Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.CO.B(F)(F)F.N>[N+](C)([O-])=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: N
Solvent: CO
Solvent: C[N+](=O)[O-]
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C

Procedure:
In 3 ml of nitromethane were dispersed 1.44 g of 7-ACA and 1.19 g of methanol. Then, to the dispersion were sequentially added 8.54 g of a complex of boron trifluoride with methanol (content of boron trifluoride: 51%) and 3.31 g of fluorosulforic acid. The resultant mixture was heated at 25° C. for 15 min while stirring to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 0° C. Then, from the reaction mixture, methanol was distilled off under reduced pressure. To the resultant residue was added 100 ml of water to obtain a solution. The solution was subjected to reversed phase adsorption chromatography using a column filled with HP-20 (tradename of a resin for adsorption produced and sold by Mitsubishi Chemical Industries, Ltd., Japan). The eluate was adjusted to pH 3.5 with 28% aqueous ammonia to thereby form a precipitate. The precipitate was collected by filtration, and washed with 15 ml of ice water and, then, with 5 ml of cold methanol to thereby obtain the desired product, namely 7-amino-3-methoxy methyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.75 g. The yield of the desired product was 55.8%.
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:40])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]OS(C)(=O)=O)=[CH:27][CH:26]=4)[C:21](=[O:38])[N:20]([CH3:39])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.O>C(#N)C>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:43][CH:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[CH:27][CH:26]=4)[C:21](=[O:38])[N:20]([CH3:39])[CH:19]=3)[C:13]=2[CH3:40])=[O:10])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCOS(C)(=O)=O)cc2)n1
Reactant: NC1CCOCC1
Solvent: CC#N
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCNC3CCOCC3)cc2)n1
Temperature: 90 °C

Procedure:
Methanesulfonic acid 2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethyl ester (3) (0.2 g; 0.34 mmol) was dissolved in acetonitrile (2 mL) and excess 4-aminotetrahydropyran (0.25 mL) was added. The reaction vessel was sealed and heated to 90° C. for 4 hr. Water (10 mL) was added to the reaction vessel and the reaction was extracted with EtOAc (3×25 mL). The EtOAc layers were pooled, washed with brine, dried over solid sodium sulfate and filtered. The filtrate was then adsorbed directly onto silica and chromatographed using methanol/CH2Cl2 (1:9) as eluent to provide 75 mg of 4-tert-butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[2-(tetrahydro-pyran-4-ylamino)-ethyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide (4) as a light tan solid. MS 594.33 (M+H).
Reaction SMILES: C([N:9]1[CH2:13][CH2:12][C@@H:11]([N:14]([CH3:31])[C:15](=[O:30])[CH2:16][N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)(=O)C1C=CC=CC=1>CO.[Pd]>[C:24]1([N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][C:15]([N:14]([CH3:31])[C@@H:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C(=O)CN(c1ccccc1)c1ccccc1)[C@@H]1CCN(C(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)CN(c1ccccc1)c1ccccc1)[C@@H]1CCNC1
Reaction time: 24 h
Yield: 114.1 %

Procedure:
To a solution of (R)—N-(1-benzoyl-pyrrolidin-3-yl)-2-diphenylamino-N-methyl-acetamide (0.68 g, 1.7 mmol) in CH3OH (30 ml) was added Pd/C 20% (170 mg). The resulting slurry was hydrogenated at 50 psi for 24 hours. The catalyst was filtered through Celite and filtrate evaporated under reduced pressure to give 0.6 g of desired product.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13].[Cl-].[NH4+].Cl>C(OCC)C>[OH:14][CH:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10][CH2:11][C:12]#[CH:13]
Reactant: Br[Mg]c1ccccc1
Reactant: C#CCCCO
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCCC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To an ice-cold solution of 3.0M phenylmagnesium bromide (100 mL, 300 mmol) under argon atmosphere was added dropwise pent-4-yn-1-ol (10 g, 120 mmol) in diethyl ether (20 mL). After stirring for 3 hours the solution was slowly added to an ice-cold solution of dilute ammonium chloride. 6N Hydrochloric acid was added to break up the gel and the layers were separated. The aqueous extract was washed with diethyl ether (3×50 mL) and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed by rotary evaporation under reduced pressure to give 17 g of the crude product which was Kugelrohr distilled to afford 11.1 g (58%) of the purified product. 1H NMR (CDCl3) δ: 1.82-1.95 (m, 2H), 1.98 (t, 1H), 2.20-2.35 (m, 2H), 2.40 (s, 1H), 4.80-4.85 (m, 1H), 7.30-7.38 (m, 5H) ppm.
Reaction SMILES: [NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](Cl)=[N:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29].[CH2:30]([N:32](CC)CC)C.CN>CN1C(=O)CCC1.O>[NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([NH:32][CH3:30])=[N:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29]
Reactant: CCN(CC)CC
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2nc(Cl)c2ccccc32)cc(Br)c1OC
Agent: CN
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1nc2c(c3ccccc13)OC(N)=C(C#N)C2c1cc(Br)c(OC)c(OC)c1
Temperature: 80 °C

Procedure:
3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-9-chloro-1H-4-oxa-10-aza-phenanthrene-2-carbonitrile (34) (47 mg, 0.1 mmol) and triethylamine (14 μl, 0.1 mmol) and methylamine (2M in MeOH, 75 μl, 0.15 mmol) were taken in dry NMP (2 ml) and stirred at 80° C. till the reaction was complete. The reaction mixture was diluted with water to about 7 ml, stirred at room temperature for 2 h, precipitates were collected by filtration, washed with water. The residue was then purified on HPLC (high pressure liquid chromatography) (21 mm×250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to pure title compound (36 mg, 77%).
Reaction SMILES: [S:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=[CH:26][CH:25]=1.C(O)C>C(Cl)Cl>[S:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([O:17][CH2:25][CH3:26])=[O:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: O=C(O)c1cc2c3ccccc3[nH]c(=S)n2n1
Reactant: c1ccncc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc2c3ccccc3[nH]c(=S)n2n1

Procedure:
1.5 g (0.006 mole) of 5,6-dihydro-5-thioxopyrazolo-[1,5-c]quinazoline-2-carboxylic acid (prepared as described in Example 1) and 1.26 g (1 equivalent) of phosphorus pentachloride are heated together in 50 ml of methylene chloride at 60° for 30 minutes. The reaction mixture is cooled and the solvent stripped off and replaced with 50 ml of dry pyridine. The solution is treated with 1.1 ml of absolute ethanol and refluxed under N2 for 2 hours.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([CH2:9][N:10]([CH2:34][CH3:35])[C:11](=[O:33])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([O:27]C)=[O:26])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:34][CH3:35])[C:11](=[O:33])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)=[CH:36][CH:37]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 73.2 %

Procedure:
Methyl 2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-ethoxy]benzoate (0.2290 g, 0.455 mmol) was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), lithium-hydroxide (0.218 g, 0.909 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.163 g of 2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoic acid (yield 73.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:6]([C:8]2(Cl)[NH:13][C:12]([NH2:14])=[N:11][CH:10]=[CH:9]2)[CH:7]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccccc1COc1ccc(Br)cc1C1(Cl)C=CN=C(N)N1
Product: COc1ccccc1COc1ccc(Br)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 57 %

Procedure:
Following the method described in Example 178, 6-[5-bromo-2-(2-methoxy-benzyloxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (57% yield). 1H NMR (CD3OD) δ 3.82 (s, 3H, CH3), 5.25 (s, 2H, CH2), 6.35 (s, 1H, Ar), 6.89-6.98 (m, 2H, Ar), 7.21-7.48 (m, 3H, Ar), 7.38-7.42 (m, 2H, Ar), 7.69-7.82 (m, 4H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:5]=[CH:6][CH:7]=1.II>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Agent: II
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC/C=C/c1cccc(Cl)c1
Yield: 26.3 %

Procedure:
A solution of cis-N-[4-(3-chlorophenyl)-but-3-enyl]-phthalimide (1.9 g) and iodine (50 mg) in 500 mL toluene was irradiated for 5 days with a 100-watt incandescent light bulb. The solvent was removed in vacuo and the residue was recrystallized from toluene/methanol to give 0.50 g of trans-N-[4-(3-chlorophenyl)-but-3-enyl]-phthalimide (no cis-isomer was observed by 1H-NMR).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) (Example 11b) in chloroform (2 mL) was added pyridine (0.099 mL, 1.226 mmol) followed by benzenesulfonyl chloride (0.059 mL, 0.460 mmol). The reaction mixture was stirred at room temperature for 1 hr. The saturated solution of NH4Cl was added, and layers were separated. Organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at the room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. trans-2-phenyl-N-((1-(phenylsulfonyl)piperidin-4-yl)methyl)cyclopropanamine (10 mg, 0.026 mmol, 8.37% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.76-7.85 (m, 2H), 7.65-7.73 (m, 1H), 7.52-7.66 (m, 2H), 7.15-7.28 (m, 2H), 7.06-7.16 (m, 1H), 6.97-7.05 (m, 2H), 3.77 (d, J=12.13 Hz, 2H), 2.57 (dd, J=1.26, 6.82 Hz, 2H), 2.13-2.35 (m, 3H), 1.72-1.97 (m, 3H), 1.36-1.54 (m, J=3.73, 3.73, 7.33, 7.33, 14.78 Hz, 1H), 1.14-1.35 (m, 2H), 0.90-1.10 (m, 2H); LC-MS Rt=0.76 min; MS (ESI): 370.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].Cl[C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>O1CCCC1>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[S:13](=[O:14])(=[O:15])[NH2:16])=[O:24]
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: COC(=O)CC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
2-Amino-5-methanesulfonylamino-benzenesulfonamide (prepared as described in Example 1d, 1.70 kg, 6.40 mol) was dissolved in tetrahydrofuran (35 L), and was then cooled to 0° C. Methyl 3-chloro-3-oxopropionate (792 mL, 7.40 mol) was added slowly, and the resulting mixture was then allowed to warm to 23° C. and stirred for 2 days. The solvent was removed in vacuo, and the residue was then diluted with water (4 L) and saturated aqueous sodium bicarbonate solution (2 L). The resulting solid was filtered, and was then washed with water (5 L). The solid was suspended in hot methanol (15 mL/g), and was then cooled to 23° C. and filtered to afford the desired product, N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (1.68 kg, 4.61 mol, 72%), as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.02 (3H, s), 3.60 (2H, s), 3.66 (3H, s), 7.38 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.53 (2H, bs), 7.73 (1H, d, J=2.4 Hz), 7.83 (1H, d, J=8.7 Hz), 9.43 (1H, s), 9.99 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:67](I)[CH3:68]>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH2:67][CH3:68])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCI
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: CCN(C(C)=O)c1nc(C)c(S(=O)(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)OC)OC[C@@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)s1

Procedure:
(S)-2-({(3R,8S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (49 mg) was reacted with ethyl iodide (16 mg) according to General Procedure T to obtain (S)-2-({(3R,8S)-7-[2-(acetyl-ethyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This was hydrolyzed according to General Procedures N and B to give the title compound (17 mg). LCMS: (m/z) 938.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=O)[CH2:4][C:5]1[C:6]2[CH:12]=[CH:11][S:10][C:7]=2[NH:8][CH:9]=1>C1COCC1>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[C:6]2[CH:12]=[CH:11][S:10][C:7]=2[NH:8][CH:9]=1)[CH3:14]
Reactant: CN(C)C(=O)Cc1c[nH]c2sccc12
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2sccc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A stirred N,N-dimethyl-2-(6H-thieno[2,3-b]pyrrol-4-yl]acetamide (1.16 g, 6 mmol) in THF is treated with LiALH4 (18 mL of 1M solution in THF, 3 equiv.) at room temperature, stirred at 40° C. for 2 h, cooled to room temperature, quenched with aqueous NaOH and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to afford the title product as a tan oil, 0.81 g (89% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH:10]([CH2:12][O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1-Boc-azetidin-3-yl)-methanol (1.06 g, 5.7 mmol), TEA (1.18 mL, 8.52 mmol) in CH2Cl2 at 0° C. was added MeSO2Cl (0.53 mL, 6.82 mmol) via a syringe. The reaction was warmed to RT over 2 h and stirring was continued at RT for 2 h. The white solid formed was removed by filtration and the filtrate was washed with 25 mL of H2O. The organic phase was dried over Na2SO4, and concentrated in vacuo to afford yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[S:17][CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH3:21][C:20]1[CH:19]=[CH:18][S:17][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: Cc1ccsc1Br
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2sccc2C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 2-bromo-3-methylthiophene (70 μL, 0.62 mmol) according to the general procedure IF to give 75 mg (53%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5): Rf=0.57 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 7.47-7.40 (m, 2H), 7.17 (dd, J=8.4, 6.7 Hz, 3H), 6.85 (d, J=5.1 Hz, 1H), 3.67 (s, 3H), 2.96 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.37 (s, 3H); 13C NMR (CDCl3) δ 173.1, 142.4, 140.8, 131.5, 129.2, 128.3, 125.7, 121.2, 118.7, 95.2, 82.0, 51.6, 35.4, 30.8, 15.0; ESI-MS m/z 307.1 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
To a solution of tert-butyl 2-[(2-chloro-6-fluorobenzoyl)carbamoyl]-2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate (3.0 g, 6.45 mmol) in DCM (30 mL) was added trifluoro acetic acid (2.0 mL). The reaction mass was stirred at RT for 2-3 h. Excess of solvent was removed at low temperature. The reaction mass was quenched in ice and filtered off to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.86 (s, 3H), 7.51-7.60 (m, 2H), 7.70 (br s, 1H), 8.09 (br s, 4H), 12.79 (br s, 1H); MS (m/z): 348.55 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[C:16]=2[N:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O>[I:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][S:22]([C:17]2[C:16]3[N:15]=[CH:14][CH:13]=[N:12][C:21]=3[CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:24])[CH:10]=1
Reactant: O=S(=O)(Cl)c1cccc2nccnc12
Reactant: Nc1cc(I)ccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
A mixture of 2-amino-4-iodo-benzoic acid (10 g, 38 mmol, 1.0 equiv.) and quinoxaline-5-sulfonyl chloride (8.7 g, 38 mmol) in 100 mL of water was basified with satd. aq. Na2CO3, with stirring, to adjust the pH to 8.0. As the reaction progressed, the pH was maintained at 8.0±0.2 by adding satd. aq. Na2CO3. After 3 h, no further pH changes were observed. The reaction mixture was stirred at rt for another 16 h. Conc. HCl was added to adjust the pH to <2. The precipitated solid was collected by filtration, washed with water and dried to afford the title compound as white solid (17 g, 37.4 mmol, 98%). MS (ESI+): calcd. for C15H10IN3O4S, 455.0; m/z found, 456 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.0 (br s, 1H), 11.6 (s, 1H), 9.10 (d, J=1.5, 1H), 9.97 (d, J=1.5, 1H), 8.60 (d, J=7.4, 1H), 8.42 (d, J=8.4, 1H), 8.06 (t, J=7.5, 1H), 7.95 (d, J=1.2, 1H), 7.51 (d, J=8.3, 1H), 7.37 (dd, J=8.3, 1.2, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17].[C:18](O)(=[O:40])[CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[O:17]=[C:12]1[CH:13]=[CH:14][C:15](=[O:16])[N:11]1[CH2:10][CH2:9][NH:8][C:18](=[O:40])[CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH3:39]
Reactant: NCCN1C(=O)C=CC1=O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
The TFA salt of 1-(2-aminoethyl)-1H-pyrrole-2,5-dione (Aldrich, 280 mg, 1.10 mmol) was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (360 mg, 1.1 mmol), HATU (460 mg, 1.2 mmol) and DIEA (0.58 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2,5-dioxo-2H-pyrrol-1(5H)-yl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (350 mg, 70%).