Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:21]Br>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:21][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: BrBr
Reactant: O=C(Nc1cnc2[nH]ccc2c1)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cnc2[nH]cc(Br)c2c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Benzyl 1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (9.48 g, 35.5 mmol) in chloroform (100 mL) was cooled to 5° C. and treated dropwise with bromine (1.86 mL, 36.21 mmol, 1.02 Eq). The reaction was allowed to stir at 0° C. for 1 hour and then at room temperature for 1 hour. The mixture was diluted with DCM and washed with a 1:1 sat. aq. sodium thiosulfate/sodium bicarbonate solution (200 mL). The organic layer was separated and the aqueous layer taken to pH 12 and re-extracted with EtOAc. The combined organics were dried over magnesium sulphate, filtered and dried under vacuum and the resultant brown solid triturated with diethyl ether/EtOAc to give 10.24 g (83%) of the title compound.
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:18]([C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:25])=[CH:22][CH:21]=1)=O.N=[C:37]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:38][C:39]([NH2:41])=[O:40]>CCO>[CH2:7]([O:6][C:4]([C:3]1[CH:18]([C:20]2[CH:35]=[CH:34][C:23]([C:24](=[O:25])[NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:22][CH:21]=2)[C:38]([C:39](=[O:40])[NH2:41])=[C:37]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:1][C:2]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C=C(N)CCc1ccc(F)cc1
Reactant: CC(C)CC(=N)CC(N)=O
Reactant: O=Cc1ccc(C(=O)NCc2cccnc2)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(CCc2ccc(F)cc2)NC(CC(C)C)=C(C(N)=O)C1c1ccc(C(=O)NCc2cccnc2)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Ethyl 3-amino-5-(4-fluorophenyl)-2-pentenoate 4 (119 mg, 0.5 mmol), 4-formyl-N-pyridin-3-ylmethyl-benzamide 8 (120 mg, 0.5 mmol) and 3-Imino-5-methyl-hexanoic acid amide 11 (92 mg, 0.65 mmol) were dissolved in EtOH (4 mL). The reaction was stirred at 120° C. overnight. The crude reaction mixture was purified via reverse phase LC/MS to yield, 29 mg of target material. The compound was characterized by NMR and LC/MS. 1H NMR (500 MHz, CDCl3): δ 8.79 (s, 1H), 8.51 (d, J=4.7 Hz, 1H), 8.29 (d, J=7.9 Hz, 1H), 7.68 (m, 4H), 7.28 (d, J=8.5 Hz, 1H), 7.08 (m, 2H), 6.90 (m, 2H), 4.63 (br. s, 2H), 4.04 (q, J=6.8 Hz, 2H), 3.37 (s, 1H), 2.86 (q, J=7.2 Hz, 2H), 2.78 (m, 3H), 2.50 (m, 1H), 1.65 (m, 1H), 1.17 (t, J=6.7 Hz, 3H), 0.82 (t, J=6.9 Hz, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38]O)=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][Br:20])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCc1nn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
To a stirring solution of 550 mg (2.09 mmol, 1.3 equiv) of triphenylphosphine in 10 mL of acetonitrile at 0° C. is added 0.1 mL (1.93 mmol, 1.2 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 383 mg (1.61 mmol) of (1-Benzyl-1H-indazol-3-yl) methanol, prepared as in Intermediate 15, in 5 mL of acetonitrile is added over 2 min. The resulting solution is stirred 1 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 305 mg of the title compound as a white solid: 1H NMR (CDCl3, 300 MHz) δ7.82 (d, 1H), 7.40-7.16 (m, 8H), 5.59 (s, 2H), 4.90 (s, 2H); Rf =0.75 in hexane/EtOAc 2/1.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:22]3[CH:30]=[CH:31][C:32]([C:34](=[N:36][OH:37])[NH2:35])=[CH:33][C:21]=3[N:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O1CCCC1>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:22]3[CH:30]=[CH:31][C:32]([C:34]4[NH:35][S:1](=[O:2])[O:37][N:36]=4)=[CH:33][C:21]=3[N:20]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=NO)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S1NC(c2ccc3c(c2)nc(-c2ccc(OCc4ccccc4)cc2)n3C2CCCCC2)=NO1
Reaction time: 3 h
Yield: 39.7 %

Procedure:
Thionyl chloride (0.010 mL, 0.14 mmol) was added dropwise to a suspension of 2-[4-(Benzyloxy)phenyl]-1-cyclohexyl-N′-hydroxy-1H-benzimidazole-5-carboximidamide (0.025 g, 0.057 mmol, see above for preparation) and pyridine (0.020 mL, 0.25 mmol) in tetrahydrofuran (2 mL) at 0° C. The resulting solution was stirred for 3 h, and then concentrated on a rotary evaporator. As starting material remained, the residue was resubjected to the reaction conditions (0.020 mL thionyl chloride and 0.040 mL pyridine). The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a yellow solid (0.011 g, 32%). 1H NMR (CD3OD) δ 8.32 (d, 1H, J=8.8 Hz), 8.25 (s, 1H), 8.04 (d, 1H, J=8.8 Hz), 7.77 (d, 2H, J=9.1 Hz), 7.49 (d, 2H, J=6.6 Hz) 7.43-7.35 (m, 5H), 5.27 (s, 2H), 4.55 (m, 1H), 2.45 (m, 2H), 2.15 (m, 2H), 2.00 (m, 2H), 1.80 (m, 1H), 1.44 (m, 3H); ESI-MS m/e 487.3 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])=[O:4]>CCO.C(Cl)Cl>[OH:4][CH2:3][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccccc1-n1ccc2c(C=O)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1ccccc1-n1ccc2c(CO)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
NaBH4 (50 mg, 1.35 mmol Eq: 0.4) was added to a solution of 2-(4-formyl-1H-indol-1-yl)benzonitrile (810 mg, 3.29 mmol, Eq: 1.00) in EtOH (30 mL) and DCM (15 mL) at 0° C. and the mixture warmed to RT. After 3 h., the mixture was concentrated to remove the DCM. The resulting mixture was diluted with sat. NH4Cl, extracted with DCM and the combined extracts concentrated. The residue was purified by silica gel chromatography to afford the title compound (810 mg, 99%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH:37]([NH2:47])CC2C=CC(OC)=CC=2)[CH:6]=1.NCCCO[C:53]1[CH:81]=[C:80]([O:82][CH3:83])[CH:79]=[CH:78][C:54]=1[C:55](NC1C=C([N+]([O-])=O)C=CC=1C(NC1C=CC(OC)=CC=1)=O)=O.COC1C=CC(C=O)=CC=1>>[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH2:37][NH:47][CH2:55][C:54]2[CH:53]=[CH:81][C:80]([O:82][CH3:83])=[CH:79][CH:78]=2)[CH:6]=1
Reactant: COc1ccc(CC(N)CCOc2cc(OC)ccc2C(=O)Nc2cc([N+](=O)[O-])ccc2C(=O)Nc2ccc(OC)cc2)cc1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Agent: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CNCCCOc2cc(OC)ccc2C(=O)Nc2cc([N+](=O)[O-])ccc2C(=O)Nc2ccc(OC)cc2)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(4-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (48 mg, 0.078 mmol, 52%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 4-methoxybenzaldehyde.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])N.[K+].O>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1nc[nH]n1
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-fluoro-2-methylnitrobenzene (2 g), 1,2,4-triazole (0.9 g) and anhydrous potassium carbamate (1.78 g) was stirred and heated in dimethylsulphoxide (50 ml) at 90° C. for 24 hours. The reaction mixture was cooled, poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was separated, dried (MgSO4) and evaporated to give an orange solid which was purified by chromatography on silica using pentane/ethyl acetate as eluant, (1.8 g, 69%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH:7]=[CH2:8].[C:10](OC)(=[O:14])[C:11]([CH3:13])=[CH2:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:10]([O:9][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH:7]=[CH2:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=CC/C=C/CCCO
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC/C=C/CCCOC(=O)C(=C)C
Yield: 87 %

Procedure:
The method of Example 1 was substantially repeated, except that a shorter vigreux head (15 cm) was used, with trans-4,7-octadien-1-ol (18.53 g, 0.146 mol), methyl methacrylate (58.8 g, 0.59 mol), phenothiazine (0.5 g), and tetraisopropyl titanate (1.0 mL). When the head temperature rose to 96° C. (pot 117° C.), the methyl methacrylate was removed at 70 mm and the product was distilled to give 24.8 g (87% yield) of clear, colorless liquid trans-4,7-octadienyl methacrylate, bp 64°-65° C./0.2 mm. IR (film): ν 2950, 1712, 1629, 1445, 1311, 1287, 1156, 964, 933, 907, 810 cm-1. UV (isooctane): end absorption. 220 MHz 1H NMR: δ 6.06 (1H, bs, methacrylate vinyl), 5.76 (1H, m, --HC=CH2), 5.50 (1H, m, methacrylate vinyl), 5.41 (2H, m, --HC=CH--), 5.02-4.92 (2H, m, --HC=CH2), 4.11 (2H, t, J=6, OCH2 --), 2.72 (2H, m, doubly allylic CH2), 2.10 (2H, m, allylic CH2), 1.95 (3H, m, allylic CH3), and 1.73 (2H, pentet, J=6, OCH2CH2CH2). 22.63 MHz 13C NMR: δ 167.2, 137.1, 136.7, 130.2, 128.9, 124.9, 115.0, 64.1, 36.8, 29.1, 28.6, 18.3.
Reaction SMILES: CC1(C)OC(=O)CC(=O)O1.C(O)CCCCCO.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22](S(O)(=O)=O)=[CH:21][CH:20]=1.[C:30]([O:43]CCCCCCO)(=[O:42])[CH2:31][C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])=[O:33].C(O)(=O)C.[NH:55]1[CH2:60][CH2:59]C[CH2:57][CH2:56]1>O.CC(C)=O>[OH:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][C:32]([C:31]1[C:30](=[O:42])[O:43][C:24]2[C:19]([CH:29]=1)=[CH:20][CH:21]=[C:22]([N:55]([CH2:60][CH3:59])[CH2:56][CH3:57])[CH:23]=2)=[O:33]
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(CC(=O)OCCCCCCO)OCCCCCCO
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: OCCCCCCO
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCN(CC)c1ccc2cc(C(=O)OCCCCCCO)c(=O)oc2c1

Procedure:
In this scheme, bis-(6-hydroxyhexyl) malonate is first produced by reacting the Meldrum's acid and 1,6-hexanediol in the presence of catalytic quantities of p-toluene-sulphonic acid with elimination of acetone and water. The bis-(6-hydroxyhexyl) malonate is then combined with 4-diethylaminosalicylic aldehyde in the presence of catalytic quantities of piperidine acetate to form the desired 3-(6-hydroxyhexoxycarbonyl)-7-diethylaminocoumarin.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCCCCCC>CC#N>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:16]2[N+:17]([O-:19])=[O:18])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: O=[N+]([O-])CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC#N
Product: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.6 %

Procedure:
To a solution of N-benzylmaleimide (5.0 g, 26.7 mmol) in MeCN (334 ml) was added bromonitromethane (1.87 ml, 26.7 mmol). K2CO3 (3.69 g, 26.7 mmol) was added and the reaction mixture vigorously stirred at r.t. After 4 h an additional portion of bromonitromethane (0.2 ml) was added. Further addition of bromonitromethane (0.2 ml) was added at further 4 h intervals (×4). After 48 h, TLC (50% DCM/heptane) indicated reaction completion. The reaction mixture was evaporated to dryness. The brown residue was purified by column chromatography (100% DCM), giving the title compound as a white solid (3.0 g, 42%). 1H NMR (300 MHz, CDCl3) δ: 3.35 (2H, s), 4.50 (1H, s), 4.55 (2H, s), 7.2-7.4 (5H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].FC(F)(F)S(O[Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])(=O)=O.C(N(CC)CC)C.[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32]>ClCCl>[C:31]([O:35][C:36](=[O:39])[CH2:37][NH:1][CH2:2][CH2:3][CH2:4][O:5][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCCCO
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OCCCNCC(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To a solution of 3-amino-1-propanol (2.0 mL, 26 mmol) in dichloromethane (20 mL) was added triisopropylsilyl trifluoromethanesulfonate (7.2 mL, 27 mmol), and the mixture was stirred at room temperature for 1 hour. Triethylamine (3.7 mL, 26 mmol) and bromoacetic acid tert-butyl ester (3.1 mL, 21 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give the title compound (1.85 g, 5.4 mmol, 25%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(=O)C(=O)N2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
A mixture of 5-methyl-1H-indole-2,3-dione (5-methylisatin, 2.0 g, 12.41 mmol), phenylboronic acid (3.027 g, 24.82 mmol), anhyd cupric acetate (4.50 g, 24.77 mmol), activated 4A molecular sieve (6.6 g), triethylamine (3.47 mL, 24.9 mmol), pyridine (2.01 mL, 24.9 mmol) and dichloromethane (165 mL) is stirred for 24 hr at room temperature. The mixture is filtered through a pad of hyflo and evaporated. The residue is stirred with ethyl acetate, the insoluble copper salts removed by filtration and the filtrate is evaporated. The residue is purified by flash chromatography eluting with dichloromethane to give the title compound (1.91 g, 65% yield) as an orange solid. MS 238 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[N:4]([S:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:24])=[O:23])[C:3]1=[O:8]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)NC(=O)N(S(=O)(=O)c2cccc3ccccc23)C1=O
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthalene sulfonyl chloride (2.38 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, 150 mL of ethyl acetate was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 369 mg of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:68][CH2:69][CH2:70][CH2:71][CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:68][CH2:69][CH2:70][CH2:71][CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: CCOC(=O)CCCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.67 mmol), HATU (281 mg, 0.74 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of ethyl 5-aminovalerate hydrochloride (145 mg, 0.80 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to give ethyl 5-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanoate as white solid. Yield: 288 mg, 75%.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[C:19]([F:21])[CH:20]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[C:19]([F:21])[CH:20]=1.[F:14][C:15]1[CH:16]=[C:17]([C:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH:3]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Fc1cc(F)cc([Mg]Br)c1
Product: COC(=O)c1cc2c([nH]1)CC=C2c1cc(F)cc(F)c1
Product: COC(=O)c1cc2c([nH]1)CCC2c1cc(F)cc(F)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) was reacted with 3,5-difluorophenylmagnesium bromide (14 mL, 6.97 mmol, 0.5 M in THF, 2.5 equiv) according to General Procedure 3 to give methyl 4-(3,5-difluorophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6 (with 5% Pd/C), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane afforded the title compound: 85 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.27 (ddt, 1H), 2.73-3.00 (m, 3H), 3.84 (s, 3H), 4.17-4.23 (m, 1H), 6.60-6.67 (m, 2H), 6.69-6.75 (m, 2H), 9.01 (br. s, 1H) and 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −110.76 (t, J=8.00 Hz).
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:9]\[CH2:10][PH:11]([CH2:13][OH:14])=[O:12])/[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[H][H]>CO>[C:1]([NH:4][C@H:5]([CH2:9][CH2:10][PH:11]([CH2:13][OH:14])=[O:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Solvent: CO
Product: CC(=O)N[C@H](CC[PH](=O)CO)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(Z)-2-acetylamino-4-hydroxymethylphosphinyl-2-butenoic acid (4.0 g, 18 mmol), (RuCl((R)-segphos)2(μ-Cl)3(Et2NH2) (0.150 g, 0.09 mmol), and methanol (40 ml) were added to a 200 ml autoclave, and a nitrogen substitution and a hydrogen substitution were performed. The temperature in the autoclave was set to 70° C., hydrogen gas was charged to 1 MPa, and the reaction solution was stirred at the same temperature for 5 hours. A part of the reaction solution was taken as a sample. After completion of the reaction was confirmed with HPLC analysis on the sample, reaction solution was cooled to room temperature, hydrogen was released, and then the reaction solution was moved to a 100 ml flask. After methanol was removed in vacuo and adding water (20 ml), the water phase was washed with toluene (10 ml) twice and a solution of (R)-2-acetylamino-4-hydroxymethylphosphinylbutanoic acid was obtained. The optical purity of the obtained (R)-2-acetylamino-4-hydroxymethylphosphinylbutanoic acid was 92.8% ee. Further, the conversion rate was 100%.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH3:12]>C(OCC)C>[ClH:3].[CH3:12][C:11]1[N:10]=[CH:9][NH:8][C:7]=1[CH2:6][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: Cc1[nH]cnc1CO
Solvent: CCOCC
Product: Cc1nc[nH]c1CCl
Product: Cl
Temperature: 10 °C
Yield: 91 %

Procedure:
Thionyl chloride (50 ml) was stirred under nitrogen in an ice bath while 4-hydroxymethyl-5-methylimidazole (11.2 g, 0.1 m) was added in very small portions over a 15 minute period. The reaction was vigorous and the temperature was maintained between 10° and 20° C. A colorless precipitate formed. When the addition was complete, the temperature was raised slowly (about 1/2 hour) to 55°±5° C. and maintained at that level for about 1/2 hour. The mixture was then cooled to 10° C. and diluted with 100 ml of diethyl ether. The colorless precipitate was collected by filtration, washed well with diethyl ether and dried in air to give 15.23 g (91% yield) of 4-methyl-5-chloromethyl imidazole hydrochloride, m.p. 208°-211° C. (dec.).