Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=[C:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:19][CH2:18]3)[C:6]=2[CH:31]=1.[BH4-].[Na+].C(O)(=O)C(O)=O>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:21][CH2:22]3)[C:6]=2[CH:31]=1
Reactant: Cc1ccc2c(c1)C=C(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.0 G. of 3-{2-[4-(8-chloro-2-methyl-dibenzo[b,f]thiepin10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone is stirred at room temperature with 50 ml. of diethyleneglycol dimethyl ether (diglyme) and 0.6 g. of sodium borohydride for 30 minutes under an atmosphere of argon. Thereafter, a solution of 2.8 g. of oxalic acid (C2H2O4 . 2H2O) in 15 ml. of diglyme is added dropwise at 20°-30°C. The mixture is stirred at 100°C. for 4 hours, and subsequently evaporated under reduced pressure. The residue is taken up in 2N sodium hydroxide and water, and extracted three times with 100 ml. of benzene each time. The combined benzene phases are washed with water, dried over magnesium sulfate, filtered and concentrated. The crystalline residue is recrystallized from ethyl acetate/petroleum ether (low boiling), whereby there is obtained 3-{2-[4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone, having a melting point of 184°-186°C. The maleate crystallizes from methanol/ether and melts at 174°-175°C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)([CH3:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(C)OC(=O)CCc1ccccc1
Yield: 94 %

Procedure:
To a mixture of 3-phenylpropionic acid (15.0 g) and isopropanol (6.61 g) in pyridine (30 ml) perchloric acid (0.150 g) and DCC (24.8 g) are added. After stirring at room temperature for 24 h acetic acid (10 ml) is added, and the reaction mixture is worked-up as described in Example 1 to give a 94% yield of isopropyl 3-phenylpropionate (b. p., see Example 2).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CS(C)=O>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([C:18](=[O:19])[NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3,N-diphenyl-propionamide in DMSO to provide the title compound in moderate yield.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](O)[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:24]([N:31]1[CH2:36][CH2:35][N:34](C2C=CC(N)=CC=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[C:45]1[N:50]=[C:49](Cl)[C:48](F)=[CH:47]N=1>>[CH2:49]([N:50]1[CH2:45][CH2:9][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:8][C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:34]5[CH2:33][CH2:32][N:31]([CH2:24][C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH2:36][CH2:35]5)=[CH:18][CH:17]=4)[C:12]([F:23])=[CH:11][N:10]=3)=[CH:3][CH:2]=2)[CH2:4][CH2:3]1)[C:48]1[CH:47]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Product: Fc1cnc(Nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 64 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 4-(N-benzylpiperazino)aniline (400 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) resulted N2,N4-bis[4-(N-benzylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine (120 mg, 64%). 1H NMR (CDCl3): δ 2.63 (p, J=2.4 Hz, 8H), 3.14 (t, J=4.8 Hz, 4H), 3.19 (t, J=4.8 Hz, 4H), 3.58 (s, 4H), 6.58 (d, 1H, NH), 6.67 (br, 1H, NH), 6.87 (d, J=9.3 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 7.33-7.39 (m, 12H), 7.46 (d, J=9.0 Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ−169.06; LCMS: 16.82 min.; purity: 96.88%; MS (m/e): 629.12 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:10])=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:4]=1
Reactant: C[C@H](N)c1ccc(F)cc1C(F)(F)F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(F)cc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(4-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 589 [M+H]+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[NH2:21][CH:22]([CH2:35][OH:36])[CH2:23][O:24][C:25]1[C:29]2[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=2[O:27][N:26]=1.C(N(CC)CC)C.Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]2[O:27][N:26]=[C:25]([O:24][CH2:23][CH:22]([NH:21][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:35][OH:36])[C:29]=2[CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(CO)COc1noc2ccc(Cl)cc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: OCC(COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 5.58 g of trityl chloride in 6 ml of N,N-dimethylformamide is added to a solution of 4.85 g of 3-(2-amino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole and 2.02 g of triethylamine in 12 ml of N,N-dimethylformamide at -40° to -30° C., and they are subjected to reaction at the same temperature for 30 minutes. Subsequently, ice water and ethyl acetate are added to the reaction mixture and the pH is adjusted to 2 with 2N hydrochloric acid. The organic layer is separated, and the separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is crystallized from n-hexane and the crystals are collected by filtration, to obtain 7.28 g of colorless, crystalline 5-chloro-3-(2-tritylamino-3-hydroxypropoxy)-1,2-benzoisoxazole having a melting point of 142°-144° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])(O)=O.[Na+].[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:45]([O:47][CH3:48])=[O:46])=[CH:31][C:32]=3[N:33]3[C:39]=2[C:38]2[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=2[NH:36][C:35](=O)[CH2:34]3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1.O>[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:45]([O:47][CH3:48])=[O:46])=[CH:31][C:32]=3[N:33]3[C:39]=2[C:38]2[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=2[NH:36][C:35](=[S:2])[CH2:34]3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Nc1ccccc1-3
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=S)Nc1ccccc1-3
Temperature: 100 °C
Reaction time: 1 h
Yield: 165.6 %

Procedure:
P4S10 (352 mg, 0.791 mmol) and NaHCO3 (554 mg, 6.60 mmol) were added to a solution of methyl 13-cyclohexyl-5H-indolo[1,2-d][1,4]benzodiazepine-6(7H)-one-10-carboxylate (511 mg, 1.32 mmol) in dioxane (10 mL). The reaction mixture was heated at 100° C. for 1 h, cooled to rt, and diluted with the dropwise addition of H2O (˜20 mL) while stirring. The resulting yellow precipitate was allowed to settle for 1 h, collected by filtration, flushed with water and dried under N2 to yield methyl 13-cyclohexyl-5H-indolo[1,2-d][1,4]benzodiazepine-6(7H)-thione-10-carboxylate (528 mg, 1.31 mmol, 99%) as yellow solid, which was used without further purification. LCMS: 405 (M+H)+, ret time 2.26 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH3:12][NH:13][C:14](=[O:17])[NH:15][NH2:16].Cl>O.C(O)C>[CH3:12][NH:13][C:14](=[O:17])[NH:15][N:16]=[CH:10][C:3]1[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=1
Reactant: CNC(=O)NN
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC(=O)NN=Cc1ncc([N+](=O)[O-])n1C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 8.5 grams (0.055 mole) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde in 50 ml. of ethanol is added a solution of 5.0 grams (0.056 mole) of 4-methylsemicarbazide in 25 ml. of ethanol and 10 ml. of water containing 2-4 drops of concentrated hydrochloric acid. The resulting solution is heated at 60°-70° C. until a yellow solid starts to separate and then stored at 0° C. for 1 hour; 12.2 grams (98%) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde-4-methylsemicarbazone is obtained melting at 221°-223° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>>[ClH:16].[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N
Reactant: N#Cc1ccc(Cl)nc1
Product: Cc1ccc2[nH]c3c(c2c1)CCCC3Nc1ccc(C#N)cn1
Product: Cl

Procedure:
6-[(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]nicotinonitrile hydrochloride salt was prepared from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine (0.10 g, 0.50 mmol) and 6-chloronicotinonitrile (0.138 g, 0.1 mmol) in a similar manner as described above to give a light brown solid (0.005 g, 3.0%). 1H-NMR (CDCl3): δ 8.49 (s, 1H), 8.33 (s, 1H), 7.56 (d, 1H), 7.28 (s, 1H), 7.18 (d, 1H), 6.99 (d, 1H), 6.42 (d, 1H), 5.31 (d, 1H), 5.15 (d, 1H) 2.77-2.70 (m, 2H), 2.28-2.25 (m, 1H), 2.00-1.92 (m, 3H); MS m/z 301 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:18]3[CH:19]=[C:20]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[CH:21]=[N:22][CH:23]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.Cl.CC(O)C>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:18]3[CH:19]=[C:20]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[CH:21]=[N:22][CH:23]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)nc34)c2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(-c3cncc(NC4CCCNC4)c3)c2n1
Temperature: 23 °C

Procedure:
A solution of tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (33 mg, 0.050 mmol) in THF (1 mL) was treated with NaOH 10N (0.050 mL, 0.500 mmol). The reaction was heated to reflux at 80° C. After 4 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-6% MeOH/DCM), affording tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (21 mg, 83%). MS (ESI, pos. ion) m/z: 506.3 (M+1) A solution of tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (21 mg, 0.042 mmol) in MeOH (1 mL) was treated with HCl, 5-6N in IPA (0.083 mL, 0.415 mmol). The reaction was heated to 50° After 1 h, the reaction was cooled to 23° C., and the product (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N-(piperidin-3-yl)pyridin-3-amine MS (ESI, pos. ion) m/z: 406.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][C:11]1[CH:21]=[N:20][CH:19]=[C:18]([CH3:22])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCOCC1>[Br-:1].[CH2:16]([O:15][C:13]([C:12]1[C:11]([CH3:10])=[CH:21][N+:20]([CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:2])=[CH:19][C:18]=1[CH3:22])=[O:14])[CH3:17]
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1c(C)cncc1C
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)c[n+](C(C)c2ccccc2)cc1C
Product: [Br-]

Procedure:
1-(bromoethyl)benzene (1.3 g, 7.03 mmol) was added to ethyl 3,5-dimethylisonicotinate (0.7 g, 3.91 mmol) in dioxane (20 mL) and the resultant mixture was stirred at reflux overnight. The resulting solution was used to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][N:26]=[N+:27]=[N-:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](CCCBr)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCN=[N+]=[N-])N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 240 h
Yield: 97.9 %

Procedure:
To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-bromobutyl]-benzenesulfonamide (0.505 g, 1.12 mmol) in THF/H2O (8/2, 10 mL) was added sodium azide (0.363 g, 5.58 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 10 days. The mixture was extracted with ether (3×20 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.455 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-azidobutyl]benzenesulfonamide as a colorless oil in 98% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12]/[C:13](/[CH3:23])=[CH:14]\[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16].[CH:24]([NH:27][C:28](=[O:33])[CH2:29][C:30]([CH3:32])=O)([CH3:26])[CH3:25]>C(O)C>[CH3:32][C:30]1[NH:12][C:13]([CH3:23])=[C:14]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:29]=1[C:28]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:33]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCCCCOC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)NC(C)C
Solvent: CCO
Product: CCCCCOC(=O)C1=C(C)NC(C)=C(C(=O)NC(C)C)C1c1ccccc1[N+](=O)[O-]
Yield: 29.8 %

Procedure:
o-Nitrobenzaldehyde (3.8 g, 0.025 mole), n-pentyl 3-aminocrotonate (4.3 g, 0.025 mole) and acetoacetic isopropylamide (3.6 g, 0.025 mole) are dissolved in ethanol (50 ml), and the mixture is refluxed for 8 hours. After the reaction, the solvent is distilled off under reduced pressure. The residue is dissolved in elution solvent [chloroform:carbon tetrachloride:ethyl formate:formic acid:ethanol (10:10:8:1:2)] (30 ml) and subjected to column chromatography [silica gel 60 Art. 9385 (Manufactured by Merck Co.), 300 g, φ40 mm×50 cm]. The fraction containing the desired compound is regulated to pH 10 with 28% aqueous ammonia, and the organic layer is separated, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is recrystallized from 80% ethanol to give the title compound (3.2 g, yield 30.0%) as yellow prisms, m.p. 186°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](Cl)=[N:14][OH:15])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:37][CH:38](Cl)[CH3:39]>>[Cl:37][C:38]1[O:15][N:14]=[C:13]([C:12]2[CH:17]=[CH:18][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:2]([Cl:1])=[CH:22][C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])=[CH:20][C:19]=3[Cl:29])=[CH:10][CH:11]=2)[CH:39]=1
Reactant: CC(Cl)Cl
Reactant: ON=C(Cl)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Solvent: CCN(CC)CC
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3cc(Cl)on3)cc2)c(Cl)c1
Reaction time: 1 h

Procedure:
150 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzimidoyl chloride are placed in 1 ml of 1,1-dichloroethane at 0° C., and a solution of 76 mg of triethylamine in 1 ml of 1,1-dichloroethane is added dropwise thereto over a period of one hour. After one hour at 0° C. and 18 hours at 25° C., the reaction mixture is poured onto water and extracted with ethyl acetate. Concentration and purification over silica gel yield the title compound (compound 1.17).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]>C(Cl)Cl>[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49]([NH:6][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.6 %

Procedure:
3,5-Bistrifluoromethylaniline (0.368 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.196 g, 0.335 mmol, 63%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:32].[CH3:33][NH2:34].CCO.[BH4-].[Na+]>C1COCC1>[CH3:33][NH:34][CH:11]([C:10]1[CH:9]=[CH:8][C:7]2[C:6](=[O:32])[O:5][CH2:4][C:3]=2[C:2]=1[CH3:1])[CH2:12][N:13]1[CH2:14][CH2:15][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH2:23][O:24][C:25](=[O:28])[C:26]=3[CH3:27])[CH2:18][CH2:17]2)[CH2:29][CH2:30]1
Reactant: CN
Reactant: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(CN1CCC2(CC1)CCN(C1=C(C)C(=O)OC1)C2=O)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 8-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (25 mg, 0.057 mmol) and methyl amine (4 mg, 0.114 mmol) in anhydrous THF was added Ti(O-iPr)4 (35 μL, 0.114 mmol). The reaction was sealed and shaken at ambient temperature for 16 hr. To this reaction, EtOH (200 proof, 0.5 mL) was added followed by adding NaBH4 (11 mg, 0.171 mmol) portion-wise within 30 min. The reaction was shaken for 3 hr and quenched with water (0.5 mL). The reaction was partitioned between EtOAc (4 mL×2) and ammonium (2N, 1.5 mL). The organic phase was combined and evaporated under reduced pressure. The residue was dissolved in DMSO (1.5 mL) and filtered. The crude product was purified by using reversed-phase HPLC (Acetonitrile with 0.1% TFA: water with 0.1% TFA from 10% to 60%) to give the title compound. LC-MS (IE, m/z): 454 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:19]([O:26][C:27](=[O:35])[C@@H:28]([NH2:34])[CH2:29][O:30][CH:31]([F:33])[F:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CN1CCOCC1>ClCCl.C(OCC)(=O)C>[CH2:19]([O:26][C:27](=[O:35])[C@@H:28]([NH:34][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][O:14][CH:15]([F:17])[F:16])[CH2:29][O:30][CH:31]([F:33])[F:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of the compound of Formula IV(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxypropionic acid (1.15 g, 4.49 mmol) and the compound of Formula V(a), (S)-2-amino-3-difluoromethoxypropionic acid benzyl ester hydrochloride salt (1.15 g, 4.08 mmol), HOBt (0.689 g, 5.10 mmol) and EDCl.HCl (0.867 g, 5.10 mmol) in dichloromethane (20 mL) was added N-methylmorpholine (0.45 mL, 8.16 mmol) dropwise at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then diluted with ethyl acetate and washed successively with water, 1N HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica-gel column chromatography, eluting with 10% to 12.5% ethyl acetate in hexanes, to give the compound of Formula II(a)(ii), (S)-2-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionylamino)-3-di-fluoromethoxy-propionic acid benzyl ester (1.29 g, 65%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.35-7.41 (m, 5H), 7.18 (td, 1H), 6.18 (wt, 1H), 6.22 (wt, 1H), 5.25-5.20 (m, 1H), 5.19 (s, 2H), 4.82 (td, 1H), 4.42 (br s, 1H), 4.31 (td, 1H), 4.20-4.15 (m, 2H), 4.01 (dd, 1H), 1.41 (s, 9H).