Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)=[CH:25][CH:24]=1)#[N:22].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Agent: CCC(=O)[O-]
Product: N#Cc1ccc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1

Procedure:
This compound is prepared according to synthesis 229, from 200 mg (0.49 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate and 115 mg (0.78 mmol) of 4-cyanophenylboronic acid to give, after purification by chromatography on silica (eluent dichloromethane/methanol 98/2) then recrystallization from methanol, 11 mg (6%) of 8-(4-cyano-phenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a pale yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([CH2:27][S:28][C:29]3[S:30][CH:31]=[C:32]([CH3:34])[N:33]=3)=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]2[CH2:17][CH2:16][NH:15][CH2:21][CH2:20][C:19]=2[C:22]=1[CH2:27][S:28][C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1
Reactant: Cc1csc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(SCc2c(Cl)ccc3c2CCNCC3)n1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Add TFA (19 mL) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-(4-methyl-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.395 g, 0.93 mmol) in anhydrous DCM (19 mL) at room temperature and stir under nitrogen overnight. Concentrate the reaction mixture in vacuo and purify by SCX chromatography (10 g) eluting with DCM and then DCM/2M ammonia in methanol (1:1). Purify again by chromatography on silica gel (40 g) eluting with DCM/2M ammonia in methanol (1:0 to 9:1 gradient over 30 min; 35 mL/min) to obtain 7-chloro-6-(4-methyl-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.297 g, 99%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32]C)=[O:31])=[CH:20][CH:19]=2)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:42])C=1>>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([OH:32])=[O:31])=[CH:20][CH:19]=2)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10]([CH3:11])=[O:42])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Product: CCCCc1nc(S(C)=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 259.4 %

Procedure:
The operation is carried out as in Example 15 starting with 1.55 g of the product obtained in Example 21 using 213 mg of metachloroperbenzoic acid. 1.8 g of crude product is obtained which is chromatographed on silica (eluant: methylene chloride - acetone (7-3)). 1.5 g of desired product is obtained.
Reaction SMILES: [OH:1][C@@H:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]=3[C:37]([F:40])([F:39])[F:38])[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]([O:12]CC)=[O:11])[CH2:5]1>Cl.C(#N)C>[OH:1][C@@H:2]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]=3[C:37]([F:40])([F:39])[F:38])[O:23][N:22]=2)=[CH:19][CH:20]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]([OH:12])=[O:11])[CH2:5]1
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Agent: Cl
Solvent: CC#N
Product: O=C(O)[C@H]1CCCN(C[C@@H](O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
(S)-Ethyl 1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (89 mg, 0.16 mmol) was heated at 50° C. in 6N HCl (5 mL) in acetonitrile (5 mL). The reaction mixture was stirred overnight and then filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 36 mg of (S)-1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.23 (2H, d, J=8.35 Hz), 7.65-7.74 (4H, m), 7.54-7.65 (3H, m), 5.29 (1H, t, J=7.03 Hz), 4.00 (1H, br. s.), 3.43-3.75 (1H, m), 3.34-3.41 (2H, m), 2.82-3.24 (2H, m), 2.26 (1H, d, J=11.86 Hz), 1.84-2.14 (2H, m), 1.52-1.75 (1H, m). MS (m+1)=529. HPLC Peak RT=3.24 minutes. Purity=98%.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:19](=[O:34])[CH:20]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[NH:21][C:22](=[O:27])[CH:23]([NH:25][CH3:26])[CH3:24])[CH2:17][CH2:18][CH:12]12)=O)C1C=CC=CC=1>CO>[CH:28]1([CH:20]([NH:21][C:22](=[O:27])[CH:23]([NH:25][CH3:26])[CH3:24])[C:19]([N:16]2[CH2:17][CH2:18][CH:12]3[NH:11][CH2:15][CH2:14][CH:13]23)=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CNC(C)C(=O)NC(C(=O)N1CCC2C1CCN2C(=O)OCc1ccccc1)C1CCCCC1
Solvent: CO
Product: CNC(C)C(=O)NC(C(=O)N1CCC2NCCC21)C1CCCCC1
Reaction time: 3 h
Yield: 52 %

Procedure:
A 500 mL Parr bottle was charged with 117 (190 mg, 0.40 mmol) and 10% Pd-on-carbon (˜0.5 g) in MeOH (20 mL). The bottle was pressurized to 55 PSI H2 (379.2 KPa) and shaken for 3 h. The catalyst was removed by filtration through diatomaceous earth (Celite®) and washed with EtOAc and MeOH. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase HPLC [Phenomenex Luna C18, 100×21.2 mm, 5-50% ACN/water containing 0.1% HOAc over 30 min; Flow: 20 mL/min]. The product-containing fraction was diluted with water, frozen, and lyophilized to afford 70 mg (52%) of 118.HOAc as a white-colored solid. 1H NMR (300 MHz, d6-DMSO), mixture of amide rotomers: δ9.72 (br s, 1H), 8.80 (d, J=8.1 Hz, 1H), 4.50 (m, 1H), 4.35 (m, 1H), 4.18 (app t, J=6.6 Hz, 1H), 3.99 (app t, J=9.3 Hz, 1H), 3.85 (app q, J=6.6 Hz, 1H), 3.75 (m, 1H), 3.36 (br s, 3H), 3.21 (m, 1H), 2.98 (m, 1H), 2.44 (s, 3H), 2.36 (m, 1H), 2.14 (m, 2H), 1.99 (m, 1H), 1.71-1.51 (m, 5H), 1.34 (d, J=6.9 Hz, 3H), 1.14-0.98 (m, 5H) ppm. 13C NMR (75 MHz, d6-DMSO), mixture of amide rotomers: δ169.5, 169.3, 61.9, 61.3, 56.4, 56.3, 46.9, 45.3, 31.6, 31.3, 29.4, 28.8, 26.3, 26.2, 26.0, 16.4 ppm. Mass spectrum, m/z [337.2] (M+H)+.
Reaction SMILES: C(#N)C.[C:4]([C:6]1[CH:7]=[C:8]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH2:17][CH2:16]2)[C:9]([O:12]C)=[N:10][CH:11]=1)#[N:5].[I-].[Na+].Cl[Si](C)(C)C>O>[C:4]([C:6]1[CH:7]=[C:8]([CH2:14][N:15]2[CH2:16][CH2:17][CH:18](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH2:19][CH2:20]2)[C:9](=[O:12])[NH:10][CH:11]=1)#[N:5]
Reactant: COc1ncc(C#N)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1c[nH]c(=O)c(CN2CCC(/C=C/c3ccccc3F)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To acetonitrile (10 ml) were added 214 mg of 1-[(5-cyano-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine, 137 mg of sodium iodide and 0.1 ml of chlorotrimethylsilane, followed by stirring at room temperature. After 5 hours, 685 mg of sodium iodide and 0.5 ml of chlorotrimethylsilane were added thereto, followed by stirring at room temperature for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium carbonate, an aqueous sodium thiosulfate and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was suspended in an aqueous sodium carbonate, followed by stirring at room temperature. The crystals were collected by filtration, to give 185 mg of the title compound as a slight yellow powder.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15]C(=O)C)[NH:13][CH:14]=2)=[CH:6][CH:5]=1>O.CO.S(=O)(=O)(O)O>[F:19][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1nc(-c2ccc(OC(F)F)cc2)c[nH]1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccc(OC(F)F)cc2)c[nH]1
Yield: 98.7 %

Procedure:
N-[4-(4-Difluoromethoxy-phenyl)-1H-imidazol-2-yl]-acetamide (1.2 g, 4.5 mmol, 1.0 eq) was dissolved in water (30 mL) and methanol (30 mL), and 30 drops of sulfuric acid were added. The reaction was refluxed for 2 days, then the mixture was dried; the residue was diluted with water, the pH adjusted to 8 with NaOH 2N, the product was extracted with DCM and concentrated under reduced pressure to give 1.0 g of the title compound (yield: 99%)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41][CH2:42]1)(=[O:11])[CH3:9]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and acetyl chloride as starting materials in 16% yield. LCMS for C26H28ClN6O2 (M+H)+: m/z=491.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)([O-:3])=[O:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:18]1[CH2:19][CH2:20][O:21][CH:16]([CH2:15][NH:14][C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1

Procedure:
A solution of EXAMPLE 369A (0.8 g) in methylene chloride (10 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hours. The solvents were evaporated and the residue was triturated with diethyl ether. The resulting solid was dissolved in 5% aqueous sodium carbonate solution (20 mL). The mixture was concentrated to dryness and the resulting solid was triturated with a solution of 10% methanol in methylene chloride several times. Evaporation of the organic solvent provided the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([CH2:26][S:27][C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][S:27][C:28]2[NH:30][C:16]([CH3:17])=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:29]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(CSC(=N)N)cc1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 79.5 %

Procedure:
A solution of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, methyl ester (5.0 g, 0.02 mole) in 20 ml of dimethylformamide under argon at room temperature was treated with S-(4-methoxybenzyl)thiopseudourea, hydrochloride (4.65 g, 0.02 mole) and sodium acetate (1.64 g, 0.02 mole). The mixture was then heated at 65±5° C. for 3 hours. Upon cooling, ethyl acetate was added and a small amount of solids were filtered. The filtrate was washed with water (twice), aqueous sodium bicarbonate and saturated brine. The aqueous washes were extracted with fresh ethyl acetate. The combined filtrate and washings were dried (magnesium sulfate) and concentrated in vacuo to give about 9 g of crude product. Crystallization from acetone-isopropyl ether gave 6.8 g of product, melting point 125°-127.5° C., tlc, silica gel, ethyl acetate/hexane (1:1), Rf =0.48.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9]Cl)(=[O:3])[CH3:2].[I-:12].[Na+]>>[C:1]([O:4][C@H:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][I:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: [I-]
Agent: [Na+]
Product: CC(=O)O[C@H](C)CCCCI

Procedure:
First, (R)-5-acetoxy-1-iodohexane was prepared in the following manner. A solution of (R)-5-acetoxy-1-chlorohexane (4.80 g:26.89 mmol) was added to sodium iodide (5.39 g:36 mmol) in a round bottomed flask fitted with magnetic stirrer bar and a reflux condenser and refluxed for 12 hrs with stirring. Acetone was removed under reduced pressure, The crude product was partitioned between ethyl acetate (50 ml) and water layer (60 ml). The organic layer was washed with 10% sodium thiosulphate solution followed by water (20 l), dried over anhydrous Mg SO4 and concentrated under reduced pressure. Yield=7 g (96%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=1.[NH4+].[Cl-]>CCO.[Fe]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=1
Reactant: CS(=O)(=O)CCCOc1cc(Br)c[n+]([O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CS(=O)(=O)CCCOc1cncc(Br)c1
Temperature: 50 °C
Yield: 32.7 %

Procedure:
To a mixture of 3-bromo-5-(3-methanesulfonyl-propoxy)-pyridine 1-oxide (800 mg, 2.6 mmol) and saturated NH4Cl aqueous solution (3.0 mL) in EtOH (100 mL) is added Fe (0.73 g, 13 mmol). The reaction mixture is heated at 50° C. for 16 hrs. Then the solid is filtered and the filtrate is concentrated. To the residue is added DCM and the mixture is filtered again and the filtrate is concentrated to give 0.25 g of 3-bromo-5-(3-methanesulfonyl-propoxy)-pyridine.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[CH3:16][CH:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CCCCCCC(C)Br
Reactant: CC(C)OCCCNc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCC(C)Nc1ccc(NCCCOC(C)C)cc1

Procedure:
A mixture of 50 g. of N-(3-isopropoxypropyl)-p-phenylenediamine, 50 g. of 2-octyl bromide, 200 ml. of 2N sodium carbonate and 1 liter of ethanol is stirred for 18 hours at 60°C. The reaction mixture is treated with 1 liter of water and extracted with 1 liter of ether. The ether layer is separated, washed with 1200 ml. of water, dried over sodium sulfate and evaporated in vacuo. A mixture of the residue in ether is treated with hydrogen chloride gas to yield the title product in dihydrochloride salt form, m.p. 200°-202°C.
Reaction SMILES: [N:1]([C@H:4]([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:5][S:6][CH2:7][C@@H:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:9][C:10](=[O:26])[O:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N+]=[N-].[C:52](Cl)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63].CCN(C(C)C)C(C)C>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:52]([NH:1][C@H:4]([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:5][S:6][CH2:7][C@@H:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:9][C:10](=[O:26])[O:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)N=[N+]=[N-]
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (5R,9R)-tert-butyl 9-azido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate (1.0 eq), Pd(OH)2 (0.5 eq), dodecanoyl chloride (2.4 eq), and DIEA (4.8 eq) in EtOAc (0.01 M) was stirred under H2 (1 atm) at 25° C. overnight. The reaction was filtered and washed with DCM. The filtrate was concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% EtOAc/Hex to give (5R,9R)-tert-butyl 9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate as a colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:11].[CH2:23]([O:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29])[CH3:24]>Cl[Pd]Cl>[CH2:23]([O:25][P:26]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:11])([O:27][CH2:28][CH3:29])=[O:30])[CH3:24]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1I
Reactant: CCOP(OCC)OCC
Agent: Cl[Pd]Cl
Product: CCOP(=O)(OCC)c1cc(Br)ccc1NC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a 30 mL vial, 1-(2-iodo-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea (2.00 g, 4.12 mmol) was added along with triethylphosphite (1.03 g, 6.0 mmol) and PdCl2 (49 mg, 0.278 mmol). The vial was flushed with N2 sealed and then heated at 130° C. while stirring overnight. The resulting solution was cooled to room temperature, dissolved in a 1:1 mixture of EtOAc/hexane and then purified on a silica column using mixtures of EtOAc/hexanes to give 1.25 g of 1-(2-diethylphosphono-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([C:39]([F:42])([F:41])[F:40])[N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][C@H:19]([NH:30]C(OC(C)(C)C)=O)[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[F:29])[CH2:13][C:12]=12)=[O:7].[ClH:44]>C(OCC)(=O)C>[ClH:44].[CH3:1][O:2][C:3](=[O:43])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([C:39]([F:41])([F:40])[F:42])[N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][C@H:19]([NH2:30])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[F:29])[CH2:13][C:12]=12)=[O:7]
Reactant: COC(=O)CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 99 %

Procedure:
(R)-({7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-amino)-acetic acid methyl ester 16a (0.09 g, 0.145 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.3 N hydrochloric acid in 4 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-({7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-amino)-acetic acid methyl ester hydrochloride 16 (80 mg, yield 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.Cl.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>C(Cl)(Cl)Cl.C(O)C.O>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[N:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:32]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:33])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Nc1ccccc1N1CCc2ccccc21
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CN1CCN(C(=O)Nc2ccccc2N2CCc3ccccc32)CC1
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
To a stirred solution, under nitrogen, of 21.0 g (0.10 mole) of 1-(2-aminophenyl)indoline and 30.4 g (0.30 mole) of triethylamine in 400 ml of chloroform was added 29.9 g (0.15 mole) of 4-methyl-1-piperazinecarbonyl chloride hydrochloride in portions over about 5 minutes. The reaction was refluxed for 6 hours when an additional 10.1 g (0.10 mole) of triethylamine and 19.9 g (0.10 mole) of 4-methyl-1-piperazinecarbonyl chloride hydrochloride were added. After refluxing overnight (total of 25 hrs), the reaction was cooled, treated with 400 ml water, and stirred vigorously for 15 minutes. The layers were separated and the organic phase was washed twice with water, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in 100 ml of absolute ethanol and treated in one portion with a warm solution of 13.2 g (0.11 mole) of maleic acid in 50 ml of ethanol. After several hours, the crystals were collected, washed with ethanol, and dried to afford 19.2 g (43%), of product, m.p. 158° dec. An additional 4.5 g of pure salt was obtained from the mother liquor making the total amount of product 23.7 g and the yield 53%. 3.0 g of product were recrystallized from ethanol to provide 2.80 g of N-[2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboximide maleate.