dropwise via a syringe. The mixture is stirred at RT overnight and then concentrated in vacuo. The crude product is extracted 6 times with EtOAc, the organic layers are combined and dried over anhydrous sodium sulfate, concentrated in vacuo and deposited on silica. Purification by column chromatography on silica gel (pre washed with 1% NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc and then to 50% MeOH in EtOAc, led to the isolation of the product as a clear, colorless oil (426 mg, 46% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8][CH2:7]1.C(N(CC)CC)C.O>CS(C)=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=[O:14])[CH2:8][CH2:7]1
Reactant: OCC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.3 %

Procedure:
To a solution of {1-[2,4-bis(trifluoromethyl)benzyl]azepan-4-yl}methanol (901.4 mg) and triethylamine (1.06 mL) in DMSO (1.01 mL) was added sulfur trioxide pyridine complex (1.21 g). The reaction mixture was stirred at room temperature for 1.5 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (289.8 mg).
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.Cl[C:33]([O:35][CH:36]([Cl:38])[CH3:37])=[O:34].[Cl:39][CH:40]([O:42][C:43](OC(COC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC)=[O:44])[CH3:41]>ClCCl>[Cl:38][CH:36]([O:35][C:33]([O:25][CH2:24][CH:21]([CH2:22][O:23][C:43]([O:42][CH:40]([Cl:39])[CH3:41])=[O:44])[O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:34])[CH3:37]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)OC(C)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)OC(C)Cl)COC(=O)OC(C)Cl
Reaction time: 8 h

Procedure:
2-Stearoylglycerol (0.1 g, 0.28 mmol) was dissolved in dichloromethane (5 ml). To this was added anhydrous pyridine (49 mg, 0.62 mmol), followed by 1-chloroethyl chloroformate (89 mg, 0.62 mmol). The reaction mixture was allowed to proceed at ambient temperature overnight and worked up as described for 2-(1-chloroethoxycarbonyl)-1,3-dipalmitoylglycerol (Example 1c). The product was purified by recrystallization from ethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc21

Procedure:
{2-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenoxy}-acetonitrile was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one in an analogous manner to Example 12211d. (120° C., 20 min) Title compound was isolated as a white foam: 67 mg (61%) after silica gel chromatography (ISCO 12 g, 0-100% EtOAc in hexanes). HPLC purity 88%, LCMS 463.24 (M+H), 1H-NMR (CDCl3, 400 MHz) δ: 8.35 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.60 (s, 2H), 7.35 (s, 1H), 7.23 (d, J=6.5 Hz, 1H), 7.21-7.05 (m, 4H), 4.90 (s, 2H), 3.90-3.50 (bm, 2H), 2.71-2.60 (m, 2H), 2.34-2.23 (m, 2H), 2.05-2.12 (m, 2H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:37])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=4)=[C:17]4[C:22](=[CH:23][C:14]=3[S:13][C:12]=2[CH:36]=1)[CH:21]=[CH:20][CH:19]=[CH:18]4>C1COCC1.CO.O>[C:32]([CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[C:15]3[C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]([OH:37])=[O:4])=[CH:36][C:12]=4[S:13][C:14]=3[CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)=[CH:25][CH:26]=1)([OH:34])=[O:33]
Reactant: COC(=O)COc1ccc(-c2c3ccccc3cc3sc4cc(OCC(=O)OC)ccc4c23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(-c2c3ccccc3cc3sc4cc(OCC(=O)O)ccc4c23)cc1
Reaction time: 3 h
Yield: 71 %

Procedure:
1.0 N Aqueous potassium hydroxide (8.0 mL, 8.0 mmol) was added to a stirred suspension of [11 -(4-methoxycarbonylmethoxy-phenyl)-benzo[b]naphtho[2,3-d ]thiophen-3-yloxy]-acetic acid methyl ester (0.750 g, 1.54 mmol) in THF (20 mL) and methanol (13 mL). Dissolution occurred. After 3 h at ambient temperature, the reaction mixture was diluted with water and extracted with ether (100 mL). The aqueous phase was acidified with 10% aqueous HCl and filtered. The solid was washed with water and triturated with pet. ether. The solid was dried in vacuo at 70° C. to provide a grey solid. This solid was recrystalized from acetic acid to provide the title compound as a white solid (0.502, 71%): mp 220-222° C.: NMR (DMSO-d6); δ12.8 (broad s, 2 H), 8.54 (s, 1 H), 8.02 (d, J=8 Hz, 1 H), 7.56-7.40 (m, 4 H), 7.31 (d, J=8 Hz, 2 H), 7.23 (d, J=8 Hz, 2 H), 6.73 (dd, J=9, 1 Hz, 1 H), 6.56 (d, J=9 Hz, 1 H), 4.85 (s, 2 H), 4.74 (s, 2 H), 1.97 (s, 2.49 H, 0.83 mol acetic acid); MS (FAB+): 459 (20%, M+H); Anal. Calc. for C26H18O6S.0.83CH3CO2 H: C, 65.46, H, 4.24, N, 0.00. Found: C, 64.47, H, 4.05, N, 0.03.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1[C:28](=O)CC[C:25]1=O.C1(N=C=NC2CCCCC2)CCCCC1.CNC>C(Cl)(Cl)Cl>[CH3:25][N:24]([CH3:28])[C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
20 mmoles (5.99 grams) of N-benzyloxycarbonyl-(L)-phenylalanine and 24 mmoles (2.76 grams) of N-hydroxysuccinimide are dissolved in 30 ml of chloroform and treated under ice cooling and stirring with 22 mmoles (4.34 grams) of dicyclohexylcarbodiimide dissolved in about 10 ml of chloroform. After 10 minutes stirring the mixture was cooled in an ice-salt bath to -10° C. and 20 mmoles (0.90 grams) of condensed, dry dimethylamine (boiling point +7° C.) added. Stirring was carried out for 24 hours, whereby the cooling bath was allowed to slowly melt. The precipitate formed was filtered off and the filtrate washed successively with each 20 ml 2N hydrochloric acid, saturated NaHCO3 solution and water. After drying over sodium sulfate and drawing off the solvent in a vacuum there was obtained an oily product. It was distilled at 240° C. air bath temperature in a high vacuum (10-4Torr). Colorless, very viscous oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:33][C:34]([OH:36])=[O:35])C=1)(=O)C>>[F:15][C:2]([F:1])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:33][C:34]([OH:36])=[O:35])[CH:6]=1)=[O:4]
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: O=C(O)Cn1cc(C(=O)C(F)(F)F)c2ccccc21

Procedure:
was prepared from 2,2,2-trifluoro-1-(1H-indol-3-yl)-ethanone in a similar manner as described in Scheme A13 (step B and C) for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. White solid. MS: 272.0 [M+H]+; tR (HPLC conditions c): 4.59 min.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH3:20]I>CN(C=O)C.O>[CH3:20][N:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 2.1 g, 41.8 mmol) in DMF (80 mL) at 0° C. was added a solution of tert-butyl 3-nitrophenylcarbamate (18) (8.3 g, 34.9 mmol) in DMF (50 mL). The mixture was stirred at 0° C. for 0.5 hour before CH3I (4.9 mL, 52.35 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, diluted with water (200 mL), and extracted with DCM (60 mL×3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford tert-butyl methyl(3-nitrophenyl)carbamate (19) 8.8 g as yellow solid (yield 100%). LC-MS (ESI): m/z (M+1) 253.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:25]/[O:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23]I)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:37]=[N+:38]=[N-:39].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:37]([CH2:23][C@@H:19]1[C@H:18]([NH:17][C:15](=[O:16])/[C:14](=[N:25]\[O:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])/[C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][CH:11]=2)[C:21](=[O:22])[NH:20]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CI)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN=[N+]=[N-])cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2S,3S)-2-(iodomethyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (24.0 g, 37.6 mmol) in THF (200 mL) at 0° C. was added TEA (10.5 mL, 75.2 mmol) followed by tetrabutylammonium azide (13.9 g, 48.9 mmol). The mixture was allowed to warm to rt and stirred for an additional 16 h, whereupon it was poured into ice-water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography, affording the title compound (17.0 g, 82%) as a pale yellow solid. LCMS: m/z=551.0 (M−1). 1H NMR data was an identical match to that described in WO2012073138(A1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25](Cl)(=O)=O)[CH:24]=1.[ClH:30]>C(OCC)C>[S:25]([C:23]1[CH:24]=[C:19]([C:9]2[C:10]([Cl:30])=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])[CH:20]=[CH:21][C:22]=1[CH3:29])[C:23]1[CH:24]=[C:19]([C:9]2[C:8]([Cl:7])=[CH:13][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:10]=2[Cl:18])[CH:20]=[CH:21][C:22]=1[CH3:29]
Reactant: Cl
Reactant: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S(=O)(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To 0.7 g (18.4 mmol) of lithium aluminum hydride in 30 ml of diethyl ether, 7.2 g (17.8 mmol) of 5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzenesulfonyl chloride in 30 ml of diethyl ether was added dropwise at −10° C. After 12 hours of stirring at room temperature, the reaction mixture was poured into 1N aqueous hydrochloric acid for separation. The organic layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography affored 4.3 g of 1,1′-thiodi-[5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzene] (yield 75.0%) as a pale yellow dough (nD 1.6066), which was used in Example 2 (1) as the starting material.
Reaction SMILES: Cl.[Cl:2][C:3]1([CH:15]([Cl:17])[Cl:16])[O:7]C(C(F)(F)F)=[N:5][C:4]1([CH2:13][CH3:14])[CH3:12].O.Cl>CO>[ClH:2].[NH2:5][C:4]([CH3:12])([CH2:13][CH3:14])[C:3](=[O:7])[CH:15]([Cl:17])[Cl:16]
Reactant: CCC1(C)N=C(C(F)(F)F)OC1(Cl)C(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CO
Product: CCC(C)(N)C(=O)C(Cl)Cl
Reaction time: 8 h

Procedure:
The 5-chloro-5-(dichloromethyl)-4-ethyl-4-methyl-2-trifluoromethyloxazoline hydrochloride prepared in the preceding step was dissolved in 1800 mL of methanol, 72 mL of water, and 190 mL of concentrated hydrochloric acid, warmed to 50 ° C., and stirred at that temperature overnight. The crude reaction mixture was cooled and poured into an ice/water/ethyl ether mixture. The phases were separated and the ether layer was extracted once with water. The ether was saved (organic I). The combined aqueous layers were washed once with ethyl ether, and the organic layer was combined with organic I (organic II). The aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted twice with ethyl ether. The combined ether layers were washed with water, brine, dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered through Celite™. To the resulting colorless solution was bubbled in anhydrous hydrogen chloride keeping the temperature below 20° C. The resulting white solid was filtered and dried yielding 124.8 g of the expected 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride as a white solid. The ethyl ether filtrate was combined with organic II and concentrated in vacuo ; the resulting residue (150 g) was taken in a mixture of methanol/water/concentrated hydrochloric acid and heated at 50° C. over the weekend. The previously described workup yielded another 51 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride. The total amount obtained was 175.8 g (61% yield).